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In this study, we discovered a directed nucleophilic aromatic substitution reaction, "directed SNAr (dSNAr)," in the reaction of ortho -iodobezamides and amine in the presence of pyridine. The reaction proceeded ortho -specifically and did not require a strong electron-withdrawing group on the arene substrate. Most reactions proceeded at room temperature in the presence of Py, and a wide range of amine nucleophiles can be applied. Furthermore, the reactions with benzamide substituted with multiple halogens were found to be 100% ortho -selective.

This review introduces the synthetic organic chemical value of α-bromocarbonyl compounds with tertiary carbons. This α-bromocarbonyl compound with a tertiary carbon has been used primarily only as a radical initiator in atom transfer radical polymerization (ATRP) reactions. However, with the recent development of photo-radical reactions (around 2010), research on the use of α-bromocarbonyl compounds as tertiary alkyl radical precursors became popular (around 2012). As more examples were reported, α-bromocarbonyl compounds were studied not only as radicals but also for their applications in organometallic and ionic reactions. That is, α-bromocarbonyl compounds act as nucleophiles as well as electrophiles. The carbonyl group of α-bromocarbonyl compounds is also attractive because it allows the skeleton to be converted after the reaction, and it is being applied to total synthesis. In our survey until 2022, α-bromocarbonyl compounds can be used to perform a full range of reactions necessary for organic synthesis, including multi-component reactions, cross-coupling, substitution, cyclization, rearrangement, stereospecific reactions, asymmetric reactions. α-Bromocarbonyl compounds have created a new trend in tertiary alkylation, which until then had limited reaction patterns in organic synthesis. This review focuses on how α-bromocarbonyl compounds can be used in synthetic organic chemistry., (© 2024 The Authors. ChemistryOpen published by Wiley-VCH GmbH.)

Efficient C-C bond cleavage is recognized as a persistent challenge in the field of synthetic methodology. In this study, we found that tertiary alkyl radicals are smoothly formed from tertiary alkylated dienones (BHT adducts) via SET, using PDI as a photocatalyst. Resulting tert -alkyl radicals could be applied to the tert -alkylation of enamides. The driving force of this C-C bond cleavage reaction is the mesolytic cleavage of the BHT adducts. The mechanistic study revealed that PDI anion radical is the key active species during the catalytic cycle.

In this study, we found that the sterically bulky α-hydroxycarboxamide moiety is a suitable framework for protecting the boronyl group of boron reagents during aminations. Condensation of α-hydroxycarboxamide with ArB(OH) 2 produced aryloxazaborolidinone (ArOxB). The reactivity of the C-B bond in ArOxB is easily controlled by the steric and weak electronic effects of the backbone. H 2 N-(or Br-)ArOxB underwent Chan-Evans-Lam (C-E-L) or Buchwald-Hartwig (B-H) amination with retaining the C-B bond. On the other hand, direct C-E-L amination of ArOxB was also possible in an oxidative atmosphere, in which the C-B bond was activated by Cu II species. Our methodology is effective for the precise synthesis of two or more arylamino group substituted arenes., (© 2024 Wiley‐VCH GmbH.)

Synthesis of diverse sterically congested molecules from a single important intermediate is one of the ideal synthetic strategies in organic synthesis. In this paper, we found that γ-oxoalkyl substituted cyclohexenone derivatives (OAC) possessing a quaternary carbon are a useful key intermediate to derive both congested fused [5,6] rings and spirocycles. For this purpose, we have established an efficient synthetic method to obtain OAC by tertiary alkylation of β-methylcyclohexenone derivatives using α-bromocarbonyl compounds as a tertiary alkyl source. The key to the success of this reaction is controlling the reactivity of the dienamine intermediate. While there have been many reports on enamine reactions, dienamine reactions have not been well studied. Herein, we report controlling reactivity of dienamines and molecular diversification from OAC., (© 2024 Wiley‐VCH GmbH.)

