Systematic characterization of short intronic splicing-regulatory elements in SMN2 pre-mRNA.

Intronic splicing enhancers and silencers (ISEs and ISSs) are two groups of splicing-regulatory elements (SREs) that play critical roles in determining splice-site selection, particularly for alternatively spliced introns or exons. SREs are often short motifs; their mutation or dysregulation of their cognate proteins frequently causes aberrant splicing and results in disease. To date, however, knowledge about SRE sequences and how they regulate splicing remains limited. Here, using an SMN2 minigene, we generated a complete pentamer-sequence library that comprises all possible combinations of 5 nucleotides in intron 7, at a fixed site downstream of the 5' splice site. We systematically analyzed the effects of all 1023 mutant pentamers on exon 7 splicing, in comparison to the wild-type minigene, in HEK293 cells. Our data show that the majority of pentamers significantly affect exon 7 splicing: 584 of them are stimulatory and 230 are inhibitory. To identify actual SREs, we utilized a motif set enrichment analysis (MSEA), from which we identified groups of stimulatory and inhibitory SRE motifs. We experimentally validated several strong SREs in SMN1/2 and other minigene settings. Our results provide a valuable resource for understanding how short RNA sequences regulate splicing. Many novel SREs can be explored further to elucidate their mechanism of action.

Unexpected consequences of afforestation in degraded drylands: Divergent impacts on soil and vegetation.

Forestry has long been considered an effective means of restoring degraded drylands worldwide. Often, afforestation in such lands relies on the establishment of runoff harvesting systems that are formed as contour bench terraces on hillslopes, increasing water availability for the planted trees and shrubs. The construction of terraces requires intensive earthworks by heavy machinery. This study assessed the long-term (>10 yrs) effects of forestry-related land-use change on soil properties and herbaceous vegetation in 16-year-old and 12-year-old afforestation sites (established in 2005 and 2009), and in nearby control ("natural") areas in the semi-arid northern Negev, Israel. Mean herbaceous vegetation height in the 2005 afforestation sites (12.1 cm) was significantly (P = 0.0009) and 23% greater than in the control areas (9.8 cm), whereas in the 2009 afforestation sites (6.2 cm) it was 37% lesser than in the control areas. Mean herbaceous vegetation aboveground biomass was similar in the 2005 afforestation (0.39 Mg ha-1) and control areas (0.38 Mg ha-1), and almost significantly (P = 0.0510) and twofold greater than in the 2009 afforestation sites (0.19 Mg ha-1). The effect of hillslope aspect on these variables was substantial; their mean values were higher in the northern (mesic) hillslopes than in the southern (xeric) hillslopes. Soil samples were obtained from depths of 0-5 and 5-10 cm and physio-chemo-biological properties were assessed in the laboratory. The overall soil quality - as calculated by two soil quality indices (SQIs), including the generalized SQI (SQIgen) and the minimum dataset SQI (SQIMDS) - was significantly (P < 0.0001 for both indices) and 13-22% greater in the control areas (0.52 and 0.61, respectively) than that in the afforestation treatments (0.44-0.46 and 0.50-0.51, respectively). These results are generally attributed to the removal of soil's A-horizon during earthworks, and the exposure of the underlying B-horizon. The similar SQI values of both hillslope aspects, as well as of both soil depths, indicate the generally degraded state of the entire region. In conclusion, while contour bench terracing may facilitate the recovery of herbacaeous vegetation to some extent, the effectiveness of this practice for soil restoration is questionable. Overall, insights of this study demonstrate a caveat that converting natural drylands to forestry systems may not yield sufficient ecological benefits, and therefore should be implemented with caution.

A single tree model to consistently simulate cooling, shading, and pollution uptake of urban trees.

