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Ooids are one of the common constituents of ancient carbonate rocks, yet the role that microbial communities may or may not play in their formation remains unresolved. To search for evidence of microbial activity in modern and Holocene ooids, samples collected from intertidal waters, beaches and outcrops in the Bahamas and in Shark Bay in Western Australia were examined for their contents of lipid biomarkers. Modern samples from Cat and Andros islands in the Bahamas and from Carbla Beach in Hamelin Pool, Western Australia, showed abundant and notably similar distributions of hydrocarbons, fatty acids ( FAs) and alcohols. A large fraction of these lipids were bound into the carbonate matrix and only released on acid dissolution, which suggests that these lipids were being incorporated continuously during ooid growth. The distributions of hydrocarbons, and their disparate carbon isotopic signatures, were consistent with mixed input from cyanobacteria together with small and variable amounts of vascular plant leaf wax [C27-C35; δ13C −25 to −32‰Vienna Pee Dee Belemnite ( VPDB)]. The FAs comprised a complex mixture of C12-C18 normal and branched short-chain compounds with the predominant straight-chain components attributable to bacteria and/or cyanobacteria. Branched FA, especially 10- MeC16 and 10- MeC17, together with the prevalence of elemental sulfur in the extracts, indicate an origin from sulfate-reducing bacteria. The iso- and anteiso- FA were quite variable in their 13C contents suggesting that they come from organisms with diverse physiologies. Hydrogen isotopic compositions provide further insight into this issue. FAs in each sample show disparate δD values consistent with inputs from autotrophs and heterotrophs. The most enigmatic lipid assemblage is an homologous series of long-chain (C24-C32) FA with pronounced even carbon number preference. Typically, such long-chain FA are thought to come from land plant leaf wax, but in this case, their 13C-enriched isotopic signatures compared to co-occurring n-alkanes (e.g., Hamelin Pool TLE FA C24-C32; δ13C −20 to −24.2‰ VPDB; TLE n-alkanes δ13C −24.1 to −26.2 −‰ VPDB) indicate a microbial origin, possibly sulfate-reducing bacteria. Lastly, we identified homohopanoic acid and bishomohopanol as the primary degradation products of bacterial hopanoids. The distributions of lipids isolated from Holocene oolites from the Rice Bay Formation of Cat Island, Bahamas were very similar to the beach ooids described above and, in total, these modern and fossil biomarker data lead us to hypothesize that ooids are colonized by a defined microbial community and that these microbes possibly mediate calcification. [ABSTRACT FROM AUTHOR]

Green power marketing—the act of differentially selling electricity generated wholly or in part from renewable sources—has emerged in more than a dozen countries around the world. Almost two million customers worldwide buy green power today. This paper reviews green power marketing activity in Australia, Canada, Japan, the US, and in a number of countries in Europe to gain an understanding of consumer demand for electricity generated from renewable sources. It also examines key factors that influence market penetration of green power products, such as product designs, pricing, incentives, marketing strategies, policies, and product certification. [Copyright &y& Elsevier]

A new binder- and carbon-free electrode for lithium-ion batteries was prepared using a hierarchically porous Ag-based current collector. The latter was produced by applying the method of selective dissolution of the less noble metals from the Cu60Ag30Al10 master alloy tape. The current collector was reaction-coated with an electrochemically active Ag2S–CuxS coating. The metallic structure provided a mechanically stable conductive scaffold on the walls of which the Ag2S–CuxS skin material was directly deposited. The ordered porosity – hierarchical and directional – provided easy penetration of the liquid electrolyte as well as short Li+ ion diffusion paths. The as-prepared electrodes were tested in a half-cell configuration vs. Li/Li+ at various current rates to study the cycling and rate performances of the electrode. The first cycling capacity of ∼1250 mA h g−1 was measured at 0.4 A g−1 current rate. After a rapid decrease, a stable reversible capacity of ∼230 mA h g−1 was established at a current rate of 0.4 A g−1 (calculated vs. the weight of the incorporated sulphur). Excellent charge/discharge cycling and rate properties were observed for over 1000 cycles at higher rates of 1.0 and 2.0 A g−1, in the potential window of 0.15–2.8 V vs. Li/Li+. The observed cycling stability was ascribed to the mechanism of a "displacement" reaction with Li ions. Additional capacity is also available from alloying–dealloying with Ag (and Cu to some extent) and S redox reactions. These results open up a new opportunity for using a Cu–Ag alloy as the precursor for making electrodes for thin Li-ion and Li–S batteries with high cycling stability at relatively high current rates. [ABSTRACT FROM AUTHOR]

