On the role of ozone feedback in the ENSO amplitude response under global warming

The El Niño Southern Oscillation (ENSO) in the tropical Pacific Ocean is of key importance to global climate and weather. However, state-of-the-art climate models still disagree on the ENSO's response under climate change. The potential role of atmospheric ozone changes in this context has not been explored before. Here, we show that differences between typical model representations of ozone can have a first-order impact on ENSO amplitude projections in climate sensitivity simulations. The vertical temperature gradient of the tropical middle-to-upper troposphere adjusts to ozone changes in the upper troposphere and lower stratosphere, modifying the Walker circulation and consequently tropical Pacific surface temperature gradients. We show that neglecting ozone changes thus results in a significant increase in the number of extreme ENSO events in our model. Climate modeling studies of the ENSO often neglect changes in ozone. We therefore highlight the need to understand better the coupling between ozone, the tropospheric circulation and climate variability.European Research Council. Grant Number: 267760 European Research Council. Grant Number: 267760 Natural Environment Research Council (NERC). Grant Number: RH/H10/19 Natural Environment Research Council (NERC). Grant Number: R8/H12/124 National Centre for Atmospheric Science (NCAS) Helmholtz-Gemeinschaft (HGF

Parental Support, Mental Health, and Alcohol and Marijuana Use in National and High-Risk African-American Adolescent Samples

African-American adolescents experience disproportionate rates of negative consequences of substance use despite using substances at average or below-average rates. Due to underrepresentation of African-American adolescents in etiological literature, risk and protective processes associated with their substance use require further study. This study examines the role of parental support in adolescents’ conduct problems (CPs), depressive symptoms (DSs), and alcohol and marijuana use in a national sample and a high-risk sample of African-American adolescents. In both samples, parental support was inversely related to adolescent CPs, DSs, and alcohol and marijuana use. CPs, but not DSs, partially mediated the relation of parental support to substance use. Results were consistent across the national and high-risk samples, suggesting that the protective effect of parental support applies to African-American adolescents from a range of demographic backgrounds

Recognized Spontaneous Abortion in Mid-Pregnancy and Patterns of Pregnancy Alcohol Use

Alcohol consumption during pregnancy is one potential risk factor for spontaneous abortion (SAb). Prior research suggested that heavy drinking during pregnancy was associated with significantly increased rates of SAb, but results for lower levels of drinking have been inconsistent. We examined the association between different levels and patterns of prenatal alcohol consumption and SAb in a high-risk inner-city sample. We hypothesized that higher levels, binge patterns, and more frequent drinking would be associated with increased rates of SAb. The quantity and frequency of self-reported peri-conceptional and repeated in-pregnancy maternal drinking volumes per beverage type were assessed with semi-structured interviews in a prospective subsample of 302 African-American mothers. Relations between various measures of prenatal alcohol exposure and SAb were assessed using logistic regression. After controlling for various potential confounders, there was a significant positive relation between average absolute alcohol use per day across pregnancy and SAb. Greater frequency of drinking episodes also predicted SAb: an average of even one day of drinking per week across pregnancy was associated with an increase in the incidence of SAb. However, contrary to our hypothesis, neither the amount of alcohol drunk per drinking day nor a measure of binge drinking was significantly related to SAb after controlling for confounders. Differences in when women who drank at risk levels initiated antenatal care may have under-estimated the impact of alcohol on SAb in this low-SES urban African-American sample. Some drinking measures averaged across pregnancy may have under-estimated consumption and overestimated risk of SAb, but other risk drinking measures that avoid this limitation show similar relations to SAb. Identifying fetal risk drinking in pregnant women is critical to increasing the effectiveness of interventions that reduce risk level alcohol consumption and protect from pregnancy loss

LHON gene therapy vector prevents visual loss and optic neuropathy induced by G11778A mutant mitochondrial DNA: biodistribution and toxicology profile

