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Alcohol dependence is a major public health challenge in need of new treatments. As alcoholism evolves, stress systems in the brain play an increasing role in motivating continued alcohol use and relapse. We investigated the role of the neurokinin 1 receptor (NK1R), a mediator of behavioral stress responses, in alcohol dependence and treatment. In preclinical studies, mice genetically deficient in NK1R showed a marked decrease in voluntary alcohol consumption and had an increased sensitivity to the sedative effects of alcohol. In a randomized controlled experimental study, we treated recently detoxified alcoholic inpatients with an NK1R antagonist (LY686017; n = 25) or placebo (n = 25). LY686017 suppressed spontaneous alcohol cravings, improved overall well-being, blunted cravings induced by a challenge procedure, and attenuated concomitant cortisol responses. Brain functional magnetic resonance imaging responses to affective stimuli likewise suggested beneficial LY686017 effects. Thus, as assessed by these surrogate markers of efficacy, NK1R antagonism warrants further investigation as a treatment in alcoholism.

The development of protocols for the in vitro expansion of human hematopoietic stem cells (HSC) has been largely based upon optimizing the conditions for proliferation of cells expressing an immunological phenotype associated with native, unmanipulated HSC. The objective of this study was to determine whether the kinetics of functional HSC division in vitro correlated with phenotype. Adult bone marrow-derived CD34+ cells were labeled with carboxyfluorescein diacetate succidimidyl ester, and the kinetics of division of committed and primitive hematopoietic progenitor cells, as well as cells capable of competitive marrow repopulation, were examined for up to five days under conditions demonstrated to produce expanded populations of engraftment-competent HSC. In endothelial cell-based and stromal cell-free cultures, a high proliferative capacity was associated with committed progenitor cells, whereas slower division was characteristic of primitive cobblestone area-forming cells. The ability of marrow CD34 + cells, isolated from the cultures on the basis of prior cell divisions, to competitively repopulate fragments of allogeneic bone implanted into severe combined immunodeficient mice was tested. While committed progenitor cells were capable of one to two divisions within the first thirty hours of expansion culture, cells capable of long-term hematopoietic activity required at least 1.5 days to undergo a single division. The progeny of these cells were characterized by asynchronous subsequent division. By 2.5 days of culture, cells with marrow repopulation activity were capable of one, but not two, divisions. The expression of a CD34+CD38− phenotype, which is associated with native, unmanipulated HSC, did not predict marrow engraftment. Rather, the number of prior divisions was the primary determinant of functional capacity. After five days of culture, marrow repopulation capacity was limited to cells that had undergone four or fewer divisions, despite the continued expression of CD34 by cells that had divided five or more times. The data indicate that engraftment-competent adult marrow HSC are refractory to early division in ex vivo expansion culture, and remain resistant to continued, synchronous division once activated to self-renew. The data further suggest that, in short-term culture, the kinetics of cell cycling may be a more reliable indicator than phenotype of HSC function.

Recent outbreaks of coral bleaching and disease have contributed to substantial declines in the abundance of reef-building coral. Significant attention has been paid to both phenomena in order to determine their effect on reef trajectories. Although each is positively correlated with high temperatures, few studies have explored the potential links between bleaching and disease. A longitudinal study of corals in the Florida Keys was therefore conducted during the 2005 Caribbean bleaching event to quantify bleaching extent and disease incidence in corals, and to determine whether they were related or if they acted as discrete phenomena. These data indicated that overall, a positive correlation exists between bleaching extent and disease incidence. However, the specific interactions between these two phenomena varied among disease bleaching combinations. Montastraea faveolata colonies with greater bleaching intensities later developed white plague (WP) infections. Meanwhile, Siderastrea siderea colonies with dark spot disease (DS) bleached more extensively than apparently healthy colonies. Finally, bleaching and black band disease (BB) co-occurred on Colpophyllia natans throughout the bleaching event. WP, BB, and bleaching are each independently capable of changing the structure of coral populations through loss of living tissue, and DS is an important indicator of reef health. Understanding the dynamics of how these mortality sources interact is critical to understanding mortality patterns and predicting how reef communities will respond to future events.

