Habenular TCF7L2 links nicotine addiction to diabetes.

Diabetes is far more prevalent in smokers than non-smokers, but the underlying mechanisms of vulnerability are unknown. Here we show that the diabetes-associated gene Tcf7l2 is densely expressed in the medial habenula (mHb) region of the rodent brain, where it regulates the function of nicotinic acetylcholine receptors. Inhibition of TCF7L2 signalling in the mHb increases nicotine intake in mice and rats. Nicotine increases levels of blood glucose by TCF7L2-dependent stimulation of the mHb. Virus-tracing experiments identify a polysynaptic connection from the mHb to the pancreas, and wild-type rats with a history of nicotine consumption show increased circulating levels of glucagon and insulin, and diabetes-like dysregulation of blood glucose homeostasis. By contrast, mutant Tcf7l2 rats are resistant to these actions of nicotine. Our findings suggest that TCF7L2 regulates the stimulatory actions of nicotine on a habenula-pancreas axis that links the addictive properties of nicotine to its diabetes-promoting actions.

Conventional and multi-omics assessments of subacute inhalation toxicity due to propylene glycol and vegetable glycerin aerosol produced by electronic cigarettes.

Propylene glycol (PG) and vegetable glycerin (VG) are the most common solvents used in electronic cigarette liquids. No long-term inhalation toxicity assessments have been performed combining conventional and multi-omics approaches on the potential respiratory effects of the solvents in vivo. In this study, the systemic toxicity of aerosol generated from a ceramic heating coil-based e-cigarette was evaluated. First, the aerosol properties were characterized, including carbonyl emissions, the particle size distribution, and aerosol temperatures. To determine toxicological effects, rats were exposed, through their nose only, to filtered air or a propylene glycol (PG)/ glycerin (VG) (50:50, %W/W) aerosol mixture at the target concentration of 3 mg/L for six hours daily over a continuous 28-day period. Compared with the air group, female rats in the PG/VG group exhibited significantly lower body weights during both the exposure period and recovery period, and this was linked to a reduced food intake. Male rats in the PG/VG group also experienced a significant decline in body weight during the exposure period. Importantly, rats exposed to the PG/VG aerosol showed only minimal biological effects compared to those with only air exposure, with no signs of toxicity. Moreover, the transcriptomic, proteomic, and metabolomic analyses of the rat lung tissues following aerosol exposure revealed a series of candidate pathways linking aerosol inhalation to altered lung functions, especially the inflammatory response and disease. Dysregulated pathways of arachidonic acids, the neuroactive ligand-receptor interaction, and the hematopoietic cell lineage were revealed through integrated multi-omics analysis. Therefore, our integrated multi-omics approach offers novel systemic insights and early evidence of environmental-related health hazards associated with an e-cigarette aerosol using two carrier solvents in a rat model.

Controlling the 2D Magnetism of CrBr3 by van der Waals Stacking Engineering.

The manipulation of two-dimensional (2D) magnetic order is of significant importance to facilitate future 2D magnets for low-power and high-speed spintronic devices. van der Waals stacking engineering makes promises for controllable magnetism via interlayer magnetic coupling. However, directly examining the stacking order changes accompanying magnetic order transitions at the atomic scale and preparing device-ready 2D magnets with controllable magnetic orders remain elusive. Here, we demonstrate the effective control of interlayer stacking in exfoliated CrBr3 via thermally assisted strain engineering. The stable interlayer ferromagnetic (FM), antiferromagnetic (AFM), and FM-AFM coexistent ground states confirmed by the magnetic circular dichroism measurements are realized. Combined with the first-principles calculations, the atomically resolved imaging technique reveals the correlation between magnetic order and interlayer stacking order in CrBr3 flakes unambiguously. A tunable exchange bias effect is obtained in the mixed phase of FM and AFM states. This work will introduce new magnetic properties by controlling the stacking order and sequence of 2D magnets, providing ample opportunities for their application in spintronic devices.

Central and peripheral actions of nicotine that influence blood glucose homeostasis and the development of diabetes.

