Development of an Easy-To-Handle Redox Active Group for Alcohols: Catalytic Transformation of Tertiary Alcohols to Nitriles.

The generation of radical intermediates via SET-mediated deoxygenation of activated alcohol derivatives is desirable, as alcohols can be utilized in various radical-mediated reactions. Herein, we introduce α-N-phthalimido-oxy isobutyrate (NPIB) as a novel activating group for alcohols. Essentially, it is a more chemically robust alternative to Overman's N-phthalimidoyl oxalate group. The utility of the NPIB group is showcased in the conversion of tertiary alcohols to nitriles under Ir/Cu dual catalysts and in the presence of TMSCN upon blue LED irradiation. With our newly developed NPIB handle, the reactivities of N-hydroxyphthalimide esters derived from carboxylic acids would be achievable with naturally and commercially more abundant alcohol substrates.

Microbial-Derived Exerkines Prevent Skeletal Muscle Atrophy.

Regular exercise yields a multitude of systemic benefits, many of which may be mediated through the gut microbiome. Here, we report that cecal microbial transplants (CMTs) from exercise-trained vs. sedentary mice have modest benefits in reducing skeletal muscle atrophy using a mouse model of unilaterally hindlimb-immobilization. Direct administration of top microbial-derived exerkines from an exercise-trained gut microbiome preserved muscle function and prevented skeletal muscle atrophy.

The effects of dietary self-monitoring intervention on anthropometric and metabolic changes via a mobile application or paper-based diary: a randomized trial.

BACKGROUND/OBJECTIVES: Weight loss via a mobile application (App) or a paper-based diary (Paper) may confer favorable metabolic and anthropometric changes. SUBJECTS/METHODS: A randomized parallel trial was conducted among 57 adults whose body mass indices (BMIs) were 25 kg/m2 or greater. Participants randomly assigned to either the App group (n = 30) or the Paper group (n = 27) were advised to record their foods and supplements through App or Paper during the 12-week intervention period. Relative changes of anthropometries and biomarker levels were compared between the 2 intervention groups. Untargeted metabolic profiling was identified to discriminate metabolic profiles. RESULTS: Out of the 57 participants, 54 participants completed the trial. Changes in body weight and BMI were not significantly different between the 2 groups (P = 0.11). However, body fat and low-density lipoprotein (LDL)-cholesterol levels increased in the App group but decreased in the Paper group, and the difference was statistically significant (P = 0.03 for body fat and 0.02 for LDL-cholesterol). In the metabolomics analysis, decreases in methylglyoxal and (S)-malate in pyruvate metabolism and phosphatidylcholine (lecithin) in linoleic acid metabolism from pre- to post-intervention were observed in the Paper group. CONCLUSIONS: In the 12-week randomized parallel trial of weight loss through a App or a Paper, we found no significant difference in change in BMI or weight between the App and Paper groups, but improvement in body fatness and LDL-cholesterol levels only in the Paper group under the circumstances with minimal contact by dietitians or health care providers. Trial Registration: Clinical Research Information Service Identifier: KCT0004226.

Synthesis of Suffranidine B.

Efficiently generating intricate molecular complexity is a coveted goal in organic synthesis. This can be realized through the implementation of inventive and audacious strategies coupled with the exploration and advancement of novel molecular reactivity pathways. Herein, we present a concise two-step synthesis of a high-oxidation state heterotrimeric securinega alkaloid, suffranidine B, from 2,3-dehydroallosecurinine and the vinylogous ketoaldehyde compound derived from kojic acid. Key to the success was the astute selection of appropriate acids during both the heterotrimerization and the desymmetrizing cyclization steps. This study underscores the value of biomimicry in the synthesis of complex natural products.

Controlling π-π Interactions of Highly Soluble Naphthalene Diimide Derivatives for Neutral pH Aqueous Redox Flow Batteries.