Extremely high temperatures, which negatively affect the human health and plant performances, are becoming more frequent in cities. Urban green infrastructure, particularly trees, can mitigate this issue through cooling due to transpiration, and shading. Temperature regulation by trees depends on feedbacks among the climate, water supply, and plant physiology. However, in contrast to forest or general ecosystem models, most current urban tree models still lack basic processes, such as the consideration of soil water limitation, or have not been evaluated sufficiently. In this study, we present a new model that couples the soil water balance with energy calculations to assess the physiological responses and microclimate effects of a common urban street-tree species (Tilia cordata Mill.) on temperature regulation. We contrast two urban sites in Munich, Germany, with different degree of surface sealing at which microclimate and transpiration had been measured. Simulations indicate that differences in wind speed and soil water supply can be made responsible for the differences in transpiration. Nevertheless, the calculation of the overall energy balance showed that the shading effect, which depends on the leaf area index and canopy cover, contributes the most to the temperature reduction at midday. Finally, we demonstrate that the consideration of soil water availability for stomatal conductance has realistic impacts on the calculation of gaseous pollutant uptake (e.g., ozone). In conclusion, the presented model has demonstrated its ability to quantify two major ecosystem services (temperature mitigation and air pollution removal) consistently in dependence on meteorological and site conditions.

Regeneration of Assembled, Molecular-Motor-Based Bionanodevices.

The guided gliding of cytoskeletal filaments, driven by biomolecular motors on nano/microstructured chips, enables novel applications in biosensing and biocomputation. However, expensive and time-consuming chip production hampers the developments. It is therefore important to establish protocols to regenerate the chips, preferably without the need to dismantle the assembled microfluidic devices which contain the structured chips. We here describe a novel method toward this end. Specifically, we use the small, nonselective proteolytic enzyme, proteinase K to cleave all surface-adsorbed proteins, including myosin and kinesin motors. Subsequently, we apply a detergent (5% SDS or 0.05% Triton X100) to remove the protein remnants. After this procedure, fresh motor proteins and filaments can be added for new experiments. Both, silanized glass surfaces for actin-myosin motility and pure glass surfaces for microtubule-kinesin motility were repeatedly regenerated using this approach. Moreover, we demonstrate the applicability of the method for the regeneration of nano/microstructured silicon-based chips with selectively functionalized areas for supporting or suppressing gliding motility for both motor systems. The results substantiate the versatility and a promising broad use of the method for regenerating a wide range of protein-based nano/microdevices.

Effect of Oxalate and Sulfate on Iron-Catalyzed Secondary Brown Carbon Formation.

Oxalate and sulfate are ubiquitous components of ambient aerosols with a high complexation affinity to iron. However, their effect on iron-driven secondary brown carbon formation in solution from soluble aromatic and aliphatic reagents was not studied. We report masses and hydrodynamic particle sizes of insoluble particles formed from the dark aqueous phase reaction of catechol, guaiacol, fumaric, and muconic acids with Fe(III) in the presence of oxalate or sulfate. Results show that oxalate decreases particle yield in solution from the reaction of Fe(III), with a stronger effect for guaiacol than catechol. For both compounds, the addition of sulfate results in the formation of more polydisperse (0.1-5 µm) and heavier particles than those from control experiments. Reactions with fumaric and muconic acids show that oxalate (not sulfate) and pH are determining factors in the efficiency of particle formation in solution. Polymerization reactions occur readily in the presence of sulfate in solution producing particles with iron-coordinated and/or pore-trapped sulfate anions. The addition of oxalate to the reactions of Fe(III) with all organics, except guaiacol, produced fewer and larger polymeric particles (>0.5 µm). These results imply that even in the presence of competing ligands, the formation of insoluble and colored particles from soluble organic precursors still dominates over the formation of soluble iron complexes.

Comparisons of false negative rates from a trend test alone and from a trend test jointly with a control-high groups pairwise test in the determination of the carcinogenicity of new drugs.