Cigarette smoking has long been recognized as a risk factor for type 2 diabetes (T2D), although the precise causal mechanisms underlying this relationship remain poorly understood. Recent evidence suggests that nicotine, the primary reinforcing component in tobacco, may play a pivotal role in connecting cigarette smoking and T2D. Extensive research conducted in both humans and animals has demonstrated that nicotine can elevate blood glucose levels, disrupt glucose homeostasis, and induce insulin resistance. The review aims to elucidate the genetic variants of nicotinic acetylcholine receptors associated with diabetes risk and provide a comprehensive overview of the available data on the mechanisms through which nicotine influences blood glucose homeostasis and the development of diabetes. Here we emphasize the central and peripheral actions of nicotine on the release of glucoregulatory hormones, as well as its effects on glucose tolerance and insulin sensitivity. Notably, the central actions of nicotine within the brain, which encompass both insulin-dependent and independent mechanisms, are highlighted as potential targets for intervention strategies in diabetes management.

Nicotine transport across calu-3 cell monolayer: effect of nicotine salts and flavored e-liquids.

OBJECTIVE: This study aimed to investigate the transport capability of nicotine across Calu-3 cell monolayer in various nicotine forms, including nicotine freebase, nicotine salts, and flavored e-liquids with nicotine benzoate. SIGNIFICANCE: Nicotine is rapidly absorbed from the respiratory system into systemic circulation during e-cigarettes use. However, the mechanism of nicotine transport in the lung has not been well understood yet. This study may offer critical biological evidence and have implications for the use and regulation of e-cigarettes. METHODS: The viability of Calu-3 cells after administration of nicotine freebase, nicotine salts and representative e-liquid were evaluated using the MTT assay, and the integrity of the Calu-3 cell monolayer was evaluated by transepithelial electrical resistance measurement and morphological analysis. Further, the nicotine transport capacity across the Calu-3 cell monolayer in various formulations of nicotine was investigated by analysis of nicotine transport amount. RESULTS: The findings indicated that nicotine transport occurred passively and was time-dependent across the Calu-3cell monolayer. In addition, the nicotine transport was influenced by the type of nicotine salts and their respective pH value. The nicotine benzoate exhibited the highest apparent permeability coefficient (Papp), and higher nicotine-to-benzoic acid ratios led to higher Papp values. The addition of flavors to e-liquid resulted in increased Papp values, with the most significant increment being observed in tobacco-flavored e-liquid. CONCLUSIONS: In summary, the transport capability of nicotine across the Calu-3 cell monolayer was influenced by the pH values of nicotine salts and flavor additives in e-liquids.

The roles of the circadian hormone melatonin in drug addiction.

Given the devastating social and health consequences of drug addiction and the limitations of current treatments, a new strategy is needed. Circadian system disruptions are frequently associated with drug addiction. Correcting abnormal circadian rhythms and improving sleep quality may thus be beneficial in the treatment of patients with drug addiction. Melatonin, an essential circadian hormone that modulates the biological clock, has anti-inflammatory, analgesic, anti-depressive, and neuroprotective effects via gut microbiota regulation and epigenetic modifications. It has attracted scientists' attention as a potential solution to drug abuse. This review summarized scientific evidence on the roles of melatonin in substance use disorders at the cellular, circuitry, and system levels, and discussed its potential applications as an intervention strategy for drug addiction.

Evaluation of the inhalation toxicity of arecoline benzoate aerosol in rats.

Arecoline is a pharmacologically active alkaloid isolated from Areca catechu. There are no published data available regarding the inhalation toxicity of arecoline in animals. This study aimed to evaluate the inhalation toxicity of arecoline in vitro and in vivo. For this purpose, arecoline benzoate (ABA) salt was prepared to stabilize arecoline in an aerosol. The MTT assay determined the half-maximal inhibitory concentration values of ABA and arecoline in A549 cell proliferation to be 832 and 412 µg/ml, respectively. The toxicity of acute and subacute inhalation in Sprague-Dawley rats was evaluated using the guidelines of the Organization for Economic Cooperation and Development. For acute inhalation, the median lethal concentration value of ABA solvent was >5175 mg/m3 . After the exposure and during the recovery period, no treatment-related clinical signs were observed. In the 28-Day inhalation toxicity test, daily nose-only exposure to 2510 mg/m3 aerosol of the ABA solvent contained 75 mg/m3 ABA for male rats and 375 mg/m3 ABA for female rats, which caused no observed adverse effects, except for the decreased body weight gain in male rats exposed to 375 mg/m3 ABA. In this study, the no observed adverse effect level (NOAEL) for the 28-day repeated dose inhalation of ABA aerosol was calculated to be around 13 mg/kg/day for male rats and 68.8 mg/kg/day for female rats, respectively.

