Search

Article Summary Strength and limitations of this study • This systematic review and a meta-analysis will investigate the associations between psychosocial factors at work and menstrual abnormalities or fertility. • This review will include only the literature that has utilized a longitudinal design. • Various outcomes related to reproductive health in female workers will be examined (e.g., fertility, premenstrual symptoms, cycle disorders, menopausal symptoms).

Abstract We have previously shown that Kyoto University Substances (KUSs), valosin-containing protein (VCP) modulators, suppress cell death in retinal ganglion cells of glaucoma mouse models through alterations of various genes expressions. In this study, among the genes whose expression in retinal ganglion cells was altered by KUS treatment in the N-methyl-d-aspartic acid (NMDA) injury model, we focused on two genes, endothelin-1 (Edn1) and endothelin receptor type B (Ednrb), whose expression was up-regulated by NMDA and down-regulated by KUS treatment. First, we confirmed that the expression of Edn1 and Ednrb was upregulated by NMDA and suppressed by KUS administration in mice retinae. Next, to clarify the influence of KUSs on cell viability in relation to the endothelin signaling, cell viability was examined with or without antagonists or agonists of endothelin and with or without KUS in 661W retinal cells under stress conditions. KUS showed a significant protective effect under glucose-free conditions and tunicamycin-induced stress. This protective effect was partially attenuated in the presence of an endothelin antagonist or agonist under glucose-free conditions. These results suggest that KUSs protect cells partially by suppressing the upregulated endothelin signaling under stress conditions.

Abstract Chimeric TK-NOG mice with a humanized liver (normal Hu-liver) are a unique animal model for predicting drug metabolism in humans. However, residual mouse hepatocytes occasionally prevent the precise evaluation of human drug metabolism. Herein, we developed a novel humanized liver TK-NOG mouse with a conditional knockout of liver-specific cytochrome P450 oxidoreductase (POR cKO Hu-liver). Immunohistochemical analysis revealed only a few POR-expressing cells around the portal vein in POR cKO mouse livers. NADPH-cytochrome c reductase and cytochrome P450 (P450)-mediated drug oxidation activity in liver microsomes from POR cKO mice was negligible. After the intravenous administration of S-warfarin, high circulating and urinary levels of S-7-hydroxywarfarin (a major human metabolite) were observed in POR cKO Hu-liver mice. Notably, the circulating and urinary levels of S-4′-hydroxywarfarin (a major warfarin metabolite in mice) were much lower in POR cKO Hu-liver mice than in normal Hu-liver mice. POR cKO Hu-liver mice with minimal interference from mouse hepatic P450 oxidation activity are a valuable model for predicting human drug metabolism.

Abstract A GA-guided multidimensional virtual-system coupled molecular dynamics (GA-mD-VcMD) simulation was conducted to elucidate binding mechanisms of a middle-sized flexible molecule, bosentan, to a GPCR protein, human endothelin receptor type B (hETB). GA-mD-VcMD is a generalized ensemble method that produces a free-energy landscape of the ligand-receptor binding by searching large-scale motions accompanied with stable maintenance of the fragile cell-membrane structure. All molecular components (bosentan, hETB, membrane, and solvent) were represented with an all-atom model. Then sampling was conducted from conformations where bosentan was distant from the binding site in the hETB binding pocket. The deepest basin in the resultant free-energy landscape was assigned to native-like complex conformation. The following binding mechanism was inferred. First, bosentan fluctuating randomly in solution is captured using a tip region of the flexible N-terminal tail of hETB via nonspecific attractive interactions (fly casting). Bosentan then slides occasionally from the tip to the root of the N-terminal tail (ligand–sliding). During this sliding, bosentan passes the gate of the binding pocket from outside to inside of the pocket with an accompanying rapid reduction of the molecular orientational variety of bosentan (orientational selection). Last, in the pocket, ligand–receptor attractive native contacts are formed. Eventually, the native-like complex is completed. The bosentan-captured conformations by the tip-region and root-region of the N-terminal tail correspond to two basins in the free-energy landscape. The ligand-sliding corresponds to overcoming of a free-energy barrier between the basins.

Unidentified Mycobacterium species are sometimes detected in respiratory specimens. We identified a novel Tsukamurella species (Tsukamurella sp. TY48, RIMD 2001001, CIP 111916T), Tsukamurella toyonakaense, from a patient given a misdiagnosis of nontuberculous mycobacterial pulmonary disease caused by unidentified mycobacteria. Genomic identification of this Tsukamurella species helped clarify its clinical characteristics and epidemiology.

Abstract Label-free image analysis has several advantages with respect to the development of drug screening platforms. However, the evaluation of drug-responsive cells based exclusively on morphological information is challenging, especially in cases of morphologically heterogeneous cells or a small subset of drug-responsive cells. We developed a novel label-free cell sub-population analysis method called “in silico FOCUS (in silico analysis of featured-objects concentrated by anomaly discrimination from unit space)” to enable robust phenotypic screening of morphologically heterogeneous spinal and bulbar muscular atrophy (SBMA) model cells. This method with the anomaly discrimination concept can sensitively evaluate drug-responsive cells as morphologically anomalous cells through in silico cytometric analysis. As this algorithm requires only morphological information of control cells for training, no labeling or drug administration experiments are needed. The responses of SBMA model cells to dihydrotestosterone revealed that in silico FOCUS can identify the characteristics of a small sub-population with drug-responsive phenotypes to facilitate robust drug response profiling. The phenotype classification model confirmed with high accuracy the SBMA-rescuing effect of pioglitazone using morphological information alone. In silico FOCUS enables the evaluation of delicate quality transitions in cells that are difficult to profile experimentally, including primary cells or cells with no known markers.

Abstract Although neoadjuvant therapy (Nac) is recommended for high-risk resectable pancreatic cancer (R-PDAC), evidence regarding specific regimes is scarce. This report aimed to investigate the efficacy of S-1 Nac for R-PDAC. In a multicenter phase II trial, we investigated the efficacy of Nac S-1 (an oral fluoropyrimidine agent containing tegafur, gimeracil, and oteracil potassium) in R-PDAC patients. The protocol involved two cycles of preoperative S-1 chemotherapy, followed by surgery, and four cycles of postoperative S-1 chemotherapy. Two-year progression-free survival (PFS) rates were the primary endpoint. Overall survival (OS) rates and median survival time (MST) were secondary endpoints. Forty-nine patients were eligible, and 31 patients underwent resection following Nac, as per protocol (31/49; 63.3%). Per-protocol analysis included data from 31 patients, yielding the 2-year PFS rate of 58.1%, and 2-, 3-, and 5-year OS rates of 96.8%, 54.8%, and 44.0%, respectively. MST was 49.2 months. Intention-to-treat analysis involved 49 patients, yielding the 2-year PFS rate of 40.8%, and the 2-, 3-, and 5-year OS rates of 87.8%, 46.9%, and 33.9%, respectively. MST was 35.5 months. S-1 single regimen might be an option for Nac in R-PDAC; however, the high drop-out rate (36.7%) was a limitation of this study.

