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Abstract Porcine organs and human induced pluripotent stem cell (iPSC)-derived organoids as alternative organs for human transplantation have garnered attention, but both face technical challenges. Interspecies chimeric organ production using human iPSCs shows promise in overcoming these challenges. Our group successfully generated chimeric renal organoids using human iPSC-derived nephron progenitor cells (NPCs) and fetal mouse kidneys. However, the current technology is limited to rodents. Therefore, this study focused on producing human-pig chimeric renal organoids, as pigs are the most promising species for xenotransplantation. Modification of existing culture systems enables continuous renal development in both species, resulting in the successful creation of human-pig chimeric renal organoids. Moreover, this method can be applied to generate humanized xenogeneic kidneys for future clinical applications. This study provides evidence that optimizing culture conditions enables the early-stage kidney development beyond species barriers, thus laying the foundation for accelerating research on humanized xenogeneic kidney fabrication for clinical purposes.

Medium-chain triglyceride (MCT) oil and fat are considered potential candidates to satisfy the nutritional demands of the increasing number of older patients requiring both dysphagia rehabilitation and nutritional therapy. Crystalline oil and fat (COF) is a unique material comprising MCT. In this study, we aimed to investigate the ways in which COF produces a cold sensation in the mouth, and assessed its facilitatory effect on swallowing initiation through two experiments. The first experiment, involving 27 participants, revealed that COF significantly reduced the onset latency of cold sensation and prolonged its duration compared to that of the control. The second experiment, involving 20 participants, revealed that the number of swallows significantly increased after swallowing COF. Our study confirms that the application of COF to the tongue induces a cold sensation and facilitates voluntary swallowing initiation. Therefore, COF holds great potential for aiding dysphagic patients.

Chronic obstructive pulmonary disease (COPD) was previously known as chronic bronchitis and emphysema. It has various main symptoms, such as dyspnea, chronic cough, and sputum, and is often accompanied by dysphagia. Although many published clinical reports have described COPD-related dysphagia, the physiological mechanisms underlying swallowing changes due to COPD remain unclear. Therefore, we analyzed how COPD affects the swallowing reflex using COPD model rats. We performed an electrophysiological study of respiration and swallowing using COPD model induced by intratracheal administration of porcine pancreatic elastase and lipopolysaccharide in Sprague-Dawley male rats. To identify the respiration and swallowing responses, electromyographic activity was recorded from the diaphragm, digastric (Dig), and thyrohyoid (TH) muscles. We confirmed COPD using micro-computed tomography analysis and hematoxylin and eosin staining of the lungs. The duty cycle was defined as the ratio of the inspiration duration to the total respiratory duration. In COPD model rats, the duty cycle was significantly higher than that in control rats. The frequency of the swallowing reflex evoked by electrical stimulation of the superior laryngeal nerve during the inspiration phase was higher in COPD model rats than in control rats. Furthermore, long-term COPD altered Dig and TH muscle activity without pathological muscle change. Our results suggest that COPD increases the frequency of swallowing initiation during the inspiration phase. Furthermore, long-term COPD affects swallowing-related muscle activity without pathological muscle changes. These physiological changes may increase the risk of developing dysphagia. Further studies are necessary to clarify the mechanisms contributing to the functional changes in respiration and swallowing in COPD.

Purpose: To investigate the disease activity in real-world patients with rheumatoid arthritis (RA) who switched from originator etanercept (ETN) to biosimilar YLB113. Methods: Forty one RA patients who switched from ETN to YLB113 were divided into 2 groups based on the Disease Activity Score based on the 28-joint count (DAS28) 12 months after switching (R group: DAS28 < 2.6, N group: DAS28 ≥ 2.6), and the baseline characteristics were statistically examined. A receiver operating characteristics (ROC) analysis was performed to estimate the cut-off value of DAS28 at baseline to achieve remission 12 months after switching. Results: There was no significant difference in the DAS28 at baseline and 12 months after switching ( p = .83). Sixteen out of the 20 patients in remission at baseline achieved remission after switching. A univariate analysis revealed the rheumatoid factor ( p = .04) and DAS28 ( p < .001) at baseline were significantly lower in the R group than in the N group. Furthermore, logistic regression analysis revealed DAS28 was an independent factor ( p = .004) for achieving remission 12 months after switching. An ROC curve analysis showed the optimal cut-off value for DAS28 at baseline to achieve remission at 12 months after switching was 2.5. Conclusions: RA patients who achieved remission using originator ETN, were able to maintain remission even if they switched to YLB113.

Breynia spp. are a key source of sulfur-containing spiroketal glycosides with potential anti-inflammatory activity. In this study, three new sulfur-containing spiroketals – breynin J (1), epibreynin J (2), and probreynogenin (3) – along with four known compounds – probreynin I (4), phyllaemblic acid (5), breynin B (6), and epibreynin B (7) – were isolated from the roots of Breynia disticha. The structures of compounds 1–7 were elucidated by extensive 1D and 2D NMR spectroscopic analyses, including 1D total correlation spectroscopy (TOCSY), HSQC, HMBC, double quantum-filtered (DQF)-COSY, heteronuclear two-bond correlation (H2BC), and HSQC-TOCSY experiments, as well as high-resolution electrospray ionization HRESIMS analysis, and quantum chemical electronic CD calculations. Furthermore, the absolute configurations of sugar residues were determined by derivatization of the hydrolysates with ʟ-cysteine methyl ester and o-tolyl isothiocyanate followed by HPLC analysis. The anti-inflammatory effects of the isolated compounds were evaluated based on the mRNA levels of proinflammatory cytokines in lipopolysaccharide (LPS)-stimulated RAW 264.7 murine macrophage cells. Compounds 1, 2, 6, and 7 inhibited the increase in interleukin (IL)-1β and IL-6 mRNA levels stimulated by LPS. Moreover, the most potent compound 7 was found to significantly inhibit the production of IL-1β and IL-6 proteins, as revealed by the analysis of culture supernatants.