Organic redox-active molecules are a promising platform for designing sustainable, cheap, and safe charge carriers for redox flow batteries. However, radical formation during the electron-transfer process causes severe side reactions and reduces cyclability. This problem is mitigated by using naphthalene diimide (NDI) molecules and regulating their π-π interactions. The long-range π-stacking of NDI molecules, which leads to precipitation, is disrupted by tethering four ammonium functionalities, and the solubility approaches 1.5 m in water. The gentle π-π interactions induce clustering and disassembling of the NDI molecules during the two-electron transfer processes. When the radical anion forms, the antiferromagnetic coupling develops tetramer and dimer and nullifies the radical character. In addition, short-range-order NDI clusters at 1 m concentration are not precipitated but inhibit crossover. They are disassembled in the subsequent electron-transfer process, and the negatively charged NDI core strongly interacts with ammonium groups. These behaviors afford excellent RFB performance, demonstrating 98% capacity retention for 500 cycles at 25 mA cm-2 and 99.5% Coulombic efficiency with 2 m electron storage capacity.

Synthesis of High-Order and High-Oxidation State Securinega Alkaloids.

Securinega alkaloids, composed of more than 100 members characterized by the compact tetracyclic scaffold, have fascinated the synthetic community with their structural diversity and notable bioactivities. On the basis of the structural phenotype, oligomerizations and oxidations are major biosynthetic diversification modes of the basic Securinega framework. Despite the rich history of synthesis of basic monomeric Securinega alkaloids, the synthesis of oligomeric Securinega alkaloids, as well as oxidized derivatives, has remained relatively unexplored because of their extra structural complexity. In the first half of this Account, our synthetic studies toward high-order Securinega alkaloids are described. We aimed to establish a reliable synthetic method to form C14-C15' and C12-C15' bonds, which are prevalent connection modes between monomers. During our total synthesis of flueggenine C (9), we have invented an accelerated Rauhut-Currier reaction capable of forming the C14-C15' bond stereoselectively. Installation of the nucleophilic functionality to the Michael acceptor, which ushers the C-C bond forming conjugate addition to follow the intramolecular pathway, was the key to success. The C12-C15' linkage, which was inaccessible via an accelerated Rauhut-Currier reaction, was established by devising a complementary cross-coupling/conjugate reduction-based dimerization strategy that enabled the total synthesis of flueggenines D (11) and I (14). In this approach, the C12-C15' linkage was established via a Stille cross-coupling, and the stereochemistry of the C15' position was controlled during the following conjugate reduction step. In the later half of this Account, our achievements in the field of high-oxidation state Securinega alkaloids synthesis are depicted. We have developed oxidative transformations at the N1 and C2-C4 positions, where the biosynthetic oxidation event occurs most frequently. The discovery of a VO(acac)2-mediated regioselective Polonovski reaction allowed us to access the key 2,3-dehydroallosecurinine (112). Divergent synthesis of secu'amamine A (62) and fluvirosaones A (60) and B (61) was accomplished by exploiting the versatile reactivities of the C2/C3 enamine moiety in 112. We have also employed a fragment-coupling strategy between menisdaurilide and piperidine units, which allowed the installation of various oxygen-containing functionality on the piperidine ring. Combined with the late-stage, light-mediated epimerization and well-orchestrated oxidative modifications, collective total synthesis of seven C4-oxygenated securinine-type natural products was achieved. Lastly, the synthesis of flueggeacosine B (70) via two synthetic routes from allosecurinine (103) was illustrated. The first-generation synthesis (seven overall steps) employing Pd-catalyzed cross-coupling between stannane and thioester to form the key C3-C15' bond enabled the structural revision of the natural product. In the second-generation synthesis, we have invented visible-light-mediated, Cu-catalyzed cross-dehydrogenative coupling (CDC) between an aldehyde and electron-deficient olefin, which streamlined the synthetic pathway into four overall steps. Organisms frequently utilize dimerization (oligomerization) and oxidations during the biosynthesis as a means to expand the chemical space of their secondary metabolites. Therefore, methods and strategies for dimerizations and oxidations that we have developed using the Securinega alkaloids as a platform would be broadly applicable to other alkaloids. It is our sincere hope that lessons we have learned during our synthetic journey would benefit other chemists working on organic synthesis.

Collective total synthesis of C4-oxygenated securinine-type alkaloids via stereocontrolled diversifications on the piperidine core.