Abstract Background In faculty development, understanding each participant’s cultural context is important. However, there is scarce evidence on how to improve cultural understanding in faculty development. Cultural anthropology is a discipline that focuses on developing cultural self-awareness by understanding different cultures. Professionals from this field can be crucial to the goal of cultivating cultural awareness among medical educators. The aims of this study are to 1) develop and modify cultural anthropology sessions in faculty development and 2) evaluate the effectiveness of these sessions, including their long-term impacts. Methods The cultural anthropology sessions were organized as part of a longitudinal faculty development program—Foundation Course for Medical Education—at Kyoto University in Japan. The study included 47 medical educators participating in faculty development and three lecturers: two cultural anthropologists and a medical educator. We developed the cultural anthropology sessions and implemented them in the longitudinal faculty development program. In these sessions, cultural anthropologists used inquiry-guided reflection. An action research methodology was employed and repeated in four cycles from 2015 to 2018. Qualitative and quantitative data were collected during the action research cycles. The qualitative data were thematically analyzed. Results The cultural anthropologists’ inquiries fostered learning during the sessions, and three themes—cultural relativism, attention to context, and reframing—were synthesized. As a long-term impact of the sessions, the learners reported becoming more aware of the cultural contexts in their daily educational and clinical activities. Conclusions The cultural anthropology sessions in the faculty development program were shown to have enhanced the participants’ awareness of cultural contexts. The concept and format of these sessions may be used more widely in faculty development programs.

Abstract Radioactive gas of Unit 1 of the Fukushima Daiichi Nuclear Power Station was released from the exhaust stack shared by Units 1 and 2 through the venting line on March 12th, 2011. In the present study, radiochemical analysis of drain water sampled at the drain pit of the exhaust stack was conducted to study radionuclides released during venting of the Unit 1. Not only volatile 129I, 134Cs and 137Cs but also 60Co, 90Sr, 125Sb and Unit 1-originated stable Mo isotopes were detected. Although Unit 1-originated stable Mo isotopes were clearly detected, their amounts were quite low compared to Cs, suggesting that the formation of Cs2MoO4 was suppressed under the accident condition. Approximately 90% of iodine existed as I− and 10% as IO3 − in November 2020. Furthermore, larger amount of 129I than 137Cs was observed, suggesting major chemical form of 131I was molecular iodine rather than CsI at the accident time. The 134Cs/137Cs radioactivity ratio decay-corrected to March 11th, 2011 was 0.86, supported the results that Unit 1 originated radiocesium in environment has smaller 134Cs/137Cs radioactivity ratio than Unit 2 and 3 originated radiocesium.

Abstract The ability to remotely control a free-floating object through surface flows on a fluid medium can facilitate numerous applications. Current studies on this problem have been limited to uni-directional motion control due to the challenging nature of the control problem. Analytical modelling of the object dynamics is difficult due to the high-dimensionality and mixing of the surface flows while the control problem is hard due to the nonlinear slow dynamics of the fluid medium, underactuation, and chaotic regions. This study presents a methodology for manipulation of free-floating objects using large-scale physical experimentation and recent advances in deep reinforcement learning. We demonstrate our methodology through the open-loop control of a free-floating object in water using a robotic arm. Our learned control policy is relatively quick to obtain, highly data efficient, and easily scalable to a higher-dimensional parameter space and/or experimental scenarios. Our results show the potential of data-driven approaches for solving and analyzing highly complex nonlinear control problems.

Abstract In this research, five sizes (100 × 100, 75 × 75, 50 × 50, 25 × 25, 10 × 10 µm2) of InGaN red micro-light emitting diode (LED) dies are produced using laser-based direct writing and maskless technology. It is observed that with increasing injection current, the smaller the size of the micro-LED, the more obvious the blue shift of the emission wavelength. When the injection current is increased from 0.1 to 1 mA, the emission wavelength of the 10 × 10 μm2 micro-LED is shifted from 617.15 to 576.87 nm. The obvious blue shift is attributed to the stress release and high current density injection. Moreover, the output power density is very similar for smaller chip micro-LEDs at the same injection current density. This behavior is different from AlGaInP micro-LEDs. The sidewall defect is more easily repaired by passivation, which is similar to the behavior of blue micro-LEDs. The results indicate that the red InGaN epilayer structure provides an opportunity to realize the full color LEDs fabricated by GaN-based LEDs.

Abstract A comprehensive analysis of clinical information in patients with chronic low back pain (CLBP) was performed to clarify the clinical characteristics of geriatric LBP from the perspective of body composition, spinal alignment, and blood findings related to senescence. We enrolled 203 patients with an average age of 79.0 years (77 men and 126 women), with non-specific CLBP as a single-center prospective cohort study, the patients were compared with age- and sex-matched controls without CLBP using a propensity score-matching. We performed laboratory analysis, radiographic evaluations for global spinal parameter and lumbar degeneration, and body composition analysis using whole-body dual-energy X-ray absorptiometry. We observed a higher red blood cell distribution width (RDW) (p

Abstract The use of sutureless securement devices during catheterization might reduce the risk of catheter-related bloodstream infection (CRBSI) by suppressing catheter-exit infection and catheter dislodgement. However, the effectiveness of these devices in reducing CRBSI risk when securing hemodialysis catheters has not been explored. This single-center retrospective observational study examined 211 non-tunneled hemodialysis catheters (NTHCs) from 110 hemodialysis inpatients, of which 121 were secured using conventional skin sutures (Suture group) and 90 with GRIP-LOK (GRIP-LOK group). The stabilized inverse probability of treatment (SIPT)-weighting method was used to generate a new population (SIPT-weighted model) without group differences for each of the 12 predictors of CRBSI development (i.e., age, sex, dialysis history, concomitant acute kidney injury or diabetes, concurrent use of immunosuppressant drugs or aspirin, NTHC insertion site, methicillin-resistant Staphylococcus aureus, carriage, bacteremia event within 3 months before catheterization, hemoglobin level, and serum albumin titer). The effect of GRIP-LOK compared with sutures on CRBSI in the SIPT-weighted model was evaluated using univariate SIPT-weighted Cox proportional regression analysis, which showed a significant CRBSI suppression effect of GRIP-LOK compared with sutures (hazard ratio: 0.17 [95% CI 0.04–0.78], p = 0.023). GRIP-LOK affords a lower risk of CRBSI due to indwelling NTHCs than conventional securement using sutures.