Abstract Cryptococcus-associated immune reconstitution inflammatory syndrome (C-IRIS) is a condition frequently occurring in immunocompromised patients receiving antiretroviral therapy. C-IRIS patients exhibit many critical symptoms, including pulmonary distress, potentially complicating the progression and recovery from this condition. Here, utilizing our previously established mouse model of unmasking C-IRIS (CnH99 preinfection and adoptive transfer of CD4+ T cells), we demonstrated that pulmonary dysfunction associated with the C-IRIS condition in mice could be attributed to the infiltration of CD4+ T cells into the brain via the CCL8-CCR5 axis, which triggers the nucleus tractus solitarius (NTS) neuronal damage and neuronal disconnection via upregulated ephrin B3 and semaphorin 6B in CD4+ T cells. Our findings provide unique insight into the mechanism behind pulmonary dysfunction in C-IRIS and nominate potential therapeutic targets for treatment.

In a companion paper, we present the first spatially resolved polarized image of Sagittarius A* on event horizon scales, captured using the Event Horizon Telescope, a global very long baseline interferometric array operating at a wavelength of 1.3 mm. Here we interpret this image using both simple analytic models and numerical general relativistic magnetohydrodynamic (GRMHD) simulations. The large spatially resolved linear polarization fraction (24%–28%, peaking at ∼40%) is the most stringent constraint on parameter space, disfavoring models that are too Faraday depolarized. Similar to our studies of M87*, polarimetric constraints reinforce a preference for GRMHD models with dynamically important magnetic fields. Although the spiral morphology of the polarization pattern is known to constrain the spin and inclination angle, the time-variable rotation measure (RM) of Sgr A* (equivalent to ≈46° ± 12° rotation at 228 GHz) limits its present utility as a constraint. If we attribute the RM to internal Faraday rotation, then the motion of accreting material is inferred to be counterclockwise, contrary to inferences based on historical polarized flares, and no model satisfies all polarimetric and total intensity constraints. On the other hand, if we attribute the mean RM to an external Faraday screen, then the motion of accreting material is inferred to be clockwise, and one model passes all applied total intensity and polarimetric constraints: a model with strong magnetic fields, a spin parameter of 0.94, and an inclination of 150°. We discuss how future 345 GHz and dynamical imaging will mitigate our present uncertainties and provide additional constraints on the black hole and its accretion flow.

The Event Horizon Telescope observed the horizon-scale synchrotron emission region around the Galactic center supermassive black hole, Sagittarius A* (Sgr A*), in 2017. These observations revealed a bright, thick ring morphology with a diameter of 51.8 ± 2.3 μ as and modest azimuthal brightness asymmetry, consistent with the expected appearance of a black hole with mass M ≈ 4 × 10 ^6 M _⊙ . From these observations, we present the first resolved linear and circular polarimetric images of Sgr A*. The linear polarization images demonstrate that the emission ring is highly polarized, exhibiting a prominent spiral electric vector polarization angle pattern with a peak fractional polarization of ∼40% in the western portion of the ring. The circular polarization images feature a modestly (∼5%–10%) polarized dipole structure along the emission ring, with negative circular polarization in the western region and positive circular polarization in the eastern region, although our methods exhibit stronger disagreement than for linear polarization. We analyze the data using multiple independent imaging and modeling methods, each of which is validated using a standardized suite of synthetic data sets. While the detailed spatial distribution of the linear polarization along the ring remains uncertain owing to the intrinsic variability of the source, the spiraling polarization structure is robust to methodological choices. The degree and orientation of the linear polarization provide stringent constraints for the black hole and its surrounding magnetic fields, which we discuss in an accompanying publication.

BackgroundEpiretinal membrane (ERM) causes visual impairment such as reduction in visual acuity and metamorphopsia due to retinal traction. With the improvement of optical coherence tomography (OCT) and microincision vitrectomy surgery (MIVS), the surgery of ERM has significantly advanced. However, there have been no large-scale studies on the following: (1) how to evaluate visual impairment in ERM, (2) the relationship between OCT findings and visual function, (3) when is the optimal timing of surgery, and (4) the relationship between the surgical instruments as well as techniques and prognosis. The purpose of this study was to obtain evidence regarding these ERM surgeries.Methods and designThis is a prospective, multicenter cohort study of ERM surgery in Japan from March 1, 2023, to March 31, 2027 (UMIN000048472, R-3468-2). Patients who underwent ERM surgery during the study period and agreed to participate in this study will be included. The goal is to have a total of 5,000 eyes surgically treated for ERM. The following data will be collected: age, gender, medical history, subjective symptoms, visual function before and 6 and 12 months after surgery, clinical findings, OCT data, surgical technique, instruments used in surgery, and complications.DiscussionThe results of this study will support the surgical decisions and procedures in ERM practices.

