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The structured debate as a means of medical education for medical students and young healthcare providers was performed, with diverse topics related to general and family medicine.

Abstract Regulatory authorities must balance ensuring evidence of efficacy and safety of new drugs. Various regulatory pathways, such as the accelerated approval program in the United States (US), allow authorities to quickly approve drugs for severely ill patients by granting market authorization based on surrogate end points and pending confirmatory trials. In this cross‐sectional study, we considered 23 indications of cancer drugs that received accelerated approval by the US Food and Drug Administration (FDA) but were subsequently withdrawn as of April 2023. Our investigation extended to assessing the regulatory status of these accelerated approvals in the European Union (EU) and Japan, examining relevant regulatory documents and identifying factors contributing to the withdrawal in the United States. Comparing regions, we found that for 52% (12/23) and 30% (7/23) of withdrawn accelerated approvals in the United States, sponsors had also sought marketing authorization from the European Medicines Agency (EMA) and Japan's Pharmaceuticals and Medical Devices Agency (PMDA), respectively. As of the April 30, 2023 study cutoff date, 83% (10/12) of drug–indication pairs remained approved by the EMA, while the PMDA retained 100% (7/7). For these indications, the time from FDA withdrawal until the study cutoff date ranged from 0.23 years to 11.45 years for EMA approvals (median: 1.28 years) and 1.10 years to 11.45 years for PMDA approvals (median: 3.22 years). These findings highlight substantial regulatory discrepancies concerning cancer drugs with unconfirmed benefits. Addressing these discrepancies may involve requiring pharmaceutical companies to confirm clinical benefits using more robust end points and fostering international harmonization in regulators' assessment.

BackgroundNonmedical use of prescription drugs can cause overdose; this represents a serious public health crisis globally. In this digital era, social networking services serve as viable platforms for illegal acquisition of excessive amounts of medications, including prescription medications. In Japan, such illegal drug transactions have been conducted through popular flea market applications, social media, and auction websites, with most of the trades being over-the-counter (OTC) medications. Recently, an emerging unique black market, where individuals trade prescription medications—predominantly nervous system drugs—using a specific keyword (“Okusuri Mogu Mogu”), has emerged on X (formerly Twitter). Hence, these dynamic methods of illicit trading should routinely be monitored to encourage the appropriate use of medications. ObjectiveThis study aimed to specify the characteristics of medications traded on X using the search term “Okusuri Mogu Mogu” and analyze individual behaviors associated with X posts, including the types of medications traded and hashtag usage. MethodsWe conducted a cross-sectional study with publicly available posts on X between September 18 and October 1, 2022. Posts that included the term “Okusuri Mogu Mogu” during this period were scrutinized. Posts were categorized on the basis of their contents: buying, selling, self-administration, heads-up, and others. Among posts categorized as buying, selling, and self-administration, medication names were systematically enumerated and categorized using the Anatomical Therapeutic Chemical (ATC) classification. Additionally, hashtags in all the analyzed posts were counted and classified into 6 categories: medication name, mental disorder, self-harm, buying and selling, community formation, and others. ResultsOut of 961 identified posts, 549 were included for analysis. Of these posts, 119 (21.7%) referenced self-administration, and 237 (43.2%; buying: n=67, 12.2%; selling: n=170, 31.0%) referenced transactions. Among these 237 posts, 1041 medication names were mentioned, exhibiting a >5-fold increase from the study in March 2021. Categorization based on the ATC classification predominantly revealed nervous system drugs, representing 82.1% (n=855) of the mentioned medications, consistent with the previous survey. Of note, the diversity of medications has expanded to include medications that have not been approved by the Japanese government. Interestingly, OTC medications were frequently mentioned in self-administration posts (odds ratio 23.6, 95% CI 6.93-80.15). Analysis of hashtags (n=866) revealed efforts to foster community connections among users. ConclusionsThis study highlighted the escalating complexity of trading of illegal prescription medication facilitated by X posts. Regulatory measures to enhance public awareness should be considered to prevent illegal transactions, which may ultimately lead to misuse or abuse such as overdose. Along with such pharmacovigilance measures, social approaches that could direct individuals to appropriate medical or psychiatric resources would also be beneficial as our hashtag analysis shed light on the formation of a cohesive or closed community among users.