Abstract Background Effective social and behavioral sciences teaching in medical education requires integration with clinical experience, as well as collaboration between social and behavioral sciences experts and clinical faculty. However, teaching models for achieving this integration have not been adequately established, nor has the collaboration process been described. This study aims to propose a collaborative clinical case conference model to integrate social and behavioral sciences and clinical experience. Additionally, we describe how social and behavioral science experts and clinical faculty collaborate during the development of the teaching method. Methods A team of medical teachers and medical anthropologists planned for the development of a case conference based on action research methodology. The initial model was planned for a 3-h session, similar to a Clinicopathological Conference (CPC) structure. We evaluated each session based on field notes taken by medical anthropologists and post-session questionnaires that surveyed participants’ reactions and points of improvement. Based on the evaluation, a reflective meeting was held to discuss revisions for the next trial. We incorporated the development process into undergraduate medical curricula in clinical years and in a postgraduate and continuous professional development session for residents and certified family physicians in Japan. We repeated the plan-act-observe-reflection process more than 15 times between 2015 and 2018. Results The development of the collaborative clinical case conference model is summarized in three phases: Quasi-CPC, Interactive, and Co-constructive with unique structures and underlying paradigms. The model successfully contributed to promoting the participants’ recognition of the clinical significance of social and behavioral sciences. The case preparation entailed unique and significant learning of how social and behavioral sciences inform clinical practice. The model development process promoted the mutual understanding between clinical faculty and anthropologists, which might function as faculty development for teachers involved in social and behavioral sciences teaching in medical education. Conclusions The application of appropriate conference models and awareness of their underlying paradigms according to educational situations promotes the integration of social and behavioral sciences with clinical medicine education. Faculty development regarding social and behavioral sciences in medical education should focus on collaboration with scholars with different paradigmatic orientations.

Abstract Almost all robotic systems in use have hard shells, which is limiting in many ways their full potential of physical interaction with humans or their surrounding environment. Robots with soft-shell covers offer an alternative morphology which is more pleasant in both appearance and for haptic human interaction. A persisting challenge in such soft-shell robotic covers is the simultaneous realization of softness and heat-conducting properties. Such heat-conducting properties are important for enabling temperature-control of robotic covers in the range that is comfortable for human touch. The presented soft-shell robotic cover is composed of a linked two-layer structure: (1) The inner layer, with built-in pipes for water circulation, is soft and acts as a thermal-isolation layer between the cover and the robot structure, whereas (2) the outer layer, which can be patterned with a given desired texture and color, allows heat transfer from the circulating water of the inner part to the surface. Moreover, we demonstrate the ability to integrate our prototype cover with a humanoid robot equipped with capacitance sensors. This fabrication technique enables robotic cover possibilities, including tunable color, surface texture, and size, that are likely to have applications in a variety of robotic systems.

Abstract Safe and noninvasive methods for breast cancer screening with improved accuracy are urgently needed. Volatile organic compounds (VOCs) in biological samples such as breath and blood have been investigated as noninvasive novel markers of cancer. We investigated volatile organic compounds in urine to assess their potential for the detection of breast cancer. One hundred and ten women with biopsy-proven breast cancer and 177 healthy volunteers were enrolled. The subjects were divided into two groups: a training set and an external validation set. Urine samples were collected and analyzed by gas chromatography and mass spectrometry. A predictive model was constructed by multivariate analysis, and the sensitivity and specificity of the model were confirmed using both a training set and an external set with reproducibility tests. The training set included 60 breast cancer patients (age 34–88 years, mean 60.3) and 60 healthy controls (age 34–81 years, mean 58.7). The external validation set included 50 breast cancer patients (age 35–85 years, mean 58.8) and 117 healthy controls (age 18–84 years, mean 51.2). One hundred and ninety-one compounds detected in at least 80% of the samples from the training set were used for further analysis. The predictive model that best-detected breast cancer at various clinical stages was constructed using a combination of two of the compounds, 2-propanol and 2-butanone. The sensitivity and specificity in the training set were 93.3% and 83.3%, respectively. Triplicated reproducibility tests were performed by randomly choosing ten samples from each group, and the results showed a matching rate of 100% for the breast cancer patient group and 90% for the healthy control group. Our prediction model using two VOCs is a useful complement to the current diagnostic tools. Further studies inclusive of benign tumors and non-breast malignancies are warranted.

Abstract Measurement of cardiac troponin I (cTnI) should be feasible for point-of-care testing (POCT) to diagnose acute myocardial infarction (AMI). Lateral flow immunoassays (LFIAs) have been long implemented in POCT and clinical settings. However, sensitivity, matrix effect and quantitation in lateral flow immunoassays (LFIAs) have been major limiting factors. The performance of LFIAs can be improved with upconverting nanoparticle (UCNP) reporters. Here we report a new methodological approach to quantify cTnI using UCNP-LFIA technology with minimized plasma interference. The performance of the developed UCNP-LFIA was evaluated using clinical plasma samples (n = 262). The developed UCNP-LFIA was compared to two reference assays, the Siemens Advia Centaur assay and an in-house well-based cTnI assay. By introducing an anti-IgM scrub line and dried EDTA in the LFIA strip, the detection of cTnI in plasma samples was fully recovered. The UCNP-LFIA was able to quantify cTnI concentrations in patient samples within the range of 30–10,000 ng/L. The LoB and LoD of the UCNP-LFIA were 8.4 ng/L and 30 ng/L. The method comparisons showed good correlation (Spearman’s correlation 0.956 and 0.949, p

Abstract Previous studies have largely failed to clarify the relationship between p16INK4A status and cervical adenocarcinoma prognosis. The current study aimed to examine the clinical and pathological significance of p16INK4A expression in several cervical adenocarcinoma subtypes. Eighty-two samples collected from patients with cervical adenocarcinoma were formalin fixed and paraffin embedded. Next, p16INK4A levels were analyzed with immunohistochemistry. Additionally, the relationship between p16INK4A expression and clinicopathological factors as well as prognosis was evaluated. The expression of p16INK4A was mostly detected in all usual cervical adenocarcinoma subtypes. In the gastric type, only a few cases were positive for p16INK4A expression. Results of the Kaplan–Meier analysis indicated that the positive p16INK4A expression in tumor cells was significantly associated with favorable progression-free survival and overall survival in patients with cervical adenocarcinoma (p = 0.018 and p = 0.047, respectively, log-rank test). Our findings suggest that the status of p16INK4A expression may influence prognosis. Thus, p16INK4A expression could be used as a biomarker for improving the prognosis of patients with cervical adenocarcinoma.

BackgroundWhether abstinence from smoking among cancer patients reduces cancer pain is still unclear. Opioids can act as a surrogate index for evaluating the incidence of severe cancer pain in countries where opioid abuse is infrequent. This study aimed to investigate whether changed smoking behavior after cancer diagnosis influences the incidence of severe cancer pain as determined by strong opioid use.MethodsUsing a large Japanese insurance claims database (n = 4,797,329), we selected 794,702 insured employees whose annual health checkup data could be confirmed ≥6 times between January 2009 and December 2018. We selected 591 study subjects from 3,256 employees who were diagnosed with cancer pain and had health checkup data at the year of cancer pain diagnosis.ResultsA significantly greater proportion of patients who continued smoking after cancer diagnosis ("current smoker", n = 133) received strong opioids (36.8%) compared with patients who had never smoked or had stopped before cancer diagnosis ("non-smoker", n = 383, 20.6%; pConclusionOur study demonstrated that patients who quit smoking after cancer diagnosis have a lower risk of severe cancer pain. This information adds clinical incentives for improving quality of life among those who smoked at the time of cancer diagnosis.