Abstract Background Image-sharpening algorithms with color adjustments enable real-time processing of the surgical field with a delay of 4 msec for heads-up surgery using digital three-dimensional displays. The aim of this study was to investigate the usefulness of the algorithms with the Artevo 800® digital microscope. Methods Seven vitreoretinal surgeons evaluated the effects of image-sharpening processing on the clarity of the surgical field with the Artevo 800® system that is used for cataract and vitreous surgeries. The scorings were made on a 10-point scale for anterior capsulotomy, phacoemulsification, cortex aspiration, core vitrectomy, and peeling of an epiretinal membrane or an internal limiting membrane. In addition, the images during the internal limiting membrane peeling were processed with or without color adjustments. We also evaluated the skewness (asymmetry in the distribution of the pixels) and kurtosis (sharpness in the distribution of the pixel) of the images to evaluate the contrast with each intensity of image-sharpening. Results Our results showed that the mean visibility score increased significantly from 4.9 ± 0.5 at 0% (original image) to 6.6 ± 0.5 at 25% intensity of the image-sharpening algorithm (P

Abstract Background To determine the incidence and characteristics of the multiple subretinal particles (SRPs) present after pars plana vitrectomy (PPV) for rhegmatogenous retinal detachment (RRD). Methods The medical records of 224 eyes of 224 patients that underwent PPV for RRD were reviewed. The presence of SRPs in the subretinal fluid blebs and the presence of subretinal deposits were determined by optical coherence tomography (OCT) and fundus autofluorescence (FAF). The characteristics of the FAF and infrared reflectance (IR) images of a scanning laser ophthalmoscope in eyes with SRPs (SRPs group) were compared to that of eyes without SRPs (control group). Results SRPs were observed in 27 eyes (12%), and they were completely resolved in 20 eyes (74%) after 6 months. The incidence of macula-off RRD (85%) and preoperative precipitates (41%) were significantly higher in the SRPs group than that in the control group (64%, P = 0.046; 12%, P = 0.002). The axial length was significantly shorter in the SRPs group than that in the control group (25.04 ± 1.54 mm, 26.00 ± 1.78 mm, P = 0.012). The preoperative and postoperative best-corrected visual acuity were not significantly different between the two groups (P = 0.702, P = 0.337). The subretinal fluid bleb determined by OCT were hyperfluorescent in the FAF images in 24 eyes (89%), and the subretinal deposits were hypofluorescent with solid appearance by OCT other than fluid in 3 eyes (11%). The hypofluorescent subretinal deposits in the FAF images were bright in the IR images in 2 eyes. Conclusions The SRPs consist of lipofuscin-related hyperfluorescent subretinal fluid and the subretinal deposits containing bright IR melanin particles of proliferating retinal pigment epithelial cells.

Abstract We conducted clinical and experimental studies to investigate the effects of image-sharpening algorithms and color adjustments, which enabled real-time processing of live surgical images with a delay of 0.004 s. The images were processed with image-sharpening intensities of 0%, 12.5%, 25%, and 50% during cataract surgery, vitrectomy, peeling of epiretinal membrane, and peeling of internal limiting membrane (ILM) with the Ngenuity 3D visualization system. In addition, the images obtained with a yellow filter during the ILM peeling were processed with color adjustments. Five vitreoretinal surgeons scored the clarity of the images on a 10-point scale. The images of a 1951 United States Air Force grating target placed in no fluid (control), saline, and 0.1% and 1% milk solution were evaluated. The results showed that the mean visibility score increased significantly from 5.0 ± 0.6 at 0% to 6.4 ± 0.6 at 12.5%, 7.3 ± 0.7 at 25%, and 7.5 ± 0.9 at 50% (P

Abstract Background This study evaluated the existence of anti-drug antibodies (ADAs) before and 52 weeks after switching from intravenous infliximab (IFX) to intravenous CT-P13 in patients with rheumatoid arthritis (RA). Methods We performed a prospective observational study. Twenty-eight patients (7 males and 21 females) received intravenous CT-P13 after intravenous IFX, and the clinical data were collected from medical records. Rheumatoid factor (RF) and anti-CCP antibody were examined at baseline. At baseline and 52 weeks after the start of CT-P13 treatment, the Disease Activity Score based on the 28-joint count and the levels of C-reactive protein, matrix metalloproteinase-3, and ADA, as well as the erythrocyte sedimentation rate were evaluated. ADAs were measured using an enzyme-linked immunosorbent assay kit. Results Seven (25%) and 6 (21.4%) cases were positive for ADAs at baseline and 52 weeks after, respectively. One case became newly positive for ADAs at week 52. Two of the ADA-positive cases became ADA-negative 52 weeks after. The ADA-positive group showed significantly higher RF values at baseline than the ADA-negative group (p = 0.03). No difference was observed between the ADA-positive group and the ADA-negative group regarding other clinical parameters. Conclusions The positive rate of ADAs did not increase after switching from intravenous IFX to intravenous CT-P13. Among the patients with ADAs, a high level of RF was observed at baseline.

The first very long baseline interferometry (VLBI) detections at 870 μ m wavelength (345 GHz frequency) are reported, achieving the highest diffraction-limited angular resolution yet obtained from the surface of the Earth and the highest-frequency example of the VLBI technique to date. These include strong detections for multiple sources observed on intercontinental baselines between telescopes in Chile, Hawaii, and Spain, obtained during observations in 2018 October. The longest-baseline detections approach 11 G λ , corresponding to an angular resolution, or fringe spacing, of 19 μ as. The Allan deviation of the visibility phase at 870 μ m is comparable to that at 1.3 mm on the relevant integration timescales between 2 and 100 s. The detections confirm that the sensitivity and signal chain stability of stations in the Event Horizon Telescope (EHT) array are suitable for VLBI observations at 870 μ m. Operation at this short wavelength, combined with anticipated enhancements of the EHT, will lead to a unique high angular resolution instrument for black hole studies, capable of resolving the event horizons of supermassive black holes in both space and time.