Abstract Background In this digital age, social networks may offer an avenue for individuals to obtain drugs illicitly beyond the prescribed amount. Users on X (Twitter)® have ingeniously fabricated fashionable accessories that employ prescription drug sheets, termed “Okusuri Charm”. Methods This cross‐sectional study scrutinized the emerging “Okusuri Charm” trend, by searching the term in Japanese on X (Twitter)® and analyzing related posts. Results Alongside illegal prescription drug trading, individuals crafted accessories from drug sheets, particularly prescribed psychiatric drugs, and dealt with other users, leading to a growing trend this year. Conclusions A positive outlook toward this trend is the emergence of a new artistic movement, but a pessimistic viewpoint is the creators' misuse of prescription drugs, potentially fostering illegal drug dealings.

The clade A APSES family transcription factors (Mbp1, Swi4, and Swi6) contribute to cell wall synthesis regulation in fungi. Herein, evolutionary relationships among these proteins were clarified by phylogenetic analysis using various ascomycetes and basidiomycetes, and then the detailed function of Mbp1 in cell wall synthesis regulation was analyzed in Pleurotus ostreatus. Our phylogenetic analysis revealed that Mbp1 and Swi6 are widely conserved among various fungi, whereas Swi4 is a protein specific for Saccharomycotina. In P. ostreatus, two putative clade A APSES family transcription factors, protein ID 83192 and 134090, were found and identified as Mbp1 and Swi6, respectively. The mbp1 gene was then disrupted through homologous recombination using P. ostreatus 20b strain (Δku80) as a host to obtain mbp1 disruption strains (Δmbp1). Disruption of mbp1 significantly decreased the growth rate and shortened aerial hyphae, suggesting that Mbp1 is involved in mycelial growth, especially aerial hyphal growth. Furthermore, thinner cell walls, decreased relative percentage of β-glucan, and downregulation of all β-glucan synthase genes were observed in Δmbp1 strains. Therefore, Mbp1 plays an essential role in β-glucan synthesis regulation in P. ostreatus. Disruption of mbp1 also impacted the expression profiles of chitin synthase genes, septum formation, and sensitivity to a chitin synthesis inhibitor, suggesting that Mbp1 also regulates chitin synthesis. In conclusion, Mbp1 is responsible for normal mycelial growth and regulates β-glucan and chitin synthesis in P. ostreatus. To the best of our knowledge, this is the first report on the detailed function of Mbp1 in cell wall synthesis regulation in fungi., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

As of October 1, 2024, Japan implemented a revised COVID-19 vaccination strategy, shifting from a fully publicly funded model to one where costs are partially or fully borne by recipients. This new annual program targets individuals aged 65 and above, and those aged 60-64 at higher risk of severe illness, requiring them to cover some vaccination expenses. For others, the vaccine remains voluntary and self-funded. Notably, this program includes the world's first self-amplifying mRNA COVID-19 vaccine, zapomeran (Kostaive®, Meiji Seika Pharma Co., Ltd) approved on November 28, 2023. This vaccine's innovative self-amplifying feature has ignited debates across media platforms, with widespread public division and confusion. The new vaccine encodes replicase proteins and the spike protein antigen, allowing for reduced doses of 5 ug compared to traditional mRNA vaccines that require 30 ug. However, concerns have been raised, primarily around four misconceptions: shedding, perpetual mRNA replication, integration into human DNA, and its non-approval situation outside Japan. Despite these scientifically unfounded concerns, they have fueled vaccine hesitancy, influenced by misleading information spreading rapidly on social media. Alarmingly, biased statements from an academic university and an academic society aggravate this hesitancy. Japan's history has experienced vaccine hesitancies in human papillomavirus and diphtheria-tetanus-pertussis vaccination cases. To prevent a public health crisis, it is crucial that governmental bodies and academic groups actively counter misinformation, advocating for evidence-based understanding and encouraging vaccination among those most at risk., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Association of Physicians. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Therapeutic oligonucleotides, such as antisense DNA, show promise in treating previously untreatable diseases. However, their applications are still hindered by the poor membrane permeability of naked oligonucleotides. Therefore, it is necessary to develop efficient methods for intracellular oligonucleotide delivery. Previously, our group successfully developed disulfide-based Membrane Permeable Oligonucleotides (MPON), which achieved enhanced cellular uptake and gene silencing effects through an endocytosis-free uptake mechanism. Herein, we report a new molecular design for the next generation of MPON, called trimer MPON. The trimer MPON consists of a tri-branched backbone, three α-lipoic acid units, and a spacer linker between the oligonucleotides and tri-branched cyclic disulfide unit. We describe the design, synthesis, and functional evaluation of the trimer MPON, offering new insights into the molecular design for efficient oligonucleotide delivery., (© 2024 The Authors. ChemMedChem published by Wiley-VCH GmbH.)