Background and aims: Perturbations in intestinal microbiota composition due to lifestyle changes may be involved in the development of atopic diseases. We examined gut microbiota composition in early infancy and the subsequent development of atopic manifestations and sensitisation. Methods: The faeces of 957 infants aged 1 month and participating in the KOALA Birth Cohort Study were analysed using quantitative real-time PCR. Information on atopic symptoms (eczema, wheeze) and potential confounders was acquired through repeated questionnaires. Total and specific IgE were measured in venous blood samples collected during home visits when the infant was 2 years old. During these home visits a clinical diagnosis of atopic dermatitis was made according to the UK-Working Party criteria. Results: The presence of Escherichia coli was associated with a higher risk of developing eczema (ORadj = 1.87; 95% CI 1.15 to 3.04), this risk being increased with increasing numbers of E coli (pfor trend = 0.016). Infants colonised with Clostridium difficile were at higher risk of developing eczema (ORadj = 1.40; 95% CI 1.02 to 1.91), recurrent wheeze (ORadj = 1.75; 95% CI 1.09 to 2.80) and allergic sensitisation (ORadj = 1.54; 95% CI 1.02 to 2.31). Furthermore, the presence of C difficile was also associated with a higher risk of a diagnosis of atopic dermatitis during the home visit (ORadj = 1.73; 95% CI 1.08 to 2.78). Conclusion: This study demonstrates that differences in gut microbiota composition precede the development of atopy. Since E coli was only associated with eczema and C difficile was associated with all atopic outcomes, the underlying mechanisms explaining these association may be different.

The nonmedical use of 'designer' cathinone analogs, such as 4-methylmethcathinone (mephedrone) and 3,4-methylenedioxymethcathinone (methylone), is increasing worldwide, yet little information is available regarding the mechanism of action for these drugs. Here, we employed in vitro and in vivo methods to compare neurobiological effects of mephedrone and methylone with those produced by the structurally related compounds, 3,4-methylenedioxymethamphetamine (MDMA) and methamphetamine. In vitro release assays using rat brain synaptosomes revealed that mephedrone and methylone are nonselective substrates for plasma membrane monoamine transporters, similar to MDMA in potency and selectivity. In vivo microdialysis in rat nucleus accumbens showed that i.v. administration of 0.3 and 1.0 mg/kg of mephedrone or methylone produces dose-related increases in extracellular dopamine and serotonin (5-HT), with the magnitude of effect on 5-HT being greater. Both methcathinone analogs were weak motor stimulants when compared with methamphetamine. Repeated administrations of mephedrone or methylone (3.0 and 10.0 mg/kg, s.c., 3 doses) caused hyperthermia but no long-term change in cortical or striatal amines, whereas similar treatment with MDMA (2.5 and 7.5 mg/kg, s.c., 3 doses) evoked robust hyperthermia and persistent depletion of cortical and striatal 5-HT. Our data demonstrate that designer methcathinone analogs are substrates for monoamine transporters, with a profile of transmitter-releasing activity comparable to MDMA. Dopaminergic effects of mephedrone and methylone may contribute to their addictive potential, but this hypothesis awaits confirmation. Given the widespread use of mephedrone and methylone, determining the consequences of repeated drug exposure warrants further study.

In this study of bariatric surgery, adolescents and adults showed marked weight loss that was similar in magnitude in the two groups 5 years after surgery. However, adolescents had remission of diabetes and hypertension more often than adults.

Survival in high-risk pediatric neuroblastoma has remained around 50% for the last 20 years, with immunotherapies and targeted therapies having had minimal impact. Here, we identify the small molecule CX-5461 as selectively cytotoxic to high-risk neuroblastoma and synergistic with low picomolar concentrations of topoisomerase I inhibitors in improving survival in vivo in orthotopic patient-derived xenograft neuroblastoma mouse models. CX-5461 recently progressed through phase I clinical trial as a first-in-human inhibitor of RNA-POL I. However, we also use a comprehensive panel of in vitro and in vivo assays to demonstrate that CX-5461 has been mischaracterized and that its primary target at pharmacologically relevant concentrations, is in fact topoisomerase II beta ( TOP2B ), not RNA-POL I. This is important because existing clinically approved chemotherapeutics have well-documented off-target interactions with TOP2B, which have previously been shown to cause both therapy-induced leukemia and cardiotoxicity—often-fatal adverse events, which can emerge several years after treatment. Thus, while we show that combination therapies involving CX-5461 have promising anti-tumor activity in vivo in neuroblastoma, our identification of TOP2B as the primary target of CX-5461 indicates unexpected safety concerns that should be examined in ongoing phase II clinical trials in adult patients before pursuing clinical studies in children. CX-5461 recently progressed through phase I clinical trial as a first-inhuman inhibitor of RNA-POL I. Here, the authors demonstrate that CX-5461 synergizes with topoisomerase I inhibitors to inhibit neuroblastoma cells and that its primary target in this disease is topoisomerase II beta and not RNA-POL I.

