Design, Synthesis, and Evaluation of B-(Trifluoromethyl)phenyl Phosphine-Borane Derivatives as Novel Progesterone Receptor Antagonists.

We previously revealed that phosphine-boranes can function as molecular frameworks for biofunctional molecules. In the present study, we exploited the diversity of available phosphines to design and synthesize a series of B-(trifluoromethyl)phenyl phosphine-borane derivatives as novel progesterone receptor (PR) antagonists. We revealed that the synthesized phosphine-borane derivatives exhibited LogP values in a predictable manner and that the P-H group in the phosphine-borane was almost nonpolar. Among the synthesized phosphine-boranes, which exhibited PR antagonistic activity, B-(4-trifluoromethyl)phenyl tricyclopropylphosphine-borane was the most potent with an IC50 value of 0.54 µM. A docking simulation indicated that the tricyclopropylphosphine moiety plays an important role in ligand-receptor interactions. These results support the idea that phosphine-boranes are versatile structural options in drug discovery, and the developed compounds are promising lead compounds for further structural development of next-generation PR antagonists.

Commonality and variation in mental representations of music revealed by a cross-cultural comparison of rhythm priors in 15 countries.

Music is present in every known society but varies from place to place. What, if anything, is universal to music cognition? We measured a signature of mental representations of rhythm in 39 participant groups in 15 countries, spanning urban societies and Indigenous populations. Listeners reproduced random 'seed' rhythms; their reproductions were fed back as the stimulus (as in the game of 'telephone'), such that their biases (the prior) could be estimated from the distribution of reproductions. Every tested group showed a sparse prior with peaks at integer-ratio rhythms. However, the importance of different integer ratios varied across groups, often reflecting local musical practices. Our results suggest a common feature of music cognition: discrete rhythm 'categories' at small-integer ratios. These discrete representations plausibly stabilize musical systems in the face of cultural transmission but interact with culture-specific traditions to yield the diversity that is evident when mental representations are probed across many cultures.

Short-Term Effect of Auditory Stimulation on Neural Activities: A Scoping Review of Longitudinal Electroencephalography and Magnetoencephalography Studies.

Explored through EEG/MEG, auditory stimuli function as a suitable research probe to reveal various neural activities, including event-related potentials, brain oscillations and functional connectivity. Accumulating evidence in this field stems from studies investigating neuroplasticity induced by long-term auditory training, specifically cross-sectional studies comparing musicians and non-musicians as well as longitudinal studies with musicians. In contrast, studies that address the neural effects of short-term interventions whose duration lasts from minutes to hours are only beginning to be featured. Over the past decade, an increasing body of evidence has shown that short-term auditory interventions evoke rapid changes in neural activities, and oscillatory fluctuations can be observed even in the prestimulus period. In this scoping review, we divided the extracted neurophysiological studies into three groups to discuss neural activities with short-term auditory interventions: the pre-stimulus period, during stimulation, and a comparison of before and after stimulation. We show that oscillatory activities vary depending on the context of the stimuli and are greatly affected by the interplay of bottom-up and top-down modulational mechanisms, including attention. We conclude that the observed rapid changes in neural activitiesin the auditory cortex and the higher-order cognitive part of the brain are causally attributed to short-term auditory interventions.

Spontaneous hemodynamic improvement after balloon pulmonary angioplasty in patients with chronic thromboembolic pulmonary hypertension is observed within a short term after balloon pulmonary angioplasty.