To demonstrate safety and efficacy of allotopic human ND4 for treatment of a Leber's hereditary optic neuropathy (LHON) mouse model harboring the G11778A mitochondrial mutation. We induced LHON in mice by intravitreal injection of mutant (G11778A) human ND4 DNA, responsible for most cases of LHON, that was directed to mitochondria using an AAV2 vector to which we appended a mitochondrial targeting sequence to the VP2 capsid. We then attempted rescue of visual loss using our test article (ScAAV2-P1ND4v2) containing a synthetic nuclear encoded G11778G ND4 gene that was allotopically expressed. Control mice either were uninjected or received AAV2-GFP or AAV2-mCherry. We performed RT-PCR and confocal microscopy at 2 weeks post injection. Pattern electroretinograms (PERGs), spectral-domain optical coherence tomography (SD-OCT), histology, and transmission electron microscopy (TEM) were performed. For toxicology and biodistribution studies, the test article was administered intravitreally to rats and rhesus macaques at different doses. Mutant and wild-type ND4 were efficiently expressed in the mitochondria of retinal ganglion cells (RGCs). Visual function assessed by serial PERGs and retinal structure by serial SD-OCT showed a significant rescue by the test article. Histology and ultrastructural analysis confirmed that loss of RGCs and demise of axons was prevented by ScAAV2-P1ND4v2. Rat and nonhuman primate biodistribution studies showed that vector spread outside the injected eye into spleen and lymph nodes was minimal. Histopathology of tissues and organs including the eyes was comparable to that of uninfected and saline-injected eyes. Allotopically expressed wild-type ND4 prevents the phenotype induced by G11778A mitochondrial DNA with a toxicology profile acceptable for testing in a phase I clinical trial

Safety and Effects of the Vector for the Leber Hereditary Optic Neuropathy Gene Therapy Clinical Trial

IMPORTANCE: We developed a novel strategy for treatment of Leber hereditary optic neuropathy (LHON) caused by a mutation in the nicotinamide adenine dinucleotide dehydrogenase subunit IV (ND4) mitochondrial gene. OBJECTIVE: To demonstrate the safety and effects of the gene therapy vector to be used in a proposed gene therapy clinical trial. DESIGN AND SETTING: In a series of laboratory experiments, we modified the mitochondrial ND4 subunit of complex I in the nuclear genetic code for import into mitochondria. The protein was targeted into the organelle by agency of a targeting sequence (allotopic expression). The gene was packaged into adeno-associated viral vectors and then vitreally injected into rodent, nonhuman primate, and ex vivo human eyes that underwent testing for expression and integration by immunohistochemical analysis and blue native polyacrylamide gel electrophoresis. During serial follow-up, the animal eyes underwent fundus photography, optical coherence tomography, and multifocal or pattern electroretinography. We tested for rescue of visual loss in rodent eyes also injected with a mutant G11778A ND4 homologue responsible for most cases of LHON. EXPOSURE: Ocular infection with recombinant adeno-associated viral vectors containing a wild-type allotopic human ND4 gene. MAIN OUTCOMES AND MEASURES: Expression of human ND4 and rescue of optic neuropathy induced by mutant human ND4. RESULTS: We found human ND4 expressed in almost all mouse retinal ganglion cells by 1 week after injection and ND4 integrated into the mouse complex I. In rodent eyes also injected with a mutant allotopic ND4, wild-type allotopic ND4 prevented defective adenosine triphosphate synthesis, suppressed visual loss, reduced apoptosis of retinal ganglion cells, and prevented demise of axons in the optic nerve. Injection of ND4 in the ex vivo human eye resulted in expression in most retinal ganglion cells. Primates undergoing vitreal injection with the ND4 test article and followed up for 3 months had no serious adverse reactions. CONCLUSIONS AND RELEVANCE: Expression of our allotopic ND4 vector in the ex vivo human eye, safety of the test article, rescue of the LHON mouse model, and the severe irreversible loss of visual function in LHON support clinical testing with mutated G11778A mitochondrial DNA in our patients