Chromic properties of dibenzo[j,l]fluoranthenes exhibiting different resonance contributions.

Chromic molecules change colour in response to external stimuli and are utilized in applications such as food additive detection, light dimmers, and biological probes. One of the common design strategies for organic chromic molecules is based on changes in the π-conjugation. We have hypothesized that non-alternant polyaromatic hydrocarbon (PAH) skeletons can be used as backbones for chromic molecules. Herein, we synthesized hydroxy-substituted dibenzo[j,l]fluoranthenes, a class of non-alternant PAHs, as novel chromic compounds and evaluated their halochromic properties by UV-vis and fluorescence spectroscopy. Under basic conditions, the 1-hydroxy derivatives show a hyperchromic shift, whereas the 9-hydroxy derivatives show a bathochromic shift and fluorescence although the skeleton of the chromophore is the same. Density functional theory calculations indicated that the different chromic properties are attributed to the differences in their resonance structures.

[Eculizumab led to beneficial clinical course in a patient with generalized myasthenia gravis who developed COVID 19-associated pneumonia].

A 74-year-old woman developed myasthenia gravis (MG) at the age of 32. She had a thymoma removed the following year, but her MG symptoms did not stabilize, and she required frequent hospitalization for fast-acting treatment (FT). She started eculizumab in March of two years ago and was followed up on an outpatient basis as her MG symptoms became milder. In February of this year, she was admitted to our hospital due to mild COVID-19-associated pneumonia with general malaise and fever. Her COVID-19-associated pneumonia was treated with intravenous sotrovimab, dexamethasone, and unfractionated heparin, and oral therapy for MG stayed the same. Eculizumab was not administered during hospitalization due to the combination of stable MG symptoms and the fact that the drug is not paid for by the Japanese insurance system. The patient's MG and COVID-19-associated pneumonia were not severe during hospitalization. However, the risk of myasthenic crisis and death is high when patients with MG develop COVID-19-associated pneumonia. Several reports suggest that the condition of patients with eculizumab-treated MG who develop COVID-19-associated pneumonia is not severe, and that that inhibition of the complement pathway with eculizumab is effective for COVID-19-associated pneumonia. Complement deposition in organ microvessels has been observed in patients with COVID-19, which suggests that complement overload may be a risk factor for COVID-19-associated pneumonia. Excessive complement activation may be involved in the pathogenesis; thus, eculizumab may function by inhibiting this pathway. In this case, eculizumab was discontinued while the patient had COVID-19-associated pneumonia, however, CH50, which is an indicator of complement, was suppressed during hospitalization due to the COVID-19-associated pneumonia. Therefore, eculizumab may have interfered with this course of events. This case demonstrates that eculizumab may be safe for and tolerated by patients with MG and COVID-19-associated pneumonia, but more cases need to be accumulated to support this conclusion.

Synthesis of mesoionic triazolones via a formal [3+2] cycloaddition between 4-phenyl-1,2,4-triazoline-3,5-dione and alkynes.

1,2,4-Triazoline-3,5-diones (TADs) are versatile reagents and have found widespread adoption in chemical science. Despite their remarkable reactivity toward a wide array of unsaturated hydrocarbons, the chemical reaction between TADs and alkynes has remained largely unexplored. Herein, we demonstrate that 1,1,1,3,3,3-hexafluoro-2-propanol facilitates the unusual [3+2] cycloaddition between 4-phenyl-1,2,4-triazoline-3,5-dione and alkynes, resulting in the formation of unprecedented mesoionic triazolones. Moreover, the structural properties of the resulting triazolone have been investigated by employing X-ray diffraction analysis and Density Functional Theory (DFT) calculations.

Histopathology of fused triplet placenta in rat.

A fused triplet placenta was observed in a Wistar Hannover rat on gestation day 15. Each placenta (referred to as PL-A, PL-B, and PL-C) of this fused placenta was attached to one fetus each, but their fetal weights were lower than that of the fetus attached to the only normal placenta (referred to as PL-N) in this dam. Histopathologically, thinning of the trophoblastic septa and dilatation of the maternal sinusoid in the labyrinth zone were observed in PL-B and PL-C, but not in PL-A or PL-N. The points of placental fusion were at the junctional zone derived from each side of the placenta without connective tissues, and the septum was composed of trophoblastic giant cells. Although PL-A had a solitary metrial gland, PL-B and PL-C shared one metrial gland with one spiral artery terminus branching towards each labyrinth zone.

