Plasma prolactin axis shift from placental to pituitary origin in late prepartum mice.

The placenta secretes a prolactin (PRL)-like hormone PRL3B1 (placental lactogen II), a luteotropic hormone essential for maintaining pregnancy until labor in mice. A report from 1984 examined the secretion pattern of PRL3B1 in prepartum mice. In the current study, we found contradictory findings in the secretion pattern that invalidate the previous report. By measuring maternal plasma PRL3B1 and PRL every 4 hrs from gestational day 17 (G17), we newly discovered that maternal plasma PRL3B1 levels decrease rapidly in prepartum C57BL/6 mice. Interestingly, the onset of this decline coincided with the PRL surge at G18, demonstrating a plasma prolactin axis shift from placental to pituitary origin. We also found that maternal plasma progesterone regression precedes the onset of the PRL shift. The level of Prl3b1 mRNA was determined by RT-qPCR in the placenta and remained stable until parturition, implying that PRL3B1 peptide production or secretion was suppressed. We hypothesized that production of the PRL family, the 25 paralogous PRL proteins exclusively expressed in mice placenta, would decrease alongside PRL3B1 during this period. To investigate this hypothesis and to seek proteomic changes, we performed a shotgun proteome analysis of the placental tissue using data-independent acquisition mass spectrometry (DIA-MS). Up to 5,891 proteins were identified, including 17 PRL family members. Relative quantitative analysis between embryonic day 17 (E17) and E18 placentas showed no significant difference in the expression of PRL3B1 and most PRL family members except PRL7C1. These results suggest that PRL3B1 secretion from the placenta is suppressed at G18 (E18).

17ß-Estradiol (E2) Activates Matrix Mineralization through Genomic/Nongenomic Pathways in MC3T3-E1 Cells.

Estrogen plays an important role in osteoporosis prevention. We herein report the possible novel signaling pathway of 17ß-estradiol (E2) in the matrix mineralization of MC3T3-E1, an osteoblast-like cell line. In the culture media-containing stripped serum, in which small lipophilic molecules such as steroid hormones including E2 were depleted, matrix mineralization was significantly reduced. However, the E2 treatment induced this. The E2 effects were suppressed by ICI182,780, the estrogen receptor (ER)α, and the ERß antagonist, as well as their mRNA knockdown, whereas Raloxifene, an inhibitor of estrogen-induced transcription, and G15, a G-protein-coupled estrogen receptor (GPER) 1 inhibitor, had little or no effect. Furthermore, the E2-activated matrix mineralization was disrupted by PMA, a PKC activator, and SB202190, a p38 MAPK inhibitor, but not by wortmannin, a PI3K inhibitor. Matrix mineralization was also induced by the culture media from the E2-stimulated cell culture. This effect was hindered by PMA or heat treatment, but not by SB202190. These results indicate that E2 activates the p38 MAPK pathway via ERs independently from actions in the nucleus. Such activation may cause the secretion of certain signaling molecule(s), which inhibit the PKC pathway. Our study provides a novel pathway of E2 action that could be a therapeutic target to activate matrix mineralization under various diseases, including osteoporosis.

Gas-Phase Structures of [Au21(SR)14]- and [Au17(SR)10]- with Eight Electrons: Can They Support an Icosahedral Au13 Core?

A prototypical thiolate (RS)-protected gold cluster [Au25(SR)18]- has high stability due to specific geometric and electronic structures: an icosahedral (Ih) Au13 core with a closed electronic shell containing eight electrons is completely protected by six units of Au2(SR)3. Nevertheless, collisional excitation of [Au25(SR)18]- in a vacuum induces the sequential release of Au4(SR)4 to form [Au21(SR)14]- and [Au17(SR)10]- both containing eight electrons. To answer a naive question of whether these fragments bear an Ih Au13(8e) core, the geometrical structures of [Au21(SC3H7)14]- and [Au17(SC3H7)10]- in the gas phase were examined by the combination of anion photoelectron spectroscopy and density functional theory (DFT) calculation of simplified models of [Au21(SCH3)14]- and [Au17(SCH3)10]-. We concluded that [Au21(SC3H7)14]- retains a slightly distorted Ih Au13(8e) core, while [Au17(SC3H7)10]- has an amorphous Au13 core composed of triangular Au3, tetrahedral Au4, and prolate Au7 units. DFT calculations on putative species [Au19(SCH3)12]- and [Au18(SCH3)11]- suggested that the Ih Au13(8e) core undergoes dramatic structural deformation due to mechanical stress from µ2 ligation of only one RS.