The Molecular Gut-Brain Axis in Early Brain Development.

Millions of nerves, immune factors, and hormones in the circulatory system connect the gut and the brain. In bidirectional communication, the gut microbiota play a crucial role in the gut-brain axis (GBA), wherein microbial metabolites of the gut microbiota regulate intestinal homeostasis, thereby influencing brain activity. Dynamic changes are observed in gut microbiota as well as during brain development. Altering the gut microbiota could serve as a therapeutic target for treating abnormalities associated with brain development. Neurophysiological development and immune regulatory disorders are affected by changes that occur in gut microbiota composition and function. The molecular aspects relevant to the GBA could help develop targeted therapies for neurodevelopmental diseases. Herein, we review the findings of recent studies on the role of the GBA in its underlying molecular mechanisms in the early stages of brain development. Furthermore, we discuss the bidirectional regulation of gut microbiota from mother to infant and the potential signaling pathways and roles of posttranscriptional modifications in brain functions. Our review summarizes the role of molecular GBA in early brain development and related disorders, providing cues for novel therapeutic targets.

Profiling of key brain nuclei involved in CNS control of stress and glucose homeostasis.

Previous work have shown several key brain nuclei involved in acute psychological stress and glucose homeostasis. Acute stress influences glucose metabolism via released stress hormones by activating the hypothalamic-pituitary-adrenal axis and the sympathetic nervous system. Little is known about the brain nuclei which response to peripheral glucose alteration are either abundant with glucosesensing neurons or the activations are secondary to stress. Here we profile and compare the brain nuclei that response to stress and glucose homeostasis in mouse models of acute restraint stress, glucose and 2-DG injections respectively. Our present work provide a comprehensive depiction on key brain nuclei involved in CNS control of stress and glucose homeostasis, which gives clue for functional identification of brain nuclei that regulate glucose homeostasis under stress.

Optical probing of acetylcholine receptors on neurons in the medial habenula with a novel caged nicotine drug analogue.

KEY POINTS: A new caged nicotinic acetylcholine receptor (nAChR) agonist was developed, ABT594, which is photolysed by one- and two-photon excitation. The caged compound is photolysed with a quantum yield of 0.20. One-photon uncaging of ABT594 elicited large currents and Ca2+ transients at the soma and dendrites of medial habenula (MHb) neurons of mouse brain slices. Unexpectedly, uncaging of ABT594 also revealed highly Ca2+ -permeable nAChRs on axons of MHb neurons. ABSTRACT: Photochemical release of neurotransmitters has been instrumental in the study of their underlying receptors, with acetylcholine being the exception due to its inaccessibility to photochemical protection. We caged a nicotinic acetylcholine receptor (nAChR) agonist, ABT594, via its secondary amine functionality. Effective photolysis could be carried out using either one- or two-photon excitation. Brief flashes (0.5-3.0 ms) of 410 nm light evoked large currents and Ca2+ transients on cell bodies and dendrites of medial habenula (MHb) neurons. Unexpectedly, photorelease of ABT594 also revealed nAChR-mediated Ca2+ signals along the axons of MHb neurons.

Controllable Synthesis of [11-2-2] Faceted InN Nanopyramids on ZnO for Photoelectrochemical Water Splitting.

