DCC-related developmental effects of abused- versus therapeutic-like amphetamine doses in adolescence.

The guidance cue receptor DCC controls mesocortical dopamine development in adolescence. Repeated exposure to an amphetamine regimen of 4 mg/kg during early adolescence induces, in male mice, downregulation of DCC expression in dopamine neurons by recruiting the Dcc microRNA repressor, microRNA-218 (miR-218). This adolescent amphetamine regimen also disrupts mesocortical dopamine connectivity and behavioral control in adulthood. Whether low doses of amphetamine in adolescence induce similar molecular and developmental effects needs to be established. Here, we quantified plasma amphetamine concentrations in early adolescent mice following a 4 or 0.5 mg/kg dose and found peak levels corresponding to those seen in humans following recreational and therapeutic settings, respectively. In contrast to the high doses, the low amphetamine regimen does not alter Dcc mRNA or miR-218 expression; instead, it upregulates DCC protein levels. Furthermore, high, but not low, drug doses downregulate the expression of the DCC receptor ligand, Netrin-1, in the nucleus accumbens and prefrontal cortex. Exposure to the low-dose regimen did not alter the expanse of mesocortical dopamine axons or their number/density of presynaptic sites in adulthood. Strikingly, adolescent exposure to the low-dose drug regimen does not impair behavioral inhibition in adulthood; instead, it induces an overall increase in performance in a go/no-go task. These results show that developmental consequences of exposure to therapeutic- versus abused-like doses of amphetamine in adolescence have dissimilar molecular signatures and opposite behavioral effects. These findings have important clinical relevance since amphetamines are widely used for therapeutic purposes in youth.

PLA-PEG Coated Multifunctional Imaging Probe for Targeted Drug Delivery.

Monitoring of drugs in vivo has been recognized as an urgent need for successful chemotherapy treatment. However, to find an appropriate tool for this purpose has been proved as a great challenge. Here, we report a PLA-PEG coated hollow X-ray and upconversion nanophosphor with folic acid as a tumor targeting ligand for a novel drug delivery system. In contrast with previously reported PLA-PEG based or PLA-PEG coated inorganic nanoparticles, our X-ray and upconversion nanophosphor based drug carriers can be used simultaneously as the drug delivery carrier and also serve as labels to track the loaded drugs (paclitaxel) by optical luminescence excited by X-ray, near-infrared light and magnetic resonance imaging. In addition, the hollow space created in our drug carriers dramatically increases the amount of loaded drug. Besides, folic acid on the surface of the drug loaded nanophosphors enhanced cellular uptake and significantly increased the drug efficacy compared with the free drug. We anticipate that these multifunctional nanocarriers will result in significant improvement and serve as a platform in the field of drug delivery.

Children's third-party punishment does not change depending on the prospect of future interaction.

Children pay a cost to punish third parties for unfairness. However, theoretical debates highlight that such behaviors could reflect a strategic attempt to manipulate others in future interactions. The personal deterrence hypothesis claims that punishment is motivated to deter future unfairness toward punishers. Here we tested this hypothesis with a total of n = 248 five- to 10-year-olds. In two experiments, participants witnessed that a divider shared resources either fairly or selfishly with a third party. Participants learned that the same divider (same divider condition) or a new divider (different divider condition) would subsequently decide how to share resources with the participant. If children's punishment is motivated by personal deterrence, they should punish unfairness more often in the same divider condition (vs. different divider). Conversely, if children fear retaliation from dividers, they should punish dividers less often in the same divider condition (vs. different divider). Children intervened by taking resources away from the divider (Experiment 1) or by sending a disapproving or an approving verbal message (Experiment 2). Children were more likely to punish unfair than fair allocations through material punishment and disapproving messages, while being more likely to reward fair than unfair allocations by sending approving messages. However, children did so at the same level regardless of their future divider's identity. We discuss how these results speak to a children's emerging concern with fairness and how it challenges the notion that children punish for self-oriented reasons as suggested by the personal deterrence hypothesis. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Amphetamine disrupts dopamine axon growth in adolescence by a sex-specific mechanism in mice.