Amphibious (air and water) drones, capable of both aerial and aquatic operations, have the potential to provide valuable drone applications in aquatic environments. However, the limited range of wireless data transmission caused by the low antenna height on water and reflection from the water surface (e.g., 45 m for vertical half-wave dipole antennas with the XBee S2CTM, estimated using the two-ray ground reflection model) persists as a formidable challenge for amphibious systems. To overcome this difficulty, we developed a wireless data relay system for amphibious drones using the mesh-type networking functions of the XBeeTM. We then conducted field tests of the developed system in a large marsh pond to provide experimental evidence of the efficiency of the multiple-drone network in amphibious settings. In these tests, hovering relaying over water was attempted for extension and bypassing obstacles using the XBee S2CTM (6.3 mW, 2.4 GHz). During testing, the hovering drone (

Abstract Anti-vascular endothelial growth factor treatment for macular edema secondary to branch retinal vein occlusion generally provides good visual acuity (VA) improvement but may require repeated injections for years. To reduce the number of patients who suffer from avoidable VA loss caused by treatment drop-out, providing prospects of the correlation between expected vision improvement and required number of injections at the early stages of treatment may be helpful. In this post hoc analysis of the phase IV, randomized, open-label ZIPANGU study, we investigated the correlation between the data from Month 2 and Month 12 in terms of VA and required ranibizumab injection numbers. Fifty-nine patients were evaluated (ranibizumab monotherapy, 29; combination therapy, 30). In the monotherapy group, patients who received 1 and 3 injections by Month 2 received a mean total of 2.8 and 8.3 injections during the year, respectively. Data from the combination group were similar. The correlation coefficients for VA scores at Months 2 and 12 were 0.60 and 0.51 for the monotherapy and combination groups, respectively (both p

Controlling the immune response with only clinically approved immunosuppressant drugs is difficult in renal heterotransplantation from pigs to nonhuman primates. Moreover, to the best of our knowledge, no reports exist on the use of fetal pigs as kidney donors. This study aimed to compare the degree of transplant rejection between neonatal and fetal kidneys, with genetically unmodified pigs as donors and cynomolgus monkeys as recipients. The left kidneys of the recipient monkeys were removed, followed by transplantation of neonatal as well as fetal pig kidneys, which had undergone vascular anastomosis at the same site, into the retroperitoneum. Immunosuppression was performed with only US Food and Drug Administration-approved drugs. The fetal kidneys were transplanted into the omentum and para-aortic regions of cynomolgus monkeys. Consequently, the engraftment and development of the transplanted tissues were pathologically examined by sampling over time (twice in each experiment). An acute rejection was observed after a few weeks in neonatal renal grafts with vascular anastomosis. However, fetal pig kidneys were spared from rejection despite the administration of the same immunosuppressive protocol to the monkeys and the recipient blood vessels flowing into the fetal kidneys. The immunogenicity of fetal kidneys in pig–monkey renal heterotransplantation was lower than that of neonatal kidneys.

The Event Horizon Telescope (EHT) is a millimeter very long baseline interferometry (VLBI) array that has imaged the apparent shadows of the supermassive black holes M87* and Sagittarius A*. Polarimetric data from these observations contain a wealth of information on the black hole and accretion flow properties. In this work, we develop polarimetric geometric modeling methods for mm-VLBI data, focusing on approaches that fit data products with differing degrees of invariance to broad classes of calibration errors. We establish a fitting procedure using a polarimetric “m-ring” model to approximate the image structure near a black hole. By fitting this model to synthetic EHT data from general relativistic magnetohydrodynamic models, we show that the linear and circular polarization structure can be successfully approximated with relatively few model parameters. We then fit this model to EHT observations of M87* taken in 2017. In total intensity and linear polarization, the m-ring fits are consistent with previous results from imaging methods. In circular polarization, the m-ring fits indicate the presence of event-horizon-scale circular polarization structure, with a persistent dipolar asymmetry and orientation across several days. The same structure was recovered independently of observing band, used data products, and model assumptions. Despite this broad agreement, imaging methods do not produce similarly consistent results. Our circular polarization results, which imposed additional assumptions on the source structure, should thus be interpreted with some caution. Polarimetric geometric modeling provides a useful and powerful method to constrain the properties of horizon-scale polarized emission, particularly for sparse arrays like the EHT.

Event Horizon Telescope (EHT) observations have revealed a bright ring of emission around the supermassive black hole at the center of the M87 galaxy. EHT images in linear polarization have further identified a coherent spiral pattern around the black hole, produced from ordered magnetic fields threading the emitting plasma. Here we present the first analysis of circular polarization using EHT data, acquired in 2017, which can potentially provide additional insights into the magnetic fields and plasma composition near the black hole. Interferometric closure quantities provide convincing evidence for the presence of circularly polarized emission on event-horizon scales. We produce images of the circular polarization using both traditional and newly developed methods. All methods find a moderate level of resolved circular polarization across the image (〈∣ v ∣〉 < 3.7%), consistent with the low image-integrated circular polarization fraction measured by the Atacama Large Millimeter/submillimeter Array (∣ v _int ∣ < 1%). Despite this broad agreement, the methods show substantial variation in the morphology of the circularly polarized emission, indicating that our conclusions are strongly dependent on the imaging assumptions because of the limited baseline coverage, uncertain telescope gain calibration, and weakly polarized signal. We include this upper limit in an updated comparison to general relativistic magnetohydrodynamic simulation models. This analysis reinforces the previously reported preference for magnetically arrested accretion flow models. We find that most simulations naturally produce a low level of circular polarization consistent with our upper limit and that Faraday conversion is likely the dominant production mechanism for circular polarization at 230 GHz in M87*.