Effects of cyclophosphamide on rat placental development.

We examined the morphological effects of cyclophosphamide (CPA) on placental development in pregnant rats. CPA was administered as a single dose to pregnant rats intraperitoneally at 0 mg/kg (the control group), 25 mg/kg on gestation day (GD) 12 (the CPA GD 12-treated group), and 25 mg/kg on GD 14 (the CPA GD 14-treated group). The fetal and placental weight decreased in the CPA-treated groups, complete fetal resorption from GD 17 onwards in the CPA GD 12-treated group, and external malformations in the CPA GD 14-treated group. Histopathologically, CPA induced apoptosis and/or cell proliferation inhibition in each part of the placenta. In the labyrinth zone, syncytiotrophoblasts were selectively reduced, resulting in a small placenta. In the basal zone, the number of spongiotrophoblasts was reduced, resulting in hypoplasia of glycogen cell islands. In addition, a small number of interstitial trophoblasts invaded the metrial gland from the basal zone on GD 15. The severity of these lesions was higher in the CPA GD 12-treated group than in the CPA GD 14-treated group. In the metrial gland, although the number of uterine natural killer cells was reduced, metrial gland development was not affected.

An Iridium/Aluminum Cooperative Strategy for the ß-C(sp3 )-H Borylation of Saturated Cyclic Amines.

Despite the widespread success in the functionalization of C(sp2 )-H bonds, the deliberate functionalization of C(sp3 )-H bonds in a highly site- and stereoselective manner remains a longstanding challenge. Herein, we report an iridium/aluminum cooperative catalytic system that enables the ß-selective C-H borylation of saturated cyclic amines and lactams. Furthermore, we have accomplished an enantioselective variant using binaphthol-derived chiral aluminum catalysts to forge C-B bonds with high levels of stereocontrol. Computational studies suggest that the formation of a Lewis pair with the substrates is crucial to lower the energy of the transition state for the rate-determining reductive elimination step.

Mechanisms of EGFR-TKI-Induced Apoptosis and Strategies Targeting Apoptosis in EGFR-Mutated Non-Small Cell Lung Cancer.

Homeostasis is achieved by balancing cell survival and death. In cancer cells, especially those carrying driver mutations, the processes and signals that promote apoptosis are inhibited, facilitating the survival and proliferation of these dysregulated cells. Apoptosis induction is an important mechanism underlying the therapeutic efficacy of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) for EGFR-mutated non-small cell lung cancer (NSCLC). However, the mechanisms by which EGFR-TKIs induce apoptosis have not been fully elucidated. A deeper understanding of the apoptotic pathways induced by EGFR-TKIs is essential for the developing novel strategies to overcome resistance to EGFR-TKIs or to enhance the initial efficacy through therapeutic synergistic combinations. Recently, therapeutic strategies targeting apoptosis have been developed for cancer. Here, we review the state of knowledge on EGFR-TKI-induced apoptotic pathways and discuss the therapeutic strategies for enhancing EGFR-TKI efficiency. We highlight the great progress achieved with third-generation EGFR-TKIs. In particular, combination therapies of EGFR-TKIs with anti-vascular endothelial growth factor/receptor inhibitors or chemotherapy have emerged as promising therapeutic strategies for patients with EGFR-mutated NSCLC. Nevertheless, further breakthroughs are needed to yield an appropriate standard care for patients with EGFR-mutated NSCLC, which requires gaining a deeper understanding of cancer cell dynamics in response to EGFR-TKIs.

1,1-Carboamination of Terminal Alkenes via a Reaction of Azo-Ene Adducts with Grignard Reagents.

Facile conversion of petrochemical feedstocks into valuable amine molecules remains a long-standing challenge in organic chemistry. Here, we report a modular and practical alkene 1,1-carboamination technology that relies on sequential azo-ene reactions and attendant base-promoted N-N bond cleavage of azo-ene adducts with Grignard reagents. By employing allylic urazoles as imine surrogates, this method bypasses the conventional retrosynthetic logic of imine synthesis, thereby allowing for rapid access to diverse α-branched allylic amine derivatives.

Remarkable Solvent Effect of Fluorinated Alcohols on Azo-Ene Reactions.