Lactational exposure to perfluorooctane sulfonate remains a potential risk in brain function of middle-aged male mice.

Perfluorooctane sulfonate (PFOS) exerts adverse effects on neuronal development in young population. Limited evidences have shown that early-life PFOS exposure holds a potential risk for developing age-related neurodegenerative diseases such as Alzheimer's disease later in life. The present study investigated the effects of lactational PFOS exposure on cognitive function using one-year-old mice. Dams were exposed to PFOS (1 mg/kg body weight) through lactation by gavage. Male offspring were used for the behavior test battery to assess cognitive function. Western blot analysis was conducted to measure the levels of proteins related to the pathogenesis of Alzheimer's disease. PFOS-exposed mice displayed a mild deficiency in social recognition. In the hippocampus, the expression of tau protein was significantly increased. These results underline a mild effect of developing PFOS exposure on cognitive function and neurodegeneration. The present study presents the long-lasting effects of PFOS in middle-aged period and warrants a potential aftermath.

Online Physiology Practice with Team-Based Learning During the COVID-19 Pandemic.

Background: The spread of the coronavirus disease (COVID-19) has significantly affected medical education. In particular, conducting practical training in a face-to-face format has become difficult. Purpose: To address this problem, online physiology practice combined with team-based learning (TBL) for deep learning of renal physiology was conducted among second-year medical students. Participants and Methods: The experiment was performed by a group of students, while other students watched online. After the experiment, all students were grouped using breakout rooms. Following a discussion of the data, a clinical case study related to the experiment was conducted using TBL. To examine the effect of online practice in a case study under TBL, the participants completed an anonymous, open-ended, web-based questionnaire after the program, enabling us to compare their expectations and satisfaction. The questionnaire consisted of questions examining students' opinions on the appropriateness of online practice, degree of understanding, ease of asking questions, time efficiency, and the usefulness of case studies using TBL. Results: There was no change in the number of students who participated in the online practice before and after class. After class, more students considered the level of understanding easier and displayed better on-time efficiency than with regular face-to-face training. However, these questions are difficult to answer. Conclusion: Online-based physiology practice combined with clinical case studies under TBL helped maintain students' expectations and satisfaction with the training.

Efficacy of Continuous Saline Irrigation Therapy for Descending Necrotizing Mediastinitis.

Objectives Descending necrotizing mediastinitis (DNM) is a poor prognosis disease. This study aims to examine the patient background and treatment of DNM and to identify more effective treatments for DNM. Methods The patient background and treatment of 11 patients who underwent surgery for DNM between November 2010 and June 2021 were studied. The patients were divided into six patients who underwent continuous saline irrigation (group I) and five patients who did not (group N). The differences in the drainage duration and length of hospital stay between the two groups were retrospectively investigated. Results Eleven patients were treated for DNM: six male and five female, with a median age of 61 years (35-79). Comorbidities included diabetes mellitus in three cases; one patient was administered steroids. The pathways of occurrence were anterior tracheal gap/vascular visceral gap/posterior visceral gap in group I (2/1/2) and group N (0/2/4). Progression was I/IIA/IIB according to Endo's classification in group I (1/1/4) and group N (3/1/1). The mean duration of irrigation was 9.0 ± 3.7 days, and the drainage duration in group I was 17.5 ± 8.2 days, which was significantly shorter than 31 ± 13.6 days in group N ( p < 0.048). The hospital stays in group I was 29.3 ± 8.4 days, which was significantly shorter than that in group N (68 ± 27.1 days; p < 0.015). Conclusions Irrigation therapy significantly shortened the drainage duration and hospital stay. Irrigation is a useful treatment for DNM.

Effects of Perfluorooctane Sulfonate on Cerebellar Cells via Inhibition of Type 2 Iodothyronine Deiodinase Activity.

