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Introduction: Gulf War illness (GWI) is an environmentally-triggered chronic multisymptom illness typified by protean symptoms, in which mitochondrial impairment is evident. It has been likened to accelerated aging. Nuclear genetics of detoxification have been linked to GWI. Objective: To see whether mitochondrial (mt) haplogroup U – a heritable profile of mitochondrial DNA that has been tied to aging-related conditions – significantly predicts greater GWI severity; and to assess whether GWI severity is influenced by mitochondrial as well as nuclear genetics. 54 consenting Gulf War veterans gave information on GWI severity, of whom 52 had nuclear DNA assessment; and 45 had both nuclear and mitochondrial DNA assessments. Regression with robust standard errors assessed prediction of GWI severity as a function of nuclear genetics (butyrylcholinesterase variants), mitochondrial genetics (haplogroup U, previously tied to aging-related conditions); or both. Results: BChE "adverse" variants significantly predicted GWI severity (β(SE) = 23.4(11.4), p = 0.046), as did mt haplogroup U (β(SE) = 36.4(13.6), p = 0.010). In a model including both, BChE was no longer significant, but mt haplogroup U retained significance (β(SE) = 36.7(13.0), p = 0.007). This is the first study to show that mitochondrial genetics are tied to GWI severity in Gulf-deployed veterans. Other data affirm a tie to nuclear genetics, making GWI indeed a "tale of two genomes." [ABSTRACT FROM AUTHOR]

This study investigated the effect of food on the plasma pharmacokinetics of bardoxolone methyl, an antioxidant inflammation modulator, at a 20 mg dose, and the dose proportionality of bardoxolone methyl pharmacokinetics from 20 to 80 mg. It was a single-dose study conducted at a single center in 32 healthy volunteers aged 18-45 years using an amorphous spray-dried dispersion formulation of bardoxolone methyl. In Part A, 16 subjects received single 20 mg doses of bardoxolone methyl under fasting and non-fasting conditions. In Part B, 16 subjects received a single 60 or 80 mg dose of bardoxolone methyl and a matching placebo dose under fasting conditions. Blood samples for pharmacokinetic analysis were taken over 120 hours following dose administration. Single dose administration of 20, 60, and 80 mg bardoxolone methyl was safe and well-tolerated in healthy volunteers. Total bardoxolone methyl exposure was unchanged in the presence of food. However, doses of bardoxolone methyl above 20 mg appear to have a saturated dissolution or absorption process and are associated with less than proportional increases in drug exposure. [ABSTRACT FROM AUTHOR]

Male Drosophila are monosomic for the X chromosome, but survive due to dosage compensation. They use the Male Specific Lethal (MSL) complex composed of noncoding roX RNA and histone modifying enzymes to hypertranscribe most genes along the X ∼1.6–1.8 fold relative to each female allele. It is not known how the MSL complex achieves this precise adjustment to a large and diverse set of target genes. We carried out a genetic screen searching for novel factors that regulate dosage compensation in flies. This strategy generated thirty alleles in a previously uncharacterized gene, over compensating males (ocm) that antagonizes some aspect of MSL activity. The mutations were initially recovered because they derepressed an MSL-dependent eye color reporter. Null ocm mutations are lethal to both sexes early in development revealing an essential function. Combinations of hypomorphic ocm alleles display a male specific lethality similar to mutations in the classic msl genes, but ocm males die due to excessive, rather than lack of dosage compensation. Males that die due to very low MSL activity can be partially rescued by ocm mutations. Likewise, males that would die from ocm mutations can be rescued by reducing the dose of various msl and roX genes. ocm encodes a large nuclear protein that shares a novel cysteine rich motif with known transcription factors. [ABSTRACT FROM AUTHOR]

In Drosophila, the MSL (Male Specific Lethal) complex up regulates transcription of active genes on the single male X-chromosome to equalize gene expression between sexes. One model argues that the MSL complex acts upon the elongation step of transcription rather than initiation. In an unbiased forward genetic screen for new factors required for dosage compensation, we found that mutations in the universally conserved transcription elongation factor Spt5 lower MSL complex dependent expression from the miniwhite reporter gene in vivo. We show that SPT5 interacts directly with MSL1 in vitro and is required downstream of MSL complex recruitment, providing the first mechanistic data corroborating the elongation model of dosage compensation. [ABSTRACT FROM AUTHOR]