Despite the long history of the ene reaction between 1,2,4-triazoline-3,5-diones (TADs) and alkenes, its efficiency has always been hampered by competing side reactions, including the overreaction of ene adducts. In this communication, we demonstrate that this inherent limitation can be overcome by using 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) as the solvent. HFIP uniquely facilitates the desired azo-ene process between alkene with TADs presumably through hydrogen-bonding interactions. In addition to TADs, diethyl azodicarboxylate is a competent azo compound that undergoes a sluggish ene reaction with terminal alkenes.

Effects of testosterone on rat placental development.

We investigated the morphological effects of testosterone on placental development in a rat model of polycystic ovarian syndrome (PCOS). Testosterone propionate (TP), which was subcutaneously administered to pregnant rats with 5 mg/animal from gestation day (GD) 14 to GD 18, induced a maternal weight reduction without mortality or clinical signs from GD 19 onwards. A decrease in fetal and placental weight, an increase in intrauterine growth retardation (IUGR) rates, and histological changes in the placenta were observed on GD 21 but not on GD15 or 17. Histopathologically, on GD 21, the trophoblast septa thickened, and the maternal sinusoids were narrowed in the labyrinth zone, resulting in a small placenta. Additionally, the placental weight, thickness, and histological morphology in the labyrinth zone on GD 21 in the TP-treated group were nearly identical to those on GD 17 in the control and TP-treated groups. Therefore, it was assumed that the testosterone-induced small placenta was induced in association with the developmental inhibition of the fetal part of the placentas from GD 17 onwards.

Spontaneous seminoma in medaka (Oryzias latipes).

Although spontaneous development of seminoma is rare in medaka, we encountered spontaneous testicular tumors located within the abdominal cavity in two adult medakas. The growth patterns of the tumors were a combination of solid and cord arrangements in one of the two cases (Case I) and lobular in the other case (Case II). The tumor cells resembled the cells at different stages of spermatogenesis, and a small number of oocyte-like cells were also scattered within the tumor. The tumor with solid and cord patterns showed loss of normal testicular architecture, and the tumor cells had partly invaded the dorsal muscular tissue and metastasized to the liver, kidney, and eye. The tumor with a lobular pattern did not exhibit local invasion or metastasis. The tumors were diagnosed as seminomas based on their histopathological characteristics, and the tumor in Case I was observed to be more malignant than that in Case II.

The interaction of competition and terrain on pacing during cross-county running races in junior athletes.

The aim of this study was to assess pacing during cross-country racing in relation to race length, surface-terrain and racing dynamics. Athletes (n = 148) competed for school teams (U15, U17, U20) over 2.9, 4.2, 6.3 km, respectively. The course lap (2.067 m) was timed using UHF-RFID and divided into six sections based on surface-terrain and length (549, 619, 207, 338, 150, 156m). Overall pace differed between races (4.56 ± 0.30, 4.42 ± 0.38, 4.40 ± 0.31 m∙s-1, p=0.042) but not for the top-20 of each race (p=0.174). Moreover, within lap pacing followed a repeated reverse-"J"-parabolic strategy for all races. Race length (no. of laps) and category affected pacing with regards to finish position banding (1st-10th, 11th-20th) where effect size differences showed large to extremely large (1.21 - >4.00) difference between top-10 and other bands. Exceptions to this included the finish sprint where it was typically trivial-moderate (<0.2-1.2) and in key areas where social facilitation occurred. Athlete/coaches need to be aware of between and within lap variations in pace/effort, the effects of race dynamics, and spectator influences, while all athletes need to be educated as part of their training to run their own optimal strategy for best performance.

A case report of RccHanTM: WIST rat with multiple neoplastic and non-neoplastic proliferative lesions.

It is extremely rare to have multiple spontaneous proliferative lesions in young adult rats. Here, we report the occurrence of different proliferative lesions in multiple tissues of a 7-week-old female rat in a 1-week repeated toxicity study. Grossly, multiple white patches and nodules in the bilateral kidneys, femoral and subcutaneous masses, and a nodule in the liver were observed. Renal lesions were diagnosed as renal mesenchymal tumors. One of the femoral subcutaneous masses was diagnosed as an adenolipoma consisting of mammary epithelial cells and mature adipocytes. The other femoral and abdominal subcutaneous masses were diagnosed as lipomas consisting of mature adipocytes. The liver nodule was diagnosed as non-regenerative hepatocellular hyperplasia, which was characterized by the proliferation of slightly hypertrophic hepatocytes. In the cauda equina, the growth of enlarged Schwann cells around the axon was observed, and this lesion was diagnosed as a neuroma.

