Metastable hexagonal close-packed palladium hydride in liquid cell TEM.

Metastable phases-kinetically favoured structures-are ubiquitous in nature1,2. Rather than forming thermodynamically stable ground-state structures, crystals grown from high-energy precursors often initially adopt metastable structures depending on the initial conditions, such as temperature, pressure or crystal size1,3,4. As the crystals grow further, they typically undergo a series of transformations from metastable phases to lower-energy and ultimately energetically stable phases1,3,4. Metastable phases sometimes exhibit superior physicochemical properties and, hence, the discovery and synthesis of new metastable phases are promising avenues for innovations in materials science1,5. However, the search for metastable materials has mainly been heuristic, performed on the basis of experiences, intuition or even speculative predictions, namely 'rules of thumb'. This limitation necessitates the advent of a new paradigm to discover new metastable phases based on rational design. Such a design rule is embodied in the discovery of a metastable hexagonal close-packed (hcp) palladium hydride (PdHx) synthesized in a liquid cell transmission electron microscope. The metastable hcp structure is stabilized through a unique interplay between the precursor concentrations in the solution: a sufficient supply of hydrogen (H) favours the hcp structure on the subnanometre scale, and an insufficient supply of Pd inhibits further growth and subsequent transition towards the thermodynamically stable face-centred cubic structure. These findings provide thermodynamic insights into metastability engineering strategies that can be deployed to discover new metastable phases.

Ultralow-dielectric-constant amorphous boron nitride.

Decrease in processing speed due to increased resistance and capacitance delay is a major obstacle for the down-scaling of electronics1-3. Minimizing the dimensions of interconnects (metal wires that connect different electronic components on a chip) is crucial for the miniaturization of devices. Interconnects are isolated from each other by non-conducting (dielectric) layers. So far, research has mostly focused on decreasing the resistance of scaled interconnects because integration of dielectrics using low-temperature deposition processes compatible with complementary metal-oxide-semiconductors is technically challenging. Interconnect isolation materials must have low relative dielectric constants (κ values), serve as diffusion barriers against the migration of metal into semiconductors, and be thermally, chemically and mechanically stable. Specifically, the International Roadmap for Devices and Systems recommends4 the development of dielectrics with κ values of less than 2 by 2028. Existing low-κ materials (such as silicon oxide derivatives, organic compounds and aerogels) have κ values greater than 2 and poor thermo-mechanical properties5. Here we report three-nanometre-thick amorphous boron nitride films with ultralow κ values of 1.78 and 1.16 (close to that of air, κ = 1) at operation frequencies of 100 kilohertz and 1 megahertz, respectively. The films are mechanically and electrically robust, with a breakdown strength of 7.3 megavolts per centimetre, which exceeds requirements. Cross-sectional imaging reveals that amorphous boron nitride prevents the diffusion of cobalt atoms into silicon under very harsh conditions, in contrast to reference barriers. Our results demonstrate that amorphous boron nitride has excellent low-κ dielectric characteristics for high-performance electronics.

Mitotic spindle formation in the absence of Polo kinase.

SignificanceMitosis is an essential process in all eukaryotes, but paradoxically, genes required for mitosis vary among species. The essentiality of many mitotic genes was bypassed by activating alternative mechanisms during evolution. However, bypass events have rarely been recapitulated experimentally. Here, using the fission yeast Schizosaccharomyces pombe, the essentiality of a kinase (Plo1) required for bipolar spindle formation was bypassed by other mutations, many of which are associated with glucose metabolism. The Plo1 bypass by the reduction in glucose uptake was dependent on another kinase (casein kinase I), which potentiated spindle microtubule formation. This study illustrates a rare experimental bypass of essentiality for mitotic genes and provides insights into the molecular diversity of mitosis.

Distinctive Roles of Medial Prefrontal Cortex Subregions in Strategic Conformity to Social Hierarchy.

