Electrochemical synthesis of sulfinic and sulfonic esters from sulfonyl hydrazides.

An electrochemical synthetic method for the synthesis of sulfinic esters and sulfonic esters from sulfonyl hydrazides was developed. Alkyl sulfinic esters were synthesized by treating sulfonyl hydrazides with trialkyl orthoformate in a DMF solvent at a constant current of 5 mA and then optimizing the reaction conditions. Conversely, alkyl sulfonic esters were exclusively obtained when the reaction was conducted in alkyl alcohol solvents at a constant current of 15 mA. The various substituted arylsulfonyl hydrazides afforded moderate to good yields of the desired sulfinic esters and sulfonic esters. Mechanistic investigations revealed that sulfonyl radicals were formed through electrochemical oxidation and that they react with alkyl radicals or alkoxy radicals to generate the respective ester products.

Discovery of a novel homoisoflavonoid derivative 5g for anti-osteoclastic bone loss via targeting FGFR1.

Several flavonoids have been shown to exert anti-osteoporosis activity. However, the structure-activity relationship and the mechanism of anti-osteoporosis activity of flavonoids remain unknown. In this study, we prepared a series of novel homoisoflavonoid (HIF) derivatives to evaluate their inhibitory effects on osteoclastogenesis using TRAP-activity in vitro assay. Then, the preliminary structure-activity relationship was studied. Among the evaluated novel flavonoids, derivative 5g exerted the most inhibitory bioactivity on primary osteoclast differentiation without interfering with osteogenesis. It was hence selected for further in vitro, in vivo and mechanism of action investigation. Results show that 5g likely directly binds to the fibroblast growth factor receptor 1 (FGFR1), decreasing the activation of ERK1/2 and IκBα/NF-κB signaling pathways, which in turn blocks osteoclastogenesis in vitro and osteoclastic bone loss in vivo. Our study shows that homoisoflavonoid (HIF) derivatives 5g can serve as a potential novel candidate for treating osteoporosis via inhibition of FGFR1.

Ring Opening of N-Acyl Lactams Using Nickel-Catalyzed Transamidation.

We successfully developed a nickel-catalyzed transamidation method for the ring opening of N-acyl lactams. The method involves a reaction between N-benzoylpyrrolidin-2-one derivatives and aniline derivatives, with Ni(PPh3)2Cl2 serving as the catalyst, 2,2'-bipyridine as the ligand, and manganese as the reducing agent. This reaction led to the formation of ring-opening-amidated products in good yields. Notably, the method exhibited excellent efficiency for producing the corresponding ring-opening transamidation products for various ring sizes, including four-, five-, six-, seven-, and eight-membered ring lactams.

Internet Use and Well-Being of Older Adults Before and During the COVID-19 Pandemic: Findings from European Social Survey.

The present study examined older adults' use of digital technology and its relation to perceived well-being before and during the COVID-19 pandemic in Europe. Three cross-sectional survey data from the European Social Survey (ESS) were employed including ESS8-2016 (n = 10,618, Mean age = 73.59 ± 6.76 years; 54.4% female), ESS9-2018 (n = 13,532, Mean age = 73.85 ± 6.58 years; 55.9% female), and ESS10-2020 (n = 4,894, Mean age = 73.49 ± 6.40 years; 59.0% female). Results showed that there was a tendency to increase Internet use on a daily basis across different European countries before and during the COVID-19 pandemic. Old age, low education, being widowed, and living in a household with more than five household members were salient factors that are correlated with lower levels of Internet use. Internet use was positively associated with happiness and life satisfaction, and negatively associated with poor general health.

Spiral-phase-objective for a compact spiral-phase-contrast microscopy.