Natural hemodynamic changes after balloon pulmonary artery angioplasty (BPA) in a unified state without oxygen administration in patients with chronic thromboembolic pulmonary hypertension (CTEPH) remains undetermined. This study aimed to clarify the delayed changes in the hemodynamics after BPA in patients with CTEPH. We analyzed 73 consecutive patients with CTEPH who underwent BPA between July 2014 and December 2022. We extracted and evaluated hemodynamic data of the right heart catheter without oxygen administration immediately before and after the first BPA; and immediately before the second BPA, as the "post-delayed changes" after BPA. BPA significantly improved the mean pulmonary artery pressure (mPAP, mmHg) and pulmonary vascular resistance (PVR, dyn-s/cm5) from 36 (32-43) mmHg and 449 (312-627) dyn-s/cm5 before the first BPA to 28 (23-32) mmHg and 275 (217-366) dyn-s/cm5 immediately after BPA, and further significantly improved the values to 23 (20-28) mmHg and 225 (175-301) dyn-s/cm5 post-delayed changes after BPA, respectively. Improvement observed on account of delayed changes was observed both with and without pulmonary hypertension drugs. The delayed changes were observed during a period of 5-180 days, which did not correlate with the changes in mPAP and PVR. Hemodynamic improvement owing to BPA was observed immediately after BPA; however, further improvement was observed as a result of delayed changes. mPAP improved by 3.4 ± 5.2 mmHg and PVR by 53 (10-99) dyn-s/cm5 as delayed improvement. mPAP and PVR showed delayed improved by approximately 10% of their values before BPA.

Efficacy of Subtraction Computed Tomography Arteriography During Preoperative Embolization in Spinal Tumors.

Background: This study aimed to evaluate the efficacy of subtraction computed tomography arteriography (s-CTA) during preoperative embolization in spinal tumors. Methods: The study analyzed 17 vertebrae in 13 patients who underwent preoperative embolization before spinal fixation surgery for malignant spinal tumors to decrease blood loss at our hospital from 2019 to 2021. Their ages ranged from 56 to 88 years (average, 73.5 years). Metastatic bone tumors were most common, including five cases originating as lung carcinomas and three as renal cancers. After digital subtraction angiography of selected tumor-feeding arteries and non-subtraction CTA (ns-CTA) were performed, s-CTA was conducted using data obtained from both procedures. A clarity score of the boundary between the normal bone and tumor was derived for each patient, which was then classified into four grades (good, 3 points; fair, 2 points; faint, 1 point; poor, 0 points) by two experienced radiologists, followed by a comparison between the s-CTA and ns-CTA groups using the Wilcoxon signed-rank test. Results: Clarity scores were significantly higher in the s-CTA group than in the ns-CTA group (P < 0.001). The agreement of Cohen's coefficients between the two radiologists was κ = 0.724 in s-CTA scoring and κ = 0.622 in ns-CTA scoring, which were moderately matched. Seven arteries were not embolized due to insufficient tumor contrast enhancement and their poor relation to the surgical invasion zone. No complications were observed during or after embolization. Conclusion: S-CTA successfully distinguished between tumor and normal bone and may help avoid unnecessary embolization.

The beneficial effects of balloon pulmonary angioplasty for patients with chronic thromboembolic pulmonary hypertension are accompanied by increased body mass index and improved nutritional status.

Although balloon pulmonary angioplasty (BPA) improves pulmonary hypertension and the prognosis of patients with chronic thromboembolic pulmonary hypertension (CTEPH), subsequent changes in body mass index (BMI), nutritional status, and appetite have not been fully investigated. This retrospective study aimed to clarify changes in BMI, nutritional status, and appetite after BPA. Fifty-two consecutive patients with CTEPH who underwent complete revascularization with BPA between July 2014 and July 2023 and were available for follow-up were evaluated. We compared the presence or absence of increased appetite, BMI change, and nutritional status before and after BPA treatment. BPA significantly improved the mean pulmonary artery pressure from 37.4 ± 8.7 mmHg to 18.7 ± 2.8 mmHg and the partial pressure of oxygen from 61.6 ± 9.3 mmHg to 82.8 ± 9.9 mmHg (both p < 0.001). Appetite was increased in 82.7% of the patients. BMI significantly increased from 23.9 ± 3.7 kg/m2 to 24.9 ± 3.7 kg/m2 (p < 0.001). As a nutritional indicator, the Geriatric Nutritional Risk Index increased from 105.3 ± 10.2 to 108.3 ± 8.3 (p < 0.001). The median Controlling Nutritional Status scores showed no significant change but the range was significantly improved from 0-9 to 0-3 (p = 0.006). In conclusion, patients with CTEPH show improved oxygenation and hemodynamics, increased BMI, and improved nutritional status following BPA. This sequence of changes may help improve patient prognosis.