Initiating drug use during adolescence increases the risk of developing addiction or other psychopathologies later in life, with long-term outcomes varying according to sex and exact timing of use. The cellular and molecular underpinnings explaining this differential sensitivity to detrimental drug effects remain unexplained. The Netrin-1/DCC guidance cue system segregates cortical and limbic dopamine pathways in adolescence. Here we show that amphetamine, by dysregulating Netrin-1/DCC signaling, triggers ectopic growth of mesolimbic dopamine axons to the prefrontal cortex, only in early-adolescent male mice, underlying a male-specific vulnerability to enduring cognitive deficits. In adolescent females, compensatory changes in Netrin-1 protect against the deleterious consequences of amphetamine on dopamine connectivity and cognitive outcomes. Netrin-1/DCC signaling functions as a molecular switch which can be differentially regulated by the same drug experience as function of an individual's sex and adolescent age, and lead to divergent long-term outcomes associated with vulnerable or resilient phenotypes.

Efficacy and Safety of Sugammadex versus Neostigmine in Reversing Neuromuscular Blockade in Morbidly Obese Adult Patients: A Systematic Review and Meta-Analysis.

CONTEXT: Sugammadex is known to reverse neuromuscular blockade (NMB) more rapidly and reliably than neostigmine. However, data remain limited in bariatric patients. In this review, we systematically evaluated the efficacy and safety of sugammadex versus neostigmine in reversing NMB in morbidly obese (MO) patients undergoing bariatric surgery. AIMS: Our primary objective was to determine the recovery time from drug administration to a train-of-four (TOF) ratio >0.9 from a moderate or deep NMB. SETTINGS AND DESIGN: This systematic review and meta-analysis (SR and MA) was conducted in accordance with the Preferred Items for SRs and MAs guidelines. SUBJECTS AND METHODS: A systematic search was conducted within multiple databases for studies that compared sugammadex and neostigmine in MO patients. STATISTICAL ANALYSIS USED: We reported data as mean difference (MD) or odds ratios (OR) and corresponding 95% confidence interval (CI) using random-effects models. A two-sided P < 0.05 was considered statistically significant. RESULTS: Seven studies with 386 participants met the inclusion criteria. Sugammadex significantly reduced the time of reversal of moderate NMB-to-TOF ratio >0.9 compared to neostigmine, with a mean time of 2.5 min (standard deviation [SD] 1.25) versus 18.2 min (SD 17.6), respectively (MD: -14.52; 95% CI: -20.08, -8.96; P < 0.00001; I 2 = 96%). The number of patients who had composite adverse events was significantly lower with sugammadex (21.2% of patients) compared to neostigmine (52.5% of patients) (OR: 0.15; 95% CI: 0.07-0.32; P < 0.00001; I 2 = 0%). CONCLUSIONS: Sugammadex reverses NMB more rapidly with fewer adverse events than neostigmine in MO patients undergoing bariatric surgery.

Phosphorus can also be a "photocopy".

The syntheses of benzoxaphospholes and new benzobisoxaphospholes that display blue fluorescence are presented. The latter compounds were accessed by the use of a new precursor, 2,5-diphosphinohydroquinone. The new compounds were fully characterized, including a structural study of 2,6-tert-butylbenzo[1,2-d;4,5-d']bisoxaphosphole. Quantum yields for photoluminescence were determined for a series of compounds. These materials feature bona fide P horizontal lineC p-p pi bonds suitable for conjugated materials having phosphorus as a participatory atom and can thus "photocopy" the properties of other conjugated organic molecules.

A chitinase-like protein in the lung and circulation of patients with severe asthma.