Perfluorooctane sulfonate (PFOS) has been used in a wide variety of industrial and commercial products. The adverse effects of PFOS on the developing brain are becoming of a great concern. However, the molecular mechanisms of PFOS on brain development have not yet been clarified. We investigated the effect of early-life exposure to PFOS on brain development and the mechanism involved. We investigated the change in thyroid hormone (TH)-induced dendrite arborization of Purkinje cells in the primary culture of newborn rat cerebellum. We further examined the mechanism of PFOS on TH signaling by reporter gene assay, quantitative RT-PCR, and type 2 iodothyronine deiodinase (D2) assay. As low as 10-7 M PFOS suppressed thyroxine (T4)-, but not triiodothyronine (T3)-induced dendrite arborization of Purkinje cells. Reporter gene assay showed that PFOS did not affect TRα1- and TRß1-mediated transcription in CV-1 cells. RT-PCR showed that PFOS suppressed D2 mRNA expression in the absence of T4 in primary cerebellar cells. D2 activity was also suppressed by PFOS in C6 glioma-derived cells. These results indicate that early-life exposure of PFOS disrupts TH-mediated cerebellar development possibly through the disruption of D2 activity and/or mRNA expression, which may cause cerebellar dysfunction.

Spore-Forming Lactic Acid-Producing Bacterium Bacillus coagulans Synthesizes and Excretes Spermidine into the Extracellular Space.

The effect of spermidine in extending healthy longevity has attracted attention. As people age, their ability to synthesize putrescine, the precursor of spermidine, declines, and its supplementation from the diet or gut bacteria is needed. Many bacteria synthesize spermidine, but no strains have been reported to excrete de novo synthesized spermidine from the cells. We found that Bacillus coagulans strain YF1, isolated from "nanohana-duke", excreted de novo synthesized spermidine from the cells under anaerobic conditions. This strain synthesizes spermidine from arginine via agmatine, putrescine, and carboxyspermidine in sequential reactions, and the genes encoding the enzymes responsible for these reactions have been identified. B. coagulans is a gastric acid-resistant spore-forming lactic acid-producing bacterium, known for its beneficial effects as a probiotic. It can be used to produce lactic acid fermented foods containing spermidine. The newly discovered ability to excrete de novo synthesized spermidine is the decisive feature of this bacterium.

Mast cell-derived prostaglandin D2 limits the subcutaneous absorption of honey bee venom in mice.

Mast cells play pivotal roles in innate host defenses against venom. Activated mast cells release large amounts of prostaglandin D2 (PGD2). However, the role of PGD2 in such host defense remains unclear. We found that c-kit-dependent and c-kit-independent mast cell-specific hematopoietic prostaglandin D synthase (H-pgds) deficiency significantly exacerbated honey bee venom (BV)-induced hypothermia and increased mortality rates in mice. BV absorption via postcapillary venules in the skin was accelerated upon endothelial barrier disruption resulting in increased plasma venom concentrations. These results suggest that mast cell-derived PGD2 may enhance host defense against BV and save lives by inhibiting BV absorption into circulation.

Amide-Ligand-Promoted Silver-Catalyzed C-H Fluorination via Radical/Polar Crossover.

We describe an efficient method for benzylic C-H fluorination via sequential hydrogen-atom transfer (HAT) and oxidative radical-polar crossover utilizing the Ag(I)/Selectfluor system. Amide ligands, such as benzamide and sulfonamide, substantially facilitate the processes leading to a carbocation intermediate, which subsequently reacts with nucleophilic fluorinating reagent to form a C-F bond. This protocol is applicable to the fluorination of all 1°, 2°, and 3° C-H bonds as well as to late-stage C-H fluorination of bioactive molecules.

The effectiveness of adjuvant chemotherapy for Stage I pancreatic cancer based on the UICC 8th edition.