People often align their behaviors and decisions with others' expectations, especially those of higher social positions, when they are being observed. However, little attention has been paid to the neural mechanisms underlying increased conformity to the social hierarchy under social observation. Using a preference rating task, we investigated whether and how individual preferences for novel stimuli were influenced by others' preferences by manipulating others' social hierarchy and observational context. The behavioral results showed that human participants of both sexes were more likely to change their preferences to match those of a superior partner in a public than in a private context. fMRI data revealed distinct contributions of the subregions of the medial prefrontal cortex (mPFC) to increased conformity to social hierarchy under observation. Specifically, the ventral mPFC showed increased activity when participants' preferences aligned with those of superior partners, regardless of behavioral manifestation. The rostral mPFC showed increased activity when conforming to a superior partner and nonconforming to an inferior one, indicating goal-dependent valuation. The dorsal mPFC showed increased activity in private conditions with a superior partner but only in those with a higher tendency to conform. These findings support the hierarchical allostatic regulation model of the mPFC function for social valuation and suggest strategic conformity as a way to minimize metabolic costs.SIGNIFICANCE STATEMENT This study revealed distinct roles of subregions of the mPFC in increased conformity to individuals of different social ranks under observation. Specifically, the ventral mPFC showed increased activity when participants' preferences aligned with those of higher-ranking partners, whereas the rostral mPFC showed increased activity when conforming to a superior partner and nonconforming to an inferior partner, indicating goal-dependent valuation. The dorsal mPFC was more active in private conditions with a superior partner but only in those with a higher tendency to conform. These findings support the hierarchical allostatic regulation model of the mPFC function for social valuation and suggest strategic conformity as a way to minimize metabolic costs.

High common-γ cytokine receptor levels promote expression of Interleukin-2/Interleukin-7 receptor α-chains with implications on T-cell differentiation and function.

Cytokines of the common-γ receptor chain (γc) family are crucial for T-cell differentiation and dysregulation of γc cytokine pathways is involved in the pathogenesis of autoimmune diseases. There is increasing evidence that the availability of the γc receptor (CD132) for the associated receptor chains has implications for T-cell functions. Here we studied the influence of differential γc expression on the expression of the IL-2Rα (CD25), the IL-7Rα (CD127) and the differentiation of activated naïve T cells. We fine-tuned the regulation of γc expression in human primary naïve T cells by lentiviral transduction using small hairpin (sh)RNAs and γc cDNA. Differential γc levels were then analysed for effects on T-cell phenotype and function after activation. Differential γc expression markedly affected IL-2Rα and IL-7Rα expression on activated naïve T cells. High γc expression (γc-high) induced significantly higher expression of IL-2Rα and re-expression of IL-7Rα after activation. Inhibition of γc caused lower IL-2Rα/IL-7Rα expression and impaired proliferation of activated naïve T cells. In contrast, γc-high T cells secreted significantly higher concentrations of effector cytokines (i.e., IFN-γ, IL-6) and showed higher cytokine-receptor induced STAT5 phosphorylation during initial stages as well as persistently higher pSTAT1 and pSTAT3 levels after activation. Finally, accelerated transition towards a CD45RO expressing effector/memory phenotype was seen especially for CD4+ γc-high naïve T cells. These results suggested that high expression of γc promotes expression of IL-2Rα and IL-7Rα on activated naïve T cells with significant effects on differentiation and effector cytokine expression.

Inhibition of receptor activator of nuclear factor kappa-B ligand-mediated osteoclast differentiation and bone resorption by Gryllus bimaculatus extract: An in vitro study.