Structural Development of Androgen Receptor Antagonists Using Phenylferrocene Framework as a Hydrophobic Pharmacophore.

We previously identified nitrophenylferrocenes and cyanophenylferrocenes as promising lead structures of novel androgen receptor (AR) antagonists, based on the structural similarity between ferrocene and the steroidal skeleton. In the present research, we explored the structure-activity relationship (SAR) of phenylferrocene derivatives. Introduction of a hydrophobic substituent such as a chlorine atom at the 2-position or 3-position of phenylferrocene derivatives significantly increased the antagonistic activity toward wild-type AR, and among the synthesized compounds, 3-chloro-4-cyanophenylferrocene (29) exhibited the most potent anti-proliferative activity toward the androgen-dependent growth of SC-3 cells expressing wild-type AR (IC50 14 nM). Like conventional antiandrogens such as hydroxyflutamide, the major active metabolite of flutamide, compound 29 exhibited agonistic activity toward T877A-AR, a mutant AR expressed in human prostate cancer cell line LNCaP. Notably, however, the 2-chloro isomer 27 showed potent antagonistic activity toward wild-type AR (IC50 49 nM) and also exhibited antagonistic activity toward T877A-AR. Our SAR data should prove helpful for the development of new-generation AR antagonists based on phenylferrocene as candidate agents to treat drug-resistant prostate cancer.

The utility of arterial spin labeling imaging for predicting prognosis after a recurrence of high-grade glioma in patients under bevacizumab treatment.

BACKGROUND AND PURPOSE: Currently, the antiangiogenic agent bevacizumab (BVZ) is used as a treatment option for high-grade glioma (HGG) patients. However, BVZ restores disruptions of the blood-brain barrier, which leads to the disappearance of contrast enhancement during radiological examinations and therefore complicates evaluations of treatment efficacy. This study aimed to investigate the radio-morphological features of recurrent lesions that newly appeared under BVZ therapy, as well as the utility of arterial spin labeling (ASL) perfusion imaging for evaluating treatment response and prognosis in HGG patients receiving BVZ. METHODS: Thirty-two patients (20 males, 12 females; age range, 35-84 years) with HGG who experienced a recurrence under BVZ therapy were enrolled. We measured the relative cerebral blood flow (rCBF) values of each recurrent lesion using ASL, and retrospectively investigated the correlation between rCBF values and prognosis. RESULTS: The optimal rCBF cut-off value for predicting prognosis was defined as 1.67 using receiver operating characteristic curve analysis. The patients in the rCBF < 1.67 group had significantly longer overall survival (OS) and post-progression survival (PPS) than those in the rCBF ≥ 1.67 group (OS: 34.0 months vs. 13.0 months, p = 0.03 and PPS: 13.0 months vs. 6.0 months, p < 0.001, respectively). CONCLUSION: The ASL-derived rCBF values of recurrent lesions may serve as an effective imaging biomarker for prognosis in HGG patients undergoing BVZ therapy. Low rCBF values may indicate that BVZ efficacy is sustainable, which will influence BVZ treatment strategies in HGG patients.

Physicochemical characterization of B-hydroxyphenyl phosphine borane derivatives and their evaluation as nuclear estrogen receptor ligands.

