Understanding the roles of compaction pressure and crystal hardness on powder tabletability through bonding area - Bonding strength interplay.

Bonding area (BA) and bonding strength (BS) interplay dictates tensile strength of a tablet and, hence, tabletability. Using a series of alkali halides with mechanical properties spanning more than one order of magnitude, the role of compaction pressure and mechanical properties on tabletability is systematically investigated and explained using the BA-BS interplay. Results reveal that BA dominates the BA-BS interplay at low pressures, where more plastic powders attain higher tensile strength due to larger BA. In contrast, BS dominates the interplay at high pressures, when difference in BA between powders is minimized. Under the typical compaction pressures of 100-300 MPa, tablet tensile strength is the highest for materials with intermediate hardness, or plasticity, due to an optimal BA-BS interplay.

Highly Reactive Peroxide Species Promoted Soot Oxidation over an Ordered Macroporous Ce0.8Zr0.2O2 Integrated Catalyzed Diesel Particulate Filter.

Particulate matter, represented by soot particles, poses a significant global environmental threat, necessitating efficient control technology. Here, we innovatively designed and elaborately fabricated ordered hierarchical macroporous catalysts of Ce0.8Zr0.2O2 (OM CZO) integrated on a catalyzed diesel particulate filter (CDPF) using the self-assembly method. An oxygen-vacancy-enriched ordered macroporous Ce0.8Zr0.2O2 catalyst (VO-OM CZO) integrated CDPF was synthesized by subsequent NaBH4 reduction. The VO-OM CZO integrated CDPF exhibited a markedly enhanced soot oxidation activity compared to OM CZO and powder CZO coated CDPFs (T50: 430 vs 490 and 545 °C, respectively). The well-defined OM structure of the VO-OM CZO catalysts effectively improves the contact efficiency between soot and the catalysts. Meanwhile, oxygen vacancies trigger the formation of a large amount of highly reactive peroxide species (O22-) from molecular oxygen (O2) through electron abstraction from the three adjacent Ce3+ (3Ce3+ + Vö + O2 → 3Ce4+ + O22-), contributing to the efficient soot oxidation. This work demonstrates the fabrication of the ordered macroporous CZO integrated CDPF and reveals the importance of structure and surface engineering in soot oxidation, which sheds light on the design of highly efficient PM capture and removal devices.

Loss of FoxO1 activates an alternate mechanism of mitochondrial quality control for healthy adipose browning.

Browning of white adipose tissue is hallmarked by increased mitochondrial density and metabolic improvements. However, it remains largely unknown how mitochondrial turnover and quality control are regulated during adipose browning. In the present study, we found that mice lacking adipocyte FoxO1, a transcription factor that regulates autophagy, adopted an alternate mechanism of mitophagy to maintain mitochondrial turnover and quality control during adipose browning. Post-developmental deletion of adipocyte FoxO1 (adO1KO) suppressed Bnip3 but activated Fundc1/Drp1/OPA1 cascade, concurrent with up-regulation of Atg7 and CTSL. In addition, mitochondrial biogenesis was stimulated via the Pgc1α/Tfam pathway in adO1KO mice. These changes were associated with enhanced mitochondrial homeostasis and metabolic health (e.g., improved glucose tolerance and insulin sensitivity). By contrast, silencing Fundc1 or Pgc1α reversed the changes induced by silencing FoxO1, which impaired mitochondrial quality control and function. Ablation of Atg7 suppressed mitochondrial turnover and function, causing metabolic disorder (e.g., impaired glucose tolerance and insulin sensitivity), regardless of elevated markers of adipose browning. Consistently, suppression of autophagy via CTSL by high-fat diet was associated with a reversal of adO1KO-induced benefits. Our data reveal a unique role of FoxO1 in coordinating mitophagy receptors (Bnip3 and Fundc1) for a fine-tuned mitochondrial turnover and quality control, underscoring autophagic clearance of mitochondria as a prerequisite for healthy browning of adipose tissue.

Research on Johnson-Cook Constitutive Model of γ-TiAl Alloy with Improved Parameters.