Abstract The effects of the inclination angle of the incisor on the speech production of the fricative consonant /s/ was investigated using an implicit compressible flow solver. The hierarchical structure grid was applied to reduce the grid generation time for the vocal tract geometry. The airflow and sound during the pronunciation of /s/ were simulated using the adaptively switched time stepping scheme, and the angle of the incisor in the vocal tract was changed from normal position up to 30°. The results showed that increasing the incisor angle affected the flow configuration and moved the location of the high turbulence intensity region thereby decreased the amplitudes of the sound in the frequency range from 8 to 12 kHz. Performing the Fourier transform on the velocity fluctuation, we found that the position of large magnitudes of the velocity at 10 kHz shifted toward the lip outlet when the incisor angle was increased. In addition, separate acoustic simulations showed that the shift in the potential sound source position decreased the far-field sound amplitudes above 8 kHz. These results provide the underlying insights necessary to design dental prostheses for the production of sibilant fricatives.

Abstract The (pro)renin receptor [(P)RR)] is a multifunctional protein that is cleaved to generate the soluble (P)RR [s(P)RR], reflecting the status of the tissue renin-angiotensin system and/or activity of the (P)RR. The serum s(P)RR level is associated with arteriosclerosis, independent of other risk factors, in patients undergoing hemodialysis (HD). This study was conducted to investigate whether the s(P)RR level was associated with new-onset cardiovascular events or malignant diseases and poor prognosis in patients undergoing HD. Overall, 258 patients [70 (61–76) years, 146 males] undergoing maintenance HD were prospectively followed up for 60 months. We investigated the relationships between s(P)RR levels and new-onset cardiovascular events/ malignant diseases and mortality during the follow-up period using Cox proportional hazard analyses. The cumulative incidence of new-onset cardiovascular events (P = 0.009) and deaths (P

Abstract We investigated the unfolding property and rotational stability of a new toric intraocular lens (IOL); TECNIS toric II (toric-II, ZCW, Johnson & Johnson) that is an improved version of TECNIS toric IOL (toric-I, ZCV). Both IOLs are based on an identical platform, except for the frosted haptics with toric-II IOL. The study consisted of two parts; experimental study and clinical, retrospective, case series. Experimental study indicated that the overall time from IOL ejection to unfolding to 11 mm was significantly shorter with toricII than toric-I IOLs (p = 0.032), due to the earlier separation of the haptics from the optic with toric-II IOL. Clinical study included 131 eyes of 99 patients who had undergone phacoemulsification and toric IOL implantation. At 3 months postoperatively, toric-II IOL showed significantly better rotational stability than toric-I IOL, including smaller residual manifest astigmatism (p = 0.018), less amount of axis misalignment from the intended axis (p = 0.04), lower incidence of misalignment > 10º (p = 0.0044), and less degree of prediction errors (p = 0.043). Postoperative uncorrected distance visual acuity tended to be better in the toric-II than in the toric-I groups, with marginal statistical difference (p = 0.057). TECNIS toric II IOL with the frosted haptics showed significantly better rotational stability than its predecessor, probably due to quicker unfolding and greater friction with the capsular bag.

Abstract Euglena gracilis is widely utilized as food or supplement to promote human and animal health, as it contains rich nutrients. In this study, we administered spray-dried powder of E. gracilis and paramylon, β-glucan stored in E. gracilis cells, to A4gnt knockout (KO) mice. A4gnt KO mice are a mutant mouse model that spontaneously develops gastric cancer through hyperplasia-dysplasia-adenocarcinoma sequence in the antrum of the stomach, and we observed the effects of E. gracilis and paramylon on the early involvements of A4gnt KO mice. Male and female 10-week-old A4gnt KO mice and their age-matched wildtype C57BL/6J mice were orally administered with 50 mg of E. gracilis or paramylon suspended in saline or saline as a control. After 3-week administration, animals were euthanatized and the stomach was examined histopathologically and immunohistochemically. Gene expression patterns of the stomach, which have been reported to be altered with A4gnt KO, and IgA concentration in small intestine were also analyzed with real-time PCR and ELISA, respectively. Administration of Euglena significantly reduced the number of stimulated CD3-positive T-lymphocytes in pyloric mucosa of A4gnt KO mice and tend to reduce polymorphonuclear leukocytes infiltration. Euglena administration further downregulated the expression of Il11 and Cxcl1 of A4gnt KO mice. Euglena administration also affected IgA concentration in small intestinal contents of A4gnt KO mice. Paramylon administration reduced the number of CD3-positive lymphocytes in pyloric mucosa of A4gnt KO mice, and downregulated the expressions of Il11 and Ccl2 of A4gnt KO mice. Although we found no significant effects on gross and microscopic signs of gastric dysplasia and cell proliferation, the present study suggests that the administration of Euglena and paramylon may ameliorate the early involvements of A4gnt mice through the effects on inflammatory reactions in the gastric mucosa. The cancer-preventing effects should be studied with long-term experiments until actual gastric cancer formation.

Abstract Actual sleep status and the association between sleep habits/disorders and emotional/behavioral problems among children in the development stage have not been fully clarified. A questionnaire survey was conducted on the sleep habits/disorders (Brief Child Sleep Questionnaire; BCSQ) and emotional/behavioral problems (Strengths and Difficulties Questionnaire; SDQ) of 87,548 children enrolled in ordinary classes in nine grade levels from the first grade of elementary school to the third grade of junior high school from December 2009 to April 2010. As school grade increased, children’s bedtimes were delayed and sleep duration was reduced by 2.0 h over the nine grade levels. Based on the BCSQ, 18.3% of children were judged to have some type of sleep disorder, and about 30% to 40% of children had sleep symptoms at bedtime, during sleep, and at wake time. Multiple regression analysis showed that emotional and behavioral problems were associated with presence of any sleep symptom, longer sleep latency, and longer awake time after sleep onset, whereas total sleep time was not. Sleep symptoms at wake time were most strongly associated with emotional and behavioral problems. Status of sleep habits/disorders should be considered when interpreting emotional/behavioral problems in school-age children.

ABSTRACT BACKGROUND: Syphilis is a major public health issue worldwide. In people living with human immunodeficiency virus (PLHIV), there are higher incidences of both syphilis and neurosyphilis. The criteria for referring PLHIV with syphilis for lumbar puncture is controversial, and the diagnosis of neurosyphilis is challenging. OBJECTIVE: To describe the knowledge, attitudes, and practices of infectious disease specialists and residents in the context of care for asymptomatic HIV-syphilis coinfection using close-ended questions and case vignettes. DESIGN AND SETTING: Cross-sectional study conducted in three public health institutions in São Paulo (SP), Brazil. METHODS: In this cross-sectional study, we invited infectious disease specialists and residents at three academic healthcare institutions to answer a self-completion questionnaire available online or in paper form. RESULTS: Of 98 participants, only 23.5% provided answers that were in line with the current Brazilian recommendation. Most participants believed that the criteria for lumbar puncture should be extended for people living with HIV with low CD4+ cell counts (52.0%); in addition, participants also believed that late latent syphilis (29.6%) and Venereal Disease Research Laboratory (VDRL) titers ≥ 1:32 (22.4%) should be conditions for lumbar puncture in PLHIV with no neurologic symptoms. CONCLUSION: This study highlights heterogeneities in the clinical management of HIV-syphilis coinfection. Most infectious disease specialists still consider syphilis stage, VDRL titers and CD4+ cell counts as important parameters when deciding which patients need lumbar puncture for investigating neurosyphilis.

