The differential effects of prenatal and/or postnatal rapamycin on neurodevelopmental defects and cognition in a neuroglial mouse model of tuberous sclerosis complex.

Tuberous sclerosis complex (TSC) is caused by heterozygous mutations in either the TSC1 (hamartin) or the TSC2 (tuberin) gene. Among the multisystemic manifestations of TSC, the neurodevelopmental features cause the most morbidity and mortality, presenting a considerable clinical challenge. Hamartin and tuberin form a heterodimer that inhibits the mammalian target of rapamycin complex 1 (mTORC1) kinase, a major cellular regulator of protein translation, cell growth and proliferation. Hyperactivated mTORC1 signaling, an important feature of TSC, has prompted a number of preclinical and clinical studies with the mTORC1 inhibitor rapamycin. Equally exciting is the prospect of treating TSC in the perinatal period to block the progression of brain pathologies and allow normal brain development to proceed. We hypothesized that low-dose rapamycin given prenatally and/or postnatally in a well-established neuroglial (Tsc2-hGFAP) model of TSC would rescue brain developmental defects. We developed three treatment regimens with low-dose intraperitoneal rapamycin (0.1 mg/kg): prenatal, postnatal and pre/postnatal (combined). Combined rapamycin treatment resulted in almost complete histologic rescue, with a well-organized cortex and hippocampus almost identical to control animals. Other treatment regimens yielded less complete, but significant improvements in brain histology. To assess how treatment regimens affected cognitive function, we continued rapamycin treatment after weaning and performed behavioral testing. Surprisingly, the animals treated with the combined therapy did not perform as well as postnatally-treated animals in learning and memory tasks. These results have important translational implications in the optimization of the timing and dosage of rapamycin treatment in TSC affected children.

Fluctuating sea-level and reversing Monsoon winds drive Holocene lagoon infill in Southeast Asia.

Many lagoons surrounded by reefs are partially or completely infilled with reef-derived detrital carbonate sediment. Sediment deposits in such restricted environments are archives of prevailing environmental conditions during lagoon infill. For Indonesia, no paleoenvironmental reconstructions based on Holocene lagoon sediments exist. Here we analyze the sedimentary record obtained from five percussion cores penetrating 10 m into the unconsolidated subsurface of a reef island in the Spermonde Archipelago, Indonesia. The combined compositional, textural and chronostratigraphic analyses reveal that the sedimentary infill of the lagoon underlying the island, starting 6900 years cal BP, was interrupted between 5800 and 4400 years cal BP, when sea level was ~ 0.5 m higher than at present, and monsoon intensity was lower. After the intensity of the monsoons increased to modern levels, and sea level dropped to its present position, lagoonal sedimentation was re-initiated and created the foundation for an island that built up since 3000 years cal BP. Our study provides the first geological evidence for the strong sensitivity of detrital carbonate systems in Indonesia to fluctuations in sea level and dominant wind direction. It thus sheds light on how changing environmental conditions in the context of global warming could affect the morphological development of reef systems, and thereby also habitable coastal areas.

Scleractinian corals incorporate microplastic particles: identification from a laboratory study.

Microplastics have been detected on beaches and in the ocean from surface habitats to the deep-sea. Microplastics can be mistaken for food items by marine organisms, posing a potential risk for bioaccumulation and biomagnification in the food chain. Our understanding of microplastic pollution effects on ecosystem and physiological processes of coral reefs is still limited. This study contributes to the understanding of effects of microplastic pollution on skeletal precipitation of hermatypic corals. In a five month aquarium-based experiment, specimens of four tropical species were temporarily exposed to high concentrations (ca. 0.5 g L-1) of polyethylene terephthalate (PET) microplastic particles (< 500 µm). The coral specimens all survived this treatment and show skeletal growth. The skeletal material produced during the experiment, however, incorporated plastic particles and plastic fibres in the aragonitic structure. Long-term consequences of such inclusions on skeletal properties such as stability are yet unknown.

Author Correction: Coral carbon isotope sensitivity to growth rate and water depth with paleo-sea level implications.

The original version of the Source Data associated with this Article included an error, in which the 'Fiji AB d13C-Suess' data point and the 'TNI2 d13C-Suess Effect' data point for the year '1950.5' where incorrectly omitted from the Figure 3 tab. The missing values are '-0.24' and '-0.64', respectively. The HTML has been updated to include a corrected version of Source Data.

Coral carbon isotope sensitivity to growth rate and water depth with paleo-sea level implications.

Although reef coral skeletal carbon isotopes (δ13C) are routinely measured, interpretation remains controversial. Here we show results of a consistent inverse relationship between coral δ13C and skeletal extension rate over the last several centuries in Porites corals at Fiji, Tonga, Rarotonga and American Samoa in the southwest Pacific. Beginning in the 1950s, this relationship breaks down as the atmospheric 13C Suess effect shifts skeletal δ13C > 1.0‰ lower. We also compiled coral δ13C from a global array of sites and find that mean coral δ13C decreases by -1.4‰ for every 5 m increase in water depth (R = 0.68, p < 0.01). This highlights the fundamental sensitivity of coral δ13C to endosymbiotic photosynthesis. Collectively, these results suggest that photosynthetic rate largely determines mean coral δ13C while changes in extension rate and metabolic effects over time modulate skeletal δ13C around this mean value. The newly quantified coral δ13C-water depth relationship may be an effective tool for improving the precision of paleo-sea level reconstruction using corals.