ObjectiveSide-effects of medications cause xerostomia. There have been cases where a medication has been discontinued owing to its severe side-effects. Therefore, the xerostomia must be treated to ensure that the primary disease is managed effectively. This study analyzed the actual status of patients with medication-induced xerostomia and investigates factors associated with its improvement.MethodsThis study assessed 490 patients diagnosed with medication-induced xerostomia who had an unstimulated salivary flow of ≤0.1 mL/min and received treatment for xerostomia at a xerostomia clinic. Patient age, sex, medical history, medications used, disease duration of xerostomia, and psychological disorders were recorded. The anticholinergic burden was assessed using the Anticholinergic Cognitive Burden scale. The unstimulated salivary flow was measured by the spitting method. According to their symptoms and diagnoses, the patients were introduced to oral lubricants, instructed on how to perform massage, and prescribed Japanese herbal medicines, and sialogogues. Factors associated with the subjective improvement of xerostomia and objective changes in the salivary flow rate were recorded at six months.ResultsXerostomia improved in 338 patients (75.3%). The improvement rate was significantly lower in patients with psychiatric disorders (63.6%) (P = 0.009). The improvement rate decreased as more anticholinergics were used (P = 0.018). However, xerostomia improved in approximately 60% of patients receiving three or more anticholinergics. The unstimulated salivary flow increased significantly more in patients who reported an improvement of xerostomia (0.033±0.053 mL/min) than in those who reported no improvement (0.013±0.02 mL/min) (P = 0.025).ConclusionXerostomia treatment improved oral dryness in 75.3% of patients receiving xerogenic medications in this study. If xerostomia due to side-effects of medications can be improved by treatment, it will greatly contribute to the quality of life of patients with xerogenic medications and may reduce the number of patients who discontinue medications.

Abstract Background Perimenopausal women experience a wide variety of systemic symptoms: hot flashes, sweating, mental health concerns and various oral sensory complaints (OSC). OSC in perimenopausal women include xerostomia, taste disturbance and burning mouth. However, the factors associated with these OSC have not been identified. The purpose of this investigation was to elucidate the factors associated with OSC in perimenopausal women. Methods The study cohort comprised 43 perimenopausal women aged 45–55 years. Data on medical history, medications, menstrual status, menopausal symptoms, quality of life, xerostomia, taste disturbance and burning mouth were collected. Volumes of unstimulated and stimulated saliva were measured. Tongue coating was evaluated according to a tongue coating index. Univariate analysis was performed to identify factors significantly associated with having xerostomia, taste disturbance, burning mouth and more than two OSC (2OSC). Next, the factors strongly associated with these symptoms were examined by logistic regression analysis. Results The number of menopausal symptoms was significantly higher, and volume of unstimulated saliva was significantly lower in participants with xerostomia, taste disturbance, burning mouth or 2OSC than in those without these characteristics. Agents targeting the central nervous system were more frequently taken by participants with burning mouth and 2OSC than by those without these characteristics. According to logistic regression analysis, the number of menopausal symptoms was an explanatory variable for xerostomia, taste disturbance, burning mouth and 2OSC. Conclusions Our findings suggested that OSC associated with the number of menopausal symptoms. Management of menopausal symptoms may decrease OSC, leading to improved quality of life of perimenopausal women.

It still remains unclear how the suprahyoid muscles function in bolus formation during mastication. This study aimed to investigate the contributory role of the suprahyoid muscles during mastication. A total of 20 healthy young volunteers were asked to perform tongue pressure generation tasks and unilateral mastication tasks using peanuts and two different types of rice crackers. Surface electromyographic (EMG) activity of the masseter and suprahyoid muscles and mandibular kinematics were recorded. Suprahyoid activity increased with increasing tongue pressure. Masticatory duration until the first deglutition differed significantly among the different foods; the harder the food, the longer the duration. This was also the case in masseter activity per masticatory cycle. Masticatory rate and suprahyoid activity per masticatory cycle were significantly higher during soft rice cracker mastication. Masseter activity was higher on the masticatory side than on the non-masticatory side, however, there was no difference in suprahyoid activity between the sides. Suprahyoid activity and jaw gape showed significant positive correlation in the early stage on both the masticatory and non-masticatory sides. The suprahyoid muscles functioned dominantly for jaw-opening during peanut mastication, and for bolus formation, especially in the late stage during soft rice cracker mastication. Bolus formation was performed dominantly on the masticatory side during rice cracker mastication. These findings clearly demonstrate a functional role of the suprahyoid muscles during mastication of solid foods from assessments using both EMG activity and mandibular kinematic recordings.