Shikonin is extracted from the roots of Lithospermum erythrorhizon , and shikonin extracts have been shown to have inhibitory effects on several bacteria. However, shikonin extracts are difficult to formulate because of their poor water solubility. In the present study, we prepared a shikonin dispersion, which was solubilized by the inclusion of β-1,3-1,6 glucan, and analysed the inhibitory effects of this dispersion on Streptococcus mutans and non-mutans streptococci. The shikonin dispersion showed pronounced anti- S. mutans activity, and inhibited growth of and biofilm formation by this bacterium. The shikonin dispersion also showed antimicrobial and antiproliferative effects against non-mutans streptococci. In addition, a clinical trial was conducted in which 20 subjects were asked to brush their teeth for 1 week using either shikonin dispersion-containing or non-containing toothpaste, respectively. The shikonin-containing toothpaste decreased the number of S. mutans in the oral cavity, while no such effect was observed after the use of the shikonin-free toothpaste. These results suggest that shikonin dispersion has an inhibitory effect on S. mutans and non-mutans streptococci, and toothpaste containing shikonin dispersion may be effective in preventing dental caries.

Purpose: We sought to develop machine learning models to predict the results of patient-specific quality assurance (QA) for volumetric modulated arc therapy (VMAT), which were represented by several dose-evaluation metrics-including the gamma passing rates (GPRs)-and criteria based on the radiomic features of 3D dose distribution in a phantom., Methods: A total of 4,250 radiomic features of 3D dose distribution in a cylindrical dummy phantom for 140 arcs from 106 clinical VMAT plans were extracted. We obtained the following dose-evaluation metrics: GPRs with global and local normalization, the dose difference (DD) in 1% and 2% passing rates (DD1% and DD2%) for 10% and 50% dose threshold, and the distance-to-agreement in 1-mm and 2-mm passing rates (DTA1 mm and DTA2 mm) for 0.5%/mm and 1.0%.mm dose gradient threshold determined by measurement using a diode array in patient-specific QA. The machine learning regression models for predicting the values of the dose-evaluation metrics using the radiomic features were developed based on the elastic net (EN) and extra trees (ET) models. The feature selection and tuning of hyperparameters were performed with nested cross-validation in which four-fold cross-validation is used within the inner loop, and the performance of each model was evaluated in terms of the root mean square error (RMSE), the mean absolute error (MAE), and Spearman's rank correlation coefficient., Results: The RMSE and MAE for the developed machine learning models ranged from <1% to nearly <10% depending on the dose-evaluation metric, the criteria, and dose and dose gradient thresholds used for both machine learning models. It was advantageous to focus on high dose region for predicating global GPR, DDs, and DTAs. For certain metrics and criteria, it was possible to create models applicable for patients' heterogeneity by training only with dose distributions in phantom., Conclusions: The developed machine learning models showed high performance for predicting dose-evaluation metrics especially for high dose region depending on the metric and criteria. Our results demonstrate that the radiomic features of dose distribution can be considered good indicators of the plan complexity and useful in predicting measured dose evaluation metrics., (© 2023 The Authors. Journal of Applied Clinical Medical Physics published by Wiley Periodicals LLC on behalf of American Association of Physicists in Medicine.)

Purpose: The purpose of this study was to create and evaluate deep learning-based models to detect and classify errors of multi-leaf collimator (MLC) modeling parameters in volumetric modulated radiation therapy (VMAT), namely the transmission factor (TF) and the dosimetric leaf gap (DLG)., Methods: A total of 33 clinical VMAT plans for prostate and head-and-neck cancer were used, assuming a cylindrical and homogeneous phantom, and error plans were created by altering the original value of the TF and the DLG by ± 10, 20, and 30% in the treatment planning system (TPS). The Gaussian filters of σ = 0.5 $\sigma = 0.5$ and 1.0 were applied to the planar dose maps of the error-free plan to mimic the measurement dose map, and thus dose difference maps between the error-free and error plans were obtained. We evaluated 3 deep learning-based models, created to perform the following detections/classifications: (1) error-free versus TF error, (2) error-free versus DLG error, and (3) TF versus DLG error. Models to classify the sign of the errors were also created and evaluated. A gamma analysis was performed for comparison., Results: The detection and classification of TF and DLG error were feasible for σ = 0.5 $\sigma = 0.5$ ; however, a considerable reduction of accuracy was observed for σ = 1.0 $\sigma = 1.0$ depending on the magnitude of error and treatment site. The sign of errors was detectable by the specifically trained models for σ = 0.5 $\sigma = 0.5$ and 1.0. The gamma analysis could not detect errors., Conclusions: We demonstrated that the deep learning-based models could feasibly detect and classify TF and DLG errors in VMAT dose distributions, depending on the magnitude of the error, treatment site, and the degree of mimicked measurement doses., (© 2023 The Authors. Journal of Applied Clinical Medical Physics published by Wiley Periodicals, LLC on behalf of The American Association of Physicists in Medicine.)