Increasing the structural options in medicinal chemistry is a promising approach to develop new drug candidates. In this research, we designed and synthesized a series of B-hydroxyphenyl phosphine borane derivatives and investigated their structure-property and structure-activity relationships. The synthesized B-phenylphosphine borane derivatives exhibited sufficient stability in aqueous media, weaker hydrophobicity than the corresponding alkanes and silanes, and sufficient affinity for lipid membranes to enable permeability. Several B-hydroxyphenyl phosphine borane derivatives exhibited significant estrogen receptor (ER) agonistic activity with superior ligand-lipophilicity efficiency (LLE). The phosphine borane framework appears to be a promising option for structural development in drug discovery studies.

Clinical Utility of Diffusion-Weighted Imaging in Gynecological Imaging: Revisited.

ABSTRACT: Diffusion-weighted imaging (DWI) is an increasingly valuable sequence in daily clinical practice, providing both functional and morphological information. The use of DWI can help quantify diffusion using the apparent diffusion coefficient, which reflects the physiological features of the tissue and tumor microcirculation. This knowledge is crucial for understanding and interpreting gynecological imaging. This article reviews the clinical utility of DWI for gynecological imaging, highlighting its ability to aid in the detection of endometrial and cervical cancers, as well as tumor extension and metastasis. In addition, DWI can easily detect the solid components of ovarian cancer (including dissemination), assist in the diagnosis of adnexal torsion, and potentially show bone marrow status. Apparent diffusion coefficient measurement is useful for differentiating between endometrial lesions, uterine leiomyomas, and sarcomas, and may provide important information for predicting the prognosis of gynecological cancers.

A review of psychological and neuroscientific research on musical groove.

When listening to music, we naturally move our bodies rhythmically to the beat, which can be pleasurable and difficult to resist. This pleasurable sensation of wanting to move the body to music has been called "groove." Following pioneering humanities research, psychological and neuroscientific studies have provided insights on associated musical features, behavioral responses, phenomenological aspects, and brain structural and functional correlates of the groove experience. Groove research has advanced the field of music science and more generally informed our understanding of bidirectional links between perception and action, and the role of the motor system in prediction. Activity in motor and reward-related brain networks during music listening is associated with the groove experience, and this neural activity is linked to temporal prediction and learning. This article reviews research on groove as a psychological phenomenon with neurophysiological correlates that link musical rhythm perception, sensorimotor prediction, and reward processing. Promising future research directions range from elucidating specific neural mechanisms to exploring clinical applications and socio-cultural implications of groove.

Relationship between autistic traits and letter-recognition under attention to face-likeness: study using a henohenomoheji-type compound stimulus.

This study aimed to clarify the relationship between autistic traits and letter information processing, specifically, the components of faces when attention is paid to face-like information. We created a new "henohenomoheji-type compound stimulus," in which letters are placed in positions in such a way as to resemble a face. In Experiment 1, we examined the relationship between autistic traits and the participants' performance in a letter-recognition task in which a henohenomoheji-type compound stimulus was used. The results showed a significant moderate negative correlation between Autism-Spectrum Quotient-Japanese Version (AQ-J) scores and letter-recognition sensitivity when the compound stimuli were arranged like a face. The letter-detection task was employed in Experiment 2 to examine how autistic traits affect tasks' performance with a lower cognitive load than in Experiment 1. We found no correlation between AQ-J scores and letter-detection sensitivity with or without face-like features. These results suggest that paying attention to faces reduces the participants' performance in letter recognition, which represents a higher cognitive load in individuals with higher autistic traits. A major implication of this study is that the henohenomoheji-type compound stimuli can be applied to several cognitive tasks, such as cognitive processing in individuals with autistic traits.

Development of subtype-selective estrogen receptor modulators using the bis(4-hydroxyphenyl)silanol core as a stable isostere of bis(4-hydroxyphenyl)methanol.