Background: Angelman syndrome (AS) is a neurodevelopmental disorder caused by a lack of expression of the maternally inherited UBE3A gene on chromosome 15. Individuals with AS due to a UBE3A mutation are more likely to have siblings who also have AS compared with those with AS due to other cytogenetic/molecular mechanisms, but it is unknown whether the developmental outcome of siblings who have AS is similar. Methods: Through an ongoing AS Natural History Study, we identified seven pairs of siblings with AS due to a UBE3A mutation. We compared the neurodevelopment of the first‐born and second‐born siblings with AS participants who have a UBE3A mutation and have either typically developing siblings or no siblings. Results: Second‐born AS participants due to a UBE3A mutation were more likely to be diagnosed at an earlier age. With the exception of higher expressive language scores among the second‐born participants, no other differences were observed in the developmental and adaptive functioning skills across the different groups. Conclusions: The presence of an older sibling with the same neurodevelopmental disorder is associated with an earlier age of diagnosis and may be associated with an improvement in expressive language skills; the developmental outcome of siblings with AS due to a UBE3A mutation is otherwise comparable. [ABSTRACT FROM AUTHOR]

Little Salt Spring (Sarasota County, FL, USA) is a sinkhole with groundwater vents at ~77 m depth. The entire water column experiences sulfidic (~50 μM) conditions seasonally, resulting in a system poised between oxic and sulfidic conditions. Red pinnacle mats occupy the sediment-water interface in the sunlit upper basin of the sinkhole, and yielded 16S rRNA gene clones affiliated with Cyanobacteria, Chlorobi, and sulfate-reducing clades of Deltaproteobacteria. Nine bacteriochlorophyll e homologues and isorenieratene indicate contributions from Chlorobi, and abundant chlorophyll a and pheophytin a are consistent with the presence of Cyanobacteria. The red pinnacle mat contains hopanoids, including 2-methyl structures that have been interpreted as biomarkers for Cyanobacteria. A single sequence of hpnP, the gene required for methylation of hopanoids at the C-2 position, was recovered in both DNA and cDNA libraries from the red pinnacle mat. The hpnP sequence was most closely related to cyanobacterial hpnP sequences, implying that Cyanobacteria are a source of 2-methyl hopanoids present in the mat. The mats are capable of light-dependent primary productivity as evidenced by 13C-bicarbonate photoassimilation. We also observed 13C-bicarbonate photoassimilation in the presence of DCMU, an inhibitor of electron transfer to Photosystem II. Our results indicate that the mats carry out light-driven primary production in the absence of oxygen production-a mechanism that may have delayed the oxygenation of the Earth's oceans and atmosphere during the Proterozoic Eon. Furthermore, our observations of the production of 2-methyl hopanoids by Cyanobacteria under conditions of low oxygen and low light are consistent with the recovery of these structures from ancient black shales as well as their paucity in modern marine environments. [ABSTRACT FROM AUTHOR]