Abstract This 5-year ecological study assessed the association between meteorological factors and rhegmatogenous retinal detachment (RRD) frequency in 571 eyes of 543 cases of primary RRD at the Jikei University Kashiwa Hospital, Japan. We examined the monthly and seasonal distributions of RRD frequency using one-way analysis of variance. We then evaluated the relationship between monthly RRD frequency and 36 meteorological parameters using Poisson regression analysis. Furthermore, we developed multivariate regression models to predict the frequency of RRD based on specific meteorological parameters. There were no significant differences in the monthly and seasonal distributions (monthly, P = 0.99; seasonal, P = 0.77). The following eight parameters were associated with a lower RRD frequency: average sea level barometric pressure and average daily variation of average temperature, maximum temperature, maximum wind speed, maximum instantaneous wind speed, humidity, average sea level barometric pressure, and minimum sea level barometric pressure (P

Abstract The unfolded protein response (UPR) controls protein homeostasis through transcriptional and translational regulation. However, dysregulated UPR signaling has been associated with the pathogenesis of many human diseases. Therefore, the compounds modulating UPR may provide molecular insights for these pathologies in the context of UPR. Here, we screened small-molecule compounds that suppress UPR, using a library of Myanmar wild plant extracts. The screening system to track X-box binding protein 1 (XBP1) splicing activity revealed that the ethanol extract of the Periploca calophylla stem inhibited the inositol-requiring enzyme 1 (IRE1)-XBP1 pathway. We isolated and identified periplocin as a potent inhibitor of the IRE1-XBP1 axis. Periplocin also suppressed other UPR axes, protein kinase R-like endoplasmic reticulum kinase (PERK), and activating transcription factor 6 (ATF6). Examining the structure–activity relationship of periplocin revealed that cardiac glycosides also inhibited UPR. Moreover, periplocin suppressed the constitutive activation of XBP1 and exerted cytotoxic effects in the human multiple myeloma cell lines, AMO1 and RPMI8226. These results reveal a novel suppressive effect of periplocin or the other cardiac glycosides on UPR regulation, suggesting that these compounds will contribute to our understanding of the pathological or physiological importance of UPR.

Abstract Current pain classifications use 1.0-kg palpation of the masseter muscle to distinguish between “pain patients” and “healthy controls” but a thorough understanding of the normal physiological responses to various somatosensory stimuli is lacking. The aim of this study was to investigate somatosensory function of the skin over the masseter muscle in healthy participants that were divided into a masseter pain prone group (MPP) (n = 22) and non-MPP group (n = 22), according to the response to a 1.0-kg palpation. Quantitative sensory testing (QST) was performed at the skin above the right masseter muscle (homotopic). In an additional experiment, 13 individuals each from MPP and non-MPP received application of 60% topical lidocaine tape to the skin over the masseter muscle for 30 min. Immediately after, mechanical pain sensitivity (MPS), dynamic mechanical allodynia, and pressure pain threshold were tested. Homotopic MPS was significantly higher and PPTs significantly lower in MPP than in N-MPP (P 0.05). After lidocaine application, no significant differences in homotopic MPS were observed between groups. The presence or absence of acute provoked pain in masseter muscle is exclusively associated with differences in homotopic MPS which is decreased following topical anesthesia.

Abstract Shear wave elastography (SWE) is a technique to non-invasively and quantitatively evaluate tissue stiffness. We aimed to investigate whether we can differentiate pancreatic cancer (PC) from normal pancreatic parenchyma (NPP) by SWE using transabdominal ultrasound. We investigated a total of 106 patients (84 with NPP and 22 with PC) whose pancreatic elastic modulus was measured by two-dimensional SWE (2D-SWE). Intra-rater reliability in this study was examined, and three measurements were sufficiently reliable. There were no differences between the two groups in factors that could affect SWE measurements. The median value of the elastic modulus was 5.70 kPa in the PC patients and 5.66 kPa in the NPP group, which was not significantly different (P = 0.785). On the contrary, the range was 8.64 kPa and 4.72 kPa, with a significantly greater range in the PC patients (P = 0.001). In conclusion, the median elastic modulus measured by 2D-SWE was not significantly different between PC and NPP, and evaluating the obtained elastic modulus itself is not useful in differentiation. However, the variability was significantly greater in PC than in NPP. Evaluating the range of elasticities will provide additional information in SWE, which may be useful in the diagnosis of PC.

Abstract Heart failure is a heterogeneous disease with multiple risk factors and various pathophysiological types, which makes it difficult to understand the molecular mechanisms involved. In this study, we proposed a trans-omics approach for predicting molecular pathological mechanisms of heart failure and identifying marker genes to distinguish heterogeneous phenotypes, by integrating multiple omics data including single-cell RNA-seq, ChIP-seq, and gene interactome data. We detected a significant increase in the expression level of natriuretic peptide A (Nppa), after stress loading with transverse aortic constriction (TAC), and showed that cardiomyocytes with high Nppa expression displayed specific gene expression patterns. Multiple NADH ubiquinone complex family, which are associated with the mitochondrial electron transport system, were negatively correlated with Nppa expression during the early stages of cardiac hypertrophy. Large-scale ChIP-seq data analysis showed that Nkx2-5 and Gtf2b were transcription factors characteristic of high-Nppa-expressing cardiomyocytes. Nppa expression levels may, therefore, represent a useful diagnostic marker for heart failure.

Abstract Dysregulation of alternative splicing is a feature of cancer, both in aetiology and progression. It occurs because of mutations in splice sites or sites that regulate splicing, or because of the altered expression and activity of splice factors and of splice factor kinases that regulate splice factor activity. Recently the CDC2-like kinases (CLKs) have attracted attention due to their increasing involvement in cancer. We measured the effect of the CLK inhibitor, the benzothiazole TG003, on two prostate cancer cell lines. TG003 reduced cell proliferation and increased apoptosis in PC3 and DU145 cells. Conversely, the overexpression of CLK1 in PC3 cells prevented TG003 from reducing cell proliferation. TG003 slowed scratch closure and reduced cell migration and invasion in a transwell assay. TG003 decisively inhibited the growth of a PC3 cell line xenograft in nude mice. We performed a transcriptomic analysis of cells treated with TG003. We report widespread and consistent changes in alternative splicing of cancer-associated genes including CENPE, ESCO2, CKAP2, MELK, ASPH and CD164 in both HeLa and PC3 cells. Together these findings suggest that targeting CLKs will provide novel therapeutic opportunities in prostate cancer.