BACKGROUND: Adjuvant chemotherapy is recommended for patients with pancreatic cancer after curative resection. However, there is limited evidence regarding the efficacy and prognostic factors for adjuvant chemotherapy in patients with stage I pancreatic cancer. This study aimed to identify patients in whom chemotherapy was effective and to detect prognostic factors for stage I pancreatic cancer based on guidelines of the 8th edition of the Union for International Cancer Control (UICC). METHODS: Between 2009 and 2017, 108 patients diagnosed with stage I pancreatic cancer were enrolled in this study. They were distributed into invasion (n = 68) and non-invasion (n = 40) groups. The relationship between clinicopathological variables, including various prognostic factors, disease-free survival (DFS), and overall survival (OS), were investigated by univariate and multivariate analyses. RESULTS: Five-year survival in all patients with stage I pancreatic cancer was 38.9%. Adjuvant chemotherapy failed to improve DFS or OS in patients with stage I cancer (DFS, p = 0.26; OS, p = 0.30). In subgroup analysis, adjuvant chemotherapy significantly improved DFS (multivariate-adjusted hazard ratio (HR), 0.40; 95% confidence interval [CI], 0.21-0.78; p = 0.007) and OS (multivariate-adjusted HR, 0.32; 95% CI, 0.15-0.68; p = 0.003) in the invasion group than in non-invasion group. In contrast, in the non-invasion group, adjuvant chemotherapy failed to improve DFS and OS in univariate analysis (DFS, p = 0.992; OS, p = 0.808). CONCLUSION: For stage I pancreatic cancer, based on guidelines of the UICC 8th edition, adjuvant chemotherapy may benefit patients with extrapancreatic invasion.

[Cunninghamella bertholletiae-infective endocarditis complicated by tricuspid valve giant vegetation in a patient with aplastic anemia].

A 62-year-old female was presented to the hospital of the current study for pancytopenia and was diagnosed with severe aplastic anemia. She was treated with a combination therapy of antithymocyte globulin, cyclosporine A, and eltrombopag. The patient also presented with febrile neutropenia after commencement of the treatment and did not respond to the various antibiotics and antifungal agents. Echocardiography showed a giant vegetation attached to the tricuspid valve on Day 78 of the immunosuppressive therapy, and the tricuspid valve replacement was performed. The vegetation was formed by Cunninghamella bertholletiae, a mucor type, and was treated with high-dose liposomal amphotericin B (L-AMB), which was terminated after six weeks due to decreased renal function. In addition, mucormycosis was controlled by posttreatment with posaconazole (PSCZ). This is a rare case of mucormycosis that developed into a giant vegetation during the immunosuppressive therapy for aplastic anemia. It was believed to be a valuable case to consider in future mucormycosis treatment, including the success of the treatment by switching from L-AMB to PSCZ.

Histone Deacetylase 3 Inhibitor Alleviates Cerebellar Defects in Perinatal Hypothyroid Mice by Stimulating Histone Acetylation and Transcription at Thyroid Hormone-Responsive Gene Loci.

Perinatal hypothyroidism impairs cerebellar organogenesis and results in motor coordination defects. The thyroid hormone receptor binds to corepressor complexes containing histone deacetylase (HDAC) 3 in the absence of ligands and acts as a transcriptional repressor. Although histone acetylation status is strongly correlated with transcriptional regulation, its role in cerebellar development remains largely unknown. We aimed to study whether the cerebellar developmental defects induced by perinatal hypothyroidism can be rescued by treatment with a specific HDAC3 inhibitor, RGFP966. Motor coordination was analyzed using three behavioral tests. The cerebella were subjected to RT-qPCR and chromatin immunoprecipitation assays for acetylated histone H3. The treatment with RGFP966 partially reversed the cerebellar morphological defects in perinatal hypothyroid mice. These findings were associated with the alleviation of motor coordination defects in these mice. In addition, the RGFP966 administration increased the mRNA levels of cerebellar thyroid hormone-responsive genes. These increases were accompanied by augmented histone acetylation status at these gene loci. These findings indicate that HDAC3 plays an important role in the cerebellar developmental defects induced by perinatal hypothyroidism. The HDAC3 inhibitor might serve as a novel therapeutic agent for hypothyroidism-induced cerebellar defects by acetylating histone tails and stimulating transcription at thyroid hormone-responsive gene loci.

Electron Affinities of Ligated Icosahedral M13 Superatoms Revisited by Gas-Phase Anion Photoelectron Spectroscopy.