Excessive bone-resorbing osteoclast activity during bone remodeling is a major feature of bone diseases, such as osteoporosis. Therefore, the inhibition of osteoclast formation and bone resorption can be an effective therapeutic target for various bone diseases. Gryllus biomaculatus (GB) has recently been approved as an alternative food source because of its high nutritional value and environmental sustainability. Traditionally, GB has been known to have various pharmacological properties, including antipyretic and blood pressure-lowering activity, and it has recently been reported to have various biological activities, including protective effects against inflammation, oxidative stress, insulin resistance, and alcohol-induced liver injury. However, the effect of GB on osteoclast differentiation and bone metabolism has not yet been demonstrated. In this study, we confirmed the inhibitory effect of GB extract (GBE) on the receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclast formation. To determine the effect of GBE on RANKL-induced osteoclast differentiation and function, we performed TRAP and F-actin staining, as well as a bone-resorbing assay. The intracellular mechanisms of GBE responsible for the regulation of osteoclastogenesis were revealed by Western blot analysis and quantitative real-time polymerase chain reaction. We investigated the relationship between GBE and expression of osteoclast-specific molecules to further elucidate the underlying mechanisms. It was found that GBE significantly suppressed osteoclastogenesis by decreasing the phosphorylation of Akt, p38, JNK, and ERK, as well as Btk-PLCγ2 signaling, in pathways involved in early osteoclastogenesis as well as through the subsequent suppression of c-Fos, NFATc1, and osteoclastogenesis-specific marker genes. Additionally, GBE inhibited the formation of F-actin ring-positive osteoclasts and bone resorption activity of mature osteoclasts. Our findings suggest that GBE is a potential functional food and therapeutic candidate for bone diseases involving osteoclasts.

Design Principles for Fluorinated Interphase Evolution via Conversion-Type Alloying Processes for Anticorrosive Lithium Metal Anodes.

Over the past decade, lithium metal has been considered the most attractive anode material for high-energy-density batteries. However, its practical application has been hindered by its high reactivity with organic electrolytes and uncontrolled dendritic growth, resulting in poor Coulombic efficiency and cycle life. In this paper, we propose a design strategy for interface engineering using a conversion-type reaction of metal fluorides to evolve a LiF passivation layer and Li-M alloy. Particularly, we propose a LiF-modified Li-Mg-C electrode, which demonstrates stable long-term cycling for over 2000 h in common organic electrolytes with fluoroethylene carbonate (FEC) additives and over 700 h even without additives, suppressing unwanted side reactions and Li dendritic growth. With the help of phase diagrams, we found that solid-solution-based alloying not only facilitates the spontaneous evolution of a LiF layer and bulk alloy but also enables reversible Li plating/stripping inward to the bulk, compared with intermetallic compounds with finite Li solubility.

Leucine supplementation in maternal high-fat diet alleviated adiposity and glucose intolerance of adult mice offspring fed a postweaning high-fat diet.

BACKGROUND: Combined maternal and postnatal high-fat (HF) diet intake predisposes offspring to metabolic dysregulation during adulthood. As the inhibitory effects of leucine consumption on obesity and metabolic disorders have been reported, the effects of maternal leucine supplementation on metabolic dysregulation in adult offspring were investigated. METHODS: Female mice were exposed to a control (C) or HF diet, with or without leucine (L) supplementation (1.5%, w/v), 3 weeks before mating, during pregnancy, and during lactation (C, CL, HF, and HFL). Male offspring were exposed to an HF diet for 12 weeks after weaning (C/HF, CL/HF, HF/HF, and HFL/HF). Serum biochemical parameters were determined for both the dams and offspring. Oral glucose tolerance test and qRT-PCR analysis were used to investigate metabolic dysregulation in the offspring. RESULTS: HFL dams exhibited higher relative adipose tissue weights than HF dams. Body weight, relative adipose tissue weight, and serum glucose levels were lower in the HFL/HF offspring than in the HF/HF offspring. Maternal leucine supplementation tended to alleviate glucose intolerance in the offspring of HF diet-fed dams. Additionally, mRNA levels of fibroblast growth factor 21 (FGF21), a hepatokine associated with glucose homeostasis, were higher in HFL/HF offspring than in HF/HF offspring and were negatively correlated with adiposity and serum glucose levels. The mRNA levels of genes encoding a FGF21 receptor complex, Fgf receptor 1 and klotho ß, and its downstream targets, proliferator-activated receptor-γ co-activator 1α and sirtuin 1, were higher in adipose tissues of the HFL/HF offspring than in those of the HF/HF offspring. Serum lipid peroxide levels were lower in HFL dams than in HF dams and positively correlated with body and adipose tissue weights of offspring. CONCLUSIONS: Leucine supplementation in HF diet-fed dams, but not in control diet-fed dams, resulted in an anti-obesity phenotype accompanied by glucose homeostasis in male offspring challenged with postnatal HF feeding. Activation of FGF21 signaling in the adipose tissue of offspring may be responsible for these beneficial effects of leucine.