Spiral-phase-contrast imaging, which utilizes a spiral phase optical element, has proven to be effective in enhancing various aspects of imaging, such as edge contrast and shadow imaging. Typically, the implementation of spiral-phase-contrast imaging requires the formation of a Fourier plane through a 4f optical configuration in addition to an existing optical microscope. In this study, we present what we believe to be a novel single spiral-phase-objective, integrating a spiral phase plate, which can be easily and simply applied to a standard microscope, such as a conventional objective. Using a new hybrid design approach that combines ray-tracing and field-tracing simulations, we theoretically realized a well-defined and high-quality vortex beam through the spiral-phase-objective. The spiral-phase-objective was designed to have conditions that are practically manufacturable while providing predictable performance. To evaluate its capabilities, we utilized the designed spiral-phase-objective to investigate isotropic spiral phase contrast and anisotropic shadow imaging through field-tracing simulations, and explored the variation of edge contrast caused by changes in the thickness of the imaging object.

Reductive cross-coupling of N-acyl pyrazole and nitroarene using tetrahydroxydiboron: synthesis of secondary amides.

We report on a new method for the synthesis of amides using acyl pyrazoles and nitroarenes under reducing conditions. It was found that acyl pyrazoles react with organo-nitro compounds in the presence of B2(OH)4, giving the corresponding amides in good yields. We demonstrated that benzoyl pyrazoles having various substituents and nitroarenes with different substituents can be used to produce a range of N-substituted benzamides. The method shows good functional group tolerance and has potential application in the synthesis of a variety of organic molecules.

Selective Synthesis of (Z)- and (E)-ß-Fluoro-α,ß-Unsaturated Amides Using Palladium-Catalyzed Aminocarbonylation.

The selective synthesis of (Z)- and (E)-ß-fluoro-α,ß-unsaturated amides via the palladium-catalyzed aminocarbonylation of 1-fluoro-2,2-diiodovinylarenes is described in the present study. Using {Pd(allyl)Cl}2 as a catalyst and DBU as a base in DMF, the primary product is (Z)-isomers. Conversely, the use of a Xantphos ligand along with {Pd(allyl)Cl}2 and Et3N as the bases in 1,4-dioxane leads to the selective formation of (E)-isomers. Notably, 1-fluoro-2,2-diiodovinylarenes with various substituents on the phenyl ring react with various secondary amines, producing the corresponding (Z)-isomeric amides with a high yield and selectivity. In contrast, (E)-isomeric amides exhibit lower yields and restricted applicability.

Study of mechanical degradation of freestanding ALD Al2O3 by a hygrothermal environment and a facile protective method for environmentally stable Al2O3: toward highly reliable wearable OLEDs.

Al2O3 deposited via atomic layer deposition (ALD) has been used as an insulating and barrier film for thin-film transistors, organic electronics, and microelectromechanical systems. However, ALD Al2O3 films are easily degraded by hydrolysis under harsh hygrothermal conditions, owing to their poor environmental stability. In this study, the mechanical properties and water-vapor transmission rate (WVTR) of environmentally degraded Al2O3 films were investigated by varying the temperature and relative humidity (RH). The hygrothermal environment led to surface and pinhole-concentrated degradation based on aluminum hydroxide, which caused an increased WVTR and reduced elongation of the films in harsher environments. In particular, the elongation of the degraded Al2O3 films was reduced to 0.3%, which is one-third of that of as-deposited Al2O3, and their WVTR increased on the order of 10-1 g m-2 day-1, which is more than 1000 times that of as-deposited Al2O3. Therefore, we introduced a functional silane-based inorganic-organic hybrid layer (silamer) onto the Al2O3 films to improve their environmental stability. The silamer helped preserve the characteristics of Al2O3 films by forming a strong and continuous aluminate phase of Al-O-Si at their interface in hygrothermal environments. Furthermore, the silamer-capped Al2O3 was shown to be an environmentally stable encapsulation for application in wearable organic devices.

Synthesis and evaluation of 2-NMPA derivatives as potential agents for prevention of osteoporosis in vitro and in vivo.