Tumor suppressor p53 plays a central role in response to DNA damage. DNA-damaging agents modulate nuclear actin dynamics, influencing cell behaviors; however, whether p53 affects the formation of nuclear actin filaments remains unclear. In this study, we found that p53 depletion promoted the formation of nuclear actin filaments in response to DNA-damaging agents, such as doxorubicin (DOXO) and etoposide (VP16). Even though the genetic probes used for the detection of nuclear actin filaments exerted a promotive effect on actin polymerization, the detected formation of nuclear actin filaments was highly dependent on both p53 depletion and DNA damage. Whilst active p53 is known to promote caspase-1 expression, the overexpression of caspase-1 reduced DNA damage-induced formation of nuclear actin filaments in p53-depleted cells. In contrast, co-treatment with DOXO and the pan-caspase inhibitor Q-VD-OPh or the caspase-1 inhibitor Z-YVAD-FMK induced the formation of nuclear actin filament formation even in cells bearing wild-type p53. These results suggest that the p53-caspase-1 axis suppresses DNA damage-induced formation of nuclear actin filaments. In addition, we found that the expression of nLifeact-GFP, the filamentous-actin-binding peptide Lifeact fused with the nuclear localization signal (NLS) and GFP, modulated the structure of nuclear actin filaments to be phalloidin-stainable in p53-depleted cells treated with the DNA-damaging agent, altering the chromatin structure and reducing the transcriptional activity. The level of phosphorylated H2AX (γH2AX), a marker of DNA damage, in these cells also reduced upon nLifeact-GFP expression, whilst details of the functional relationship between the formation of nLifeact-GFP-decorated nuclear actin filaments and DNA repair remained to be elucidated. Considering that the loss of p53 is associated with cancer progression, the results of this study raise a possibility that the artificial reinforcement of nuclear actin filaments by nLifeact-GFP may enhance the cytotoxic effect of DNA-damaging agents in aggressive cancer cells through a reduction in gene transcription., (© 2023. The Author(s).)

Globins have been studied as model proteins to elucidate the principles of protein evolution. This was achieved by understanding the relationship between amino acid sequence, three-dimensional structure, physicochemical properties, and physiological function. Previous molecular phylogenies of chordate globin genes revealed the monophyletic evolution of urochordate globins and suggested convergent evolution. However, to provide evidence of convergent evolution, it is necessary to determine the physicochemical and functional similarities between vertebrates and urochordate globins. In this study, we determined the expression patterns of Ciona globin genes using real-time RT-PCR. Two genes (Gb-1 and Gb-2) were predominantly expressed in the branchial sac, heart, and hemocytes and were induced under hypoxia. Combined with the sequence analysis, our findings suggest that Gb-1/-2 correspond to vertebrate hemoglobin-α/-β. However, we did not find a robust similarity between Gb-3, Gb-4, and vertebrate globins. These results suggested that, even though Ciona globins obtained their unique functions differently from vertebrate globins, the two of them shared some physicochemical features and physiological functions. Our findings offer a good example for understanding the molecular mechanisms underlying gene co-option and convergence, which could lead to evolutionary innovations.

Cancer cells generally exhibit increased iron uptake, which contributes to their abnormal growth and metastatic ability. Iron chelators have thus recently attracted attention as potential anticancer agents. Here, we show that deferriferrichrysin (Dfcy), a natural product from Aspergillus oryzae acts as an iron chelator to induce paraptosis (a programmed cell death pathway characterized by ER dilation) in MCF-7 human breast cancer cells and H1299 human lung cancer cells. We first examined the anticancer efficacy of Dfcy in cancer cells and found that Dfcy induced ER dilation and reduced the number of viable cells. Extracellular signal-related kinase (ERK) was activated by Dfcy treatment, and the MEK inhibitor U0126, a small molecule commonly used to inhibit ERK activity, prevented the increase in ER dilation in Dfcy-treated cells. Concomitantly, the decrease in the number of viable cells upon treatment with Dfcy was attenuated by U0126. Taken together, these results demonstrate that the iron chelator Dfcy exhibits anticancer effects via induction of ERK-dependent paraptosis., (© 2023 Molecular Biology Society of Japan and John Wiley & Sons Australia, Ltd.)