Objectives: We sought to determine whether spectral- and cepstral-based acoustic measures were effective in distinguishing dysphonic-strained voice quality from normal voice quality and whether these measures were related to auditory-perceptual ratings of strain severity. Methods: Voice samples from 23 speakers with dysphonia characterized predominantly by strained voice quality and 23 speakers with normal voice were acoustically analyzed. Measures related to the prominence of the cepstral peak and the ratio of low- to high-frequency spectral energies, as well as the variation of each, were computed from continuous speech and a sustained vowel. Correlations to perceptually rated strain severity were determined. Results: Measures related to the cepstrum were the strongest discriminators between dysphonic-strained voice and normal voice. Variation in the ratio of low- to high-frequency spectral energies also significantly differentiated the two speaker groups. All measures were significantly correlated with perceptually rated strain severity, including an acoustic severity index that incorporated both cepstral- and spectral-based measures. Conclusions: Cepstral- and spectral-based measures that have been previously studied in dysphonia characterized by breathiness and roughness are effective in distinguishing strained dysphonia from normal voice quality. The utility of these acoustic measures is supported by their moderate-to-high relationship with perceptually rated strain severity. [ABSTRACT FROM AUTHOR]

The science and an overview of the Soft X-ray Spectrometer onboard the STRO-H mission are presented. The SXS consists of X-ray focusing mirrors and a microcalorimeter array and is developed by international collaboration lead by JAXA and NASA with European participation. The detector is a 6×6 format microcalorimeter array operated at a cryogenic temperature of 50 mK and covers a 3′×3′ field of view of the X-ray telescope of 5.6 m focal length. We expect an energy resolution better than 7 eV (FWHM, requirement) with a goal of 4 eV. The effective area of the instrument will be 225 cm at 7 keV; by a factor of about two larger than that of the X-ray microcalorimeter on board Suzaku. One of the main scientific objectives of the SXS is to investigate turbulent and/or macroscopic motions of hot gas in clusters of galaxies. [ABSTRACT FROM AUTHOR]

Most genes along the male single X chromosome in Drosophila are hypertranscribed about two-fold relative to each of the two female X chromosomes. This is accomplished by the MSL (male-specific lethal) complex that acetylates histone H4 at lysine 16. The MSL complex contains two large noncoding RNAs, roX1 (RNA on X) and roX2, that help target chromatin modifying enzymes to the X. The roX RNAs are functionally redundant but differ in size, sequence, and transcriptional control. We wanted to find out how roX1 production is regulated. Ectopic DC can be induced in wild-type (roX1+ roX2+) females if we provide a heterologous source of MSL2. However, in the absence of roX2, we found that roX1 expression failed to come on reliably. Using an in situ hybridization probe that is specific only to endogenous roX1, we found that expression was restored if we introduced either roX2 or a truncated but functional version of roX1. This shows that pre-existing roX RNA is required to positively autoregulate roX1 expression. We also observed massive cis spreading of the MSL complex from the site of roX1 transcription at its endogenous location on the X chromosome. We propose that retention of newly assembled MSL complex around the roX gene is needed to drive sustained transcription and that spreading into flanking chromatin contributes to the X chromosome targeting specificity. Finally, we found that the gene encoding the key male-limited protein subunit, msl2, is transcribed predominantly during DNA replication. This suggests that new MSL complex is made as the chromatin template doubles. We offer a model describing how the production of roX1 and msl2, two key components of the MSL complex, are coordinated to meet the dosage compensation demands of the male cell. [ABSTRACT FROM AUTHOR]

As service robots become increasingly common in society, so too will accidents involving service robots. Current law functions effectively to adjudicate the disputes that arise from such accidents, but as technology improves and robot autonomy grows, it will become much harder to apply currently existing laws. Instead, new legal frameworks will have to be developed to address questions of liability in human-robot interaction. We have already proposed the framework 'Robots as Animals', in which robots are analogized to domesticated animals for legal purposes in disputes about liability. In our initial presentation, though, we focused exclusively on the common law in the US Federal Government. In this paper, we examine the laws concerning domesticated animals in countries in Europe, Asia and North America. We apply the lessons learned from our analysis to build an expanded framework that better reflects the established norms of several nations, and more explicitly balances the competing interests of producers and consumers of robot technology. We also provide examples of ways in which our new framework may be applied. [ABSTRACT FROM AUTHOR]

Background: The Drosophila Male Specific Lethal (MSL) complex contains chromatin modifying enzymes and noncoding roX RNA. It paints the male X at hundreds of bands where it acetylates histone H4 at lysine 16. This epigenetic mark increases expression from the single male X chromosome approximately twofold above what gene-specific factors produce from each female X chromosome. This equalises X-linked gene expression between the sexes. Previous screens for components of dosage compensation relied on a distinctive male-specific lethal phenotype. Results: Here, we report a new strategy relying upon an unusual male-specific mosaic eye pigmentation phenotype produced when the MSL complex acts upon autosomal roX1 transgenes. Screening the second chromosome identified at least five loci, two of which are previously described components of the MSL complex. We focused our analysis on the modifier alleles of MSL1 and MLE (for 'maleless'). The MSL1 lesions are not simple nulls, but rather alter the PEHE domain that recruits the MSL3 chromodomain and MOF ('males absent on first') histone acetyltransferase subunits to the complex. These mutants are compromised in their ability to recruit MSL3 and MOF, dosage compensate the X, and support long distance spreading from roX1 transgenes. Yet, paradoxically, they were isolated because they somehow increase MSL complex activity immediately around roX1 transgenes in combination with wildtype MSL1 subunits. Conclusions: We propose that these diverse phenotypes arise from perturbations in assembly of MSL subunits onto nascent roX transcripts. This strategy is a promising alternative route for identifying previously unknown components of the dosage compensation pathway and novel alleles of known MSL proteins. [ABSTRACT FROM AUTHOR]