Surface ocean pH variations since 1689 CE and recent ocean acidification in the tropical South Pacific.

Increasing atmospheric CO2 from man-made climate change is reducing surface ocean pH. Due to limited instrumental measurements and historical pH records in the world's oceans, seawater pH variability at the decadal and centennial scale remains largely unknown and requires documentation. Here we present evidence of striking secular trends of decreasing pH since the late nineteenth century with pronounced interannual to decadal-interdecadal pH variability in the South Pacific Ocean from 1689 to 2011 CE. High-amplitude oceanic pH changes, likely related to atmospheric CO2 uptake and seawater dissolved inorganic carbon fluctuations, reveal a coupled relationship to sea surface temperature variations and highlight the marked influence of El Niño/Southern Oscillation and Interdecadal Pacific Oscillation. We suggest changing surface winds strength and zonal advection processes as the main drivers responsible for regional pH variability up to 1881 CE, followed by the prominent role of anthropogenic CO2 in accelerating the process of ocean acidification.

Changes to Yucatán Peninsula precipitation associated with salinity and temperature extremes of the Caribbean Sea during the Maya civilization collapse.

Explanations of the Classic Maya civilization demise on the Yucatán Peninsula during the Terminal Classic Period (TCP; ~CE 750-1050) are controversial. Multiyear droughts are one likely cause, but the role of the Caribbean Sea, the dominant moisture source for Mesoamerica, remains largely unknown. Here we present bimonthly-resolved snapshots of reconstructed sea surface temperature (SST) and salinity (SSS) variability in the southern Caribbean from precisely dated fossil corals. The results indicate pronounced interannual to decadal SST and SSS variability during the TCP, which may be temporally coherent to precipitation anomalies on the Yucatán. Our results are best explained by changed Caribbean SST gradients affecting the Caribbean low-level atmospheric jet with consequences for Mesoamerican precipitation, which are possibly linked to changes in Atlantic Meridional Overturning Circulation strength. Our findings provide a new perspective on the anomalous hydrological changes during the TCP that complement the oft-suggested southward displacement of the Intertropical Convergence Zone. We advocate for a strong role of Caribbean SST and SSS condition changes and related ocean-atmosphere interactions that notably influenced the propagation and transport of precipitation to the Yucatán Peninsula during the TCP.

Exon organization and novel alternative splicing of Ank3 in mouse heart.

Ankyrin-G is an adaptor protein that links membrane proteins to the underlying cytoskeletal network. Alternative splicing of the Ank3 gene gives rise to multiple ankyrin-G isoforms in numerous tissues. To date, only one ankyrin-G isoform has been characterized in heart and transcriptional regulation of the Ank3 gene is completely unknown. In this study, we describe the first comprehensive analysis of Ank3 expression in heart. Using a PCR-based screen of cardiac mRNA transcripts, we identify two new exons and 28 alternative splice variants of the Ank3 gene. We measure the relative expression of each splice variant using quantitative real-time PCR and exon-exon boundary spanning primers that specifically amplify individual Ank3 variants. Six variants are rarely expressed (<1%), while the remaining variants display similar expression patterns in three hearts. Of the five first exons in the Ank3 gene, exon 1d is only expressed in heart and skeletal muscle as it was not detected in brain, kidney, cerebellum, and lung. Immunoblot analysis reveals multiple ankyrin-G isoforms in heart, and two ankyrin-G subpopulations are detected in adult cardiomyocytes by immunofluorescence. One population co-localizes with the voltage-gated sodium channel NaV1.5 at the intercalated disc, while the other population expresses at the Z-line. Two of the rare splice variants excise a portion of the ZU5 motif, which encodes the minimal spectrin-binding domain, and these variants lack ß-spectrin binding. Together, these data demonstrate that Ank3 is subject to complex splicing regulation resulting in a diverse population of ankyrin-G isoforms in heart.

Identification and characterization of two ankyrin-B isoforms in mammalian heart.

AIMS: Excitation-contraction coupling in cardiomyocytes requires the proper targeting and retention of membrane proteins to unique domains by adaptor proteins like ankyrin-B. While ankyrin-B has been shown to interact with a variety of membrane and structural proteins located at different subcellular domains in cardiomyocytes, what regulates the specificity of ankyrin-B for particular interacting proteins remains elusive. METHODS AND RESULTS: Here, we report the identification of two novel ankyrin-B isoforms AnkB-188 and AnkB-212 in human, rat, and mouse hearts. Novel cDNAs for both isoforms were isolated by long-range PCR of reverse-transcribed mRNA isolated from human ventricular tissue. The isoforms can be discriminated based on their function and subcellular distribution in cardiomyocytes. Heterologous overexpression of AnkB-188 increases sodium-calcium exchanger (NCX) membrane expression and current, while selective knockdown of AnkB-188 in cardiomyocytes reduces NCX expression and localization in addition to causing irregular contraction rhythms. Using an isoform-specific antibody, we demonstrate that the expression of AnkB-212 is restricted to striated muscles and is localized to the M-line of cardiomyocytes by interacting with obscurin. Selective knockdown of AnkB-212 significantly attenuates the expression of endogenous ankyrin-B at the M-line but does not disrupt NCX expression at transverse tubules in cardiomyocytes. CONCLUSION: The identification and characterization of two functionally distinct ankyrin-B isoforms in heart provide compelling evidence that alternative splicing of the ANK2 gene regulates the fidelity of ankyrin-B interactions with proteins.