In this study, we synthesized and evaluated silanol-based bisphenol derivatives as stable isosteres of bis(4-hydroxyphenyl)methanol. The developed silanols exhibited estrogen receptor (ER)-modulating activity. Among them, bis(4-hydroxyphenyl)(methyl)silanol (5a) showed a characteristic ER subtype selectivity, namely, antagonistic activity toward ERα and agonistic activity toward ERß. Docking simulation indicated that the silanol moiety plays a key role in this selectivity. Our results suggest that silanol-based bisphenols offer a unique scaffold for biologically active compounds.

Bimanual finger coordination in professional and amateur darbuka players.

Professional hand percussionists who play the darbuka (a drum from the Middle East) show fast and stable bimanual finger coordination compared to amateur players. A cross-recurrence quantification analysis clarifies how stable bimanual coordination is achieved by dissociating stochastic noise and attractor strength in the dynamic system. This study employed a cross-recurrence quantification analysis to examine professional and amateur darbuka players' fast and stable bimanual finger coordination. Eight professional and eight amateur percussion players participated in the study and played a darbuka with their right and left ring fingers, alternating as fast as possible for 12 s. We then analyzed the finger position data and calculated the stochastic noise and attractor strength from the density and the longest diagonal line in the recurrence plot, respectively. We used linear mixed-effects models to test whether stochastic noise and attractor strength differed between professional and amateur players. The results indicate that professional darbuka players achieve fast and stable bimanual finger coordination by enhancing attractor strength rather than reducing stochastic noise in the dynamic system.

Glutamatergic neurometabolite levels in the caudate are associated with the ability of rhythm production.

Introduction: Glutamatergic neurometabolites play important roles in the basal ganglia, a hub of the brain networks involved in musical rhythm processing. We aimed to investigate the relationship between rhythm processing abilities and glutamatergic neurometabolites in the caudate. Methods: We aquired Glutamatergic function in healthy individuals employing proton magnetic resonance spectroscopy. We targeted the right caudate and the dorsal anterior cingulate cortex (dACC) as a control region. Rhythm processing ability was assessed by the Harvard Beat Assessment Test (H-BAT). Results: We found negative correlations between the production part of the Beat Saliency Test in the H-BAT and glutamate and glutamine levels in the caudate (r = -0.693, p = 0.002) whereas there was no such association in the dACC. Conclusion: These results suggest that higher glutamatergic neurometabolite levels in the caudate may contribute to rhythm processing, especially the ability to produce meter in music precisely.

Sex-dependent behavioral alterations in a poly(I:C)-induced maternal immune activation mouse model without segment filamentous bacteria.

Maternal immune activation is one of the environmental risk factors for offspring to develop psychiatric disorders. A synthetic viral mimetic immunogen, polyinosinic-polycytidylic acid (poly(I:C)), is used to induce maternal immune activation in animal models of psychiatric disorders. In the mouse poly(I:C) model, the existence of segment filamentous bacteria (SFB) in the maternal intestine has been reported to be important for the induction of ASD-related behavioral alterations as well as atypical cortical development called cortical patches. This study aimed to elucidate the effect of a single poly(I:C) injection during embryonic day (E) 9 to E16 on offspring's behavior in the ensured absence of maternal SFB by vancomycin drinking in C57BL/6N mice. The cortical patches were not found at either injection timings with poly(I:C) or PBS vehicle, tested in male or female offspring at postnatal day 0 or 1. Prepulse inhibition was decreased in male adult offspring most strongly at poly(I:C) injection timings later than E11, whereas a modest but significant decrease was observed in female offspring with an injection during E12 to E15. The decrease in social interaction was observed in female offspring most conspicuously at injection timings later than E11, whereas a significant decrease was observed in male offspring with an injection during E12 to E15. In conclusion, this study indicated that behavioral alterations could be induced without maternal SFB. The effect on behavior was substantially different between males and females.

Solvent-Dependent Conformational Switching of N-Methyl-N,N'-diarylsquaramide.