Understanding HIV-1 persistence despite antiretroviral therapy (ART) is of paramount importance. Both single-genome sequencing (SGS) and integration site analysis (ISA) provide useful information regarding the structure of persistent HIV DNA populations; however, until recently, there was noway to link integration sites to their cognate proviral sequences. Here, we used multiple-displacement amplification (MDA) of cellular DNA diluted to a proviral endpoint to obtain full-length proviral sequences and their corresponding sites of integration. We applied this method to lymph node and peripheral blood mononuclear cells from 5 ART-treated donors to determine whether groups of identical subgenomic sequences in the 2 compartments are the result of clonal expansion of infected cells or a viral genetic bottleneck. We found that identical proviral sequences can result from both cellular expansion and viral genetic bottlenecks occurring prior to ART initiation and following ART failure. We identified an expanded T cell clone carrying an intact provirus that matched a variant previously detected by viral outgrowth assays and expanded clones with wild-type and drug-resistant defective proviruses. We also found 2 clones from 1 donor that carried identical proviruses except for nonoverlapping deletions, from which we could infer the sequence of the intact parental virus. Thus, MDA-SGS can be used for “viral reconstruction” to better understand intrapatient HIV-1 evolution and to determine the clonality and structure of proviruses within expanded clones, including those with drug-resistant mutations. Importantly, we demonstrate that identical sequences observed by standard SGS are not always sufficient to establish proviral clonality.

The antiplatelet drug clopidogrel requires activation by cytochrome P-450 (CYP) enzymes. This study shows that CYP polymorphisms that reduce clopidogrel activation result in reduced antiplatelet effect and less clinical benefit in patients with acute coronary syndromes. The antiplatelet drug clopidogrel requires activation by cytochrome P-450 (CYP) enzymes. This study shows that CYP polymorphisms that reduce clopidogrel activation result in reduced antiplatelet effect and less clinical benefit in patients with acute coronary syndromes. Across the spectrum of acute coronary syndromes and in patients undergoing percutaneous coronary interventions (PCI) with stenting, dual antiplatelet therapy with aspirin and clopidogrel, a thienopyridine inhibitor of the platelet P2Y 12 adenosine diphosphate (ADP) receptor, is the standard of care. 1 – 3 However, the pharmacodynamic response to clopidogrel has substantial interpatient variability, 4 – 6 and patients with coronary disease with lesser degrees of platelet inhibition in response to clopidogrel appear to be at increased risk for cardiovascular events. 7 – 10 Clopidogrel is a prodrug that requires biotransformation to an active metabolite by cytochrome P-450 (CYP) enzymes (Figure 1 in the Supplementary Appendix, available . . .

The solar wind gradually slows with increasing distance from the Sun as interstellar material becomes ionized and picked up by the solar wind. When observing the solar wind in the outer heliosphere, it is difficult to differentiate temporal decreases in the speed originating at the Sun from the slowing of the solar wind with increase distance as interstellar material is picked up. In order to resolve this issue, we examine the solar wind speed in the outer heliosphere relative to the corresponding solar wind speed observed at 1 au. Additionally, we use a simulation to help discern the temporal and spatial changes in speed at New Horizons (NH) by driving the inner boundary of a heliospheric simulation with 1 au speed measurements. We conclude that the long interval of slow solar wind from 2018–2023 found at NH was caused by a combination of slow wind being directed toward NH owing to a low current sheet tilt angle keeping the streamers in the ecliptic, and the gradual slowing with increasing distance caused by additional pickup of interstellar material as the solar wind travels farther way from the Sun. When NH was between 50 and 58.5 au, the measured solar wind speed was reduced by ∼13%–15% relative to 1 au owing to pickup of interstellar material. This reduction is a further decrease from the previously reported slowing of 5%–7% in the 30–43 au region.