Comparison of diagnosis-based risk adjustment methods for episode-based costs to apply in efficiency measurement.

BACKGROUND: The recent rising health spending intrigued efficiency and cost-based performance measures. However, mortality risk adjustment methods are still under consideration in cost estimation, though methods specific to cost estimate have been developed. Therefore, we aimed to compare the performance of diagnosis-based risk adjustment methods based on the episode-based cost to utilize in efficiency measurement. METHODS: We used the Health Insurance Review and Assessment Service-National Patient Sample as the data source. A separate linear regression model was constructed within each Major Diagnostic Category (MDC). Individual models included explanatory (demographics, insurance type, institutional type, Adjacent Diagnosis Related Group [ADRG], diagnosis-based risk adjustment methods) and response variables (episode-based costs). The following risk adjustment methods were used: Refined Diagnosis Related Group (RDRG), Charlson Comorbidity Index (CCI), National Health Insurance Service Hierarchical Condition Categories (NHIS-HCC), and Department of Health and Human Service-HCC (HHS-HCC). The model accuracy was compared using R-squared (R2), mean absolute error, and predictive ratio. For external validity, we used the 2017 dataset. RESULTS: The model including RDRG improved the mean adjusted R2 from 40.8% to 45.8% compared to the adjacent DRG. RDRG was inferior to both HCCs (RDRG adjusted R2 45.8%, NHIS-HCC adjusted R2 46.3%, HHS-HCC adjusted R2 45.9%) but superior to CCI (adjusted R2 42.7%). Model performance varied depending on the MDC groups. While both HCCs had the highest explanatory power in 12 MDCs, including MDC P (Newborns), RDRG showed the highest adjusted R2 in 6 MDCs, such as MDC O (pregnancy, childbirth, and puerperium). The overall mean absolute errors were the lowest in the model with RDRG ($1,099). The predictive ratios showed similar patterns among the models regardless of the  subgroups according to age, sex, insurance type, institutional type, and the upper and lower 10th percentiles of actual costs. External validity also showed a similar pattern in the model performance. CONCLUSIONS: Our research showed that either NHIS-HCC or HHS-HCC can be useful in adjusting comorbidities for episode-based costs in the process of efficiency measurement.

Comprehensive Measurement of the Burden of Disease due to Adverse Events: A New Analysis of the Cross-Sectional Patient Safety Incident Inquiry.