There is no established treatment for lung adenocarcinoma with uncommon/compound epidermal growth factor receptor (EGFR) mutations. We report a case of a 73-year-old man with stage IVB lung adenocarcinoma harboring E709G and L861Q EGFR mutations. After 2 months of afatinib treatment, significant tumor shrinkage was observed, and the patient's condition remained stable for 1 year. This case highlights the potential effectiveness of afatinib for treating rare stage IV lung adenocarcinoma with these specific EGFR mutations., Competing Interests: The authors declare that they have no conflicts of interest., (© 2024 The Authors.)

Background: Extramammary Paget's disease (EMPD) is a rare intraepithelial adenocarcinoma that mainly affects the anogenital and axillary regions. Although its etiology has not been fully elucidated, there is evidence that androgen receptors (AR) are expressed in most cases of EMPD. However, the role of androgen signaling in the pathogenesis of EMPD remains unclear., Objective: To evaluate the role of androgen signaling in tumor growth of AR-positive EMPD., Methods: Patient-derived organoids were established and cultured from two AR-positive EMPD patients: one man and one woman. Cultured organoids were treated with androgen agonists and/or antagonists, then subjected to analysis of changes in organoid proliferation, as well as changes in androgen signaling pathway-specific genes., Results: Organoid cultures were established from each EMPD sample. These organoids were immunohistologically and genetically identical to the original tumor. For each organoid sample, viable cell number increased in response to androgen exposure. The mRNA level of Fkbp5, a known AR target gene, increased in a concentration-dependent manner in organoids exposed to the synthetic androgen R1881. Conversely, the AR inhibitor darolutamide suppressed the viable cell number in a concentration-dependent manner. The mRNA expression levels of MKI67 and Fkbp5 were also suppressed by darolutamide., Conclusion: Our results indicate that androgen signaling is a key pathway involved in the growth of AR-positive EMPD. Therefore, androgen signaling inhibition may be a novel treatment option for EMPD patients who require systemic therapy., Competing Interests: Conflict of interest HM, TT and MU belong to JSR corporation., (Copyright © 2023. Published by Elsevier B.V.)

The technologies used to generate human induced pluripotent stem cell (iPSC) from somatic cells potentially enable the wide application of iPSC-derived differentiated cells in industrial research fields as a replacement for animals. However, as highly trained individuals are required to obtain reproducible results, this approach has limited social implementation. In the research field of iPSC, it is believed that documentable information is not enough for reproducing the quality of the differentiated cells. Therefore, automated culture machines for cell processing should make the starting of iPSC-using researches easier. We developed a programmable all-in-one automated culture machine, with dense and compact constitution that fits within a normal biosafety cabinet (200 mm wide, 233 mm height, and 110 mm depth). This instrument was fabricated using novel x-y-z-axes-rail-system, such as an overhead traveling crane, in a factory, which served as the main handling machinery. This machine enabled stable and efficient expansion of human iPSC under the feeder-free condition, without karyotype alterations, and simultaneously differentiated the cells into various cell types, including cardiomyocytes, hepatocytes, neural progenitors, and keratinocytes. Overall, this machine would facilitate the social implementation of human pluripotent stem cells and contribute to the accumulation of sharable knowledge for the standardization of the entire handling processes of iPSC in pharmaceutical, food, and cosmetic research., Competing Interests: MT, HM, and KO are employed by the Panasonic Production Engineering Co., Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Bando, Yamashita, Tsumori, Minoura, Okumura and Hattori.)