Abstract: The dosage compensation complex in Drosophila is composed of at least five MSL proteins and two noncoding roX RNAs that bind hundreds of sites along the single male X chromosome. The roX RNAs are transcribed from X-linked genes and their RNA products “paint” the male X. The roX RNAs and bound MSL proteins can spread in cis from sites of roX transcription, but the mechanism controlling spreading is unknown. Here we find that cis spreading from autosomal roX1 transgenes is coupled to the level of roX transcription. Low to moderate transcription favors, and vigorous transcription abolishes local spreading. We constructed a roX1 minigene one third the size of wild type as a starting point for mutagenesis. This allowed us to test which evolutionarily conserved motifs were required for activity. One short repeat element shared between roX1 and roX2 was found to be particularly important. When all copies were deleted, the RNA was inactive and unstable, while extra copies seem to promote local spreading of the MSL complex from sites of roX1 synthesis. We propose that assembly of the MSL proteins onto the extreme 3′ region of elongating roX1 transcripts determines whether the MSL complex spreads in cis. [Copyright &y& Elsevier]

Background: Previous reports indicate an association between autism spectrum disorders (ASD) and disorders of mitochondrial oxidative phosphorylation. One study suggested that children with both diagnoses are clinically indistinguishable from children with idiopathic autism. There are, however, no detailed analyses of the clinical and laboratory findings in a large cohort of these children. Therefore, we undertook a comprehensive review of patients with ASD and a mitochondrial disorder. Methodology/Principal Findings: We reviewed medical records of 25 patients with a primary diagnosis of ASD by DSM-IVTR criteria, later determined to have enzyme- or mutation-defined mitochondrial electron transport chain (ETC) dysfunction. Twenty-four of 25 patients had one or more major clinical abnormalities uncommon in idiopathic autism. Twenty-one patients had histories of significant non-neurological medical problems. Nineteen patients exhibited constitutional symptoms, especially excessive fatigability. Fifteen patients had abnormal neurological findings. Unusual developmental phenotypes included marked delay in early gross motor milestones (32%) and unusual patterns of regression (40%). Levels of blood lactate, plasma alanine, and serum ALT and/or AST were increased at least once in 76%, 36%, and 52% of patients, respectively. The most common ETC disorders were deficiencies of complex I (64%) and complex III (20%). Two patients had rare mtDNA mutations of likely pathogenicity. Conclusions/Significance: Although all patients' initial diagnosis was idiopathic autism, careful clinical and biochemical assessment identified clinical findings that differentiated them from children with idiopathic autism. These and prior data suggest a disturbance of mitochondrial energy production as an underlying pathophysiological mechanism in a subset of individuals with autism. [ABSTRACT FROM AUTHOR]

The synthesis and photophysical properties of butadlyne-linked chlorophyll and porphyrin dimers in toluene solution and in several self-assembled prismatic structures are described. The butadiyne linkage between the 20-positions of the macrocycles results in new electronic transitions polarized along the long axes of the dimers. These transitions greatly increase the ability of these dimers to absorb the solar spectrum over a broad wavelength range. Femtosecond transient absorption spectroscopy reveals the relative rate of rotation of the macrocycles around the butadiyne bond joining them. Following addition of 3-fold symmetric, metal-coordinating ligands, both macrocyclic dimers self-assemble into prismatic structures in which the dimers comprise the faces of the prisms. These structures were confirmed by small-angle X-ray scattering experiments in solution using a synchrotron source. Photoexcitation of the prismatic assemblies reveals that efficient, through-space energy transfer occurs between the macrocyclic dimers within the prisms. The distance dependence of energy transfer between the faces of the prisms was observed by varying the size of the prismatic assemblies through the use of 3-fold symmetric ligands having arms with different lengths. These results show that self-assembly of discrete macrocyclic prisms provides a useful new strategy for controlling singlet exciton flow in antenna systems for artificial photosynthesis and solar cell applications. [ABSTRACT FROM AUTHOR]

We report the synthesis and photophysical characterization of a multichromophore array, (Z3PN)4PDI, consisting of four zinc 5-phenyl-10,15,20-tri(n-pentyl)porphyrins (Z3PN) attached to the 1,7,N,N′-positions of perylene-3,4:9,10-bis(dicarboximide) (PDI). The dynamics of energy and charge transport within this system were compared to those of two model compounds, N,N′-(Z3PN)2PDI and 1,7-(Z3PN)2PDI. The symmetry of the lowest unoccupied and highest occupied molecular orbitals of PDI results in significantly different electronic couplings between Z3PN and PDI when they are connected at the 1,7-positions vs the N,N′-positions of PDI. This results in two distinct pathways for electron transfer in (Z3PN)4PDI. Using a combination of metal-ligand binding with the bidentate ligand 1,4-diazabicyclo[2.2.2.]-octane (DABCO) and π-π stacking, (Z3PN4)PDI forms a supramolecular assembly, [[(Z3PN)4PDI]2-DABCO4]2, in toluene solution. The structure of this hierarchical assembly is characterized with the use of solution-phase X-ray scattering techniques and demonstrates both efficient light harvesting and facile charge separation and transport using multiple pathways. [ABSTRACT FROM AUTHOR]