Abstract Currently, large-scale cohort studies for metabolome analysis have been launched globally. However, only a few studies have evaluated the reliability of urinary metabolome analysis. This study aimed to establish the reliability of urinary metabolomic profiling in cohort studies. In the Tsuruoka Metabolomics Cohort Study, 123 charged metabolites were identified and routinely quantified using capillary electrophoresis-mass spectrometry (CE-MS). We evaluated approximately 750 quality control (QC) samples and 6,720 participants’ spot urine samples. We calculated inter- and intra-batch coefficients of variation in the QC and participant samples and technical intraclass correlation coefficients (ICC). A correlation of metabolite concentrations between spot and 24-h urine samples obtained from 32 sub-cohort participants was also evaluated. The coefficient of variation (CV) was less than 20% for 87 metabolites (70.7%) and 20–30% for 19 metabolites (15.4%) in the QC samples. There was less than 20% inter-batch CV for 106 metabolites (86.2%). Most urinary metabolites would have reliability for measurement. The 96 metabolites (78.0%) was above 0.75 for the estimated ICC, and those might be useful for epidemiological analysis. Among individuals, the Pearson correlation coefficient of 24-h and spot urine was more than 70% for 59 of the 99 metabolites. These results show that the profiling of charged metabolites using CE-MS in morning spot human urine is suitable for epidemiological metabolomics studies.

Abstract Ovarian clear cell carcinoma (OCCC) is a subtype of epithelial ovarian cancer (EOC) that is associated with elevated interleukin-6 (IL-6) expression, resistance to chemotherapy, and increased mortality. Although bevacizumab (Bev) is a widely used anti-angiogenic agent for EOC, the efficacy of Bev and the role of IL-6 in modulating angiogenesis in OCCC are unknown. We performed tube formation assays using human umbilical vein endothelial cells (HUVEC) cultured in OCCC cell-conditioned medium and using cells directly co-cultured with OCCC cells. We observed that IL-6 inhibition significantly mitigated the ability of Bev to impede tube formation in both cases. Furthermore, IL-6 blockade disrupted the anti-angiogenic efficacy of Bev and its concomitant anti-tumor activity. In addition, IL-6 inhibition resulted in a significant increase in angiopoietin-1 (Ang1) secretion and decreased vascular endothelial growth factor (VEGF) expression. Clinical specimens also exhibited this reciprocal relationship between IL-6 and Ang1 expression. Finally, depletion of Ang1 abrogated the effects of IL-6 inhibition on Bev activity, demonstrating that IL-6 supports the anti-angiogenic activity of Bev by suppressing Ang1 expression and promoting dependence on VEGF for angiogenesis. Altogether, our data suggest that OCCC tumors with high IL-6 levels are candidates for Bev therapy.

Abstract Central venous port (CVP) is a widely used totally implantable venous access device. Recognition of risks associated with CVP-related complications is clinically important for safe, reliable, and long-term intravenous access. We therefore investigated factors associated with CVP infection and evulsion, including the device type. A total of 308 consecutive patients with initial CVP implantation between January 2011 and December 2017 were retrospectively reviewed, and the association of clinical features with CVP-related complications were analyzed. Intraoperative and postoperative complications occurred in 11 (3.6%) and 39 (12.7%) patients, respectively. The overall rate of CVP availability at six months was 91.4%. Malignancy and 2-Methacryloyloxyethyl phosphorylcholine (MPC) polymer-coated catheter use were negatively associated with the incidence of CVP infections. Accordingly, malignancy and MPC polymer-coated catheter use were independent predictors for lower CVP evulsion rate (odds ratio, 0.23 and 0.18, respectively). Furthermore, both factors were significantly associated with longer CVP availability (hazard ratio, 0.24 and 0.27, respectively). This retrospective study identified factors associated with CVP-related complications and long-term CVP availability. Notably, MPC polymer-coated catheter use was significantly associated with a lower rate of CVP infection and longer CVP availability, suggesting the preventive effect of MPC coating on CVP infection.

Abstract A novel acidic morpholine-derivative containing glyceride (M-glyceride) was isolated from the cells of two strains of the thraustochytrid, Aurantiochytrium. The glyceride accounted for approximately 0.1 -0.4% of the lyophilized cells. The glyceride consisted of peaks I (85%) and II (15%). The structures of the intact and acetylated glycerides were elucidated by liquid chromatography-quadrupole time-of-flight chromatograph mass spectrometer (LC–Q/TOF) and NMR spectroscopy. The hydrate type of M-glyceride was detected as a minor component by LC–MS/MS. By 2D-NMR experiments, peaks I of the intact M-glyceride were elucidated as 1,2-didocosapentaenoyl-glyceryl-2′-oxy-3′-oxomorpholino propionic acid, and peak II was estimated 1,2-palmitoyldocosapentaenoyl- and/or 1,2-docosapentaenoylpalmitoyl-glyceryl-2′-oxy-3′-oxomorpholino propionic acid. The double bond position of docosapentaenoic acid was of the ω − 6 type (C22 = 5.ω − 6). The M-glyceride content varied by the cell cycle. The content was 0.4% of lyophilized cells at the mid logarithmic phase, and decreased to 0.1% at the mid stationary phase. When cells were grown in 1.0 µM M-glyceride-containing growth media, cell growth was stimulated to 110% of the control. With 0.1 µM acetyl M-glyceride, stimulation of 113% of the control was observed. Finding morpholine derivatives in biological components is rare, and 2-hydroxy-3-oxomorpholino propionic acid (auranic acid) is a novel morpholine derivative.

Abstract The recent realisations of hydrogen doped LnFeAsO (Ln = Nd and Sm) superconducting epitaxial thin films call for further investigation of their structural and electrical transport properties. Here, we report on the microstructure of a NdFeAs(O,H) epitaxial thin film and its temperature, field, and orientation dependencies of the resistivity and the critical current density J c. The superconducting transition temperature T c is comparable to NdFeAs(O,F). Transmission electron microscopy investigation supported that hydrogen is homogenously substituted for oxygen. A high self-field J c of over 10 MA/cm2 was recorded at 5 K, which is likely to be caused by a short London penetration depth. The anisotropic Ginzburg–Landau scaling for the angle dependence of J c yielded temperature-dependent scaling parameters γJ that decreased from 1.6 at 30 K to 1.3 at 5 K. This is opposite to the behaviour of NdFeAs(O,F). Additionally, γJ of NdFeAs(O,H) is smaller than that of NdFeAs(O,F). Our results indicate that heavily electron doping by means of hydrogen substitution for oxygen in LnFeAsO is highly beneficial for achieving high J c with low anisotropy without compromising T c, which is favourable for high-field magnet applications.

Abstract To share the experiences of organizing the epilepsy surgery program in Indonesia. This study was divided into two periods based on the presurgical evaluation method: the first period (1999–2004), when interictal electroencephalogram (EEG) and magnetic resonance imaging (MRI) were used mainly for confirmation, and the second period (2005–2017), when long-term non-invasive and invasive video-EEG was involved in the evaluation. Long-term outcomes were recorded up to December 2019 based on the Engel scale. All 65 surgical recruits in the first period possessed temporal lobe epilepsy (TLE), while 524 patients were treated in the second period. In the first period, 76.8%, 16.1%, and 7.1% of patients with TLE achieved Classes I, II, and III, respectively, and in the second period, 89.4%, 5.5%, and 4.9% achieved Classes I, II, and III, respectively, alongside Class IV, at 0.3%. The overall median survival times for patients with focal impaired awareness seizures (FIAS), focal to bilateral tonic–clonic seizures and generalized tonic–clonic seizures were 9, 11 and 11 years (95% CI: 8.170–9.830, 10.170–11.830, and 7.265–14.735), respectively, with p = 0.04. The utilization of stringent and selective criteria to reserve surgeries is important for a successful epilepsy program with limited resources.