Hydroxyapatite adsorbs various substances, but little is known about the effects on oral bacteria of adsorption onto hydroxyapatite derived from scallop shells. In the present study, we analyzed the effects of adsorption of Streptococcus mutans onto scallop-derived hydroxyapatite. When scallop-derived hydroxyapatite was mixed with S. mutans , a high proportion of the bacterial cells adsorbed onto the hydroxyapatite in a time-dependent manner. An RNA sequencing analysis of S. mutans adsorbed onto hydroxyapatite showed that the upregulation of genes resulted in abnormalities in pathways involved in glycogen and histidine metabolism and biosynthesis compared with cells in the absence of hydroxyapatite. S. mutans adsorbed onto hydroxyapatite was not killed, but the growth of the bacteria was inhibited. Electron microscopy showed morphological changes in S. mutans cells adsorbed onto hydroxyapatite. Our results suggest that hydroxyapatite derived from scallop shells showed a high adsorption ability for S. mutans . This hydroxyapatite also caused changes in gene expression related to the metabolic and biosynthetic processes, including the glycogen and histidine of S. mutans , which may result in a morphological change in the surface layer and the inhibition of the growth of the bacteria.

Herein, we report a copper-catalyzed stereospecific fluorination involving CsF and α-bromocarboxamides as tertiary alkyl sources that, unlike traditional stereospecific routes involving stereoinversive S N 2 reactions, proceeds with retention of stereochemistry. The developed stereospecific Cu-catalyzed reaction is among the most efficient methods for synthesizing fluorinated molecules that possess highly congested stereogenic carbon centers. Mechanistic studies revealed that the combined reactivity of CuF 2 and Cs salt is essential for completing the catalytic cycle. Our catalytic system underwent fluorination exclusively with tertiary alkyl bromides and did not react with primary alkyl bromides, indicating that this stereospecific fluorination methodology is suitable for synthesizing fluorinated building blocks possessing stereo-defined F-containing tertiary carbon stereogenic center., (© 2023 Wiley-VCH GmbH.)

We report the sequence-regulated radical additions of tert -alkyl radicals to two different olefins controlled by a Cu catalyst, which we term the "atom-transfer radical addition-substitution" reaction. The reactions of α-bromocarbonyl compounds, such as tert -alkyl radical sources, with methacrylates and styrenes occur in a sequence-regulated manner to give the corresponding three-component product possessing skipped quaternary carbon centers. Our method provides new insight into how to control the reactivities of tert -alkyl radicals during the synthesis of regulated aliphatic chains.

Although the phagocytic activity of macrophages has long been studied, the involvement of microtubules in the process is not well understood. In this study, we improved the fixation protocol and revealed a dynamically rearranging microtubule network in macrophages, consisting of a basal meshwork, thick bundles at the cell edge, and astral microtubules. Some astral microtubules extended beneath the cell cortex and continued to form bundles at the cell edge. These microtubule assemblies were mutually exclusive of actin accumulation during membrane ruffling. Although the stabilization of microtubules with paclitaxel did not affect the resting stage of the macrophages, it reduced the phagocytic activity and membrane ruffling of macrophages activated with serum-MAF, which induced rapid phagocytosis. In contrast, the destabilization of microtubules with nocodazole enhanced membrane ruffling and the internalization of phagocytic targets suggesting an inhibitory effect of the microtubule network on the remodeling of the actin network. Meanwhile, the microtubule network was necessary for phagosome maturation. Our detailed analyses of cytoskeletal filaments suggest a phagocytosis control system involving Ca 2+ influx, the destabilization of microtubules, and activation of actin network remodeling, followed by the translocation and acidification of phagosomes on the microtubule bundles.

Herein, we report a remote nucleophilic substitution reaction via 1,4-hydrogen atom transfer (1,4-HAT) to synthesize N -acyl- N , O -acetal moieties. α-Bromocarboxamide undergoes rS N at a C(sp 3 )-H bond in the presence of an alcohol/phenol and a copper catalyst. Mechanistic studies using deuterated α-bromocarboxamide confirmed that the 1,4-HAT process is the rate-determining step. Topologically complex N -acyl- N , O -acetal molecules can be accessed using our rS N reaction with various α-bromocarboxamides via chemoselective reactions.