BACKGROUND: A methodology for comprehensively and reasonably measuring the burden of disease due to adverse events has yet to be clearly established. In this study, a new and systematic method for measuring the burden of disease due to adverse events was tested by utilizing the results of a medical record review, which is commonly used as a gold standard. METHODS: Using the characteristics of preventable adverse events identified in the 2019 Patient Safety Incidents Inquiry (PSII), conducted to monitor the level of patient safety in Korea accurately, the resulting disability-adjusted life years (DALYs) and economic costs were estimated. DALYs were calculated as the sum of the years lived with a disability for patients who suffered permanent disability, or more, due to preventable adverse events, and the years of life lost due to premature mortality was calculated for patients who died due to preventable adverse events. The economic cost was calculated using the main diagnostic codes of patients who suffered preventable adverse events, identified as prolonged hospitalization in PSII, and the average medical cost by disease category and age group. RESULTS: Estimates of DALYs due to preventable adverse events were 1,114.4 DALYs per 100,000 population for the minimum standard and 1,658.5 DALYs per 100,000 population for the maximum standard. Compared to the 2015 Korea Burden of Disease results, the ranking of DALYs due to preventable adverse events was sixth for the minimum standard and third for the maximum standard. The annual medical cost of adverse events in 2016 was estimated to be approximately Korean Republic Won (KRW) 870 billion (700 million US dollars). Medical expenses due to preventable adverse events were calculated to be approximately KRW 150 billion (120 million US dollars) as a minimum standard and approximately KRW 300 billion (240 million US dollars) as a maximum standard. CONCLUSION: If this more standard method of systematically calculating the disease burden due to adverse events is used, it will be possible to compare the size of the patient safety problem with that of other diseases. The results of this study indicate that we still need to pay more attention to the issue of patient safety.

Neural representation in MPFC reveals hidden selfish motivation in white lies.

Identifying true motivation for Pareto lies, which are mutually beneficial for both the liar and others, can be challenging because different covert motivations can lead to identical overt behavior. In this study, we adopted a brain-fingerprinting approach, combining both univariate and multivariate analyses to estimate individual measures of selfish motivation in Pareto lies by the degree of multivoxel neural representation in the medial prefrontal cortex (MPFC) for Pareto lies conforms with those for selfish vs. altruistic lies in human participants of either sex. An increase in selfish motivation for Pareto lies was associated with higher mean-level activity in both ventral and rostral MPFC. The former showed an increased pattern similarity to selfish lies and the latter showed a decreased pattern similarity to altruistic lies. Higher ventral MPFC pattern similarity predicted faster response time in Pareto lies. Our findings demonstrated that hidden selfish motivation in white lies can be revealed by neural representation in the MPFC.SIGNIFICANCE STATEMENT:True motivation for dishonesty serving both self and others cannot be accurately discerned from observed behaviors. Here we showed that fMRI combining both univariate and multivariate analyses can be effectively used to reveal hidden selfish motivation of Pareto lies serving both self and others. The present study suggests that selfish motivation for prosocial dishonesty is encoded primarily by increased activity of the ventromedial and the rostromedial prefrontal cortex, representing intuitive self-serving valuation and strategic switching of motivation depending on beneficiary of dishonesty, respectively.

A novel function of HRP-3 in regulating cell cycle progression via the HDAC-E2F1-Cyclin E pathway in lung cancer.

To improve the poor survival rate of lung cancer patients, we investigated the role of HDGF-related protein 3 (HRP-3) as a potential biomarker for lung cancer. The expression of endogenous HRP-3 in human lung cancer tissues and xenograft tumor models is indicative of its clinical relevance in lung cancer. Additionally, we demonstrated that HRP-3 directly binds to the E2F1 promoter on chromatin. Interestingly, HRP-3 depletion in A549 cells impedes the binding of HRP-3 to the E2F1 promoter; this in turn hampers the interaction between Histone H3/H4 and HDAC1/2 on the E2F1 promoter, while concomitantly inducing Histone H3/H4 acetylation around the E2F1 promoter. The enhanced Histone H3/H4 acetylation on the E2F1 promoter through HRP-3 depletion increases the transcription level of E2F1. Furthermore, the increased E2F1 transcription levels lead to the enhanced transcription of Cyclin E, known as the E2F1-responsive gene, thus inducing S-phase accumulation. Therefore, our study provides evidence for the utility of HRP-3 as a biomarker for the prognosis and treatment of lung cancer. Furthermore, we delineated the capacity of HRP-3 to regulate the E2F1 transcription level via histone deacetylation.