Tracheal perforation is a rare complication of intubation. In the pediatric population, the rates of morbidity and mortality are high if diagnosis and management are delayed. Recommendations for treatment in these patients are based on the several reports of this injury in the adult and neonate populations. Surgical repair is generally favored over conservative care in the majority of cases. We describe the case of a 10-year-old girl who presented with subcutaneous emphysema after intubation in the emergency department. The patient had a 3-cm injury to the distal trachea. Nonsurgical management resulted in a normal-appearing trachea and a healed perforation site as confirmed by repeat tracheobronchoscopy 4 months after the initial injury. In clinically stable pediatric patients, nonsurgical management of tracheal perforations should be considered. [ABSTRACT FROM AUTHOR]

Abstract: The Japan/US Suzaku (formerly Astro-E2) astrophysics mission has been successfully launched. Suzaku is a powerful new orbiting observatory for studying extremely energetic processes in the universe. Sensitive X-ray spectrometers have been designed to enable precise measurements of high-energy processes in stars, supernova remnants, galaxies, clusters of galaxies, and the environments around neutron stars and black holes. One of the instruments is the high resolution X-ray spectrometer (XRS) that features a 32-pixel array of microcalorimeters with 6eV (FWHM) spectral resolution, the first such device to be placed into orbit. We will describe the capabilities of the XRS instrument and present some of the very early in-flight results, which clearly show that this new technology can work extremely well in space. [Copyright &y& Elsevier]

Suzuki cross-coupling reactions have afforded 20-phenyl-substituted Chlorophyll a derivatives (ZCPh) in good yields and significant quantities from readily available Chl a. A series of donor-acceptor dyads was synthesized in which naphthalene-1,8:4,5-bis(dicarboximide) or either of two perylene-3,4:9,-10-bis(dicarboximide) electron acceptors is attached to the para position of the 20-phenyl group. Comparisons with the analogous dyads based on a zinc 5, 10, 15-tri(n-pentyl)-20-phenylporphyrin donor show that, for a given acceptor and solvent, the rates of photoinduced charge separation and recombination as well as the calculated electronic coupling matrix elements, V, for these reactions differ by less than a factor of 2. However, EPR and ENDOR spectroscopy corroborated by DFT calculations show that the highest occupied MO of ZCPh+· has little spin (charge) density at the 20-carbon atom, whereas Z3PnPh+· has significant spin (charge) density there, implying that V, and therefore the electron-transfer rates, should differ significantly for these two macrocyclic donors. DFT calculations on ZCPh+· and Z3PnPh+·, with two -0.5 charges located where the nearest carbonyl oxygen atoms of the acceptor would reside in the donor-acceptor dyads, show that the presence of the negative charges significantly shifts the charge density of both ZCPh+· and Z3PnPh+· from the macrocycle onto the phenyl rings. Thus, the presence of adjacent covalently linked radical anions at a fixed location relative to each of these radical cations results in nearly identical electronic coupling matrix elements for electron transfer and therefore very similar rates. [ABSTRACT FROM AUTHOR]

Male flies hypertranscribe most genes along their single X chromosome to match the output of females with two X chromosomes. This is mediated by chromatin modifications carried out by the MSL complex composed of noncoding roX RNA and at least five MSL proteins. New results indicate that one of these subunits, the MOF acetyltransferase, not only acts on histone H4, but on itself and MSL3. Cycles of covalent modifications of the MSL subunits may determine the proper level of hypertranscription or control cis spreading along the chromosome. The MSL complex binds to the roX genes, the very source of the RNA component of the complex. New details of how this interaction occurs hint at a possible autoregulatory function. Finally, despite intensive efforts, the molecular mechanism by which the MSL complex distinguishes the X from the autosomes remains a mystery. The MSL complex is able to spread epigenetically from the site of roX transcription, and recent work has defined the conditions that control local cis spreading. However, it is equally clear that soluble MSL complex can distinguish the X chromosome from autosomes. Reconciling all these findings into a unified model presents a challenge. [Copyright &y& Elsevier]

X-ray microcalorimeter arrays are well suited to address key problems in high-energy astrophysics. The Japan/US Astro-E2 mission will deploy a 32-pixel array of microcalorimeters with 6 eV resolution. This mission is scheduled for launch in 2005. Beyond Astro-E2, NASA is formulating the Constellation-X mission to provide a dramatic increase in collecting area with four separate spacecraft each with large area optics and 1 k-pixel calorimeter arrays providing an energy resolution of 2–4 eV.We will describe the microcalorimeter instrumentation on these missions and mention some of their scientific objectives. [Copyright &y& Elsevier]