There are several reports of lactam cyclizations, but most yield less-substituted lactam rings. Therefore, diastereoselective cyclization to yield highly substituted lactams is one of the challenges in this field. We therefore propose a strategy involving the reactions of α-halocarboxamides with E / Z -mixed internal olefins here. An Fe/triphos catalyst system is effective in reactions between α-bromocarboxamides and internal olefins to form trans lactams with quaternary carbons. Control experiments reveal that the reaction involves a radical process. This reaction may be useful in the field of pharmaceuticals, as γ-lactam moieties constitute the core structures of numerous drugs and natural alkaloids.

Cu-Catalyzed radical/iminium domino strategy (RIDS) for the efficient synthesis of quaternary-carbon-containing γ-lactam-based multiheterocyclic structures from α-bromocarboxamides is reported. This domino reaction strategy enables the construction of multiheterocycles in one step. Mechanistic studies showed that two catalytically generated iminiums are likely to be key intermediates in the catalytic cycle. The developed method can be used in a chemoselective manner to produce multicyclic products in the reaction with ketones possessing two different carbonyls., (© 2022 Wiley-VCH GmbH.)

Background and Purpose: Odor preference is one of the key factors for the rehabilitation of the swallowing function. On the other hand, sensitivity to odor differs between sexes and decreases with age. These factors rely on brain neuronal circuits. However, it remains not fully clarified which neuronal circuit determines the sex and age differences in odor sensitivity. In this study, we carried out both the odor sensitivity test and functional MRI (fMRI) to find the key neuronal circuits determining sex and age differences in odor sensitivity., Methods: Healthy volunteers (28 males, aged 27-62 years, and 30 females, aged 21-59 years) participated in this study. Some of them (seven males and seven females) underwent fMRI. We prepared five odorous test substances and presented each substance at 1 minute intervals. After 5 minutes of questioning about food intake, the subjects were asked to recall each of the test substances presented from the list. In the fMRI study, all the subjects underwent 15 minutes of the prestimulation, stimulation with peppermint odor, and poststimulation sessions., Results: The odor test score was significantly higher in females than in males and showed an age-dependent decrease. We found four functional connectivities whose degrees were significantly different between males and females. One of them, the functional connectivity between the frontal medial cortex (MedFC) and the left angular gyrus (AG. l), showed an age-dependent change., Conclusions: The functional MedFC-AG.l connectivity is one of the important neuronal circuits that affect the sex- and age-dependent odor sensitivity., (© 2022 American Society of Neuroimaging.)

In this study, we discovered that α-bromocarboxamides react with alkynols containing tertiary alcohol moieties to produce congested ethers or heterocycles. Here, the etherification and hydroamidation reactions can be controlled by a suitable base. Both C-O and C-N bond formations occurred without a transition-metal catalyst. The stereospecific etherification and cyclization of diastereo-enriched α-bromocarboxamide afforded the corresponding diastereo-enriched ether and heterocyclic compound.

Objective: Diffusion-weighted whole-body imaging with background body signal suppression (DWIBS) is now recommended as a first-line staging modality in prostate cancer patients, and the widespread use of DWIBS may lead to an increased frequency of incidental findings. The aim of this study was to evaluate the prevalence and clinical significance of incidental findings on whole-body magnetic resonance imaging (WB-MRI) with DWIBS., Methods: Data from 124 patients with prostate cancer (age, 76.5 ± 5.6 years), who underwent 1.5 T WB-MRI with STIR, TSE-T2, TSE-T1, In/Out GRE, and DWIBS sequences, were retrospectively analyzed. Findings unrelated to prostate cancer were considered as incidental findings and categorized into two groups based on their clinical implications as follows: imaging follow-up or additional examinations was required (significant incidental findings) and no need to additional work-up (non-significant incidental findings). A chi-square test was performed to compare the differences in the prevalence of significant incidental findings based on age (≤75 and>75 years old)., Results: A total of 334 incidental findings were found with 8.1% ( n = 27) as significant incidental findings. Significant incidental findings were more frequent in patients over 75 years old than those of 75 years old or younger (28.6% vs  11.1%, p = 0.018)., Conclusion: Clinically significant incidental findings, which required imaging follow-up or additional examinations, were commonly observed in prostate cancer patients on WB-MRI/DWIBS., Advances in Knowledge: Some incidental findings were clinically significant that may lead to changes in treatment strategy. Checking the entire organ carefully for abnormalities and reporting any incidental findings detected are important.