Protein-protein interactions in fatty acid elongase complexes are important for very-long-chain fatty acid synthesis.

Fatty acid elongase (FAE), which catalyzes the synthesis of very-long-chain fatty acids (VLCFAs), is a multiprotein complex; however, little is known about its quaternary structure. In this study, bimolecular fluorescence complementation and/or yeast two-hybrid assays showed that homo-interactions were observed in ß-ketoacyl-CoA synthases (KCS2, KCS9, and KCS6), Eceriferum2-like proteins [CER2 and CER2-Like2 (C2L2)], and FAE complex proteins (KCR1, PAS2, ECR, and PAS1), except for CER2-Like1 (C2L1). Hetero-interactions were observed between KCSs (KCS2, KCS9, and KCS6), between CER2-LIKEs (CER2, C2L2, and C2L1), and between FAE complex proteins (KCR1, PAS2, ECR, and PAS1). PAS1 interacts with FAE complex proteins (KCR1, PAS2, and ECR), but not with KCSs (KCS2, KCS9, and KCS6) and CER2-LIKEs (CER2, C2L2, and C2L1). Asp308 and Arg309-Arg311 of KCS9 were essential for the homo-interactions of KCS9 and hetero-interactions between KCS9 and PAS2 or ECR. Asp339 of KCS9 is involved in its homo- and hetero-interactions with ECR. Complementation analysis of the Arabidopsis kcs9 mutant by the expression of amino acid-substituted KCS9 mutant genes showed that Asp308 and Asp339 of KCS9 are involved in the synthesis of C24 VLCFAs from C22. This study suggests that protein-protein interaction in FAE complexes is important for VLCFA synthesis and provides insight into the quaternary structure of FAE complexes for efficient synthesis of VLCFAs.

Chronic stress predicts post-traumatic stress disorder symptoms via executive function deficits among urban American Indian children.

Little is known about how chronic exposure to stress affects mental health among American Indian (AI) children. The current study aimed to fill this gap by exploring if hair cortisol concentration (HCC), an indicator of chronic stress, predicted post-traumatic stress disorder (PTSD) symptoms through deficits in executive function (EF) skills commonly referred to as inhibitory control, working memory, and cognitive flexibility. A total of 163 urban AI children between 8- and 15-years old participated in the study (92 girls, 56.4%; Mage = 11.19, SD = 1.98). Chronic stress was measured as the concentration of cortisol in children's hair. EF deficits and PTSD symptoms were reported by primary caregivers using the Behavior Rating Inventory of Executive Function and the Trauma Symptom Checklist for Young Children. The results demonstrated that higher HCC was indirectly associated with more PTSD symptoms through deficits in EF skills. Specifically, higher levels of HCC were related to more symptoms of PTSD arousal through impaired working memory, and more symptoms of PTSD avoidance and Intrusion through deficits in cognitive flexibility. The findings suggest interventions that reduce or buffer chronic stress, or that focus on improving EF skills, may promote not only cognitive development but also the mental health of AI children.

Different Impacts of Blood and Sputum Eosinophil Counts on Lung Function and Clinical Outcomes in Asthma: Findings from the COREA Cohort.