Comparison of acute inhalation toxicity of sulfuric acid by the inhalation and intratracheal instillation methods.

Recently, intratracheal instillation has been focused on as a simple, low-cost alternative to the inhalation method. In this study, intratracheal instillation of sulfuric acid, a typical acidic compound, was performed to compare the acute toxicity of acidic compounds that could cause damage to the respiratory system between intratracheal instillation and inhalation. Sulfuric acid was administered to male rats at doses of 0.7, 2, 7, 20, and 60 mg/kg by dividing the total dose into four doses. General condition and body weight were examined up to 14 days after administration, and macropathological and histopathological examinations were performed. The half-lethal dose was then estimated. All animals administered 20 and 60 mg/kg sulfuric acid and one animal administered 2 mg/kg sulfuric acid died within 4 h after administration. No abnormalities were observed in other animals. At 20 and 60 mg/kg, multiple red foci or diffuse red areas were macroscopically observed in the lungs. In these lesions, histopathologically, clefts between the mucosal epithelium and basement membrane and necrosis of the alveolar epithelium were observed. Deaths in these groups may have resulted from lung injury. No notable changes were observed in other animals. Therefore, the half-lethal dose of sulfuric acid by intratracheal instillation was estimated as 7-20 mg/kg. The acute toxicity by intratracheal instillation was evaluated with two-fold sensitivity since the exposure at the half-lethal sulfuric acid concentration in inhalation studies was calculated as 43.2 mg/kg.

Swim bladder tumor in the young adult scoliotic medaka (Oryzias latipes).

A swim bladder tumor was detected in one scoliotic medaka aged 22 weeks. The tumor was located in the dorsal abdominal cavity, with maximum dimension of 1,850 × 1,500 µm. No swim bladder lumen was identified, and the region where the swim bladder lumen would have been located, was replaced with adipose tissues. The tumor was a non-invasive, expansile, and encapsulated solid mass with a few cysts, and comprised a homogenous population of well-differentiated, densely packed, gas glandular epithelium-like cells. The tumor mass was connected to a rete mirabile that showed a hyperplastic capillary plexus; however, the tumor cells did not invade the rete mirabile, thereby revealing that the tumor was an adenoma originating from the gas glandular epithelium of the swim bladder. Since proliferative lesions in the swim bladder have been reported in some teleosts with skeletal deformations, including medaka, the occurrence of a spontaneous swim bladder tumor in teleosts is considered to be closely associated with various types of skeletal deformation, and spinal curvature in particular.

Swim bladder tumors in the wavy medaka (Oryzias latipes).

Swim bladder tumors were detected in three out of 28 wavy medakas aged about 2 years old, all of which displayed abnormal swimming patterns caused by their spinal curvature. The tumors were located in the dorsal abdominal cavity. The swim bladder lumen was not detected in the region where it was originally assumed to be located, and that region was replaced with adipose tissue. The tumors were non-invasive, expansile, and encapsulated solid masses composed of a homogenous population of well-differentiated, densely packed, gas glandular epithelium-like cells. The tumor masses were connected to the rete mirabile, but the tumor cells did not infiltrate into them. Histopathologically, these tumors were diagnosed as adenomas originating from the gas glandular epithelium of the swim bladder. Spontaneous swim bladder tumors are rare in medaka, with an incidence of 0.02%; however, in the present study of wavy medaka, the incidence was much higher (10.7%). The long-term physical effects on the gas gland caused by swim bladder deformation considered to be a secondary effect of the spinal curvature may be an important factor in the proliferation of the gas glandular epithelium in the wavy medaka, resulting in the higher incidence of swim bladder tumors.

Personality and motivational predictors of well-being and coping during COVID-19: A reversal theory analysis.

This study used reversal theory to examine motivational predictors of well-being and coping during the COVID-19 pandemic in 2020. 149 UK based respondents completed an online survey including measures of demographics, well-being, coping, motivational style, and dominance. Well-being was predicted by optimism (positively), autic and mastery (negatively) dominances, by alloic sympathy, optimism and paratelic motivation styles (positively), and, negatively by arousal seeking, arousability and pessimism. Coping was positively predicted by optimism and negativism dominances and by negativist, paratelic and telic motivations, and, negatively by arousability and pessimism. Using motivational dominances, indirect support was identified for the link between psychodiversity and well-being, but not coping. Findings suggest that well-being and, to a lesser degree, coping could be enhanced by encouraging individuals to experience a range of motivations, possibly focusing on those identified here as significant predictors. Future research needs to determine the context specificity of these findings and explore psychodiversity, well-being and coping using both metamotivational states and composite profiles incorporating the full range of motivational constructs.