Due to its excellent physical properties, γ-TiAl alloy has been widely used in thin-walled components of aerospace engines. However, issues such as low thermal conductivity, poor machinability, and high cutting temperatures often result in difficulties in ensuring the geometric accuracy and surface integrity of the parts. This paper focuses on the study of the thermal deformation behavior of γ-TiAl alloy within a range of higher temperatures and strain rates. Firstly, by conducting quasi-static tests and Hopkinson bar tests on γ-TiAl alloy, the true stress-strain curves of γ-TiAl alloy are obtained within a temperature range of 20~500 °C and a strain rate range of 3000~11,000/s. Based on the Johnson-Cook model, the true stress-strain curves are fitted and analyzed with consideration of the coupling effect of strain rate, temperature, and strain. The strain rate hardening coefficient C and thermal softening exponent m are polynomialized, improving the Johnson-Cook constitutive model of γ-TiAl alloy. The improved model shows significant improvements in the correlation coefficient and absolute errors between the predicted values and experimental values, providing a better reflection of the thermal deformation behavior of γ-TiAl alloy within a range of higher temperatures and strain rates.

TFEB regulates cellular labile iron and prevents ferroptosis in a TfR1-dependent manner.

Autophagy is a major clearance pathway for misfolded α-synuclein which promotes ferroptosis through NCOA4-mediated ferritin degradation. The regulation of these two processes to achieve improved neuroprotection in Parkinson's disease (PD) must be elucidated. Transcription factor EB (TFEB) is a master regulator of both autophagy and lysosome biogenesis, and lysosomes are important cellular iron storage organelles; however, the role of TFEB in ferroptosis and iron metabolism remains unclear. In this study, TFEB overexpression promoted the clearance of misfolded α-synuclein and prevented ferroptosis and iron overload. TFEB overexpression up-regulated transferrin receptor 1 (TfR1) synthesis and increased the localization of TfR1 in the lysosome, facilitating lysosomal iron import and transient lysosomal iron storage. TFEB overexpression increased the levels of cellular iron-safe storage proteins (both ferritin light and heavy chains). These functions in iron metabolism maintain the cellular labile iron at a low level and electrical activity, even under iron overload conditions. Notably, lower levels of cellular labile iron and the upregulation of ferritin light and heavy chains were reversed after TfR1 knockdown in cells overexpressing TFEB, indicating that TFEB regulates cellular labile iron and suppresses ferroptosis in a TfR1 dependent manner. Taken together, this evidence of the regulation of iron metabolism enriches our understanding of the function of TFEB. In addition, TFEB overexpression protects against ferroptosis and iron overload and provides a new direction and perspective for autophagy regulation in PD.

Chemogenetic and optogenetic stimulation of zona incerta GABAergic neurons ameliorates motor impairment in Parkinson's disease.

Parkinson's disease (PD) is characterized by the degeneration of dopaminergic neurons in the substantia nigra and leads to progressive motor dysfunction. While studies have focused on the basal ganglia network, recent evidence suggests neuronal systems outside the basal ganglia are also related to PD pathogenesis. The zona incerta (ZI) is a predominantly inhibitory subthalamic region for global behavioral modulation. This study investigates the role of GABAergic neurons in the ZI in a mouse model of 6-hydroxydopamine (6-OHDA)-induced PD. First, we found a decrease in GABA-positive neurons in the ZI, and then the mice used chemogenetic/optogenetic stimulation to activate or inhibit GABAergic neurons. The motor performance of PD mice was significantly improved by chemogenetic/optogenetic activation of GABAergic neurons, and repeated chemogenetic activation of ZI GABAergic neurons increased the dopamine content in the striatum. Our work identifies the role of ZI GABAergic neurons in regulating motor behaviors in 6-OHDA-lesioned PD model mice.

Development of Child-Friendly Lisdexamfetamine Chewable Tablets Using Ion Exchange Resin as a Taste-Masking Carrier Based on the Concept of Quality by Design (QbD).

Taste masking is critical to improving the compliance of pediatric oral dosage forms. However, it is challenging for extremely bitter lisdexamfetamine dimesylate (LDX) with a long half-life and given in large dose. The present study aims to develop an immediate-release, taste-masked lisdexamfetamine chewable tablet. Lisdexamfetamine-resin complexes (LRCs) were prepared using the batch method. The molecular mechanism of taste masking was explored by PXRD, PLM, STA, and FT-IR. The results showed that taste masking was attributed to the ionic interaction between drug and the resin. The ion exchange process conformed to first-order kinetics. The rate-limiting step of drug release was the diffusion of ions inside the particles, and the concentration of H+ was the key factor for immediate release. The masking efficiency of the prepared LRCs in saliva exceeded 96%, and the drug could be completely released within 15 min in aqueous HCl (pH 1.2). Furthermore, the SeDeM expert system was used for the first time to comprehensively study the powder properties of LRCs and to quickly visualize their defects (compressibility, lubricity/stability, and lubricity/dosage). The selection of excipients was targeted rather than traditional screening, thus obtaining a robust chewable tablet formulation suitable for direct compression. Finally, the difference between chewable tablets containing LRCs and chewable tablets containing lisdexamfetamine dimesylate was compared by in vitro dissolution test, electronic tongue, and disintegration test. In conclusion, an immediate-released, child-friendly lisdexamfetamine chewable tablets without bitterness was successfully developed by the QbD approach, using the SeDeM system, which may help in further development of chewable tablets.