PURPOSE: Blood (EOS-B) and sputum (EOS-S) eosinophil counts may contribute differently to asthma pathogenesis. We compared the impact of the baseline EOS-B and EOS-S levels on lung function, asthma control, and exacerbation in Korean asthma patients. METHODS: Asthma patients with baseline EOS-B (n = 4257) and EOS-S (n = 1049) levels from a multicenter cohort (COREA) were included. Pulmonary function test (%FEV1 predicted), asthma control test (ACT), and asthma exacerbation incidence were followed-up every 3 months for one year. Linear mixed-effect models and survival analyses were used to examine the association between eosinophilic groups defined by EOS-B or EOS-S and outcomes. RESULTS: High eosinophilic groups were associated with a low baseline value and a high improvement in the %FEV1 predicted and ACT scores over time. The magnitude of group difference in %FEV1 predicted was twofold higher in the EOS-S versus EOS-B classification [mean and 95% CI: 4.7 (0.6-8.8) versus 2.0 (0.2-3.7) for the baseline value and - 1.5 (- 2.3 to - 0.8) versus - 0.8(- 1.1 to -0.4) for the slope of change], whereas it was identical in ACT score. The magnitude of the impact increased linearly with the elevation of the cut-off level for the EOS-B but remained stable for the EOS-S classification. Patients with an elevation of both their EOS-B and EOS-S showed a higher increment in the %FEV1 predicted and ACT over time. Neither the EOS-B nor EOS-S was associated with asthma exacerbation. CONCLUSION: EOS-S and EOS-B contribute differently to the clinical outcomes and should be taken into account independently to improve asthma care.

Cost analysis of coronavirus disease 2019 test strategies using pooled reverse transcriptase-polymerase chain reaction technique.

BACKGROUND: This study aimed to compare the testing strategies for COVID-19 (i.e., individual, simple pooling, and matrix pooling) in terms of cost. METHODS: We simulated the total expenditures of each testing strategy for running 10,000 tests. Three parameters were used: positive rate (PR), pool size, and test cost. We compared the total testing costs under two hypothetical scenarios in South Korea. We also simulated country-specific circumstances in India, South Africa, South Korea, the UK, and the USA. RESULTS: At extreme PRs of 0.01% and 10%, simple pooling was the most economic option and resulted in cost reductions of 98.0% (pool size ≥80) and 36.7% (pool size = 3), respectively. At moderate PRs of 0.1%, 1%, 2%, and 5%, the matrix pooling strategy was the most economic option and resulted in cost reductions of 97.0% (pool size ≥88), 86.1% (pool size = 22), 77.9% (pool size = 14), and 59.2% (pool size = 7), respectively. In both hypothetical scenarios of South Korea, simple pooling costs less than matrix pooling. However, the preferable options for achieving cost savings differed depending on each country's cost per test and PRs. CONCLUSIONS: Both pooling strategies resulted in notable cost reductions compared with individual testing in most scenarios pertinent to real-life situations. The appropriate type of testing strategy should be chosen by considering the PR of COVID-19 in the community and the test cost while using an appropriate pooling size such as five specimens.

Physicochemical characterization of dapagliflozin and its solid-state behavior in stress stability test.

As an active pharmaceutical ingredient, dapagliflozin propanediol monohydrate (D-PD) has been used in the solvated form consisting of dapagliflozin compounded with (S)-propylene glycol and monohydrate at a 1:1:1 ratio. However, dapagliflozin propanediol loses the solvent's reduced lattice structure at slightly higher temperatures. Due to its sensitive solid-state stability, the temperature and humidity are strictly controlled during the production and storage of dapagliflozin. Thus, crystalline molecular complexes containing pharmaceutical salts, solvates, monohydrates, and cocrystals have recently been developed as alternative strategies. This study investigated the dapagliflozin free base (D-FB), D-PD, and dapagliflozin l-proline cocrystals (D-LP). Their solid-state behavior was also evaluated in stress stability studies. The compounds were analyzed using scanning electron microscopy (SEM), powder X-ray diffraction (PXRD), thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), Fourier-transform infrared (FT-IR) spectroscopy, dynamic vapor sorption (DVS), and powder rheology testing. In addition, Carr's index, the Hausner ratio, contact angle, and intrinsic dissolution rate were calculated. Dapagliflozin exhibited distinct physical properties depending upon the differences in solid form and also showed significant differences in solid-state behavior in the stress stability test. In conclusion, D-LP was superior to D-FB or D-PD in physicochemical and mechanical properties.

Self-Healing of Nanoporous Gold Under Ambient Conditions.