DMD is a rare, degenerative, genetic disease that results in progressive muscle loss and premature death. Affecting 1 in 5000 male births, DMD is caused by the inability to produce the dystrophin protein. There are no approved drugs available to treat DMD, although glucocorticoids show a modest effect with long-term efficacy limited by side effects. Eteplirsen is an investigational therapy designed to enable functional dystrophin production in boys who are amenable to exon 51-skipping therapy (∼13%). Twelve boys aged 7–13years with eligible genotypes were randomized 1:1:1 to 30mg/kg, 50mg/kg, or placebo. Upon completion of a 24-week double-blind, placebo-controlled study phase, all subjects were enrolled in an open-label extension and the placebo-treated subjects initiated eteplirsen treatment. The critical clinical endpoint was the change in 6-min walk test (6MWT) distance from baseline compared to the placebo/delayed-treatment cohort. Previously reported 48-week results showed a statistically significant increase in 6MWT distance for eteplirsen versus the placebo/delayed-treatment arm. At 62weeks, a significant clinical benefit of 62m was observed (p ⩽0.007) on the 6MWT for ambulatory-evaluable subjects in the combined eteplirsen-treated cohorts (n =6) versus the placebo/delayed-treatment cohort (n =4). The eteplirsen-treated cohorts showed less than a 5% decline in 6MWT distance from baseline. No clinically significant treatment-related adverse events were seen through 62weeks. Through 62weeks of treatment, eteplirsen demonstrated a significant clinical benefit on the 6MWT with no clinically significant treatment-related adverse events. Data on these outcomes will be reported through 2years of treatment. [Copyright &y& Elsevier]

DMD, a rare, degenerative, genetic disease that results in progressive muscle loss and premature death affects 1:5000 male births. It is caused by deletions in the dystrophin gene, which prevents production of the dystrophin protein. There are no approved treatments available, although corticosteroids have shown some benefit. Eteplirsen is an investigational drug designed to enable functional dystrophin production in boys who are amenable to skipping exon 51. Twelve boys aged 7–13 years with eligible genotypes were randomized 1:1:1 to eteplirsen 30 mg/kg/wk, 50 mg/kg/wk, or placebo IV for 24-weeks. All patients transitioned into an ongoing open-label extension with 30 or 50 mg/kg eteplirsen. Clinical efficacy endpoints included the 6-min walk test (6MWT) and pulmonary function testing. Safety assessments included adverse event recording, EKG, ECHO, hematology, blood chemistry and urinalysis. After 120 weeks of treatment, a significant clinical benefit of 65 m was observed ( p = 0.006) on the 6MWT for ambulatory-evaluable patients in the combined eteplirsen-treated cohorts ( n = 6) versus the placebo/delayed-treatment cohort ( n = 4). The eteplirsen-treated cohorts showed a decline of less than 14 m in walking ability from baseline, which was not statistically significant. After a substantial decline in the first 36 weeks of the study, the placebo/delayed-treatment cohort demonstrated stabilization in walking ability at week 48, i.e., 12 weeks after initiation of treatment with eteplirsen when meaningful levels of dystrophin were likely produced, with <10 m decline through 120 weeks. No deaths, discontinuations due to AEs, treatment-related SAEs, or clinically significant abnormal laboratory, ECG, or ECHO findings were reported. Eteplirsen demonstrated a significant clinical benefit on the 6MWT over 120 weeks, was well tolerated, and exhibited an unremarkable safety profile. Week 144 data will be presented. [ABSTRACT FROM AUTHOR]

Eteplirsen, SRP-4045 and SRP-4053 are three PMOs developed as treatments for DMD. DMD is mostly caused by mutations in the dystrophin gene that lead to a reading frame shift and premature translation termination. PMOs promote exon skipping during splicing of dystrophin pre-mRNA, restoring the reading frame and translation of internally truncated, but functional dystrophin protein. Eteplirsen, SRP-4045, and SRP-4053 are intended to treat patients with mutations amenable to skipping exon 51, 45 and 53, respectively. IND enabling preclinical studies have been completed for eteplirsen, SRP-4045, and SRP-4053. In vitro metabolism data and PK profiles in animals were similar for all three PMOs. No adverse responses were detected in safety pharmacology studies in non-human primates (NHPs). Genotoxicity studies were negative. NHPs given 12 weekly IV doses up to 320 mg/kg showed no significant sequence-specific toxicities. A clinical study of eteplirsen with doses of 30 and 50 mg/kg/wk reported no clinically significant treatment-related adverse events through 120 weeks of treatment. A few cases of transient, mild urine protein elevation resolved without intervention or drug interruption and one femur fracture was determined to be treatment-unrelated. There were no hospitalizations, discontinuations, or clinically significant treatment-related changes for lab parameters, including liver enzymes, kidney function, coagulation, or platelet counts. Plasma Cmax and AUC increased proportionally with dose, and half-life was approximately 3 h with no plasma accumulation observed. The consistent preclinical profiles and lack of significant, sequence-specific toxicities for eteplirsen, SRP-4045, and SRP-4053 demonstrate PMOs to be a well-tolerated therapeutic class, with potential applications in a wide variety of disease indications. [ABSTRACT FROM AUTHOR]