FoxO1 regulates adipose transdifferentiation and iron influx by mediating Tgfß1 signaling pathway.

Adipose plasticity is critical for metabolic homeostasis. Adipocyte transdifferentiation plays an important role in adipose plasticity, but the molecular mechanism of transdifferentiation remains incompletely understood. Here we show that the transcription factor FoxO1 regulates adipose transdifferentiation by mediating Tgfß1 signaling pathway. Tgfß1 treatment induced whitening phenotype in beige adipocytes, reducing UCP1 and mitochondrial capacity and enlarging lipid droplets. Deletion of adipose FoxO1 (adO1KO) dampened Tgfß1 signaling by downregulating Tgfbr2 and Smad3 and induced browning of adipose tissue in mice, increasing UCP1 and mitochondrial content and activating metabolic pathways. Silencing FoxO1 also abolished the whitening effect of Tgfß1 on beige adipocytes. The adO1KO mice exhibited a significantly higher energy expenditure, lower fat mass, and smaller adipocytes than the control mice. The browning phenotype in adO1KO mice was associated with an increased iron content in adipose tissue, concurrent with upregulation of proteins that facilitate iron uptake (DMT1 and TfR1) and iron import into mitochondria (Mfrn1). Analysis of hepatic and serum iron along with hepatic iron-regulatory proteins (ferritin and ferroportin) in the adO1KO mice revealed an adipose tissue-liver crosstalk that meets the increased iron requirement for adipose browning. The FoxO1-Tgfß1 signaling cascade also underlay adipose browning induced by ß3-AR agonist CL316243. Our study provides the first evidence of a FoxO1-Tgfß1 axis in the regulation of adipose browning-whitening transdifferentiation and iron influx, which sheds light on the compromised adipose plasticity in conditions of dysregulated FoxO1 and Tgfß1 signaling.

4-Aminopyridine Protects Nigral Dopaminergic Neurons in the MPTP Mouse Model of Parkinson's Disease.

Various pharmacological blockers targeting K+ channel have been identified to be related to the treatment of Parkinson's disease (PD). Previous studies showed that 4-Aminopyridine (4-AP), a wide-spectrum K+ channel blocker, was able to attenuate apomorphine-induced rotation in parkinsonism rats, indicating the possible beneficial effects in attenuation of PD motor symptoms. However, it is unclear whether 4-AP exhibits neuroprotective effects against the neurodegeneration of substantia nigra (SN)-striatum system in PD. In this study, the 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mouse model was employed to evaluate the neuroprotective effects of 4-AP. Results showed that 4-AP inhibited MPTP-induced dopaminergic neuronal loss in the SN as well as dopamine depletion in the striatum. Behavior indexes of open field test and rotarod test confirmed that 4-AP attenuated MPTP-induced motor deficits. We also showed that 4-AP treatment could significantly attenuate the MPTP-induced increase in malonaldehyde (MDA) levels and decrease in superoxide dismutase (SOD) levels. Additionally, MPTP significantly reduced the Bcl-2 expression and promoted the Caspase-3 activation; 4-AP protected dopaminergic neurons against MPTP-induced neurotoxicity by reversing these changes. These results indicate that 4-AP exerts a neuroprotective effect on dopaminergic neurons against MPTP by decreasing oxidative stress and apoptosis. This provides a promising therapeutic target for the treatment of PD.

Assessing the Activity of Transcription Factor FoxO1.

The transcription factor FoxO1 (forkhead box O1) regulates genes that are involved in development, metabolism, cellular innovation, longevity, and stress responses. Assessment of FoxO1 activity is therefore critical to understand the regulatory network of this transcription factor. FoxO1 transactivation activity relies on its ability to bind to the promoters of target genes, which is controlled by posttranslational modifications (e.g., dephosphorylation or phosphorylation) that may promote nuclear translocation or exclusion of FoxO1. In this chapter we describe the protocols for FoxO1 activity assessment using Western blotting analysis of the posttranslational modification of FoxO1 in whole cell lysates and ELISA of DNA binding activity of FoxO1 in nuclear extracts.