Interest has been expressed in using a joint test procedure that requires that the results of both a trend test and a pairwise comparison test between the control and the high groups be statistically significant simultaneously at the levels of significance recommended in the FDA 2001 draft guidance for industry document for the separate tests in order for the drug effect on the development of an individual tumor type to be considered as statistically significant. Results of our simulation studies show that there is a serious consequence of large inflations of the false negative rate through large decreases of false positive rate in the use of the above joint test procedure in the final interpretation of the carcinogenicity potential of a new drug if the levels of significance recommended for separate tests are used. The inflation can be as high as 204.5% of the false negative rate when the trend test alone is required to test if the effect is statistically significant. To correct the problem, new sets of levels of significance have also been developed for those who want to use the joint test in reviews of carcinogenicity studies.

Blebbistatin Effects Expose Hidden Secrets in the Force-Generating Cycle of Actin and Myosin.

Cyclic interactions between myosin II motors and actin filaments driven by ATP turnover underlie muscle contraction and have key roles in the motility of nonmuscle cells. A remaining enigma in the understanding of this interaction is the relationship between the force-generating structural change and the release of the ATP-hydrolysis product, inorganic phosphate (Pi), from the active site of myosin. Here, we use the small molecular compound blebbistatin to probe otherwise hidden states and transitions in this process. Different hypotheses for the Pi release mechanism are tested by interpreting experimental results from in vitro motility assays and isolated muscle fibers in terms of mechanokinetic actomyosin models. The data fit with ideas that actomyosin force generation is preceded by Pi release, which in turn is preceded by two serial transitions after/coincident with cross-bridge attachment. Blebbistatin changes the rate limitation of the cycle from the first to the second of these transitions, uncovering functional roles of an otherwise short-lived pre-power stroke state that has been implicated by structural data.

Comparative analysis of widely used methods to remove nonfunctional myosin heads for the in vitro motility assay.

The in vitro motility assay allows studies of muscle contraction through observation of actin filament propulsion by surface-adsorbed myosin motors or motor fragments isolated from muscle. A possible problem is that motility may be compromised by nonfunctional, "dead", motors, obtained in the isolation process. Here we investigate the effects on motile function of two approaches designed to eliminate the effects of these dead motors. We first tested the removal of heavy meromyosin (HMM) molecules with ATP-insensitive "dead" heads by pelleting them with actin filaments, using ultracentrifugation in the presence of 1 mM MgATP ("affinity purification"). Alternatively we incubated motility assay flow cells, after HMM surface adsorption, with non-fluorescent "blocking actin" (1 µM) to block the dead heads. Both affinity purification and use of blocking actin increased the fraction of motile filaments compared to control conditions. However, affinity purification significantly reduced the actin sliding speed in five out of seven experiments on silanized surfaces and in one out of four experiments on nitrocellulose surfaces. Similar effects on velocity were not observed with the use of blocking actin. However, a reduced speed was also seen (without affinity purification) if HMM or myosin subfragment 1 was mixed with 1 mM MgATP before and during surface adsorption. We conclude that affinity purification can produce unexpected effects that may complicate the interpretation of in vitro motility assays and other experiments with surface adsorbed HMM, e.g. single molecule mechanics experiments. The presence of MgATP during incubation with myosin motor fragments is critical for the complicating effects.

Controlled Surface Silanization for Actin-Myosin Based Nanodevices and Biocompatibility of New Polymer Resists.