The extent of indirect decompression after oblique lateral interbody fusion (OLIF) is one of the most important factors in deciding the strategy. To assess the radiographical predictors of the effect of indirect decompression in patients with lumbar degenerative spondylosis by OLIF. Thirty-two consecutive patients who underwent OLIF at 58 lumbar disc levels were enrolled in this study. The radiographic measurements included central disc height (cDH), dorsal disc height (dDH), right/left foraminal height in sagittal plane computed tomography (CT), and cross-sectional dural sac antero-posterior diameter (CDSD) in axial plane CT. All patients were followed up for 1 year after surgery. All CT parameters (cDH, dDH, CDSD, right foraminal height [RFH], and left foraminal height [LFH]) significantly increased after OLIF (P < .0001). The mean raised height difference was 4.3, 3.4, 3.4, and 2.6 mm for cDH, dDH, RFH, and LFH, respectively. The mean CDSD increase was 1.4 mm. The median values of post/pre-operation (change rates) were 1.5 times in cDH, 1.9 times in dDH, and 1.2 times in CDSD, RFH, and LFH. RFH and LFH change rates were related with both cDH and dDH change rates, while the CDSD change rate was only associated with the dDH change rate (P = .0206*) but not with cDH (P = .2061). There was a significant negative relationship between the CDSD change rate and preoperative dDH (P = .0311*, R2 = 0.0817) but not with preoperative cDH (P = .4864). OLIF should be avoided for patients with preserved high dDH., Competing Interests: All data generated or analyzed during this study are included in this published article [and its supplementary information files].The authors have no funding and conflicts of interest to disclose., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

Ovarian cysts develop rarely in fetuses during pregnancy and usually disappear after birth. However, during pregnancy, torsion and rupture of the cyst can occur and it is necessary to manage such cases. At present, there is no standardized prenatal or neonatal treatment. However, the preservation of ovarian function is an important consideration. Here, we present a case involving a 35-year-old woman who gave birth to an infant with a complicated ovarian cyst, which was resolved through laparoscopic surgery on the third day after birth. The prenatal diagnosis of the fetal ovarian cyst was performed prenatally using ultrasound and magnetic resonance imaging (MRI). However, torsion of the ovarian pedicle was suspected because of dorsal thickening of the cyst wall and fluid formation indicated by high intensity on T1- and T2-weighted MRI. Surgery was complicated due to involvement in the torqued pedicle of the left fallopian tubal fimbria, which was released. The cyst was drained and partially resected, and then the pedicle torsion was released. By four years and five months of follow-up, there had been no ovarian cyst findings on ultrasound or MRI. Larger cysts are more likely to involve torsion of the ovarian pedicle and potential bleeding. Considering that, in this case, the cyst was large and proved to be ischemic-hemorrhagic, the decision to operate seemed justified., Competing Interests: The authors declare that there is no conflict of interest regarding the publication of this paper., (© 2022 The Authors.)