Indium nitride (InN) is one of the promising narrow band gap semiconductors for utilizing solar energy in photoelectrochemical (PEC) water splitting. However, its widespread application is still hindered by the difficulties in growing high-quality InN samples. Here, high-quality InN nanopyramid arrays are synthesized via epitaxial growth on ZnO single-crystals. The as-prepared InN nanopyramids have well-defined exposed facets of [0001], [11-2-2], [1-212], and [-2112], which provide a possible routine for understanding water oxidation processes on the different facets of nanostructures in nanoscale. First-principles density functional calculations reveal that the nonpolar [11-2-2] face has the highest catalytic activity for water oxidation. PEC investigations demonstrate that the band positions of the InN nanopyramids are strongly altered by the ZnO substrate and a heterogeneous n-n junction is naturally formed at the InN/ZnO interface. The formation of the n-n junction and the built-in electric field is ascribed to the efficient separation of the photogenerated electron-hole pairs and the good PEC performance of the InN/ZnO. The InN/ZnO shows good photostability and the hydrogen evolution is about 0.56 µmol cm-2 h-1 , which is about 30 times higher than that of the ZnO substrate. This study demonstrates the potential application of the InN/ZnO photoanodes for PEC water splitting.

Ca2+ channel to synaptic vesicle distance accounts for the readily releasable pool kinetics at a functionally mature auditory synapse.

Precise regulation of synaptic vesicle (SV) release at the calyx of Held is critical for auditory processing. At the prehearing calyx of Held, synchronous and asynchronous release is mediated by fast and slow releasing SVs within the readily releasable pool (RRP). However, the posthearing calyx has dramatically different release properties. Whether developmental alterations in RRP properties contribute to the accelerated release time course found in posthearing calyces is not known. To study these questions, we performed paired patch-clamp recordings, deconvolution analysis, and numerical simulations of buffered Ca(2+) diffusion and SV release in postnatal day (P) 16-19 mouse calyces, as their release properties resemble mature calyces of Held. We found the P16-P19 calyx RRP consists of two pools: a fast pool (τ ≤ 0.9 ms) and slow pool (τ ∼4 ms), in which release kinetics and relative composition of the two pools were unaffected by 5 mm EGTA. Simulations of SV release from the RRP revealed that two populations of SVs were necessary to reproduce the experimental release rates: (1) SVs located close (∼5-25 nm) and (2) more distal (25-100 nm) to VGCC clusters. This positional coupling was confirmed by experiments showing 20 mm EGTA preferentially blocked distally coupled SVs. Lowering external [Ca(2+)] to in vivo levels reduced only the fraction SVs released from the fast pool. Therefore, we conclude that a dominant parameter regulating the mature calyx RRP release kinetics is the distance between SVs and VGCC clusters.

The Munc13 proteins differentially regulate readily releasable pool dynamics and calcium-dependent recovery at a central synapse.

The Munc13 gene family encodes molecules located at the synaptic active zone that regulate the reliability of synapses to encode information over a wide range of frequencies in response to action potentials. In the CNS, proteins of the Munc13 family are critical in regulating neurotransmitter release and synaptic plasticity. Although Munc13-1 is essential for synaptic transmission, it is paradoxical that Munc13-2 and Munc13-3 are functionally dispensable at some synapses, although their loss in other synapses leads to increases in frequency-dependent facilitation. We addressed this issue at the calyx of Held synapse, a giant glutamatergic synapse that we found to express all these Munc13 isoforms. We studied their roles in the regulation of synaptic transmission and their impact on the reliability of information transfer. Through detailed electrophysiological analyses of Munc13-2, Munc13-3, and Munc13-2-3 knock-out and wild-type mice, we report that the combined loss of Munc13-2 and Munc13-3 led to an increase in the rate of calcium-dependent recovery and a change in kinetics of release of the readily releasable pool. Furthermore, viral-mediated overexpression of a dominant-negative form of Munc13-1 at the calyx demonstrated that these effects are Munc13-1 dependent. Quantitative immunohistochemistry using Munc13-fluorescent protein knock-in mice revealed that Munc13-1 is the most highly expressed Munc13 isoform at the calyx and the only one highly colocalized with Bassoon at the active zone. Based on these data, we conclude that Munc13-2 and Munc13-3 isoforms limit the ability of Munc13-1 to regulate calcium-dependent replenishment of readily releasable pool and slow pool to fast pool conversion in central synapses.

Bandgap-engineered CdxZn1-xO nanowires as active regions for green-light-emitting diodes.