Molecular motor-based nanodevices require organized cytoskeletal filament guiding along motility-promoting tracks, confined by motility-inhibiting walls. One way to enhance motility quality on the tracks, particularly in terms of filament velocity but also the fraction of motile filaments, is to optimize the surface hydrophobicity. We have investigated the potential to achieve this for the actin-myosin II motor system on trimethylchlorosilane (TMCS)-derivatized SiO2 surfaces to be used as channel floors in nanodevices. We have also investigated the ability to supress motility on two new polymer resists, TU7 (for nanoimprint lithography) and CSAR 62 (for electron beam and deep UV lithography), to be used as channel walls. We developed a chemical-vapor deposition tool for silanizing SiO2 surfaces in a controlled environment to achieve different surface hydrophobicities (measured by water contact angle). In contrast to previous work, we were able to fabricate a wide range of contact angles by varying the silanization time and chamber pressure using only one type of silane. This resulted in a significant improvement of the silanization procedure, producing a predictable contact angle on the surface and thereby predictable quality of the heavy meromyosin (HMM)-driven actin motility with regard to velocity. We observed a high degree of correlation between the filament sliding velocity and contact angle in the range 10-86°, expanding the previously studied range. We found that the sliding velocity on TU7 surfaces was superior to that on CSAR 62 surfaces despite similar contact angles. In addition, we were able to suppress the motility on both TU7 and CSAR 62 by plasma oxygen treatment before silanization. These results are discussed in relation to previously proposed surface adsorption mechanisms of HMM and their relationship to the water contact angle. Additionally, the results are considered for the development of actin-myosin based nanodevices with superior performance with respect to actin-myosin functionality.

Mesoporous magnetic silica particles modified with stimuli-responsive P(NIPAM-DMA) valve for controlled loading and release of biologically active molecules.

Mesoporous magnetic silica particles bearing a stimuli-responsive polymer valve were prepared and their performance as a microcapsule was evaluated. In this study, first, mesoporous magnetic iron oxide (Fe3O4) particles were prepared by a solvothermal method. Then, the magnetic particles were coated with silica and functionalized with vinyl groups using 3-(trimethoxysilyl)-propyl methacrylate (MPS). Subsequently, the Fe3O4/SiO2 composite particles grafted with MPS were used to carry out the seeded precipitation copolymerization of N-isopropylacrylamide (NIPAM) and 2,2-dimethylaminoethyl methacrylate (DMA). Here N,N'-methylenebisacrylamide (MBA) was used as a cross-linker. Brunauer-Emmett-Teller (BET) surface analysis suggested that the mesoporous structure was retained in the final Fe3O4/SiO2/P(NIPAM-DMA-MBA) composite hydrogel particles. The prepared Fe3O4/SiO2/P(NIPAM-DMA-MBA) composite hydrogel microspheres exhibited a pH-dependent volume phase transition. At lower pH values (<7), the inclusion of DMA shifted the volume phase transition to higher temperature because of the protonation of the tertiary amine groups. The composite hydrogel particles possessed a high saturation magnetization (51 emu g-1) and moved under the influence of an external magnetic field. The loading-release behaviour of these biologically active molecules suggested that a portion of the encapsulated guest molecules was released at a temperature below the lower critical solution temperature, LCST (<35 °C).

Specific packaging and circulation of cytochromes P450, especially 2E1 isozyme, in human plasma exosomes and their implications in cellular communications.

Cytochrome P450 (CYP) enzymes metabolize the majority of xenobiotics and are mainly found in hepatic and some extra-hepatic cells. However, their presence and functional role in exosomes, small extracellular vesicles that are secreted from various cells into extracellular fluids including plasma, is unknown. In this study, we analyzed the expression and biological activity of CYP enzymes in human plasma exosomes. First, we optimized isolation of plasma exosomes and characterized them for their physical properties and quality. The results showed that the purity of exosomes (<200 nm) improved upon prior filtration of plasma using a 0.22 micron filter. We then analyzed the relative level of exosomal CYP mRNAs, proteins, and enzyme activity. The results showed that the relative level of CYP enzymes in exosomes is higher than in plasma, suggesting their specific packaging in exosomes. Of the seven CYP enzymes tested, the mRNA of CYP1B1, CYP2A6, CYP2E1, and CYP3A4 were detectable in exosomes. Interestingly, the relative level of CYP2E1 mRNA was >500-fold higher than the other CYPs. The results from the Western blot showed detectable levels of CYP1A1, CYP1B1, CYP2A6, CYP2E1, and CYP3A4. Our results also demonstrated that exosomal CYP2E1 and CYP3A4 show appreciable activity relative to their respective positive controls (CYP-induced baculosomes). Our results also showed that CYP2E1 is expressed relatively higher in plasma exosomes than hepatic and monocytic cells and exosomes derived from these cells. In conclusion, this is the first evidence of the specific packaging and circulation of CYP enzymes, especially CYP2E1, in human plasma exosomes. The findings have biological and clinical significance in terms of their implications in cellular communications and potential use of plasma exosomal CYPs as biomarkers.