The mixed anion compound, Ni2SbTe2, has been prepared from the elements in a potassium iodide flux. The crystal structure is solved in the hexagonal space group P63/mmc (no. 194) with lattice parameters a=b=3.9030(9) A˚ and c=15.634(3) A˚. Sb and Te occupy crystallographically distinct anion sites within the crystal structure. The Seebeck coefficient, electrical resistivity, and magnetic susceptibility have been measured for the title compound, and shows typical metallic behavior. Extended Hu¨ckel band structure calculations also predict metallic behavior in bands dominated by Ni and Te orbital contributions. [Copyright &y& Elsevier]

Mitochondrial cardiolipin (CL) contains unique fatty acid patterns, but it is not known how the characteristic molecular species of CL are formed. We found a novel reaction that transfers acyl groups from phosphatidylcholine or phosphatidylethanolamine to CL in mitochondria of rat liver and human lymphoblasts. Acyl transfer was stimulated by ADP, ATP, and ATPγS, but not by other nucleotides. Coenzyme A stimulated the reaction only in the absence of adenine nucleotides. Free fatty acids were not incorporated into CL under the same incubation condition. The transacylation required addition of exogenous CL or monolyso-CL, whereas dilyso-CL was not a substrate. Transacylase activity was decreased in lymphoblasts from patients with Barth syndrome (tafazzin deletion), and this was accompanied by drastic changes in the molecular composition of CL. In rat liver, where linoleic acid was the most abundant residue of CL, only linoleoyl groups were transferred into CL, but not oleoyl or arachidonoyl groups. We demonstrated complete remodeling of tetraoleoyl-CL to tetralinoleoyl-CL in rat liver mitochondria and identified the intermediates linoleoyl-trioleoyl-CL, dilinoleoyl-dioleoyl-CL, and trilinoleoyl-oleoyl-CL by high-performance liquid chromatography. The data suggest that CL is remodeled by acyl specific phospholipid transacylation and that tafazzin is an acyltransferase involved in this mechanism. [ABSTRACT FROM AUTHOR]

: ObjectivesWe sought to identify characteristic lipid abnormalities in patients with Barth syndrome (BTHS) and to correlate the lipid profile to phenotype and genotype.: BackgroundBarth syndrome typically includes cardiomyopathy, skeletal myopathy, neutropenia, growth retardation, and 3-methylglutaconic aciduria, and it is commonly associated with mutations in the tafazzin (TAZ) gene, whose products are homologous to phospholipid acyltransferases. However, clinical features of BTHS have also been found in patients with normal TAZ gene.: MethodsWe analyzed molecular species of phospholipids in left and right ventricle, skeletal muscle, platelets, lymphoblasts, and fibroblasts from 19 children with BTHS (positive TAZ mutation), 6 children with BTHS-like syndromes (wild-type TAZ), 4 children with isolated cardiomyopathy (wild-type TAZ), and various controls.: ResultsCardiolipin, the specific lipid found only in mitochondria, was decreased in all tissues from BTHS patients, whereas concentrations of other phospholipids were normal. The molecular composition of cardiolipin was altered in all tissues from BTHS patients. The molecular compositions of phosphatidylcholine and phosphatidylethanolamine were altered in the heart. Cardiolipin abnormalities were only found in children with true BTHS, not in children with BTHS-like disease or with isolated cardiomyopathy. The degree of cardiolipin deficiency was tissue-specific but did not correlate with severity or specific phenotypic expression of BTHS.: ConclusionsAbnormal cardiolipin is a specific diagnostic marker of cardiomyopathies caused by TAZ mutations. These mutations lead to alterations in the fatty acid composition of several phospholipids, supporting the idea that TAZ encodes a human acyltransferase. [Copyright &y& Elsevier]

The Drosophila MSL complex consists of at least six proteins and two noncoding roXRNAs that mediate dosage compensation. It acts to remodel the male's X chromatin by covalently modifying the amino terminal tails of histories. The roX1 and roX2 genes are thought to be nucleation sites for assembly and spreading of MSL complexes into surrounding chromatin where they roughly double the rates of transcription. We generated many transgenic stocks in which the roX1 gene was moved from its normal location on the X to new autosomal sites. Approximately 10% of such lines displayed unusual sexually dimorphic expression patterns of the transgene's mini-white eye-color marker. Males often displayed striking mosaic pigmentation patterns similar to those seen in position-effect variegation and yet most inserts were in euchromatic locations. In many of these stocks, female mini-white expression was very low or absent. The male-specific activation of mini-white depended upon the MSL complex. We propose that these transgenes are inserted in several different types of repressive chromatin environments that inhibit mini-white expression. Males are able to overcome this silencing through the action of the MSL complex spreading from the roX1 gene and remodeling the local chromatin to allow transcription. The potency with which an ectopic MSL complex overcomes silent chromatin suggests that its normal action on the X must be under strict regulation. [ABSTRACT FROM AUTHOR]