Securinega alkaloids have fascinated the synthetic chemical community for over six decades. Historically, major research foci in securinega alkaloid synthesis have been on the efficient construction of the fused tetracyclic framework that bears a butenolide moiety and tertiary amine-based heterocycles. These "basic" securinega alkaloids have evolved to undergo biosynthetic oxidative diversifications, especially on the piperidine core. However, a general synthetic solution to access these high-oxidation state securinega alkaloids is lacking. In this study, we have completed the total synthesis of various C4-oxygenated securinine-type alkaloids including securingines A, C, D, securitinine, secu'amamine D, phyllanthine, and 4-epi-phyllanthine. Our synthetic strategy features stereocontrolled oxidation, rearrangement, and epimerization at N1 and C2-C4 positions of the piperidine core within (neo)securinane scaffolds. Our discoveries provide a fundamental synthetic solution to all known securinine-type natural products with various oxidative and stereochemical variations around the central piperidine ring.

Synthesis of Dimeric Securinega Alkaloid Flueggeacosine B: From Pd-Catalyzed Cross-Coupling to Cu-Catalyzed Cross-Dehydrogenative Coupling.

We completed the synthesis of dimeric high-oxidation-state securinega alkaloid flueggeacosine B via two synthetic routes from allosecurinine. The first-generation synthesis (seven overall steps) involved a Liebeskind-Srogl cross-coupling reaction for the union of two functionalized fragments, the organostannane and the thioester. As a means to further streamline the synthetic route, we have developed a visible-light-mediated Cu-catalyzed cross-dehydrogenative coupling (CDC) reaction between an aldehyde and an electron-deficient olefin. This enabled the second-generation synthesis of flueggeacosine B from allosecurinine in four overall steps. The newly developed CDC reaction paves a direct way to a conjugated dicarbonyl moiety, a ubiquitous structural moiety present in various natural products.

On the Erosion of Enantiopurity of Rhodonoids via Their Asymmetric Total Synthesis.

Rhodonoid natural products are found in nature as a scalemic mixture. This interesting phytochemical feature is presumed to originate from a reversible electrocyclic ring opening of the chromene core present in the biogenetic precursors of rhodonoids. Herein, we systematically investigated factors that are responsible for this racemization event. This eventually led us to complete the asymmetric total synthesis of rhodonoids A, C, D, and G.

Test-retest reliability and validity of the Sitting Balance Measure-Korean in individuals with incomplete spinal cord injury.

STUDY DESIGN: Cross-cultural reliability and validity. OBJECTIVES: To develop and validate the Korean version of the Sitting Balance Measure (SBM-K) in Korean persons with incomplete spinal cord injury (ISCI). SETTING: Tertiary care center. METHODS: Twenty-nine persons with ISCI were evaluated using SBM-K, which was validated using the kappa coefficient and intraclass coefficient (ICC). The correlation between SBM-K individual items and total score was analyzed using Spearman's correlation, and the internal consistency of test items was measured using Cronbach's alpha. Additionally, the standard error measurement (SEM) and minimal detectable change (MDC) were measured. For the clinical validity of SBM-K, the correlation of SBM-K with the modified Sitting Balance Scale (mSBS) and the Korean-Spinal Cord Independence Measure-III (KSCIM-III) was determined via Spearman's correlation. Linear regression was performed to determine whether SBM-K could predict KSCIM-III. RESULTS: The weighted kappa score of the SBM-K individual items and ICC of SBM-K total score were 0.76-0.83 (good-very good) and 0.98 (0.95-0.99), respectively. The correlation between the SBM-K total score and individual items was notable (r = 0.78-0.98). Cronbach's alpha, SEM, and MDC of SBM-K were 0.98, 0.59, and 1.64, respectively. The clinical validity of SBM-K correlated with mSBS (r = 0.88) and KSCIM-III (r = 0.65-0.89). SBM-K accounted for 17-72% of the variance in predicting KSCIM-III. CONCLUSIONS: SBM-K showed sufficient test-retest reliability, validity, and marginal measurement errors. SBM-K can serve as an optimal clinical assessment tool for Korean ISCI patients and may provide clinicians with reliable sitting balance assessment in Korean clinical settings.