ATR-FTIR and Flow Microcalorimetry Studies on the Initial Binding Kinetics of Arsenicals at the Organic-Hematite Interface.

The environmental fate of arsenic compounds depends on their surface interactions with geosorbents that include clays, metal oxides, and natural organic matter (NOM). While a number of batch studies reported that NOM inhibits the uptake of arsenicals, it remains unclear how different classes of organic functional groups affect their binding mechanisms. We report herein the adsorption kinetics of arsenate and dimethylarsinic acid (DMA) with hematite nanoparticles pre-exposed to three types of low molecular weight organics: citrate, oxalate, and pyrocatechol as representatives to the majority of reactive organic functional groups in NOM. These studies were conducted using attenuated total internal reflection Fourier transform infrared spectroscopy (ATR-FTIR) and flow microcalorimetry at pH 7 with an emphasis on the role that electrolytes (KCl, NaCl, and KBr) play in the adsorption process. Results show that (1) negatively charged carboxylate versus hydrophobic phenyl groups influence amounts and initial rates of arsenicals adsorption on hematite nanoparticles to varying degrees depending on the type of complexes they form, (2) the type of electrolytes affects initial adsorption rate of DMA to a greater extent than arsenate when oxalate is present on the surface, and (3) the extent of organics retention by hematite nanoparticles is influenced by the type of the desorbing agent.

Inter- and intraannual growth patterns of urban small-leaved lime (Tilia cordata mill.) at two public squares with contrasting microclimatic conditions.

The effects of urban conditions on tree growth have been investigated in an increasing number of studies over the last decades, emphasizing the harsh environment of cities. Urban trees often grow in highly paved, compacted sites with consequently less soil moisture, higher soil temperatures, and greater vapor pressure deficits. However, there is still a knowledge gap regarding the impact of harsh paved environments on urban tree growth during drought years on the growth patterns of urban trees. The present study investigated the structure and growth of the common urban tree species small-leaved lime (Tilia cordata) at a highly paved public square (CPS) compared with a contrasting more open, greener square (OGS). Continuously, measured high precision dendrometer data along with meteorological data of the extreme dry and warm summer 2015 as well as dendrochronological data of the sampled trees were investigated to analyze tree growth during a drought year. The results highlight different tree dimensions and growth patterns of the trees at both sites, influenced by tree age and distinct site conditions. While the trees at OGS grew up to 2.5 mm from July until mid of August, the trees at CPS had only 0.4-mm diameter increment. After the initial expansion at CPS, tree diameter contracted again during summer to the point of shrinkage (up to 0.8 mm) at the end of our investigation. Further drought year analysis confirmed the patterns of significant stem growth reductions in the consecutive two years following the drought. A correlation analysis revealed that transpiration, air temperature, and vapor pressure deficit were negatively correlated with the daily diameter growth, whereas precipitation had a strong positive effect. Due to high transpiration rates associated with anisohydric water use behavior, T. cordata was able to provide evaporative cooling even during drought. However, this anisohydric behavior resulted in substantial growth decline afterwards especially at paved sites like CPS. Our results suggest selection of tree species, such as those with isohydric water use behavior, which may achieve a better balance between growth, transpiration, and hence evaporative cooling.

Myosin-Induced Gliding Patterns at Varied [MgATP] Unveil a Dynamic Actin Filament.