The identification, structure-activity relationships (SARs), and biological effects of new antimalarials consisting of a 2,3,4,9-tetrahydro-1H-β-carboline core, a coumarin ring, and an oxyalkanoyl linker are described. A cell-based phenotypic approach was employed in this search for novel antimalarial drugs with unique modes of action. Our screening campaign of the RIKEN compound library succeeded in the identification of the known tetrahydro-β-carboline derivative (4e) as a hit compound showing significant in vitro activity. SAR studies on this chemical series led to the discovery of compound 4h having a (R)-methyl group on the oxyacetyl linker with potent inhibition of parasite growth (IC 50  = 2.0 nM). Compound 4h was also found to exhibit significant in vivo antimalarial effects in mouse models. Furthermore, molecular modeling studies on 4e, 4h, and its diastereomer (4j) suggested that the (R)-methyl group of 4h forces the preferential adoption of a specific conformer which is considered to be an active conformer., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Non-medical use of prescription medications is a serious public health crisis. The black market for prescription medications should be routinely surveyed to encourage their appropriate use. Herein, we focused on Twitter to investigate the possibility of illicit drug trading in Japan. From March 1 to 8, 2021, we examined the characteristics of Twitter posts, identified using the search term "Okusuri Mogu Mogu", a Japanese argot used for trading of medications. The captured data included the date of the posts, whether with a hashtag was used, an indication of the trades type (buy, sell, self-administration, and unknown), and the name of the mentioned pharmaceutical products. The number of named medications in the posts was counted and further categorized according to the Anatomical Therapeutic Chemical (ATC) classification. Two hundred and thirty-eight posts were identified with the searching term "Okusuri Mogu Mogu", of which 154 (64.7%) named specific medications. Of note, 73 posts (30.7%) were associated with buying or selling medications. We examined the 73 posts. These posts included 118 medications (26 types), of which 107 (88.4%) were classified as nervous system drugs. Hypnotics and sedatives were the most frequently mentioned medications. The present study sheds light on pharmaceutical medication trading via Twitter. Reinforcing the surveillance practices or cracking down on traders by authorities may be insufficient. We consider the possible effectiveness of socially supportive approaches to help those who lack support to access the appropriate psychiatric care.

Asthma is a disease that consists of three main components: airway inflammation, airway hyperresponsiveness, and airway remodeling. Persistent airway inflammation leads to the destruction and degeneration of normal airway tissues, resulting in thickening of the airway wall, decreased reversibility, and increased airway hyperresponsiveness. The progression of irreversible airway narrowing and the associated increase in airway hyperresponsiveness are major factors in severe asthma. This has led to the identification of effective pharmacological targets and the recognition of several biomarkers that enable a more personalized approach to asthma. However, the efficacies of current antibody therapeutics and biomarkers are still unsatisfactory in clinical practice. The establishment of an ideal phenotype classification that will predict the response of antibody treatment is urgently needed. Here, we review recent advancements in antibody therapeutics and novel findings related to the disease process for severe asthma.

Imaging the dynamics of proteins in living cells is a powerful means for understanding cellular functions at a deeper level. Here, we report a versatile method for spatiotemporal imaging of specific endogenous proteins in living mammalian cells. The method employs a bifunctional aptamer capable of selective protein recognition and fluorescent probe-binding, which is induced only when the aptamer specifically binds to its target protein. An aptamer for β-actin protein preferentially recognizes its monomer forms over filamentous forms, resulting in selective G-actin staining in both fixed and living cells. Through actin-drug treatment, the method permitted direct monitoring of the intracellular concentration change of endogenous G-actin. This protein-labeling method, which is highly selective and non-covalent, provides rich insights into the study of spatiotemporal protein dynamics in living cells., (© The Author(s) 2021. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Sigmoid volvulus requires urgent treatment, and it is particularly rare among pregnant women without a history of laparotomy. A delay in diagnosis may lead to serious consequences for the mother and fetus, and a rapid diagnosis and treatment in this setting is essential. The patient was a 19-year-old primiparous woman. She complained of repeated exacerbations and remissions of abrupt lower abdominal pain for the past 2 days and was transported to our hospital at 33 weeks of gestation. Ultrasonography revealed no placental thickening, and maternal bowel dilation was difficult to identify. Plain abdominal X-ray showed a dilated colon on the left side of the abdomen. Contrast-enhanced CT scan of the abdomen revealed a volvulus on the dorsal side of the uterus. The proximal end of the transverse to sigmoid colon was markedly dilated, and the distal end was collapsed. The elevated lactate level on blood gas analysis suggested intestinal ischemia. She was suspected of having a sigmoid volvulus at 33 weeks and 3 days of gestation. We decided to perform a cesarean section to secure the operative field for an intestinal resection following delivery. A male weighing 1840 g with Apgar scores 8/8 was delivered. The sigmoid colon was approximately 80 cm in length. A 360-degree clockwise rotation of was observed with a very distended but viable sigmoid loop. Following reduction of the volvulus, the sigmoid colon was fixed to the left side of the peritoneum. The mother had an uneventful postoperative course, and the infant was discharged without any sequelae. This case demonstrates two important lessons. First, sigmoid volvulus can occur in pregnant women even if they never had a laparotomy. Second, abdominal contrast-enhanced CT is useful for rapid diagnostic and treatment decisions relative to this pathology., Competing Interests: The authors declare that there is no conflict of interest regarding the publication of this paper., (Copyright © 2021 Toshiaki Watanabe et al.)