A green-light-emitting diode device was fabricated based on a p-type Sb-doped ZnO segments/Cd-alloyed ZnO/n-type ZnO film/heteronanowires array structure. The structures and chemical components of the heteronanowire sample were studied by energy dispersive spectrometer, x-ray photoelectron spectrometer, etc, from which the statuses of Cd and Sb in the sample were confirmed. Spatially resolved photoluminescence measurement on a single heteronanowire revealed a large bandgap shift in the Cd(x)Zn(1 - x)O active region. In electroluminescence characterizations, the device showed that the green emission was centered at 550 nm, suggesting the successful formation and functioning of the double heterojunction nanowire light-emitting diodes.

Hybrid material based on plasmonic nanodisks decorated ZnO and its application on nanoscale lasers.

Plasmonic noble metal nanodisks with regular (triangular or hexagonal) shapes have been epitaxially formed on ZnO nanorods' (0002) surfaces. The composite material's crystal structures, epitaxial relationships between metal nanodisks, and ZnO host crystals were fully investigated. The effects from metal nanodisks on lasing characteristics of two types of ZnO nanoscale cavities (Fabry-Perot and Whispering Gallery Mode cavity) were studied. The results suggest that metal nanodisks can effectively enhance the lasing performance by lowering the lasing threshold in the ZnO Whispering Gallery Mode nanoplate laser, whereas the Fabry-Perot ZnO nanorods lasers were much less affected by the metal decoration. The plasmonic enhancement mechanism for the ZnO nanoplate cavities was further studied using numerical simulations as well as spatially resolved photoluminescence measurement.

Theoretical prediction on the stability, elastic, electronic and optical properties of MAB-phase M4AlB4 compounds (M = Cr, Mo, W).

This research employs first-principles calculations to address the challenges presented by processing complexity and low damage tolerance in transition metal borides. The study focuses on designing and investigating MAB phase compounds of M4AlB4 (M = Cr, Mo, W). We conduct a comprehensive assessment of the stability, phononic, electronic, elastic, and optical properties of Cr4AlB4, Mo4AlB4, and W4AlB4. The calculated results reveal formation enthalpies of -0.516, -0.490, and -0.336 eV per atom for Cr4AlB4, Mo4AlB4, and W4AlB4, respectively. Notably, W4AlB4 emerges as a promising precursor material for MABene synthesis, demonstrating exceptional thermal shock resistance. The dielectric constants ε1(0) were determined as 126.466, 80.277, and 136.267 for Cr4AlB4, Mo4AlB4, and W4AlB4, respectively. Significantly, W4AlB4 exhibits remarkably high reflectivity (>80%) within the wavelength range of 19.84-23.6 nm, making it an ideal candidate for extreme ultraviolet (EUV) reflective coatings. The insights gleaned from this study provide a strong research framework and theoretical guidance for advancing the synthesis of innovative MAB-phase compounds.

Unexpected versatile electrical transport behaviors of ferromagnetic nickel films.

Perpendicular magnetic anisotropy (PMA) of magnets is paramount for electrically controlled spintronics due to their intrinsic potentials for higher memory density, scalability, thermal stability and endurance, surpassing an in-plane magnetic anisotropy (IMA). Nickel film is a long-lived fundamental element ferromagnet, yet its electrical transport behavior associated with magnetism has not been comprehensively studied, hindering corresponding spintronic applications exploiting nickel-based compounds. Here, we systematically investigate the highly versatile magnetism and corresponding transport behavior of nickel films. As the thickness reduces within the general thickness regime of a magnet layer for a memory device, the hardness of nickel films' ferromagnetic loop of anomalous Hall effect increases and then decreases, reflecting the magnetic transitions from IMA to PMA and back to IMA. Additionally, the square ferromagnetic loop changes from a hard to a soft one at rising temperatures, indicating a shift from PMA to IMA. Furthermore, we observe a butterfly magnetoresistance resulting from the anisotropic magnetoresistance effect, which evolves in conjunction with the thickness and temperature-dependent magnetic transformations as a complementary support. Our findings unveil the rich magnetic dynamics and most importantly settle down the most useful guiding information for current-driven spintronic applications based on nickel film: The hysteresis loop is squarest for the ∼8 nm-thick nickel film, of highest hardness withRxyr/Rxys∼ 1 and minimumHs-Hc, up to 125 K; otherwise, extra care should be taken for a different thickness or at a higher temperature.