Abstract The effects of intravenous sedation with midazolam on the cerebral function of elderly patients with severe dementia are unclear. This study aimed to evaluate its effects on parameters such as brainwaves and cerebral blood flow (CBF) and compare them between elderly individuals with dementia and without cognitive impairment. Ten patients with severe dementia and 10 without cognitive impairment were registered. The bispectral index (BIS) and normalized tissue hemoglobin index (nTHI), which reflects CBF using near-infrared spectroscopy, were measured. Midazolam was administered until a Modified Observer’s Assessment of Alertness/Sedation score of 2 was reached. The chi-squared, Mann–Whitney U, Wilcoxon signed-rank, and Friedman tests and multiple regression analysis were used for comparisons. Whereas a similar decline in BIS values was observed in both groups after midazolam administration (P

Abstract Dental biofilm present on the tooth surface is associated with oral diseases, such as dental caries and periodontal disease. Because bacterial numbers rapidly increase in saliva during sleep, oral care before sleeping is recommended for the prevention of chronic oral diseases. However, temporal circadian changes in the quantity and quality of dental biofilms are poorly understood. This study aimed to investigate the impacts of sleeping on dental biofilm amounts and compositions by using an in situ model. The use of this in situ model enabled us to investigate dental biofilm formed in the oral cavity and to perform a quantitative analysis. Subjects began wearing oral splints in the morning or before sleeping, and biofilm samples were collected at 8, 16, and 24 h after the subjects began wearing oral splints; these samples were then used in various experiments. No significant changes in the numbers of biofilm-forming bacteria were caused by sleep. However, the relative abundances of genera related to periodontitis (i.e., Fusobacterium and Prevotella) increased after awakening. In conclusion, the numbers of biofilm-forming bacteria were not affected by sleep, and the abundances of obligate anaerobes increased after sleep. This research may aid in defining efficacious preventive oral care.

Abstract Gravity is a critical environmental factor affecting the morphology and function of plants on Earth. Gravistimulation triggered by changes in the gravity vector induces an increase in the cytoplasmic free calcium ion concentration ([Ca2+]c) as an early process of gravity sensing; however, its role and molecular mechanism are still unclear. When seedlings of Arabidopsis thaliana expressing apoaequorin were rotated from the upright position to the upside-down position, a biphasic [Ca2+]c-increase composed of a fast-transient [Ca2+]c-increase followed by a slow [Ca2+]c-increase was observed. We find here a novel type [Ca2+]c-increase, designated a very slow [Ca2+]c-increase that is observed when the seedlings were rotated back to the upright position from the upside-down position. The very slow [Ca2+]c-increase was strongly attenuated in knockout seedlings defective in MCA1, a mechanosensitive Ca2+-permeable channel (MSCC), and was partially restored in MCA1-complemented seedlings. The mechanosensitive ion channel blocker, gadolinium, blocked the very slow [Ca2+]c-increase. This is the first report suggesting the possible involvement of MCA1 in an early event related to gravity sensing in Arabidopsis seedlings.

Abstract Autoimmune pancreatitis (AIP) is recognized as the pancreatic manifestation of a systemic IgG4-related disease that can involve various organs, including the kidney. However, renal lesions tend to be overlooked when AIP is diagnosed, and the clinical characteristics and long-term prognosis of AIP with renal lesions are unclear. We retrospectively reviewed 153 patients with AIP diagnosed at our hospital with a median follow-up period of 41 months (interquartile range, 10–86) and classified them into two groups: the KD group (n = 17), with characteristic renal imaging features, and the non-KD group (n = 136). Serum IgG4 levels were significantly higher in the KD group (663 vs. 304.5 mg/dl, P = 0.014). No differences were observed between the two groups in terms of steroid treatment [14/17 (82.4%) vs. 112/136 (82.4%), P = 1] or in the number of patients who exhibited exacerbation of renal function during treatment [1/17 (5.9%) vs. 8/136 (5.9%), P = 1]. However, the cumulative relapse rate was significantly higher in the KD group [61% vs. 21.9% (3 years), P

Study Design Case series. Purpose To evaluate the radiographic and clinical results of C1 laminoplasty without fusion. Overview of Literature C1 laminectomy has been the standard procedure for decompression at the C1 level. However, there have been some reports of trouble cases after C1 laminectomy. C1 laminoplasty might be superior to C1 laminectomy with regard to maintaining the original C1 anatomical shape, preventing compression from the posterior soft tissue, and ensuring an adequate bone-grafting site around the C1 posterior part if additional salvage fusion surgery is necessary afterward. Methods Seven patients with spinal cord compression without obvious segmental instability at the C1/2 level treated by C1 laminoplasty were included. The indication of C1 laminoplasty was same as that of C1 laminectomy. C1 laminoplasty was performed in the same way as subaxial double-door laminoplasty. The imaging findings were evaluated using X-ray, computed tomography, and magnetic resonance imaging. The clinical results were evaluated using the Japanese Orthopaedic Association (JOA) Cervical Myelopathy Evaluation Questionnaire (JOACMEQ) and JOA score. Peri- and postoperative complications were also investigated. Results No patient showed increased C1/2 segmental instability after the surgery. The mean pre- and postoperative JOA scores were 8.6 and 11.7, respectively. The mean recovery rate was 40.2%. The effective rate in the JOACMEQ was 50% for the cervical spine function, 33% for the upper extremity function, 50% for the lower extremity function, 17% for the bladder function, and 17% for the quality of life. No major complication that seemed to be unique to C1 laminoplasty was observed over a period of about 4 years follow-up. Conclusions C1 laminoplasty for patients without obvious segmental instability might be a viable alternative procedure to C1 laminectomy.

Abstract Objective It is unknown whether low serum levels of salivary and pancreatic amylases are associated with the high combustion of carbohydrates or lipids for energy. Elevated blood ketones and a low respiratory quotient (RQ) can reflect the preferential combustion of lipids relative to carbohydrates. Therefore, using the data from our previous study, we investigated if low levels of serum amylases were associated with a high serum ketone level and low RQ in 60 healthy non-obese young women aged 20–39 years old. Results Serum ketones [3-hydroxybutyric acid (3-HBA) and acetoacetic acid (AA)] were inversely correlated with RQs, but not body mass index (BMI) or glycated haemoglobin (HbA1c) levels. Logistic regression analysis showed that high levels of serum ketones (3-HBA ≥ 24 μmol/L and AA ≥ 17 μmol/L) and a low RQ (

Abstract Our understanding regarding the influence of intensive agricultural practices, including cover cropping and tillage, on communities of arbuscular mycorrhizal fungi (AMF) is lacking. This would prove to be an obstacle in the improvement of current maize (Zea mays L.) production. Therefore, using amplicon sequencing, we aimed to clarify how AMF communities and their diversity in maize roots vary under different cover cropping systems and two types of tillage (rotary and no tillage). Two kinds of cover crops (hairy vetch and brown mustard) and fallow treatments were established with rotary or no tillage in rotation with maize crops. Tillage and no tillage yielded a set of relatively common AMF operational taxonomic units (OTUs) in the maize crops, representing 78.3% of the total OTUs. The percentage of maize crop OTUs that were specific to only tillage and no tillage were 9.6% and 12.0%, respectively. We found that tillage system significantly altered the AMF communities in maize roots. However, the AMF communities of maize crops among cover cropping treatments did not vary considerably. Our findings indicate that compared with cover cropping, tillage may shape AMF communities in maize more strongly.