The untranslated roX1 and roX2 RNAs are components of the Drosophila male-specific lethal (MSL) complex, which modifies histones to up-regutate transcription of the male X chromosome. roX genes are normally located on the X chromosome, and roX transgenes can misdirect the dosage compensation machinery to spread locally on other chromosomes. Here we define MSL protein abundance as a determinant of whether the MSL complex will spread in cis from an autosomal roX transgene. The number of expressed roX genes in a nucleus was inversely correlated with spreading from roX transgenes. We suggest a model in which MSL proteins assemble into active complexes by binding nascent roX transcripts. When MSL protein/roX RNA ratios are high, assembly will be efficient, and complexes may be completed while still tethered to the DNA template. We propose that this local production of MSL complexes determines the extent of spreading into flanking chromatin. [ABSTRACT FROM AUTHOR]

Investigates disorders associated with errors of sterol biosynthesis. Overview of human cholesterol biosynthesis; Discussion of the phenotype, biochemistry and molecular genetics of the conditions; Implications of the sterol disorders.

Examines the genetics of the amish nemaline myopathy phenotype in Lancaster County, Pennsylvania. Identification of the molecular cause of the disorder; Association of nemaline myopathies with an abnormality of a protein component of the thin filament of the sarcomere; Clinical manifestations of the disease.

Focuses on the different ribonucleic acid (RNA) genes involved in dosage compensations in Drosophila and in mice. Effect of noncoded RNA's on chromosomal action; Experiments applied to flies and mammals; Opposite imprinting of imprinted genes on noncoding RNA genes.

Examines the epigenetic spreading of Drosophila dosage compensation complex from roX RNA genes into flanking chromatin. Functions of roX RNA genes; Site of MSL complex spreading; Recognition process of X chromosome by the MSL complex; Mechanism of MSL action; Incorporation of roX RNA into MSL complexes;

Discusses the function of sex lethal (SXL), a female-specific RNA-binding protein in Drosophila that regulates alternative splicing in the sex-determination hierarchy. The association of the SXL protein with multiple sites in the 5' and 3' untranslated regions of the mx12 transcript; The repression of SXL translation in females.

Describes the cloning of the Drosophila k43 gene by chromosomal walking. Identification of the gene by phenotypic rescue using germ-line transformation; Measurement of chorion gene amplification; DNA sequencing results.

Reports on the subtle alterations of chromatin structure of two model organisms that adjust the dosage of X-chromosomal expression which encodes many functions required equally in males and females. Dosage compensation in Drosophila melanogaster; Sex-specific regulation through 3' and 5' untranslated regions; Dosage compensation in Caenorhabditis; Sex specificity of X chromosome repression.

Suggests that Msl-2 RNA in Drosophila is the primary target of Sxl regulation in the dosage compensation pathway and presents a speculative model for the regulation of two distinct modes of dosage compensation by Sxl. Male-specific expression of Msl-2; Decreasing viability and development delay in female expression of Msl-2 protein.

High quantum efficiency (QE) X-ray absorbers are needed for future X-ray astrophysics telescopes. The Advanced Telescope for High ENergy Astrophysics (ATHENA) mission requirements for the X-ray Integral Field Unit (X-IFU) instrument dictate, at their most stringent, that the absorber achieve vertical QE > 90.6% at 7 keV and low total heat capacity, 0.731 pJ/K. The absorber we have designed is 313 µm square composed of 1.05 μm Au and 5.51 μm electroplated Bi films (Barret et al. in Exp Astron 55:373–426, 2023). Overhanging the TES, the absorber is mechanically supported by 6 small legs whose 5 μm diameter is tuned to the target thermal conductance for the device. Further requirements for the absorber for X-IFU include a > 40% reflectance at wavelengths from 1 to 20 μm to reduce shot noise from infrared radiation from higher temperature stages in the cryostat. We meet this requirement by capping our absorbers with an evaporated Ti/Au thin film. Additionally, narrow gaps between absorbers are required for high fill fraction, as well as low levels of fine particulate remaining on the substrate and zero shorts between absorbers that may cause thermal crosstalk. The Light Element Mapper (LEM) is an X-ray probe concept optimized to explore the soft X-ray emission from 0.2 to 2.0 keV. These pixels for LEM require high residual resistance ratio (RRR) thin 0.5 µm Au absorbers to thermalize uniformly and narrow < 2 μm gaps between pixels for high areal fill fraction. This paper reports upon technology developments required to successfully yield arrays of pixels for both mission concepts and presents first testing results of devices with these new absorber recipes. [ABSTRACT FROM AUTHOR]