Interventional benefit of Pilates using Oov and mat on middle-aged women with lower urinary tract symptoms: emphasis on abdominal muscle thickness and muscular function.

Lower urinary tract symptoms (LUTS) have been considered as clinically prevalent symptom in women, and can be ameliorated by the change of abdominal muscles and pelvic floor muscle (PFM). This study investigated the efficacy of Pilates program using Oov and mat on the change of abdominal muscle thickness, PFM function, and LUTS clinical score. 53 women experiencing LUTS were randomly assigned to Oov Pilates exercise group (OPEG) (n=20), mat Pilates exercise group (MPEG) (n= 16), and symptomatic control group (SCG) (n=17), respectively, and two groups using Oov and mat participated in 8-week Pilates program. Thickness of abdominal muscle, functional movement of PFM, and LUTS clinical score were measured from all groups. Thickness of rectus abdominis, internal oblique abdominis, transversus abdominis was significantly improved in OPEG (P<0.05), however, MPEG showed a significant change only in transversus abdominis (P<0.05). In all abdominal muscles, OPEG had a significantly improved abdominal muscle thickness compared to SCG (P<0.05). Functional movement of PFM in OPEG was significantly decreased (P<0.005), but not in MPEG and SCG. In LUTS clinical score, OPEG and MPEG showed a significantly abated symptoms in degree of voiding-related symptoms and discomfort (P<0.005), but not in SCG. Our study highlighted that Pilates using Oov can be an effective intervention to ameliorate the quantitative quality of abdominal muscle thickness and PFM, which ultimately provides the satisfied self-clinical index in degree of voiding-related symptoms and discomfort.

The Efficacy of Pilates on Urinary Incontinence in Korean Women: A Metabolomics Approach.

Pilates has been known as exercise intervention that improves the function of pelvic floor muscle (PFM) associated with impacting urinary incontinence (UI). This study investigated the effect of Pilates on UI in Korean women by determining the change in functional movement of PFM (FMP) and metabolic profiles. UI group with Pilates (UIP, n = 13) participated in 8-weeks Oov Pilates program, and 8 subjects were assigned to Control and UI group with no Pilates (UINP), respectively. Before and after 8 weeks, plasma samples were collected from all participants, and ultrasonography was used to measure the functional change of PFM for calculating FMP ratio. Plasma samples were analyzed by mass spectrometry to identify the change of metabolic features. After 8-weeks intervention, FMP ratio was remarkably decreased in UIP (48.1% ↓, p < 0.001), but not in Control and UINP (p > 0.05). In metabolic features, L-Glutamine (m/z: 147.07 [M + H]+), L-Cystathionine (m/z: 240.09 [M + NH4]+), L-Arginine (m/z: 197.1 [M + Na]+), and L-1-Pyrroline-3-hydroxy-5-carboxylate (m/z: 147.07 [M + NH4]+) were significantly elevated solely in UIP (p < 0.001). Our study elucidated that Pilates can ameliorate the FMP and enhance the specific metabolic characteristics, which was potentially associated with invigorated PFM contractility to effectively control the bladder base and continence.

Biosynthetically Inspired Syntheses of Secu'amamine A and Fluvirosaones A and B.

Presented here is a concise synthesis of secu'amamine A, and fluvirosaones A and B from readily available allosecurinine and viroallosecurinine. The key C2-enamine derivative of (viro)allosecurinine, the presumed biosynthetic precursors of these natural products, was accessed, for the first time, by a VO(acac)2 -mediated regioselective Polonovski reaction. Formal hydration and 1,2-amine shift of this pluripotent enamine compound afforded secu'amamine A. Formal oxidative [3+2] cycloaddition reaction between this enamine and TMS-substituted methallyl iodide reagent paved the way to the precursors of fluvirosaones A and B. The relative stereochemistry at the C2 position of these advanced intermediates governs the fate of 1,2-amine shift leading to fluvirosaones A and B. The syntheses of potential biosynthetic precursors and investigations of their chemical reactivities have provided insights regarding the biogenesis of these natural products.