Abstract: Historically, newborn screening for DMD has been challenging in part due to elevations in serum CK related to birth trauma, resulting in false-positive results when used as a screening test. Nevertheless, the rationale for newborn screening is supported by several lines of argument. One is that new techniques for molecular diagnostics hold promise for improved rapid mutational analysis from small amounts of starting material. Another is that new potential therapeutics are entering clinical trials, and these or future therapies may significantly impact disease course if offered in infancy. A complementary argument regards clinical trial readiness; studies addressing efficacy in children of this age cannot be performed if a reliable method of early detection is unavailable. We have established and validated a two-tier system of screening and molecular diagnosis that uses a dried blood spot obtained within the first 48h to first assess CK via a fluorometric assay as the first step. Preliminary studies established a population-based range of CK in newborns using 30,547 deidentified anonymous dried blood spot samples. Mutation analysis used genomic DNA extracted from the dried blood spot for whole genome amplification followed by MLPA and/or direct sequencing methods. DMD gene mutations (all exonic deletions) were found in 6 of 37,649 newborn males, all of whom had CK levels >2000U/l. In three newborns with CK >2000U/l in whom DMD gene abnormalities were not found, we identified limb-girdle muscular dystrophy gene mutations affecting the DYSF, SGCB, and FKRP genes. This data is currently in press elsewhere, but here we will review this path for screening that fits the US health care system, minimizes false-positive testing, and uses predetermined levels of CK on dried blood spots to predict DMD gene mutations, and we will discuss prospects and challenges for widespread utilization. [Copyright &y& Elsevier]

The adaptor protein Grb2 and the large multi-site docking protein Gab2 form a complex that is crucial for the oncogenic signalling of some cancer cells. Binding of the C-terminal SH3 (SH3C) domain of Grb2 to Gab2 is essential for the interaction, but molecular details of the complex formation have remained undefined. Using peptide array SH3 overlay blots, isothermal titration calorimetry and protein crystallography, two atypical SH3 domain binding sites in Gab2 (Gab2-1 and Gab2-2) were confirmed and characterised. Gab2-1 has considerable similarity to an epitope in the cell cycle regulator p27Kip1 that also binds Grb2SH3C. The SH3C binding sites in Gab2 differ approximately 5-fold in their affinity and also with respect to the residues important for the interaction apart from a shared core motif RxxK. Both SH3 domain interaction sites in Gab2 are conserved throughout evolution and found, for example, in the Gab homolog daughter of sevenless (Dos) of Drosophila melanogaster, which binds to the Grb2 homolog Drk. Mutagenesis of the Drk binding sites in Dos in vivo impairs fly eye and wing vein development and documents that both sites are functionally important. A high-resolution crystal structure was generated of the Gab2-2 epitope in complex with the Grb2SH3C domain. This reveals a binding mode reminiscent of the interaction of haematopoietic Grb2-relative Mona/Gads with the T-cell adaptor SLP-76 and haematopoietic progenitor kinase 1 (HPK1). However, subtle differences exist, which could potentially be exploited to generate SH3C domain inhibitors with preference for a specific Grb2 family member. [ABSTRACT FROM AUTHOR]