Opioid overdose deaths have increased exponentially in the United States. Bystander response to opioid overdose ideally involves administering naloxone, providing rescue breathing, and calling 911 to summon emergency medical assistance. Recently in the US, public health and public safety agencies have begun seeking to use 911 calls as a method to identify and deliver post-overdose interventions to opioid overdose patients. Little is known about the opinions of PWUDs about the barriers, benefits, or potential harms of post-overdose interventions linked to the 911 system. We sought to understand the perspectives of PWUDs about a method for using 911 data to identify opioid overdose cases and trigger a post-overdose intervention. We conducted three focus groups with 11 PWUDs in 2018. Results are organized into 4 categories: willingness to call 911 (benefits and risks of calling), thoughts about a technique to identify opioid overdoses in 911 data (benefits and concerns), thoughts about the proposed post-overdose intervention (benefits and concerns), and recommendations for developing an ideal post-overdose intervention. For most participants, calling 911 was synonymous with "calling the police" and law enforcement-related fears were pervasive, limiting willingness to engage with the 911 system. The technique to identify opioid overdoses and the proposed post-overdose intervention were identified as potentially lifesaving, but the benefits were balanced by concerns related to law enforcement involvement, intervention timing, and risks to privacy/reputation. Nearly universally, participants wished for a way to summon emergency medical assistance without triggering a law enforcement response. The fact that the 911 system in the US inextricably links emergency medical assistance with law enforcement response inherently problematizes calling 911 for PWUDs, and has implications for surveillance and intervention. It is imperative to center the perspectives of PWUDs when designing and implementing interventions that rely on the 911 system for activation. [ABSTRACT FROM AUTHOR]

The article examines the study on ultrafast energy transfer within cyclic chlorophyll tetramers. The orientation of the zinc chlorophyll transition moments predict that the microscopic rate constants for Forster energy transfer between adjacent chromophores will be identical. In addition, the cross-diagonal energy transfer rates should be significantly slower than those between adjacent chromophores owing to the unfavorable orientation of the transition dipoles.

The article presents the solution-phase structure of an artificial foldamer using x-ray scattering. Foldamers are synthetic oligomers that adopt ordered confirmations in solution due to noncovalent interactions. They possess unique functionality resulting from their folded structures, foldamers also provide important insights into the fundamentals of noncovalent folding, which is of primary importance for understanding biological systems and developing novel self-assembling materials.

The article discusses electron hopping in π-stacked covalent and self-assembled perylene dimides observed by electron-nuclear double resonance (ENDOR) spectroscopy. The delocalization or rapid hopping of charge among neighboring molecules is a requirement for organic electronics including photovoltaics. Electron paramagnetic resonance and ENDOR spectroscopy are used to reveal charge sharing in dimers. The combination of electronic absorption and ENDOR spectroscopy establishes limits on the time scale for electron transfer between π- stacked chromophores. The 50% reduction of hfcc's for the dimeric systems relative to the monomer models reveals that the rate of electron hopping between the PDIs in both 3.- and (4).-2 is many times faster than the ENDOR time scale (1O7 Hz).

Discusses research which identified the SDC-2 protein in Caenorhabditis elegans as the targeting factor in hermaphrodite X chromosome assembly. Relation of proteins to mitotic chromosome condensation and segregation; Mediation of dosage compensation; Research in this issue by Dawes et al; SDC-2 and hermaphrodite sexual development; Role of SDC-3 in sex determination; Future research.

Editorial. Discusses the role of carnitine supplementation in valproic acid therapy. Role in human nutrition and metabolism; Chemical properties; Description of metabolic actions.

The Athena X-ray Integral Unit (X-IFU) is the high resolution X-ray spectrometer studied since 2015 for flying in the mid-30s on the Athena space X-ray Observatory. Athena is a versatile observatory designed to address the Hot and Energetic Universe science theme, as selected in November 2013 by the Survey Science Committee. Based on a large format array of Transition Edge Sensors (TES), X-IFU aims to provide spatially resolved X-ray spectroscopy, with a spectral resolution of 2.5 eV (up to 7 keV) over a hexagonal field of view of 5 arc minutes (equivalent diameter). The X-IFU entered its System Requirement Review (SRR) in June 2022, at about the same time when ESA called for an overall X-IFU redesign (including the X-IFU cryostat and the cooling chain), due to an unanticipated cost overrun of Athena. In this paper, after illustrating the breakthrough capabilities of the X-IFU, we describe the instrument as presented at its SRR (i.e. in the course of its preliminary definition phase, so-called B1), browsing through all the subsystems and associated requirements. We then show the instrument budgets, with a particular emphasis on the anticipated budgets of some of its key performance parameters, such as the instrument efficiency, spectral resolution, energy scale knowledge, count rate capability, non X-ray background and target of opportunity efficiency. Finally, we briefly discuss the ongoing key technology demonstration activities, the calibration and the activities foreseen in the X-IFU Instrument Science Center, touch on communication and outreach activities, the consortium organisation and the life cycle assessment of X-IFU aiming at minimising the environmental footprint, associated with the development of the instrument. Thanks to the studies conducted so far on X-IFU, it is expected that along the design-to-cost exercise requested by ESA, the X-IFU will maintain flagship capabilities in spatially resolved high resolution X-ray spectroscopy, enabling most of the original X-IFU related scientific objectives of the Athena mission to be retained. The X-IFU will be provided by an international consortium led by France, The Netherlands and Italy, with ESA member state contributions from Belgium, Czech Republic, Finland, Germany, Poland, Spain, Switzerland, with additional contributions from the United States and Japan. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to an article by Joost P.H. Drenth and Jos W.M. van der Meer about hereditary periodic fever in the December 13, 2001 issue.