Updates on brain regions and neuronal circuits of movement disorders in Parkinson's disease.

Parkinson's disease (PD) is a progressive neurodegenerative disease with a global burden that affects more often in the elderly. The basal ganglia (BG) is believed to account for movement disorders in PD. More recently, new findings in the original regions in BG involved in motor control, as well as the new circuits or new nucleuses previously not specifically considered were explored. In the present review, we provide up-to-date information related to movement disorders and modulations in PD, especially from the perspectives of brain regions and neuronal circuits. Meanwhile, there are updates in deep brain stimulation (DBS) and other factors for the motor improvement in PD. Comprehensive understandings of brain regions and neuronal circuits involved in motor control could benefit the development of novel therapeutical strategies in PD.

Controlled Synthesis of Mesoporous π-Conjugated Polymer Nanoarchitectures as Anodes for Lithium-Ion Batteries.

Conjugated polymers possess better electron conductivity due to large π-electron conjugated configuration endowing them significant scientific and technological interest. However, the obvious deficiency of active-site underutilization impairs their electrochemical performance. Therefore, designing and engineering π-conjugated polymers with rich redox functional groups and mesoporous architectures could offer new opportunities for them in these emerging applications and further expand their application scopes. Herein, a series of 1,3,5-tris(4-aminophenyl) benzene (TAPB)-based π-conjugated mesoporous polymers (π-CMPs) are constructed by one-pot emulsion-induced interface assembly strategy. Furthermore, co-induced in situ polymerization on 2D interfaces by emulsion and micelles is explored, which delivers sandwiched 2D mesoporous π-CMPs-coated graphene oxides (GO@mPTAPB). Benefiting from specific redox-active functional groups, excellent electron conductivity and a 2D mesoporous conjugated framework, GO@mPTAPB exhibits high capability of accommodating Li+ anions (up to 382 mAh g-1 at 0.2 A g-1 ) and outstanding electrochemical stability (87.6% capacity retention after 1000 cycles). The ex situ Raman and impedance spectra are further applied to reveal the high reversibility of GO@mPTAPB. This work will greatly promote the development of advanced π-CMPs-based organic anodes toward energy storage devices.

Palladium catalyzed cascade umpolung allylation/acetalation for the construction of quaternary 3-amino oxindoles.

Herein we reported a highly diastereoselective synthesis of quaternary 3-amino oxindoles bearing an acetal unit via a palladium catalyzed three-component cascade umpolung allylation/acetalation process. An array of 3-amino 3-allyl oxindoles incorporating diversified functional groups were prepared in good yields with exclusive diastereoselectivities. Further investigation demonstrated that the current method could also be extended to cascade umpolung allenylation/acetalation.

Oxygen Vacancies and Lewis Acid Sites Synergistically Promoted Catalytic Methane Combustion over Perovskite Oxides.

An in-depth understanding of the surface properties-activity relationship could provide a fundamental guidance for the design of highly efficient perovskite-based catalysts for the control of anthropogenic methane emission. Herein, both oxygen vacancies and Con+ Lewis acid sites were purposely introduced on ordered macroporous La0.8Sr0.2CoO3 monolithic catalysts by one-step reduction and selective etching in oxalic acid, and their synergistic effect on methane combustion was investigated. Combined with experimental and theoretical investigations, we revealed that the positively charged Con+ Lewis acid sites and single-electron-trapped oxygen vacancies (Vo·) formed an active pair, which enabled an effective localized electron cloud shift from Vo· to Con+. The characteristic electronic effect modulates surface electronic properties and coordination structures, thus resulting in superior oxygen activation capacity, lattice oxygen mobility, and reducibility, as well as favorable CH4 interaction and oxidation. Our work not only gives insights into surface properties-activity relationships on perovskite for hydrocarbon combustion but also sheds substantial light on future environmental catalyst design and modulation for hydrocarbon pollutants elimination.

Tracking Ultrafast Structural Dynamics in a Dual-Emission Anti-Kasha-Active Fluorophore Using Femtosecond Stimulated Raman Spectroscopy.