This report describes the development of a non-genetic cell-surface modification method, in which a self-assembling small molecule is combined with Halo-tag proteins. Cell-surface functionalization with cancer-linked extracellular proteins led to enhanced cell motility, angiogenesis, and immune shielding of the cells, paving the way for translational opportunities for cell therapy.

A condensed film formation of surfactants with a charged head group at the oil/water interface was achieved by mixing surfactants of different geometric shapes to control molecular packing at the interface. The adsorbed films of mixed tetradecyltrimethylammonium bromide (C14TAB)-cholesterol (Chol) and tetradecylphosphocholine (C14PC)-Chol systems at the hexane/water interface were examined by interfacial tension and X-ray reflectivity measurements. The interfacial tension versus Chol concentration curves have break points because of the expanded-condensed phase transition of the adsorbed film. A two dimensional (2D) phase diagram, phase diagram of adsorption, indicated that 1:1 mixing in the condensed film is energetically favorable because of stronger mutual interaction between different molecules than between the same ones. The electron density profile normal to the interface manifested that the packing of C14TAB (or C14PC) and Chol molecules is like a 2D solid in the condensed state. As C14TAB and C14PC molecules take a corn shape with a large head group (critical packing parameter: CPP ≈ 1/3) and Chol takes an inverted corn shape with a bulky sterol ring (CPP > 1), the mixing of corn shape and inverted corn shape molecules produces well-ordered packing to promote solid-like molecular packing at the interface by energy gain because of vdW interaction between hydrophobic chains in addition to attractive ion-dipole interaction between head groups. Furthermore, the heterogeneous feature in the adsorbed film of the C14TAB-Chol system is explained by an interplay between contact energy and dipole interaction, which contribute to line tension at the domain boundary.

Pseudoaneurysms generally develop when an arterial puncture site is inadequately sealed. We encountered a case of vaginal pseudoaneurysm that developed 3 years after cesarean section in a 35-year-old gravida 7 para 4 woman who was prescribed with anticoagulant and antiplatelet drugs after surgeries for ventricular septal defect and aortic valve replacement. Pelvic computed tomography scan revealed a large mass, which showed a dappled contrast filling on the arterial phase, located in the posterior vaginal wall. The vaginal pseudoaneurysm was completely occluded by embolization of the left vaginal artery. Anticoagulation and antiplatelet therapies can be potential causes of spontaneous pseudoaneurysm rupture. Extrauterine pseudoaneurysm has a long period of time between cesarean section and pseudoaneurysm discovery. Considering that pseudoaneurysm shows different clinical features for each patient, we should always consider pseudoaneurysm when we assess a patient with postpartum hemorrhage., Competing Interests: The authors declare that there is no conflict of interest regarding the publication of this paper., (Copyright © 2020 Yui Kinjo et al.)

Heart failure and chronic kidney disease are major causes of morbidity and mortality internationally. Although these dysfunctions are common and frequently coexist, the factors involved in their relationship in cardiorenal regulation are still largely unknown, mainly due to a lack of detailed molecular targets. Here, we found the increased plasma histamine in a preclinical mouse model of severe cardiac dysfunction, that had been cotreated with angiotensin II (Ang II), nephrectomy, and salt (ANS). The ANS mice exhibited impaired renal function accompanied with heart failure, and histamine depletion, by the genetic inactivation of histidine decarboxylase in mice, exacerbated the ANS-induced cardiac and renal abnormalities, including the reduction of left ventricular fractional shortening and renal glomerular and tubular injuries. Interestingly, while the pharmacological inhibition of the histamine receptor H3 facilitated heart failure and kidney injury in ANS mice, administration of the H3 agonist immethridine (Imm) was protective against cardiorenal damages. Transcriptome analysis of the kidney and biochemical examinations using blood samples illustrated that the increased inflammation in ANS mice was alleviated by Imm. Our results extend the pharmacological use of H3 agonists beyond the initial purposes of its drug development for neurogenerative diseases and have implications for therapeutic potential of H3 agonists that invoke the anti-inflammatory gene expression programming against cardiorenal damages., (Copyright © 2020 the Author(s). Published by PNAS.)