Abstract Group A Streptococcus (GAS) secretes deoxyribonucleases and evades neutrophil extracellular killing by degrading neutrophil extracellular traps (NETs). However, limited information is currently available on the interaction between GAS and NETs in the pathogenicity of GAS pharyngitis. In this study, we modified a mouse model of GAS pharyngitis and revealed an essential role for DNase in this model. After intranasal infection, the nasal mucosa was markedly damaged near the nasal cavity, at which GAS was surrounded by neutrophils. When neutrophils were depleted from mice, GAS colonization and damage to the nasal mucosa were significantly decreased. Furthermore, mice infected with deoxyribonuclease knockout GAS mutants (∆spd, ∆endA, and ∆sdaD2) survived significantly better than those infected with wild-type GAS. In addition, the supernatants of digested NETs enhanced GAS-induced cell death in vitro. Collectively, these results indicate that NET degradation products may contribute to the establishment of pharyngeal infection caused by GAS.

With the renewed interest in low-carbohydrate diets (LCDs) in the sports field, a few animal studies have investigated their potential. However, most rodent studies have used an LCD containing low protein, which does not recapitulate a human LCD, and the muscle-specific adaptation in response to an LCD remains unclear. Therefore, we investigated the effects of two types of LCDs, both containing the same proportion of protein as a regular diet (isonitrogenous LCD; INLCD), on body composition, exercise performance, and metabolic fuel selection at the genetic level in the skeletal muscles of exercise-trained mice. Three groups of mice (n = 8 in each group), one fed a regular AIN-93G diet served as the control, and the others fed either of the two INLCDs containing 20% protein and 10% carbohydrate (INLCD-10%) or 20% protein and 1% carbohydrate (INLCD-1%) had a regular exercise load (5 times/week) for 12 weeks. Body weight and muscle mass did not decrease in either of the INLCD-fed groups, and the muscle glycogen levels and endurance capacity did not differ among the three groups. Only in the mice fed INLCD-1% did the plasma ketone concentration significantly increase, and gene expression related to glucose utilization significantly declined in the muscles. Both INLCD-1% and INLCD-10% consumption increased gene expression related to lipid utilization. These results suggest that, although INLCD treatment did not affect endurance capacity, it helped maintain muscle mass and glycogen content regardless of the glucose intake restrictions in trained mice. Moreover, an INLCD containing a low carbohydrate content might present an advantage by increasing lipid oxidation without ketosis and suppressing muscle glucose utilization.

d-allulose is a rare sugar that has been reported to possess anti-hyperglycemic effects. In the present study, we hypothesized that d-allulose is effective in attenuating the progression of diabetic nephropathy in the Otsuka Long-Evans Tokushima Fatty (OLETF) rat model of type 2 diabetes mellitus. Drinking water with or without 3% d-allulose was administered to OLETF rats for 13 weeks. Long-Evans Tokushima Otsuka rats that received drinking water without d-allulose were used as non-diabetic control rats. d-allulose significantly attenuated the increase in blood glucose levels and progressive mesangial expansion in the glomerulus, which is regarded as a characteristic of diabetic nephropathy, in OLETF rats. d-allulose also attenuated the significant increases in renal IL-6 and tumor necrosis factor-α mRNA levels in OLETF rats, which is a proinflammatory parameter. Additionally, we showed that d-allulose suppresses mesangial matrix expansion, but its correlation with suppressing renal inflammation in OLETF rats should be investigated further. Collectively, our results support the hypothesis that d-allulose can prevent diabetic nephropathy in rats.

Claudin-1 (CL-1) is responsible for the paracellular barrier function of glomerular parietal epithelial cells (PEC) in kidneys, but the role of CL-1 in proximal tubules remains to be elucidated. In this study, to evaluate CL-1 as a potential therapeutic drug target for chronic kidney disease, we investigated change of CL-1 expression in the proximal tubules of diseased kidney and elucidated the factors that induced this change. We established Alport mice as a kidney disease model and investigated the expression of CL-1 in diseased kidney using quantitative PCR and immunohistochemistry (IHC). Compared to wild type mice, Alport mice showed significant increases in plasma creatinine, urea nitrogen and urinary albumin excretion. CL-1 mRNA was increased significantly in the kidney cortex and CL-1 was localized on the adjacent cell surfaces of PECs and proximal tubular epithelial cells. The infiltration of inflammatory cells around proximal tubules and a significant increase in TNF-α mRNA were observed in diseased kidneys. To reveal factors that induce CL-1, we analyzed the induction of CL-1 by albumin or tumor necrosis factor (TNF)-α in human proximal tubular cells (RPTEC/TERT1) using quantitative PCR and Western blotting. TNF-α increased CL-1 expression dose-dependently, though albumin did not affect CL-1 expression in RPTEC/TERT1. In addition, both CL-1 and TNF-α expression were significantly increased in UUO mice, which are commonly used as a model of tubulointerstitial inflammation without albuminuria. These results indicate that CL-1 expression is induced by inflammation, not by albuminuria in diseased proximal tubules. Moreover, we examined the localization of CL-1 in the kidney of IgA nephropathy patients by IHC and found CL-1 expression was also elevated in the proximal tubular cells. Taken together, CL-1 expression is increased in the proximal tubular epithelial cells of diseased kidney. Inflammatory cells around the tubular epithelium may produce TNF-α which in turn induces CL-1 expression.

The degradation of SARS-CoV-2 specific ribonucleic acid (RNA) was investigated by a numerical modeling approach based on nucleic acid amplification test (NAAT) results utilizing the SmartAmp technique. The precision of the measurement was verified by the relative standard deviation (RSD) of repeated measurements at each calibration point. The precision and detection limits were found to be 6% RSD (seven repeated measurements) and 94 copies/tube, respectively, at the lowest calibration point. RNA degradation curves obtained from NAAT data on four different temperatures were in good agreement with the first-order reaction model. By referring to rate constants derived from the results, the Arrhenius model was applied to predict RNA degradation behavior. If the initial RNA concentration was high enough, such as in samples taken from infected bodies, the NAAT results were expected to be positive during testing. On the other hand, if initial RNA concentrations were relatively low, such as RNA in residual viruses on environmental surfaces, special attention should be paid to avoid false-negative results. The results obtained in this study provide a practical guide for RNA sample management in the NAAT of non-human samples.