The anti-Kasha process provides the possibility of using high-energy excited states to develop novel applications. Our previous research (Nature communications, 2020, 11, 793) has demonstrated a dual-emission anti-Kasha-active fluorophore for bioimaging application, which exhibits near-infrared emissions from the S1 state and visible anti-Kasha emissions from the S2 state. Here, we applied tunable blue-side femtosecond stimulated Raman spectroscopy (FSRS) and transient absorption spectroscopy, assisted by quantum calculations, to reveal the anti-Kasha dual emission mechanism, in which the emergence of two fluorescing states is due to the retardation of internal conversion from the S2 state to the S1 state. It has been demonstrated that the facts of anti-Kasha high-energy emission are commonly attributed to a large energy gap between the two excited states, leading to a decrease in the internal conversion rate due to a poor Franck-Condon factor. In this study, analysis of the calculation and FSRS experimental results provide us further insight into the dual-emission anti-Kasha mechanism, where the observation of hydrogen out-of-plane Raman modes from FSRS suggested that, in addition to the energy-gap law, the initial photoinduced molecular conformational change plays a key role in influencing the rate of internal conversion.

The Emerging Role of Neuropeptides in Parkinson's Disease.

Parkinson's disease (PD), the second most common age-related neurodegenerative disease, results from the loss of dopamine neurons in the substantia nigra. This disease is characterized by cardinal non-motor and motor symptoms. Several studies have demonstrated that neuropeptides, such as ghrelin, neuropeptide Y, pituitary adenylate cyclase-activating polypeptide, substance P, and neurotensin, are related to the onset of PD. This review mainly describes the changes in these neuropeptides and their receptors in the substantia nigra-striatum system as well as the other PD-related brain regions. Based on several in vitro and in vivo studies, most neuropeptides play a significant neuroprotective role in PD by preventing caspase-3 activation, decreasing mitochondrial-related oxidative stress, increasing mitochondrial biogenesis, inhibiting microglial activation, and anti-autophagic activity. Thus, neuropeptides may provide a new strategy for PD therapy.

Sirt1 coordinates with ERα to regulate autophagy and adiposity.

Sex difference in adiposity has long been recognized but the mechanism remains incompletely understood. Previous studies suggested that adiposity was regulated by autophagy in response to energy status change. Here, we show that the energy sensor Sirt1 mediates sex difference in adiposity by regulating autophagy and adipogenesis in partnership with estrogen receptor α (ERα). Autophagy and adipogenesis were suppressed by Sirt1 activation or overexpression, which was associated with reduced sex difference in adiposity. Mechanistically, Sirt1 deacetylated and activated AKT and STAT3, resulting in suppression of autophagy and adipogenesis via mTOR-ULK1 and p55 cascades. ERα induced Sirt1 expression and inhibited autophagy in adipocytes, while silencing Sirt1 reversed the effects of ERα on autophagy and promoted adipogenesis. Moreover, Sirt1 deacetylated ERα, which constituted a positive feedback loop in the regulation of autophagy and adiposity. Our results revealed a new mechanism of Sirt1 regulating autophagy in adipocytes and shed light on sex difference in adiposity.

Effects of ghrelin on the electrical activities of substantia nigra dopaminergic neurons treated with MPP.

Ghrelin, a 28 amino acid brain-gut peptide, has attracted increasing attention for its neuroprotective effect in Parkinson's disease (PD). In view of the pivotal role of excitability of dopaminergic neurons in substantia nigra pars compacta (SNc) in the function of nigrostriatal system, it is of great significance to elucidate the regulation of electrical activity of dopaminergic neurons by ghrelin, especially in PD pathogenesis. In this study, we tackled this issue by probing the effects of ghrelin on the electrophysiological properties of dopaminergic neurons in acute application of Methyl-4-phenylpyridinium (MPP+), a potent parkinsonizing agent in primates and rodents, with whole cell patch clamp technique. We first observed that MPP+ (10, 20 and 50 µM) inhibited the spontaneous firing activity of dopaminergic neurons with dose-dependent and time-dependent properties. MPP+ also hyperpolarized the membrane potential, inhibited the evoked firing activity and reduced the amplitude of the inward rectification characteristic (Sag) in dopaminergic neurons. Importantly, ghrelin (100 nM) could improve the above effects of MPP+ on the electrical activities of dopaminergic neurons. The potential mechanism of this phenomenon may be that ghrelin upregulated hyperpolarization-activated cyclic nucleotide-gated channel current (Ih) to antagonize the inhibition of MPP+ on Ih, thereby improving the electrical activities of dopaminergic neurons.