Potential inhibitors of a target biomolecule, NAD-dependent deacetylase Sirtuin 1, were identified by a contest-based approach, in which participants were asked to propose a prioritized list of 400 compounds from a designated compound library containing 2.5 million compounds using in silico methods and scoring. Our aim was to identify target enzyme inhibitors and to benchmark computer-aided drug discovery methods under the same experimental conditions. Collecting compound lists derived from various methods is advantageous for aggregating compounds with structurally diversified properties compared with the use of a single method. The inhibitory action on Sirtuin 1 of approximately half of the proposed compounds was experimentally accessed. Ultimately, seven structurally diverse compounds were identified.

Protein arginine methyltransferase PRMT5 synthesizes the symmetric dimethylarginine in nuclear and cytoplasmic proteins such as histone H2A, H4 and several non-histone proteins that are required for a variety of biological processes. Currently, two splice variants (v1 and v2) of murine PRMT5 have been deposited in the NCBI sequence database, in which PRMT5-v1 and -v2 contain different 33 and 16 amino acids at the N-terminal sequences, respectively. Here we showed that murine PRMT5-v1 is stable, but PRMT5-v2 is constantly degraded through both the ubiquitin proteasome system (UPS) and the autophagic-lysosomal pathway (ALP) in an N-terminal sequence-dependent manner. Furthermore, inhibition of UPS and ALP elevated the stability of PRMT5-v2 that made it localized in the nucleus and the cytoplasm. In addition, PRMT5-v2 exhibited the enzyme activity to catalyze histone H2A and H4 methylation. Notably, we found that the heat shock protein (Hsp) 70 specially recognizes the N-terminal sequence of PRMT5-v2 and the carboxyl terminus of Hsp70-interacting protein (CHIP) is required for poly-ubiquitination and the degradation of PRMT5-v2. These results suggest that Hsp70/CHIP chaperone-mediated protein degradation system is crucial in the regulation of PRMT5-v2 turnover, which has the potential to balance the symmetrical arginine dimethylation in cells., (Copyright © 2019 Elsevier Inc. All rights reserved.)

The effect of oil on condensed film formation in the adsorbed film of hexadecyltrimethylammonium bromide (C16TAB) at the tetradecane (C14)/water (W) interface was examined by interfacial tension and X-ray reflectivity measurements. The interfacial tension vs temperature curves have break point due to the expanded?condensed phase transition of the adsorbed film. The partial molar entropy of C16TAB at the interface changes discontinuously, whereas the interfacial density changes almost continuously at the phase transition point. The electron density profile normal to the interface manifested that the condensed film is regarded as a two-dimensional (2D) solid rotator phase in which C16TAB and C14 molecules are densely packed with perpendicular orientation. Combining the interfacial tension and X-ray reflectivity data, the mixing ratio of C16TAB to C14 in the solid film was determined to be 2:3 and thus the film is enriched in oil molecules than surfactant ones. Furthermore, the partial molar entropy change of C14 associated with solid film formation was found to be largely negative and very close to that of surface freezing of liquid alkane, manifesting that C14 molecules are well ordered to form a 2D solid film by mixing with C16TAB molecules at the interface. The solid film formation of the present system is driven by effective vdW interactions between adsorbed C16TAB and intercalated C14 molecules. The morphology of the condensed domain observed during phase transition suggested that the contact energy is more predominant than the dipole repulsion at the domain boundary, which promotes coalescence of small domains into large ones during phase transition.