Purpose: To determine the characteristics and clinical course of an eye with a peripapillary staphyloma and an optic disc pit associated with a retinal detachment (RD) and retinoschisis. Observations: A 44-year-old woman had a peripapillary staphyloma with a shallow RD and retinoschisis in her right eye. The optic disc was located in the peripapillary staphyloma with steep walls, and an optic disc pit was located on the temporal area of the optic disc cup. Optical coherence tomography (OCT) revealed a separation of the lamina cribrosa, herniated retinal tissue, and a subarachnoid space corresponding to the optic disc pit. Pars plana vitrectomy with laser photocoagulation around the temporal margin of the peripapillary staphyloma was performed to treat the RD, and the treatment was successful. Conclusion and importance: Clinicians should be aware that eyes with a RD and retinoschisis associated with a deep peripapillary staphyloma and an optic disc pit exist. The RD and retinoschisis can be successfully treated by vitrectomy.

Abstract The ZIPANGU study assessed the efficacy and safety of ranibizumab as a one loading dose + pro re nata (one + PRN) regimen with/without focal/grid laser among treatment-naïve patients suffering from macular edema (ME) following branch retinal vein occlusion (BRVO). ZIPANGU was a phase IV, prospective, randomized, open-label, active-controlled, 12-month, two-arm, multicenter study. Treatment-naïve patients with visual impairment (19–73 letters) caused by ME, defined as central subfield thickness (CSFT) > 300 µm, due to BRVO were randomly assigned to ranibizumab monotherapy (n = 29) or combination therapy (ranibizumab + focal/grid short-pulse laser, n = 30). The primary endpoint was the number of ranibizumab injections. Secondary endpoints were mean changes in best-corrected visual acuity (BCVA) and CSFT, and safety. There were no statistically significant differences in the mean number of ranibizumab injections between monotherapy (4.3 injections) vs. combination (4.1 injections) therapy, or in CSFT. BCVA improvement in the monotherapy arm (22.0 letters) was better than the combination therapy arm (15.0 letters) (p = 0.035). Overall, both regimens appeared to be safe and well tolerated. One + PRN ranibizumab is safe and efficacious in treatment-naïve patients with ME secondary to BRVO. A conjunctive laser treatment did not lead to better functional outcomes or fewer ranibizumab injections.

Early life trauma has been associated with multiple sclerosis, but the causal link is unclear. Here the authors show in mice that early life trauma can result in IFN-β-resistant EAE as a result of β-adrenergic desensitization in immune cells and that a β1 adrenergic receptor agonist can reverse this susceptibility.

Inflammasomes are a class of innate immune signaling platforms that activate in response to an array of cellular damage and pathogens. Inflammasomes promote inflammation under many circumstances to enhance immunity against pathogens and inflammatory responses through their effector cytokines, IL-1β and IL-18. Multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE), are autoimmune conditions influenced by inflammasomes. Despite work investigating inflammasomes during EAE, little remains known concerning the role of inflammasomes in the central nervous system (CNS) during the disease. Here, we used multiple genetically modified mouse models to monitor activated inflammasomes in situ based on oligomerization of apoptosis-associated speck-like protein containing a CARD (ASC) in the spinal cord. Using inflammasome reporter mice, we found heightened inflammasome activation in astrocytes after the disease peak. In contrast, microglia and CNS-infiltrated myeloid cells had few activated inflammasomes in the CNS during EAE. Astrocyte inflammasome activation during EAE was dependent on absent in melanoma 2 (AIM2), but low IL-1β release and no significant signs of cell death were found. Thus, the AIM2 inflammasome activation in astrocytes may have a distinct role from traditional inflammasome-mediated inflammation.

Two new azaphilones, namely muyocopronones A (1) and B (2), were isolated from the cultures of an endophytic fungus Muyocopron laterale ECN279. Their structures were elucidated by extensive spectroscopic analysis. Their absolute configurations were determined using the modified Mosher’s method and through comparisons of experimental and calculated electronic circular dichroism data. In addition, muyocopronone B (2) was found to exhibit a weak antibacterial activity against some Gram-positive bacteria.

Talaromycones A (1) and B (2), new xanthenediones, were isolated from the cultures of Talaromyces sp. ECN211, an endophytic fungus, along with α-diversonolic ester (3), aspergillusone B (4), glauconic acid (5), and rosellisin (6). The planar structures of 1 and 2 were elucidated by extensive spectroscopic analyses. Furthermore, the absolute configurations of 1–4 were determined by single-crystal X-ray diffraction and electronic circular dichroism spectroscopy (ECD). In addition, the crystallographic data for 5 were updated for the first time in over 50 years.