Effect of sampling time on somatic and germ cell mutations induced by acrylamide in gpt delta mice.

BACKGROUND: Acrylamide (AA) is a rodent carcinogen and classified by the IARC into Group 2A (probable human carcinogen). AA has been reported to induce mutations in transgenic rodent gene mutation assays (TGR assays), the extent of which is presumed to depend on exposure length and the duration of expression after exposure. In particular, it is not clear in germ cells. To investigate mutagenicity with AA in somatic and germ cells at different sampling times, we conducted TGR assays using gpt delta transgenic mice. RESULTS: The male gpt delta mice at 8 weeks of age were treated with AA at 7.5, 15 and 30 mg/kg/day by gavage for 28 days. Peripheral blood was sampled on the last day of the treatment for micronucleus tests and tissues were sampled for gene mutation assays at day 31 and day 77, those being 3 and 49 days after the final treatment (28 + 3d and 28 + 49d), respectively. Another group of mice was treated with N-Ethyl-N-nitrosourea (ENU) at 50 mg/kg/day by intraperitoneal administration for 5 consecutive days and tissues were sampled at the day 31 and day 77 (5 + 26d and 5 + 72d). Frequencies of micronucleated erythrocytes in the peripheral blood significantly increased at AA doses of 15 and 30 mg/kg/day. Two- to three-fold increases in gpt mutation frequencies (MFs) compared to vehicle control were observed in the testes and lung treated with 30 mg/kg/day of AA at both sampling time. In the sperm, the gpt MFs and G:C to T:A transversions were significantly increased at 28 + 3d, but not at 28 + 49d. ENU induced gpt mutations in these tissues were examined at both 5 + 26d and 5 + 72d. A higher mutant frequency in the ENU-treated sperm was observed at 5 + 72d than that at 5 + 26d. CONCLUSIONS: The gpt MFs in the testes, sperm and lung of the AA-treated mice were determined and compared between different sampling times (3 days or 49 days following 28 day-treatment). These results suggest that spermatogonial stem cells are less sensitive to AA mutagenicity under the experimental condition. Prolonged expression time after exposure to AA to detect mutagenicity may be effective in somatic cells but not in germ cells.

Intradural Extramedullary Epithelioid Hemangioendothelioma of the Thoracic Spinal Cord: A Case Report.

Epithelioid hemangioendothelioma (EHE) is a rare vascular tumor, and develops infrequently in the central nervous system. To our knowledge, this is the first case of EHE of the spinal cord. An 85-year-old man presented with about 6-month progressive myelopathy. Magnetic resonance imaging (MRI) demonstrated an oval-shaped intradural extramedullary mass at T10 level with extensive intramedullary edema. A reddish tumor was removed via a total laminectomy of T9-T10. Histologically, the tumor cells with nuclear atypia and active mitoses were immunopositive for vascular tumor markers, and formed a lobular architecture associated with capillary-sized vessels lined with edematous endothelial cells. Although very rare, EHE should be considered in the differential diagnosis of a spinal intradural extramedullary tumor.

Dural Arteriovenous Fistula Formation as Eagle Jugular Syndrome: A Case Report and Literature Review.

BACKGROUND: An elongated styloid process can less frequently lead to symptomatic compression of the internal jugular vein (IJV). We present the first case of dural arteriovenous fistula (DAVF) in association with compressed IJV by an elongated styloid process. CASE DESCRIPTION: A 77-year-old woman presented with pulsating tinnitus. DAVF at the right hypoglossal canal was diagnosed, and she underwent transvenous embolization. The shunt flow was reduced, and the symptom disappeared after transvenous embolization. However, 2 years and 8 months later, retrograde sinus drainage from the residual shunt was asymptomatically found on magnetic resonance imaging, and angiography revealed progression of IJV stenosis caused by an elongated styloid process. Subsequently, she underwent a second transvenous embolization, and the arteriovenous shunt was almost completely obliterated. CONCLUSIONS: The present case suggests that venous hypertension by compressed IJV can induce the development of DAVF. It is helpful for the diagnosis and treatment of DAVF to keep in mind the possibility of IJV stenosis owing to an elongated styloid process.