BACKGROUND: The evolutionarily conserved 18-glycosyl-hydrolase family contains true chitinases and chitinase-like proteins that lack enzymatic activity. Acidic mammalian chitinase has recently been associated with animal models of asthma. The related chitinase-like protein, YKL-40 (also called human cartilage glycoprotein 39 [HCgp-39] and chitinase 3-like 1), can be readily measured in the serum. However, its relationship to asthma has not been evaluated. METHODS: We quantified serum YKL-40 levels in three cohorts of patients with asthma--one recruited from the patient population at Yale University, one from the University of Paris, and one from the University of Wisconsin--as well as in controls from the surrounding communities. In the Paris cohort, immunohistochemical analysis and morphometric quantitation were used to evaluate the locus of expression of YKL-40 in the lung. The clinical characteristics of the patients with high serum or lung YKL-40 levels were also evaluated. RESULTS: Serum YKL-40 levels were significantly elevated in patients with asthma as compared with controls. In the Paris cohort, lung YKL-40 levels were elevated and were correlated with circulating YKL-40 levels (r=0.55, P<0.001) and with airway remodeling (measured as the thickness of the subepithelial basement membrane) (r=0.51, P=0.003). In all three cohorts, serum YKL-40 levels correlated positively with the severity of asthma and inversely with the forced expiratory volume in 1 second. Patients with elevated levels of YKL-40 had significantly more frequent rescue-inhaler use, greater oral corticosteroid use, and a greater rate of hospitalization than patients with lower levels. CONCLUSIONS: YKL-40 is found in increased quantities in the serum and lungs in a subgroup of patients with asthma, in whom expression of chitinase in both compartments correlates with the severity of asthma. The recovery of YKL-40 from these patients indicates either a causative or a sentinel role for this molecule in asthma.

Steric coordination control of interchain interactions in conducting metallopolymers.

The solution processability of a conducting metallopolymer (CMP1) based on a 2,2'-bipyridyl (bipy) derivatized poly(p-phenylene vinylene) (PPV) backbone has been accomplished by the strategic placement of sterically demanding mesityl side chains. The enhanced solubility of CMP1 can be traced to the prevention of coordinative crosslinking between polymer chains. The sterically enforced 1:1 bipy/metal ratio was confirmed by job analysis of absorption spectroscopic titration data. In addition to enhanced processability, this strategy also leads to twice as many metal ions, and consequently twice the charge, on CMP1 versus traditional bipyridyl-PPV metallopolymers that are typified by a 2:1 bipy/metal ratio with certain metals.

Dizinc enzyme model/complexometric indicator pairs in indicator displacement assays for inorganic phosphates under physiological conditions.

A dizinc phosphohydrolase enzyme model complex employing the dinucleating ligand 2,6-bis-[(bis-pyridin-2-ylmethyl-amino)methyl]-4-methylphenol (L1) was tested for binding to a series of 11 commercially available complexometric indicators in aqueous N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid (HEPES) buffer at pH 7.4, with the aim of determining the applicability of these indicators in indicator displacement assays (IDAs) under physiological conditions. Dissociation constants (Kd) were determined for 11 indicator-Zn2L1 complexes, spanning 2 orders of magnitude from 2.8 x 10(-4) M (alizarin red S) to 2.7 x 10(-6) M (bromo pyrogallol red). Phosphate and pyrophosphate were tested for their ability to displace bound indicator and produce a detectable colorimetric response. Three indicators (bromo pyrogallol red, mordant blue 9, and zincon) complex to Zn2L1 to form an indicator displacement assay selective for pyrophosphate over phosphate. Because selection of an indicator/analyte pair having appropriate relative Kd values is critical for their successful application in IDAs, the binding data for these 11 indicators should assist their extension to IDAs for other analytes.

Pulmonary type II cell hypertrophy and pulmonary lipoproteinosis are features of chronic IL-13 exposure.

Interleukin (IL)-13, a key mediator of Th2-mediated immunity, contributes to the pathogenesis of asthma and other pulmonary diseases via its ability to generate fibrosis, mucus metaplasia, eosinophilic inflammation, and airway hyperresponsiveness. In these studies, we compared surfactant accumulation in wild-type mice and mice in which IL-13 was overexpressed in the lung. When compared with littermate controls, transgenic animals showed alveolar type II cell hypertrophy under light and electron microscopy. Over time, their alveoli also filled with surfactant in a pulmonary alveolar proteinosis pattern. At the same time, prominent interstitial fibrosis occurs. Bronchoalveolar lavage fluid from these mice had a three- to sixfold increase in surfactant phospholipids. Surfactant proteins (SP)-A, -B, and -C showed two- to threefold increases, whereas SP-D increased 70-fold. These results indicate that IL-13 is a potent stimulator of surfactant phospholipid and surfactant accumulation in the lung. IL-13 may therefore play a central role in the broad range of chronic pulmonary conditions in which fibrosis, type II cell hypertrophy, and surfactant accumulation occur.