Abstract Background Multiple sclerosis (MS) is a chronic debilitating immune-mediated disease of the central nervous system (CNS) driven by demyelination and gray matter neurodegeneration. We previously reported an experimental autoimmune encephalomyelitis (EAE) MS mouse model with elevated serum CXCL1 that developed severe and prolonged neuron damage. Our findings suggested that CXCR2 signaling may be important in neuronal damage, thus implicating neutrophils, which express CXCR2 in abundance, as a potential cell type involved. The goals of this study were to determine if CXCR2 signaling in neutrophils mediate neuronal damage and to identify potential mechanisms of damage. Methods EAE was induced in wild-type control and neutrophil-specific Cxcr2 knockout (Cxcr2 cKO) mice by repeated high-dose injections of heat-killed Mycobacterium tuberculosis and MOG35–55 peptide. Mice were examined daily for motor deficit. Serum CXCL1 level was determined at different time points throughout disease development. Neuronal morphology in Golgi-Cox stained lumbar spinal cord ventral horn was assessed using recently developed confocal reflection super-resolution technique. Immune cells from CNS and lymphoid organs were quantified by flow cytometry. CNS-derived neutrophils were co-cultured with neuronal crest cells and neuronal cell death was measured. Neutrophils isolated from lymphoid organs were examined for expression of reactive oxygen species (ROS) and ROS-related genes. Thioglycolate-activated neutrophils were isolated, treated with recombinant CXCL1, and measured for ROS production. Results Cxcr2 cKO mice had less severe disease symptoms at peak and late phase when compared to control mice with similar levels of CNS-infiltrating neutrophils and other immune cells despite high levels of circulating CXCL1. Additionally, Cxcr2 cKO mice had significantly reduced CNS neuronal damage in the ventral horn of the spinal cord. Neutrophils isolated from control EAE mice induced vast neuronal cell death in vitro when compared with neutrophils isolated from Cxcr2 cKO EAE mice. Neutrophils isolated from control EAE mice, but not Cxcr2 cKO mice, exhibited elevated ROS generation, in addition to heightened Ncf1 and Il1b transcription. Furthermore, recombinant CXCL1 was sufficient to significantly increase neutrophils ROS production. Conclusions CXCR2 signal in neutrophils is critical in triggering CNS neuronal damage via ROS generation, which leads to prolonged EAE disease. These findings emphasize that CXCR2 signaling in neutrophils may be a viable target for therapeutic intervention against CNS neuronal damage.

In 2017 the Event Horizon Telescope (EHT) observed the supermassive black hole at the center of the Milky Way, Sagittarius A* (Sgr A*), at a frequency of 228.1 GHz ( λ = 1.3 mm). The fundamental physics tests that even a single pulsar orbiting Sgr A* would enable motivate searching for pulsars in EHT data sets. The high observing frequency means that pulsars—which typically exhibit steep emission spectra—are expected to be very faint. However, it also negates pulse scattering, an effect that could hinder pulsar detections in the Galactic center. Additionally, magnetars or a secondary inverse Compton emission could be stronger at millimeter wavelengths than at lower frequencies. We present a search for pulsars close to Sgr A* using the data from the three most sensitive stations in the EHT 2017 campaign: the Atacama Large Millimeter/submillimeter Array, the Large Millimeter Telescope, and the IRAM 30 m Telescope. We apply three detection methods based on Fourier-domain analysis, the fast folding algorithm, and single-pulse searches targeting both pulsars and burst-like transient emission. We use the simultaneity of the observations to confirm potential candidates. No new pulsars or significant bursts were found. Being the first pulsar search ever carried out at such high radio frequencies, we detail our analysis methods and give a detailed estimation of the sensitivity of the search. We conclude that the EHT 2017 observations are only sensitive to a small fraction (≲2.2%) of the pulsars that may exist close to Sgr A*, motivating further searches for fainter pulsars in the region.

Interpretation of resolved polarized images of black holes by the Event Horizon Telescope (EHT) requires predictions of the polarized emission observable by an Earth-based instrument for a particular model of the black hole accretion system. Such predictions are generated by general relativistic radiative transfer (GRRT) codes, which integrate the equations of polarized radiative transfer in curved spacetime. A selection of ray-tracing GRRT codes used within the EHT Collaboration is evaluated for accuracy and consistency in producing a selection of test images, demonstrating that the various methods and implementations of radiative transfer calculations are highly consistent. When imaging an analytic accretion model, we find that all codes produce images similar within a pixel-wise normalized mean squared error (NMSE) of 0.012 in the worst case. When imaging a snapshot from a cell-based magnetohydrodynamic simulation, we find all test images to be similar within NMSEs of 0.02, 0.04, 0.04, and 0.12 in Stokes I , Q , U , and V , respectively. We additionally find the values of several image metrics relevant to published EHT results to be in agreement to much better precision than measurement uncertainties.

We present millimeter and submillimeter continuum observations for 36 sources with potentially large black hole shadows at 230 and 345 GHz using the Submillimeter Array. The sources are selected based on the criterion of the large diameter of the black hole shadows. Our motivation is to explore the nature of the accretion flow of the potential candidates of low-luminosity active galactic nuclei (LLAGNs) through photometry at millimeter/submillimeter wavelengths. The detected result serves as the pathfinder of future high-angular resolution observations such as the Event Horizon Telescope. As a result, we successfully detected 17 and eight sources at 230 and 345 GHz, respectively. We reveal that three of the detected sources (IC 310, NGC 1277, and NGC 5846) show significant excess at millimeter/submillimeter wavelengths in comparison with the extrapolation both from low-frequency radio and infrared, which are considered to be attributed to the extended jet and dust component, respectively. One possible explanation is that these excesses are associated with the hot accretion flow onto the supermassive black holes of the LLAGNs. By adopting the advection-dominated accretion flow model's semi-analytic model, we obtained the upper bound of the mass accretion rate. Those are less than 10 ^−2 ${\dot{M}}_{\mathrm{EDD}}$ , where ${\dot{M}}_{\mathrm{EDD}}$ is the Eddington mass accretion rate computed via the Eddington luminosity. This is in good agreement with the expected range of the LLAGNs. The ∼200 mJy flux densities and negative spectral index of IC 1459 within millimeter and submillimeter wavelengths make it a promising candidate for future submillimeter high-angular resolution experiments for imaging the black hole shadow.