Visible light induced alkene aminopyridylation using N-aminopyridinium salts as bifunctional reagents.

The development of intermolecular alkene aminopyridylation has great potential for quickly increasing molecular complexity with two valuable groups. Here we report a strategy for the photocatalytic aminopyridylation of alkenes using a variety of N-aminopyridinium salts as both aminating and pyridylating reagents. Using Eosin Y as a photocatalyst, amino and pyridyl groups are simultaneously incorporated into alkenes, affording synthetically useful aminoethyl pyridine derivatives under mild reaction conditions. Remarkably, the C4-regioselectivity in radical trapping with N-aminopyridinium salt can be controlled by electrostatic interaction between the pyridinium nitrogen and sulfonyl group of ß-amino radical. This transformation is characterized by a broad substrate scope, good functional group compatibility, and the utility of this transformation was further demonstrated by late-stage functionalization of complex biorelevant molecules. Combining experiments and DFT calculations on the mechanism of the reaction is investigated to propose a complete mechanism and regioselectivity.

The effect of cardiac rehabilitation at 4 weeks postoperatively on quality of life in patients treated with totally thoracoscopic ablation.

There is a lack of evidence on the effect of exercise-based cardiac rehabilitation (EBCR) in patients treated with total thoracoscopic ablation (TTA) for atrial fibrillation (AF). Our study investigated the efficacy and safety of postoperative exercise intervention in patients recovering from TTA. Twenty-four patients participated in the study, and were divided into the two groups, exercise group (EG) (n=12) and control group (n= 12). Patients in EG performed the exercise intervention including the aerobic and resistance exercise program twice a week for 8 weeks, which was used as a hospital-based cardiac rehabilitation for the out-patient. A cardiopulmonary exercise test was administered to evaluate aerobic exercise capacity, and qualitative aspect of patient's life was assessed using the Short Form 36 questionnaires to compare pre and postoperative wellness of patient's life. Although there was an increase of VO2peak (peak oxygen uptake) after exercise intervention, no significant improvement was found (P=0.055). Two of 4 physical health scores (role-physical, P=0.013 and general health, P=0.05) and three of four mental health scores (vitality, P=0.027, social function, P=0.016, and mental health, P=0.003) were significantly improved after 8 weeks of EBCR. Each summarized scale in the physical (P=0.022) and mental (P= 0.004) survey section was also significantly improved in postoperative assessment compared to the preoperative one. In this context, we concluded that EBCR initiated at the time point of 4th week after TTA operation can guarantee the secure postoperative physical activity, and the 8 weeks of EBCR can effectively improve the quality of life in AF Patients.

Effect of 8-week Nordic walking training on nondominant hand grip and shoulder strength in middle-aged women.

Nordic walking (NW) is a full body training that can be performed with special pole, and has been recognized as an effective out-door activity which can improve the strength of upper extremity. Most previous studies mainly analyzed the effect of NW on the strength of dominant (DN) hand-grip strength, however, a clear scientific examination is needed whether nondominant (NDN) extremity can also be ameliorated by the NW. Therefore, the aim of our study is to investigate the effectiveness of 8 weeks NW training on the NDN handgrip and shoulder strength in healthy middle-aged women. 29 subjects were randomly divided into three groups: Nordic walking group (NWG, n=10), brisk walking group (BWG, n=11), and control group (CG, n=8). Handgrip and shoulder strength were measured by the hand dynamometer and isokinetic machine. NW training was performed 3 times a week, and had 10-min warm-up, 40-min main program consisted of ALFA (Attention, Long arms, Flat poles, Adaptes) technique and Turbo walking, and 10-min cool-down. In handgrip strength of DN hand and the shoulder flexor strength in the both sides, NWG and BWG showed significantly higher value compared to CG. In the NDN hand, NWG also showed significantly higher strength compared to CG, however, there was no significant difference in the handgrip strength/weight among groups. In NDN shoulder extension, significantly higher improvement was found in NWG and BWG compared to that of CG. In conclusion, our study showed that NW can improve the strength of upper extremity in subjects, and can be better approach to improve the NDN handgrip strength than brisk walking method could.