The electron binding energies of the ligand-protected gold/silver-based cluster anions, [Au25(SR)18]-, [XAg24(SR')18]2- (X = Ag+, Au+, Pd0, or Pt0), and [PdAu24(C≡CR″)18]2- having icosahedral M13 superatomic cores, were reexamined by gas-phase photoelectron spectroscopy (PES) on a significantly intensified mass-selected ion beam. Laser fluence-dependent PE spectra and pump-probe PES revealed that the previous PE spectra were contaminated by PE signals due to the two-photon electron detachment via long-lived photoexcited states. Although the adiabatic electron affinities (AEAs) of the corresponding oxidized forms were found to be 1-2 eV larger than those previously reported, the effects of doping and ligation were not qualitatively affected. (1) The AEA of the Ag13 superatom (∼4 eV) was not appreciably affected by doping a Au atom at the center but was reduced by ∼2 eV by doping Pd or Pt, and (2) the AEA of PdAu12 protected by Au2(C≡CR″)3 units was much larger than that of PdAg12 protected by Ag2(SR')3 units.

Atrogin-1 knockdown inhibits the autophagy-lysosome system in mammalian and avian myotubes.

Atrogin-1 plays an important role in ubiquitin-proteasome proteolysis in vertebrate skeletal muscles. Recently, atrogin-1 has been shown to be involved in the autophagy-lysosome system, another proteolytic system, in the murine and fish hearts and skeletal muscles. With the aim to elucidate the effect of atrogin-1 on the autophagy-lysosome system in mammalian and avian skeletal muscles, this study has examined the effects of atrogin-1 knockdown on autophagy-lysosome-related proteins in C2C12 and chicken embryonic myotubes. Using the levels of microtubule-associated protein light chain 3 (LC3)-II protein, it was confirmed that atrogin-1 knockdown blocked the autophagic flux in both the myotubes. In addition, atrogin-1 knockdown in C2C12 myotubes significantly decreased the level of autophagy-related gene (ATG)12-ATG5 conjugate, which is supposedly necessary for the fusion of autophagosomes and lysosomes. Atrogin-1 knockdown also resulted in downregulation of forkhead box O3, a transcription factor for ATG12. These data suggest that atrogin-1 is essential for the normal autophagy-lysosome system in the striated muscles of vertebrates.

Combination treatment by the cervical approach with mediastinal drainage and continuous saline irrigation for descending necrotizing mediastinitis type IIb: a three-case series.

Descending necrotizing mediastinitis (DNM) is a severe, life-threatening disease and requires prompt treatment. The primary treatment for DNM is cervical and mediastinal drainage in addition to antibiotic treatment. However, the most appropriate drainage approach and the effectiveness of additional treatment remain unclear. In this study, we performed cervical and mediastinal drainage for three patients with type IIB DNM using the cervical approach alone. Continuous saline irrigation was administered as additional treatment. There is little evidence for the use of saline irrigation for DNM. We propose that this combination treatment may be more effective and has the potential to improve patient prognosis. In our report, the average drainage duration was 13 days, and the average hospital stay was 30 days. Furthermore, both drainage duration and hospital stay were shorter than those in previously reported cases. Our case series provides valuable insight into the use of combination treatment to treat DNM.

Higher incidence of thrombocytopenia during obinutuzumab plus bendamustine therapy for untreated follicular lymphoma: a retrospective analysis by the Okayama Hematology Study Group.

Progression-free survival in patients with untreated follicular lymphoma (FL) has significantly improved with obinutuzumab plus chemotherapy followed by obinutuzumab maintenance, compared with rituximab plus chemotherapy. However, the survival outcome and adverse event profile in Japanese FL patients treated with obinutuzumab plus bendamustine (GB) therapy are not well investigated. Recently, we encountered some cases of grade 3-4 thrombocytopenia during GB therapy in patients with FL. This retrospective multicenter survey aimed to identify the characteristics of patients who received GB therapy and developed thrombocytopenia. A total of 54 patients with FL treated by GB therapy between August 2018 and December 2020 were investigated. After a median follow-up of 12.6 months, thrombocytopenia of any grade was observed in 48 (88.9%) patients, including 9 (16.7%) patients with grade 3-4 thrombocytopenia. Notably, although eight of nine patients with grade 3-4 thrombocytopenia were female, no patient characteristics (including gender) were significantly associated with grade 3-4 thrombocytopenia. Importantly, grade 3-4 thrombocytopenia frequently occurred in the first GB therapy cycle, which suggests that platelet count should be monitored carefully in patients who have just started GB therapy.