Abnormal osteoclast differentiation causes various bone disorders such as osteoporosis. Targeting the formation and activation of osteoclasts has been recognized as an effective approach for preventing osteoporosis. Herein, we synthesized eleven 2-NMPA derivatives which are (2-(2-chlorophenoxy)-N-(4-alkoxy-2-morpholinophenyl) acetamides, and evaluated their suppression effects on osteoclastogenesis in vitro by using TRAP-staining assay. Among the synthesized eleven novel 2-NMPAs, 4-(2-(2-chlorophenoxy)acetamido)-3-morpholinophenyl trifluoromethanesulfonate (11b), 4-(2-(2-chlorophenoxy) acetamido)-3-morpholinophenyl-3-(N-(2-oxo-2-((2-(phenylthio) phenyl) amino) ethyl)methylsulfonamido)benzoate (11d), and 4-(2-(2-chlorophenoxy) acetamido)-3-morpholinophenyl 4-acetamidobenzenesulfonate (11h) displayed highly inhibitory bioactivity on the differentiation of primary osteoclasts. 11h was selected for further investigation of the inhibitory effects and potential mechanism involved in the suppression of osteoclastogenesis. In vitro analysis suggested that 11h inhibited osteoclastogenesis with an IC50 of 358.29 nM, decreased the formation of F-action belts and bone resorption, without interfering cell viability and osteoblast differentiation. Furthermore, the mRNA expressions of osteoclast-specific genes such as Acp5, Nfatc1, Dc-stamp, Atp6v0d2, Mmp9, and Ctsk significantly decreased following 11h treatment. RANKL-induced osteoclast-specific proteins analysis demonstrated that 11h suppressed osteoclast differentiation by downregulating of RANKL-mediated TRAF6 expression, followed by inactivation of PI3K/AKT and IκBα/NF-κB signaling pathways. Finally, 11h inhibited ovariectomy-induced bone loss in vivo. Therefore, the current work highlighted the therapeutic potential of 11h as an anti-osteoporosis lead compound.

Germline pathogenic variants in HNRNPU are associated with alterations in blood methylome.

HNRNPU encodes a multifunctional RNA-binding protein that plays critical roles in regulating pre-mRNA splicing, mRNA stability, and translation. Aberrant expression and dysregulation of HNRNPU have been implicated in various human diseases, including cancers and neurological disorders. We applied a next generation sequencing based assay (EPIC-NGS) to investigate genome-wide methylation profiling for >2 M CpGs for 7 individuals with a neurodevelopmental disorder associated with HNRNPU germline pathogenic loss-of-function variants. Compared to healthy individuals, 227 HNRNPU-associated differentially methylated positions were detected. Both hyper- and hypomethylation alterations were identified but the former predominated. The identification of a methylation episignature for HNRNPU-associated neurodevelopmental disorder (NDD) implicates HNPRNPU-related chromatin alterations in the aetiopathogenesis of this disorder and suggests that episignature profiling should have clinical utility as a predictor for the pathogenicity of HNRNPU variants of uncertain significance. The detection of a methylation episignaure for HNRNPU-associated NDD is consistent with a recent report of a methylation episignature for HNRNPK-associated NDD.

Geographically varying associations between mentally unhealthy days and social vulnerability in the USA.

OBJECTIVES: A growing body of research has incorporated the Social Vulnerability Index (SVI) into an expanded understanding of the social determinants of health. Although each component of SVI and its association with individual-level mental health conditions have been well discussed, variation in mentally unhealthy days (MUDs) at a county level is still unexplored. To systematically examine the geographically varying relationships between SVI and MUDs across the US counties, our study adopted two different methods: 1) aspatial regression modeling (ordinary least square [OLS]); and 2) locally calibrated spatial regression (geographically weighted regression [GWR]). STUDY DESIGN: This study used a cross-sectional statistical design and geospatial data manipulation/analysis techniques. Analytical unit is each of the 3109 counties in the continental USA. METHODS: We tested the model performance of two different methods and suggest using both methods to reduce potential issues (e.g., Simpson's paradox) when researchers apply aspatial analysis to spatially coded data sets. We applied GWR after checking the spatial dependence of residuals and non-stationary issues in OLS. GWR split a single OLS equation into 3109 equations for each county. RESULTS: Among 15 SVI variables, a combination of eight variables showed the best model performance. Notably, unemployment, person with a disability, and single-parent households with children aged under 18 years especially impacted the variation of MUDs in OLS. GWR showed better model performance than OLS and specified each county's varying relationships between subcomponents of SVI and MUDs. For example, GWR specified that 69.3% (2157 of 3109) of counties showed positive relationships between single-parent households and MUDs across the USA. Higher positive relationships were concentrated in Michigan, Kansas, Texas, and Louisiana. CONCLUSIONS: Our findings could contribute to the literature regarding social determinants of community mental health by specifying spatially varying relationships between SVI and MUDs across US counties. Regarding policy implementation, in counties containing more social and physical minorities (e.g., single-parent households and disabled population), policymakers should attend to these groups of people and increase intervention programs to reduce potential or current mental health illness. The results of GWR could help policymakers determine the specific counties that need more support to reduce regional mental health disparities.