Site-Selective Functionalization of Pyridinium Derivatives via Visible-Light-Driven Photocatalysis with Quinolinone.

The selective installation of phosphinoyl and carbamoyl moieties on the pyridine scaffold is an important transformation in synthetic and medicinal chemistry. By employing quinolinone as an efficient organic photocatalyst, we developed a catalytic system driven by visible light that forms phosphinoyl and carbamoyl radicals, which react with various heteroarenium derivatives under mild, transition-metal-free conditions. This straightforward and environmentally friendly synthetic method represents a new approach to site-divergent pyridine functionalization that offers considerable advantages in both simplicity and efficiency. Ambient temperature is sufficient for the formation of the reactive radicals, and the site-selectivity can be switched from C2 to C4 by changing the radical coupling sources. Under standard reaction conditions, phosphinoyl radicals give access to C4 products, while carbamoyl radicals selectively give C2 products. We found that the carbamoyl radical overcomes the intrinsic preference for forming the ortho-product by allowing the oxo functionality of the carbamoyl radical to electrostatically engage the nitrogen of the pyridinium substrate, which preferentially gives the ortho-product. The phosphinoyl radical cannot engage in the same interaction, because the phosphorus is too large. This novel synthetic route tolerates a broad range of substrates and provides a convenient and powerful synthetic tool for accessing the core structures of numerous privileged scaffolds.

Dimerization Strategies for the Synthesis of High-Order Securinega Alkaloids.

We describe different modes of dimerization of various α',γ-dioxyenone derivatives with potential applications to the synthesis of high-order securinega alkaloids. We learned that the relative stereochemical relationship between α'- and γ-hydroxyl groups of the α',γ-dihydroxyenone derivative determines the mode of dimerization. While cis-α',γ-dioxyenone 26 provided the Rauhut-Currier-type (RC-type) dimer 31 upon reaction with TBAF, trans-α',γ-dihydroxyenone 34 afforded dimeric tetrahydrofuran derivative 41 under the same reaction conditions. We also noticed that the protection of the γ-hydroxyl group drastically changes the reaction outcomes. While cis-α'-oxy-γ-OPiv-enone 49 did not show any reactivity in the presence of TBAF, trans-α'-hydroxy-γ-OPiv-enone 45 produced the RC-type dimer 46 under the same reaction conditions. Computational analysis revealed the detailed mechanism of the latter transformation.

Visible-Light-Induced Pyridylation of Remote C(sp3 )-H Bonds by Radical Translocation of N-Alkoxypyridinium Salts.

Metal-free, visible-light-induced site-selective heteroarylation of remote C(sp3 )-H bonds has been accomplished through the design of N-alkoxyheteroarenium salts serving as both alkoxy radical precursors and heteroaryl sources. The transient alkoxy radical can be generated by the single-electron reduction of an N-alkoxypyridinium substrate by a photoexcited quinolinone catalyst. Subsequent radical translocation of the alkoxy radical forms a nucleophilic alkyl radical intermediate, which undergoes addition to the substrate to achieve remote C(sp3 )-H heteroarylation. This cascade strategy provides a powerful platform for remote C(sp3 )-H heteroarylation in a controllable and selective manner and is well suited for late-stage functionalization of complex bioactive molecules.

The effects of whole-body vibration exercise on isokinetic muscular function of the knee and jump performance depending on squatting position.

[Purpose] The purpose of this study was to investigate the effects of whole-body vibration exercise (WBVE) on isokinetic muscular function of the knee and jump performance depending on different squatting positions. [Subjects] The subjects were 12 healthy adult men who did not exercise regularly between the ages of 27 and 34. [Methods] WBVE was performed with high squat position (SP), middle SP, and low SP. Before and after the intervention, isokinetic muscular function of the knees and jump performance were measured. [Results] Knee flexion peak torque at 60°/s and total work at 180°/s were significantly increased after implementing WBVE. Jump height also significantly increased after completing the exercise at all positions in comparison with the pre-exercise programs. [Conclusion] The results of this study suggest that SP during WBVE is an important factor stimulating positive effects on muscular function.