Actin filaments have key roles in cell motility but are generally claimed to be passive interaction partners in actin-myosin-based motion generation. Here, we present evidence against this static view based on an altered myosin-induced actin filament gliding pattern in an in vitro motility assay at varied [MgATP]. The statistics that characterize the degree of meandering of the actin filament paths suggest that for [MgATP] ≥ 0.25 mM, the flexural rigidity of heavy meromyosin (HMM)-propelled actin filaments is similar (without phalloidin) or slightly lower (with phalloidin) than that of HMM-free filaments observed in solution without surface tethering. When [MgATP] was reduced to ≤0.1 mM, the actin filament paths in the in vitro motility assay became appreciably more winding in both the presence and absence of phalloidin. This effect of lowered [MgATP] was qualitatively different from that seen when HMM was mixed with ATP-insensitive, N-ethylmaleimide-treated HMM (NEM-HMM; 25-30%). In particular, the addition of NEM-HMM increased a non-Gaussian tail in the path curvature distribution as well as the number of events in which different parts of an actin filament followed different paths. These effects were the opposite of those observed with reduced [MgATP]. Theoretical modeling suggests a 30-40% lowered flexural rigidity of the actin filaments at [MgATP] ≤ 0.1 mM and local bending of the filament front upon each myosin head attachment. Overall, the results fit with appreciable structural changes in the actin filament during actomyosin-based motion generation, and modulation of the actin filament mechanical properties by the dominating chemomechanical actomyosin state.

Differential gene expression and alternative splicing between diploid and tetraploid watermelon.

The exploitation of synthetic polyploids for producing seedless fruits is well known in watermelon. Tetraploid progenitors of triploid watermelon plants, compared with their diploid counterparts, exhibit wide phenotypic differences. Although many factors modulate alternative splicing (AS) in plants, the effects of autopolyploidization on AS are still unknown. In this study, we used tissues of leaf, stem, and fruit of diploid and tetraploid sweet watermelon to understand changes in gene expression and the occurrence of AS. RNA-sequencing analysis was performed along with reverse transcription quantitative PCR and rapid amplification of cDNA ends (RACE)-PCR to demonstrate changes in expression and splicing. All vegetative tissues except fruit showed an increased level of AS in the tetraploid watermelon throughout the growth period. The ploidy levels of diploids and the tetraploid were confirmed using a ploidy analyser. We identified 5362 and 1288 genes that were up- and downregulated, respectively, in tetraploid as compared with diploid plants. We further confirmed that 22 genes underwent AS events across tissues, indicating possibilities of generating different protein isoforms with altered functions of important transcription factors and transporters. Arginine biosynthesis, chlorophyllide synthesis, GDP mannose biosynthesis, trehalose biosynthesis, and starch and sucrose degradation pathways were upregulated in autotetraploids. Phloem protein 2, chloroplastic PGR5-like protein, zinc-finger protein, fructokinase-like 2, MYB transcription factor, and nodulin MtN21 showed AS in fruit tissues. These results should help in developing high-quality seedless watermelon and provide additional transcriptomic information related to other cucurbits.

Prevalence of iron-deficiency anaemia among university students in Noakhali region, Bangladesh.