Epigenotype-genotype-phenotype correlations in SETD1A and SETD2 chromatin disorders.

Germline pathogenic variants in two genes encoding the lysine-specific histone methyltransferase genes SETD1A and SETD2 are associated with neurodevelopmental disorders (NDDs) characterized by developmental delay and congenital anomalies. The SETD1A and SETD2 gene products play a critical role in chromatin-mediated regulation of gene expression. Specific methylation episignatures have been detected for a range of chromatin gene-related NDDs and have impacted clinical practice by improving the interpretation of variant pathogenicity. To investigate if SETD1A and/or SETD2-related NDDs are associated with a detectable episignature, we undertook targeted genome-wide methylation profiling of > 2 M CpGs using a next-generation sequencing-based assay. A comparison of methylation profiles in patients with SETD1A variants (n = 6) did not reveal evidence of a strong methylation episignature. A review of the clinical and genetic features of the SETD2 patient group revealed that, as reported previously, there were phenotypic differences between patients with truncating mutations (n = 4, Luscan-Lumish syndrome; MIM:616831) and those with missense codon 1740 variants [p.Arg1740Trp (n = 4) and p.Arg1740Gln (n = 2)]. Both SETD2 subgroups demonstrated a methylation episignature, which was characterized by hypomethylation and hypermethylation events, respectively. Within the codon 1740 subgroup, both the methylation changes and clinical phenotype were more severe in those with p.Arg1740Trp variants. We also noted that two of 10 cases with a SETD2-NDD had developed a neoplasm. These findings reveal novel epigenotype-genotype-phenotype correlations in SETD2-NDDs and predict a gain-of-function mechanism for SETD2 codon 1740 pathogenic variants.

Cross-Lagged Associations Between Physical Activity, Self-Rated Health, and Psychological Resilience Among Older American Adults: A 3-Wave Study.

The current study examined the reciprocal association between psychological resilience, physical activity, and self-rated health in older America adults. A 3-wave cross-lagged panel design was employed using data sampled from the Health and Retirement Study 2010, 2014, and 2018. In total, 8380 older adults, age ranged between 56 and 95 years at the baseline (mean age = 68.06, SD = 7.77), were analyzed. Using structural equation modeling, standardized path coefficients were estimated to determine the relationship between physical activity, self-rated health, and psychological resilience across 2 follow-up points. Cross-lagged analysis revealed that higher levels of physical activity at T1 and T2 were significantly associated with higher levels of self-rated health at T2 and T3, respectively. Self-rated health at T1 and T2 were significantly associated with physical activity at T2 and T3, respectively. Self-rated health and psychological resilience were positively related to one another at each time point. However, relationship between physical activity and psychological resilience was complex across time. Study findings support reciprocal prospective relationship between physical activity and self-rated health and the relationship between self-rated health and psychological resilience.

Discovery of PMSA Derivative 11 as a Novel Lead Compound for Therapeutic Treatment of Osteoporosis In Vitro and In Vivo.