Phase-selective in-plane heteroepitaxial growth of H-phase CrSe2.

Phase engineering of two-dimensional transition metal dichalcogenides (2D-TMDs) offers opportunities for exploring unique phase-specific properties and achieving new desired functionalities. Here, we report a phase-selective in-plane heteroepitaxial method to grow semiconducting H-phase CrSe2. The lattice-matched MoSe2 nanoribbons are utilized as the in-plane heteroepitaxial template to seed the growth of H-phase CrSe2 with the formation of MoSe2-CrSe2 heterostructures. Scanning tunneling microscopy and non-contact atomic force microscopy studies reveal the atomically sharp heterostructure interfaces and the characteristic defects of mirror twin boundaries emerging in the H-phase CrSe2 monolayers. The type-I straddling band alignments with band bending at the heterostructure interfaces are directly visualized with atomic precision. The mirror twin boundaries in the H-phase CrSe2 exhibit the Tomonaga-Luttinger liquid behavior in the confined one-dimensional electronic system. Our work provides a promising strategy for phase engineering of 2D TMDs, thereby promoting the property research and device applications of specific phases.

Distinct correlation network of clinical characteristics in suicide attempters having adolescent major depressive disorder with non-suicidal self-injury.

Suicidal behavior and non-suicidal self-injury (NSSI) are common in adolescent patients with major depressive disorder (MDD). Thus, delineating the unique characteristics of suicide attempters having adolescent MDD with NSSI is important for suicide prediction in the clinical setting. Here, we performed psychological and biochemical assessments of 130 youths having MDD with NSSI. Participants were divided into two groups according to the presence/absence of suicide attempts (SAs). Our results demonstrated that the age of suicide attempters is lower than that of non-attempters in participants having adolescent MDD with NSSI; suicide attempters had higher Barratt Impulsiveness Scale (BIS-11) impulsivity scores and lower serum CRP and cortisol levels than those having MDD with NSSI alone, suggesting levels of cortisol and CRP were inversely correlated with SAs in patients with adolescent MDD with NSSI. Furthermore, multivariate regression analysis revealed that NSSI frequency in the last month and CRP levels were suicidal ideation predictors in adolescent MDD with NSSI, which may indicate that the increased frequency of NSSI behavior is a potential risk factor for suicide. Additionally, we explored the correlation between psychological and blood biochemical indicators to distinguish suicide attempters among participants having adolescent MDD with NSSI and identified a unique correlation network that could serve as a marker for suicide attempters. Our research data further suggested a complex correlation between the psychological and behavioral indicators of impulsivity and anger. Therefore, our study findings may provide clues to identify good clinical warning signs for SA in patients with adolescent MDD with NSSI.

2D Free-Standing GeS1-xSex with Composition-Tunable Bandgap for Tailored Polarimetric Optoelectronics.

Germanium-based monochalcogenides (i.e., GeS and GeSe) with desirable properties are promising candidates for the development of next-generation optoelectronic devices. However, they are still stuck with challenges, such as relatively fixed electronic band structure, unconfigurable optoelectronic characteristics, and difficulty in achieving free-standing growth. Herein, it is demonstrated that two-dimensional (2D) free-standing GeS1-xSex (0 ≤ x ≤ 1) nanoplates can be grown by low-pressure rapid physical vapor deposition (LPRPVD), fulfilling a continuously composition-tunable optical bandgap and electronic band structure. By leveraging the synergistic effect of composition-dependent modulation and free-standing growth, GeS1-xSex-based optoelectronic devices exhibit significantly configurable hole mobility from 6.22 × 10-4 to 1.24 cm2V-1s⁻1 and tunable responsivity from 8.6 to 311 A W-1 (635 nm), as x varies from 0 to 1. Furthermore, the polarimetric sensitivity can be tailored from 4.3 (GeS0.29Se0.71) to 1.8 (GeSe) benefiting from alloy engineering. Finally, the tailored imaging capability is also demonstrated to show the application potential of GeS1-xSex alloy nanoplates. This work broadens the functionality of conventional binary materials and motivates the development of tailored polarimetric optoelectronic devices.