Iron-deficiency anaemia (IDA) is a common health problem in rural women and young children of Bangladesh. The university students usually take food from residential halls, and the food value of their diets is not always balanced. This cross-sectional study was conducted to estimate the prevalence of iron-deficiency anaemia among the university students of Noakhali region, Bangladesh. Haemoglobin level of 300 randomly-selected students was measured calorimetrically, using Sahli's haemoglobinometer during October to December 2011. Statistical analysis was done by using SPSS software for Windows (version 16) (SPSS Inc., Chicago, IL, USA). In the study, 55.3% students were found anaemic, of whom 36.7% were male, and 63.3% were female. Students aged 20-22 years were more anaemic (43.4%) than other age-groups. Majority (51.3%) of male students showed their haemoglobin level in the range of 13-15 g/dL, followed by 26.0% and 21.3% with 10-12 g/dL and 16-18 g/dL respectively. Although 50.5% anaemic and 51.1% non-anaemic female students showed normal BMI--lower percentage than anaemic (60.7%) and non-anaemic (71.9%) male students, the underweight students were found more anaemic than the overweight and obese subjects. Regular breakfast-taking habit showed significant (p = 0.035, 95% CI 0.5-1.0) influence on IDA compared to non-regular breakfast takers. Consumption of meat, fish, poultry, eggs, or peanut butter regularly; junk food; multivitamins; and iron/iron-rich food showed insignificant (p = 0.097, 95% CI 0.5-1.1; p = 0.053, 95% CI 1.1-2.3; p = 0.148, 95% CI 0.6-1.2; and p = 0.487, 95% CI 0.7-1.4 respectively) role in provoking IDA. In the case of non-anaemic subjects, all of the above parameters were significant, except the junk food consumption (p = 0.342, 95% CI 0.5-1.2). Our study revealed that majority of university students, especially female, were anaemic that might be aggravated by food habit and lack of awareness. The results suggest that anaemia can be prevented by providing proper knowledge on the healthful diet, improved lifestyle, and harmful effect of anaemia to the students.

Unraveling the Origin of an Unusual Shift in the Electroluminescence of 1D CsCu2I3 Light-Emitting Diodes.

Lead-free low-dimensional copper-based metal halides are promising luminescent materials for broadband LEDs owing to their broad self-trapped exciton (STE) emission. However, recently, in 1D CsCu2I3, a discrepancy between their electroluminescence (EL) and photoluminescence (PL) has been observed. As a result, the overall output color from LEDs is significantly different than the anticipated emission. To unveil the origin of this discrepancy, here, we provide comprehensive analyses and show that the shift in the EL is caused neither by any structural/optical interactions between CsCu2I3 and electron transport layers (ETL) nor by the degradation of 1D CsCu2I3. Instead, it depends on the carrier imbalance on CsCu2I3, mainly due to the difference in the electron mobility of the ETLs and the electron density on the CsCu2I3 layer. By varying the ETLs, different colored 1D CsCu2I3 LEDs with peaks at 556, 590, and 647 nm are fabricated, and a maximum luminance of over 2000 cd/m2 is achieved for a 556 nm LED. Further, by limiting the electron mobility and injection to 1D CsCu2I3 using an insulating LiF layer at the CsCu2I3/ETL interface, more red-shifted LEDs are achieved confirming the critical role of electron density on the EL characteristics of 1D CsCu2I3.

The CB1 negative allosteric modulator PSNCBAM-1 reduces ethanol self-administration via a nonspecific hypophagic effect.

Alcohol use disorder (AUD) affects >15 million people in the United States. Current pharmacotherapeutic treatments for AUD are only modestly effective, necessitating the identification of new targets for medications development. The cannabinoid receptor type 1 (CB1) has been a target of interest for the development of medications for substance use disorders and other compulsive disorders. However, CB1 antagonists/inverse agonists (e.g., rimonabant) have severe side effects that limit their clinical utility, including anxiety, depression, and suicide. Recent development of CB1 negative allosteric modulators (NAMs), including PSNCBAM-1, may provide an alternative mechanism of attenuating CB1 signaling with reduced side effects. PSNCBAM-1 has not yet been evaluated for effects in models of AUD. In this study, we investigated the effects of the CB1 NAM, PSNCBAM-1, in rodent models of AUD using adult male mice. PSNCBAM-1 dose-dependently attenuated oral ethanol self-administration (8 % w/v ethanol in water), significantly reducing ethanol rewards at a dose of 30 mg/kg, but not at 10 or 18 mg/kg. PSNCBAM-1 also dose-dependently attenuated palatable food self-administration (diluted vanilla Ensure), significantly reducing food rewards at 18 and 30 mg/kg PSNCBAM-1. PSNCBAM-1 did not affect conditioned place preference for 2 g/kg ethanol. These results suggest PSNCBAM-1 reduces ethanol-taking behavior via a nonspecific hypophagic effect and does not reduce the rewarding effects of ethanol.