We previously reported a mutation in the cholesterol biosynthesis gene, hydroxysteroid ( 17-beta ) dehydrogenase 7 ( Hsd17b7 rudolph ), that results in striking embryonic forebrain dysgenesis. Here we describe abnormal patterns of neuroprogenitor proliferation in the mutant forebrain, namely, a decrease in mitotic cells within the ventricular zone (VZ) and an increase through the remainder of the cortex by E11.5. Further evidence suggests mutant cells undergo abnormal interkinetic nuclear migration (IKNM). Furthermore, intermediate progenitors are increased at the expense of apical progenitors by E12.5, and post-mitotic neurons are expanded by E14.5. In vitro primary neuron culture further supports our model of accelerated cortical differentiation in the mutant. Combined administration of a statin and dietary cholesterol in utero achieved partial reversal of multiple developmental abnormalities in the Hsd17b7 rudolph embryo, including the forebrain. These results suggest that abnormally increased levels of specific cholesterol precursors in the Hsd17b7 rudolph embryo cause cortical dysgenesis by altering patterns of neurogenesis. [ABSTRACT FROM AUTHOR]

A perylenediimide chromophore (P) was incorporated into DNA hairpins as a base-pair surrogate to prevent the self-aggregation of P that is typical when it is used as the hairpin linker. The photoinduced charge-transfer and spin dynamics of these hairpins were studied using femtosecond transient absorption spectroscopy and time-resolved EPR spectroscopy (TREPR). P is a photooxidant that is sufficiently powerful to quantitatively inject holes into adjacent adenine (A) and guanine (G) nucleobases. The charge-transfer dynamics observed following hole injection from P into the A-tract of the DNA hairpins is consistent with formation of a polaron involving an estimated 3-4 A bases. Trapping of the (A3-4)+• polaron by a C base at the opposite end of the A-tract from P is competitive with charge recombination of the polaron and P-• only at short P-C distances. In a hairpin having 3 A-T base pairs between P and C (4G), the radical ion pair that results from trapping of the hole by G is spin-correlated and displays TREPR spectra at 295 and 85 K that are consistent with its formation from 1*P by the radical-pair intersystem crossing mechanism. Charge recombination is spin-selective and produces 3*P, which at 85 K exhibits a spin-polarized TREPR spectrum that is diagnostic of its origin from the spin-correlated radical ion pair. Interestingly, in a hairpin having no G bases (0G), TREPR spectra at 85 K revealed a spin-correlated radical pair with a dipolar interaction identical to that of 4G, implying that the A-base in the fourth A-T base pair away from the P chromophore serves as a hole trap. Our data suggest that hole injection and transport in these hairpins is completely dominated by polaron generation and movement to a trap site rather than by superexchange. On the other hand, the barrier for charge injection from G+• back onto the A-T base pairs is strongly activated, so charge recombination from G (or even A trap sites at 85 K) most likely proceeds by a superexchange mechanism. [ABSTRACT FROM AUTHOR]

The EBIT calorimeter spectrometer (ECS) is a new high-resolution, broadband x-ray spectrometer that has recently been installed at the Electron Beam Ion Trap Facility (EBIT) at the Lawrence Livermore National Laboratory. The ECS is an entirely new production class spectrometer that replaces the XRS/EBIT spectrometer that has been operating at EBIT since 2000. The ECS utilizes a 32-pixel x-ray calorimeter array from the XRS instrument on the Suzaku x-ray observatory. Eighteen of the pixels are optimized for the 0.1–10 keV band and yield 4.5 eV full width at half maximum energy resolution and 95% quantum efficiency at 6 keV. In addition, the ECS includes 14 detector pixels that are optimized for the high-energy band with a bandpass from 0.5 to over 100 keV with 34 eV resolution and 32% quantum efficiency at 60 keV. The ECS detector array is operated at 50 mK using a five stage cryogenic system that is entirely automated. The instrument takes data continuously for over 65 h with a 2.5 h recycle time. The ECS is a nondispersive, broadband, highly efficient spectrometer that is one of the prime instruments at the EBIT facility. The instrument is used for studies of absolute cross sections, charge exchange recombination, and x-ray emission from nonequilibrium plasmas, among other measurements in our laboratory astrophysics program. [ABSTRACT FROM AUTHOR]