Failure of a material is an irreversible process since the material loses its original characteristics and properties. The catastrophic brittle failure under tensile stress of nanoporous gold (np-Au) with a bicontinuous open-cell structure makes impossible otherwise attractive applications. Here, we first demonstrate a self-healing process in tensile-fractured np-Au to overcome the limit of fragility via mechanically assisted cold-welding under ambient conditions. The self-healing ability of np-Au in terms of mechanical properties shows strength recovery up to 64.4% and fully recovered elastic modulus compared with initial tensile properties. Topological parameters obtained by three-dimensional reconstruction of self-healed np-Au clarify the strength, elastic modulus, and strain distribution. The self-healing process in np-Au is attributed to surface diffusion expedited by local compressive stress in the ultrasmall dimension of ligaments formed by ductile failures of individual ligaments.

ß-Boswellic Acid Inhibits RANKL-Induced Osteoclast Differentiation and Function by Attenuating NF-κB and Btk-PLCγ2 Signaling Pathways.

Osteoporosis is a systemic metabolic bone disorder that is caused by an imbalance in the functions of osteoclasts and osteoblasts and is characterized by excessive bone resorption by osteoclasts. Targeting osteoclast differentiation and bone resorption is considered a good fundamental solution for overcoming bone diseases. ß-boswellic acid (ßBA) is a natural compound found in Boswellia serrata, which is an active ingredient with anti-inflammatory, anti-rheumatic, and anti-cancer effects. Here, we explored the anti-resorptive effect of ßBA on osteoclastogenesis. ßBA significantly inhibited the formation of tartrate-resistant acid phosphatase-positive osteoclasts induced by receptor activator of nuclear factor-B ligand (RANKL) and suppressed bone resorption without any cytotoxicity. Interestingly, ßBA significantly inhibited the phosphorylation of IκB, Btk, and PLCγ2 and the degradation of IκB. Additionally, ßBA strongly inhibited the mRNA and protein expression of c-Fos and NFATc1 induced by RANKL and subsequently attenuated the expression of osteoclast marker genes, such as OC-STAMP, DC-STAMP, ß3-integrin, MMP9, ATP6v0d2, and CtsK. These results suggest that ßBA is a potential therapeutic candidate for the treatment of excessive osteoclast-induced bone diseases such as osteoporosis.

Betulinic Acid Inhibits RANKL-Induced Osteoclastogenesis via Attenuating Akt, NF-κB, and PLCγ2-Ca2+ Signaling and Prevents Inflammatory Bone Loss.

The increase of bone-resorbing osteoclast activity in bone remodeling is the major characteristic of various bone diseases. Thus, inhibiting osteoclastogenesis and bone-resorbing function may be an effective therapeutic target for bone diseases. Betulinic acid (BA), a natural plant-derived pentacyclic triterpenoid compound, is known to possess numerous pharmacological and biochemical properties including anti-inflammatory, anticancer, and antiadipogenic activity. However, the effect of BA on osteoclast differentiation and function in bone metabolism has not been demonstrated so far. In this study, we investigated whether BA could suppress RANKL-induced osteoclastogenesis and bone resorption. Interestingly, BA significantly suppressed osteoclastogenesis by decreasing the phosphorylation of Akt and IκB, as well as PLCγ2-Ca2+ signaling, in pathways involved in early osteoclastogenesis as well as through the subsequent suppression of c-Fos and NFATc1. The inhibition of these pathways by BA was once more confirmed by retrovirus infection of constitutively active (CA)-Akt and CA-Ikkß retrovirus and measurement of Ca2+ influx. BA also significantly inhibited the expression of osteoclastogenesis-specific marker genes. Moreover, we found that BA administration restored the bone loss induced through acute lipopolysaccharide injection in mice by a micro-CT and histological analysis. Our findings suggest that BA is a potential therapeutic candidate for bone diseases involving osteoclasts.