To discover a potent candidate for suppressing mature osteoclasts formation in vitro using a TRAP staining assay. A series of PMSA derivatives were synthesized and evaluated for their bioactivity in our current study. Our results showed that PMSA derivative 11 exhibited the most promising bioactivity, with an IC50 value of 322.9 nM, which was ∼15-fold better than PMSA-3-Ac in suppressing osteoclastogenesis in vitro. Additionally, 11 blocked the formation of F-action belts and bone resorption in a concentration-dependent manner. Mechanistically, 11 decreased the expression of genes required for osteoclastogenesis by blocking NFATc1 translocation from the cytoplasm to nucleus. Furthermore, 11 demonstrated a therapeutic inhibitory effect on the differentiation of human iPSC-derived primary osteoclasts. In vivo investigation showed that 11 prevented excessive osteoclastogenesis-mediated bone loss in ovariectomized osteoporosis mimic mice. These findings highlighted the therapeutic potential of 11 as a lead compound for anti-osteoporosis by targeting NFATc1 translocation.

High-Performance Intrinsically Stretchable Polymer Solar Cell with Record Efficiency and Stretchability Enabled by Thymine-Functionalized Terpolymer.

Designing new polymer semiconductors for intrinsically stretchable polymer solar cells (IS-PSCs) with high power conversion efficiency (PCE) and durability is critical for wearable electronics applications. Nearly all high-performance PSCs are constructed using fully conjugated polymer donors (PD) and small-molecule acceptors (SMA). However, a successful molecular design of PDs for high-performance and mechanically durable IS-PSCs without sacrificing conjugation has not been realized. In this study, we design a novel thymine side chain terminated 6,7-difluoro-quinoxaline (Q-Thy) monomer and synthesize a series of fully conjugated PDs (PM7-Thy5, PM7-Thy10, PM7-Thy20) featuring Q-Thy. The Q-Thy units capable of inducing dimerizable hydrogen bonding enable strong intermolecular PD assembly and highly efficient and mechanically robust PSCs. The PM7-Thy10:SMA blend demonstrates a combination of high PCE (>17%) in rigid devices and excellent stretchability (crack-onset value >13.5%). More importantly, PM7-Thy10-based IS-PSCs show an unprecedented combination of PCE (13.7%) and ultrahigh mechanical durability (maintaining 80% of initial PCE after 43% strain), illustrating the promising potential for commercialization in wearable applications.

Base-Mediated Synthesis of Anhydrides from Activated Amides.

Symmetrical anhydrides were synthesized from activated amides such as N-benzoylsaccharins and N-Boc-protected benzamides. The activated amides reacted with H2O in the presence of 1,4-diazabicyclo[2.2.2]octane (DABCO) at 25 °C to produce the corresponding symmetrical anhydrides in high yields through C-N bond cleavage. In addition, N-benzoylsaccharins reacted with benzoic acid derivatives to generate unsymmetrical anhydrides in high yields.

Molecular characterisation of 36 multilocus imprinting disturbance (MLID) patients: a comprehensive approach.

BACKGROUND: Imprinting disorders (ImpDis) comprise diseases which are caused by aberrant regulation of monoallelically and parent-of-origin-dependent expressed genes. A characteristic molecular change in ImpDis patients is aberrant methylation signatures at disease-specific loci, without an obvious DNA change at the specific differentially methylated region (DMR). However, there is a growing number of reports on multilocus imprinting disturbances (MLIDs), i.e. aberrant methylation at different DMRs in the same patient. These MLIDs account for a significant number of patients with specific ImpDis, and several reports indicate a central role of pathogenic maternal effect variants in their aetiology by affecting the maturation of the oocyte and the early embryo. Though several studies on the prevalence and the molecular causes of MLID have been conducted, homogeneous datasets comprising both genomic and methylation data are still lacking. RESULTS: Based on a cohort of 36 MLID patients, we here present both methylation data obtained from next-generation sequencing (NGS, ImprintSeq) approaches and whole-exome sequencing (WES). The compilation of methylation data did not reveal a disease-specific MLID episignature, and a predisposition for the phenotypic modification was not obvious as well. In fact, this lack of epigenotype-phenotype correlation might be related to the mosaic distribution of imprinting defects and their functional relevance in specific tissues. CONCLUSIONS: Due to the higher sensitivity of NGS-based approaches, we suggest that ImprintSeq might be offered at reference centres in case of ImpDis patients with unusual phenotypes but MLID negative by conventional tests. By WES, additional MLID causes than the already known maternal effect variants could not be identified, neither in the patients nor in the maternal exomes. In cases with negative WES results, it is currently unclear to what extent either environmental factors or undetected genetic variants contribute to MLID.