In many animal species, the body axis is determined by the relocalization of maternal determinants, organelles, or unique cell populations in a cytoskeleton-dependent manner. In the ascidian first cell cycle, the myoplasm, including mitochondria, endoplasmic reticulum (ER), and maternal mRNAs, move to the future posterior side concomitantly (called ooplasmic segregation or cytoplasmic and cortical reorganization). This translocation consists of first and second phases depending on the actin and microtubule, respectively. However, the transition from first to second phase, that is, translocation of myoplasmic components from microfilaments to microtubules, has been poorly investigated. In this study, we analyzed the relationship between these cytoskeletons and myoplasmic components during the first cell cycle and their role in morphogenesis by inhibitor experiments. Owing to our improved visualization techniques, there was unexpected F-actin accumulation at the vegetal pole during this transition period. When this F-actin was depolymerized, the microtubule structure was strongly affected, the myoplasmic components, including maternal mRNA, were mislocalized, and the anteroposterior axis formation was disordered. These results suggested the importance of F-actin during the first cell cycle and the existence of interactions between microfilaments and microtubules, implying the enigmatic mechanism of ooplasmic segregation. Solving this mystery leads us to an improved understanding of ascidian early development.

Axis formation is one of the most important events occurring at the beginning of animal development. In the ascidian egg, the antero-posterior axis is established at this time owing to a dynamic cytoplasmic movement called cytoplasmic and cortical reorganisation. During this movement, mitochondria, endoplasmic reticulum (ER), and maternal mRNAs (postplasmic/PEM RNAs) are translocated to the future posterior side. Although accumulating evidence indicates the crucial roles played by the asymmetrical localisation of these organelles and the translational regulation of postplasmic/PEM RNAs, the organisation of ER has not been described in sufficient detail to date owing to technical difficulties. In this study, we developed three different multiple staining protocols for visualising the ER in combination with mitochondria, microtubules, or mRNAs in whole-mount specimens. We defined the internally expanded "dense ER" using these protocols and described cisterna-like structures of the dense ER using focused ion beam-scanning electron microscopy. Most importantly, we described the dynamic changes in the colocalisation of postplasmic/PEM mRNAs and dense ER; for example, macho-1 mRNA was detached and excluded from the dense ER during the second phase of ooplasmic movements. These detailed descriptions of the association between maternal mRNA and ER can provide clues for understanding the translational regulation mechanisms underlying axis determination during ascidian early embryogenesis., (© 2021. The Author(s).)

We identified cytosine-rich regions adjacent to guanine-rich regions in protease genes. A typical GC-rich sequence derived from the TMPRSS2 gene showed structural competition between a G-quadruplex and a hairpin loop, and this competition significantly affected transcription efficiency. These results suggest an impact of neighboring sequences on the gene expression of guanine-rich sequences.

Background/aim: Serum-derived macrophage activating factor (serum-MAF) is expected to have adjuvant effects through rapid phagocytic activation, which depends on F-actin accumulation in multi-layered membrane ruffles induced within 5 min after serum-MAF addition. This study aimed to elucidate the importance of annexin A2, which is a multifunctional Ca 2+ -binding protein related to cytoskeletal membrane dynamics, in serum-MAF signalling., Materials and Methods: Annexin A2 and F-actin localizations were analyzed via immunostaining and confocal microscopy. Using EGTA as chelator, the role of Ca 2+ in serum-MAF signalling was examined., Results: Annexin A2 was found to translocate from the cytosol to the cell cortex within 30 s of serum-MAF stimulation. Ca 2+ chelation inhibited the translocation of annexin A2, frill-like structure formation, and phagocytic activation by serum-MAF., Conclusion: Annexin A2 and Ca 2+ were responsible for the rapid phagocytic activation by serum-MAF. This study provides an understanding of phagocytic activation in macrophages, which could be beneficial for cancer immunotherapy., (Copyright © 2021 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)