N,N'-Diarylsquaramide and N,N'-dialkylsquaramide are conformationally stable linkers with extended (trans, trans) and folded (cis, cis) structures, respectively, independently of external conditions. Here, we show that N-monomethylated N,N'-diarylsquaramides generally take a (trans, cis) structure in the crystal but show a solvent-dependent conformational equilibrium in solution. In particular, the stable conformer of N-methyl-N,N'-bis(1-naphthyl)squaramide (1f) changes depending upon the solvent. Thus, aromatic N-monomethylated squaramides could find application as components of environment-responsive molecular switches.

Percutaneous ethanolamine oleate sclerotherapy for aggressive vertebral hemangioma: A case report.

Vertebral hemangiomas are the most common benign lesion of the spine which are often an asymptomatic incidental finding. However, a few hemangiomas are aggressive and characterized by bone expansion and extraosseous extension into the paraspinal and epidural spaces. We report the case of a patient presenting an aggressive vertebral hemangioma causing back pain and bilateral numbness of the legs. Among various treatment modalities, a minimally invasive percutaneous sclerotherapy procedure using ethanolamine oleate under computed tomography and fluoroscopic guidance was safely and successfully performed with good clinical outcomes.

Targeting transglutaminase 2 mediated exostosin glycosyltransferase 1 signaling in liver cancer stem cells with acyclic retinoid.

Transglutaminase 2 (TG2) is a multifunctional protein that promotes or suppresses tumorigenesis, depending on intracellular location and conformational structure. Acyclic retinoid (ACR) is an orally administered vitamin A derivative that prevents hepatocellular carcinoma (HCC) recurrence by targeting liver cancer stem cells (CSCs). In this study, we examined the subcellular location-dependent effects of ACR on TG2 activity at a structural level and characterized the functional role of TG2 and its downstream molecular mechanism in the selective depletion of liver CSCs. A binding assay with high-performance magnetic nanobeads and structural dynamic analysis with native gel electrophoresis and size-exclusion chromatography-coupled multi-angle light scattering or small-angle X-ray scattering showed that ACR binds directly to TG2, induces oligomer formation of TG2, and inhibits the transamidase activity of cytoplasmic TG2 in HCC cells. The loss-of-function of TG2 suppressed the expression of stemness-related genes, spheroid proliferation and selectively induced cell death in an EpCAM+ liver CSC subpopulation in HCC cells. Proteome analysis revealed that TG2 inhibition suppressed the gene and protein expression of exostosin glycosyltransferase 1 (EXT1) and heparan sulfate biosynthesis in HCC cells. In contrast, high levels of ACR increased intracellular Ca2+ concentrations along with an increase in apoptotic cells, which probably contributed to the enhanced transamidase activity of nuclear TG2. This study demonstrates that ACR could act as a novel TG2 inhibitor; TG2-mediated EXT1 signaling is a promising therapeutic target in the prevention of HCC by disrupting liver CSCs.

Skin Cold Stimulation Can Modulate the Perceptual Rating of Musical Chords.

We studied the effect of cutaneous cold stimulus on the perceptual rating of musical chords. Despite the shown influence of music and tactile stimuli on human psychological evaluation, the effect of a cold stimulus on sound perception remains underexplored. We examined the effect of a cold stimulus on four psychological measures (frisson, arousal, pleasantness, and valence) as participants listened to two-note chords (consonance and dissonance). The cold-stimulus condition involved an experimenter touching the back of the participant's neck with a cooling device while listening to the sounds, while the control condition used a cooling device with the power off. For the frisson and arousal measures, the main effect of the stimulus condition was significant, showing that the cold stimulus increased the frisson and arousal measures. For the pleasantness and valence measures, there was a significant main effect of two-note chords, showing that a consonance was perceived as more pleasant than a dissonance; however, there was no significant main effect of stimulus condition, showing that the cold stimulus did not affect pleasantness and valence ratings. The results showed that a cold stimulus could bias frisson and arousal without affecting pleasantness and valence ratings when listening to musical sound.