Exploring the Role of Resilience and Optimism during the COVID-19 Pandemic in Older European Adults.

This study examined how resilience and optimism were related to psychological well-being among older European adults during the early pandemic. The study used data sampled from the Eurofound COVID-19 survey conducted in 27 European countries during the first lockdown (April 2020). The study sample included 10,674 older adults (mean age = 69.71 ± 5.15, 68.6% women, 87.3% retired). Using structural equation modeling, the relationship between pandemic adversities, resilience, optimism, and well-being was investigated. Results indicated that resilience and optimism in part mediated the association between adversities and psychological well-being. Resilience and optimism have the potential to help older adults cope with stressful life events and other adversities. Future studies should more precisely explore the role of resilience and optimism, its formation, and the protective mechanisms that promote the psychological well-being of older adults.

Empagliflozin is associated with lower risk of cardiovascular events and all-cause mortality in routine care in East Asia: Results from the EMPRISE study.

AIMS/INTRODUCTION: The EMPA-REG OUTCOME® trial demonstrated benefits of empagliflozin, a sodium-glucose cotransporter-2 inhibitor (SGLT2i), on cardiovascular, renal outcomes and all-cause mortality in patients with type 2 diabetes and established cardiovascular disease. The EMPRISE study program evaluates how these effects translate in a broad population of patients with type 2 diabetes in routine clinical care across countries. MATERIALS AND METHODS: The study included patients ≥18 years with type 2 diabetes initiating empagliflozin or any dipeptidyl peptidase-4 inhibitors (DPP-4i) from large administrative databases in Japan, South Korea, and Taiwan. Propensity score-matched (1:1) 'as-treated' analyses comparing the risk of cardiovascular outcomes and all-cause mortality between empagliflozin and DPP-4i use were performed in each country. Pooled hazard ratios (pHR) with 95% confidence intervals (CI) were computed using random effects meta-analysis models comparing both empagliflozin and SGLT2i with DPP-4i use, respectively. Intention-to-treat and subgroup analyses in patients with/without cardiovascular disease and in patients receiving 10 mg empagliflozin were performed. RESULTS: The study included 28,712 and 70,233 matched patient pairs for empagliflozin/DPP-4i and SGLT2i/DPP-4i analyses, respectively. The risk of composite outcomes including (i) hospitalization for heart failure (HHF) and all-cause mortality was lower with empagliflozin (pHR 0.76, 95% CI 0.67-0.86) and SGLT2i (0.71, 0.65-0.77); (ii) combined myocardial infarction, stroke, and all-cause mortality was also lower with empagliflozin (0.74, 0.61-0.88) and SGLT2i (0.69, 0.60-0.78) compared to DPP-4i. The intention-to-treat and three subgroup analyses were consistent with results of the main analyses. CONCLUSIONS: The results suggest that both empagliflozin and SGLT2i compared with DPP-4i are associated with a lower risk of cardiovascular events and all-cause mortality in routine clinical care in East Asia.

Achieving small-batch accuracy with large-batch scalability via Hessian-aware learning rate adjustment.

We consider synchronous data-parallel neural network training with a fixed large batch size. While the large batch size provides a high degree of parallelism, it degrades the generalization performance due to the low gradient noise scale. We propose a general learning rate adjustment framework and three critical heuristics that tackle the poor generalization issue. The key idea is to adjust the learning rate based on geometric information of loss landscape and encourage the model to converge into a flat minimum that is known to better generalize to the unknown data. Our empirical study demonstrates that the Hessian-aware learning rate schedule remarkably improves the generalization performance in large-batch training. For CIFAR-10 classification with ResNet20, our method achieves 92.31% accuracy using 16,384 batch size, which is close to 92.83% achieved using 128 batch size, at a negligible extra computational cost.