We report on the observations of the quasar NRAO 530 with the Event Horizon Telescope (EHT) on 2017 April 5−7, when NRAO 530 was used as a calibrator for the EHT observations of Sagittarius A*. At z = 0.902, this is the most distant object imaged by the EHT so far. We reconstruct the first images of the source at 230 GHz, at an unprecedented angular resolution of ∼20 μ as, both in total intensity and in linear polarization (LP). We do not detect source variability, allowing us to represent the whole data set with static images. The images reveal a bright feature located on the southern end of the jet, which we associate with the core. The feature is linearly polarized, with a fractional polarization of ∼5%–8%, and it has a substructure consisting of two components. Their observed brightness temperature suggests that the energy density of the jet is dominated by the magnetic field. The jet extends over 60 μ as along a position angle ∼ −28°. It includes two features with orthogonal directions of polarization (electric vector position angle), parallel and perpendicular to the jet axis, consistent with a helical structure of the magnetic field in the jet. The outermost feature has a particularly high degree of LP, suggestive of a nearly uniform magnetic field. Future EHT observations will probe the variability of the jet structure on microarcsecond scales, while simultaneous multiwavelength monitoring will provide insight into the high-energy emission origin.

Examining the coordination of respiration and swallowing is important for elucidating the mechanisms underlying these functions and assessing how respiration is linked to swallowing impairment in dysphagic patients. In this study, we assessed the coordination of respiration and swallowing to clarify how voluntary swallowing is coordinated with respiration and how mastication modulates the coordination of respiration and swallowing in healthy humans. Twenty-one healthy volunteers participated in three experiments. The participants were asked to swallow 3 ml of water with or without a cue, to drink 100 ml of water using a cup without breathing between swallows, and to eat a 4-g portion of corned beef. The major coordination pattern of respiration and swallowing was expiration–swallow–expiration (EE type) while swallowing 3 ml of water either with or without a cue, swallowing 100 ml of water, and chewing. Although cueing did not affect swallowing movements, the expiratory time was lengthened with the cue. During 100-ml water swallowing, the respiratory cycle time and expiratory time immediately before swallowing were significantly shorter compared with during and after swallowing, whereas the inspiratory time did not differ throughout the recording period. During chewing, the respiratory cycle time was decreased in a time-dependent manner, probably because of metabolic demand. The coordination of the two functions is maintained not only in voluntary swallowing but also in involuntary swallowing during chewing. Understanding the mechanisms underlying respiration and swallowing is important for evaluating how coordination affects physiological swallowing in dysphagic patients.

It is known that the retinal detachments (RDs) associated with a morning glory disc anomaly (MGDA) usually appear from around the disc anomaly and complications by peripheral fibrovascular proliferation and tractional RD are very rare. We report our findings in an eye with MGDA that had a tractional RD, massive exudation from a peripheral temporal fibrovascular proliferation and vasculatures stretched by this proliferation and by a contraction of the hyaloidal membrane. The RD was successfully treated by vitrectomy and encircling buckling surgery.

ABSTRACT Purpose As a classical xenotransplantation model, porcine kidneys have been transplanted into the lower abdomen of non-human primates. However, we have improved upon this model by using size-matched grafting in the orthotopic position. The beneficial aspects and surgical details of our method are reported herein. Methods Donors were two newborn pigs (weighting 5 to 6 kg) and recipients were two cynomolgus monkeys (weighting, approximately, 7 kg). After bilateral nephrectomy, kidneys were cold-transported in Euro-Collins solution. The porcine kidney was transplanted to the site of a left nephrectomy and fixed to the peritoneum. Results Kidneys transplanted to the lower abdomen by the conventional method were more susceptible to torsion of the renal vein (two cases). In contrast, early-stage blood flow insufficiency did not occur in orthotopic transplants of theleft kidney. Conclusions Size-matched porcine-primate renal grafting using our method of transplanting tothe natural position of the kidneys contributes to stable post-transplant blood flow to the kidney.

Abstract Background To compare the efficacy of 12-month denosumab treatment on bone mineral density (BMD) and bone turnover markers (BTMs) between treatment-naïve osteoporosis patients with rheumatoid arthritis (RA) and those with previous bisphosphonate (BP) therapy. Methods A total of 36 RA patients with osteoporosis completed 12-month follow-up. Twenty-five patients were osteoporotic treatment-naïve (naïve group), and 11 patients were previously treated with BPs (switch group) (average 7.9 years). BMD and BTMs were measured before and 6 and 12 months after treatment. Results BTM levels were higher in the naïve group at baseline. However, the same level of suppression was achieved at 6 months in both groups. Spine BMD increased significantly in both groups. There was no significant difference in the mean percent changes of BMD of the spine (naïve group: 6.8 ± 0.8, switch group: 5.1 ± 1.5), femoral neck (2.9 ± 1.4, 2.9 ± 1.3), and total hip (1.7 ± 0.9, 1.4 ± 1.1) between these two groups at 12 months. Conclusions The effects of denosumab on BMD and BTMs of the switch group after long-term BP treatment are comparable to those of the naïve group in RA patients. Thus, switching BPs to denosumab is one of the useful options to treat osteoporosis with RA.

Abstract Background To compare the quality of the ultra-widefield images acquired by Optos® 200Tx to those acquired by Optos® California. Methods Images of the posterior surface of a Gullstrand’s model eye obtained by Optos® 200Tx were compared to those obtained by Optos® California in terms of the angular field of view and the symmetry of the image, i.e., vertical and horizontal aspect ratios at the center (0°) and at the periphery (40° and 80°) in each direction. In addition, we compared the enlargement of the image on the posterior surface as the square ratio, and the differences in the contrasts. Results No significant differences were detected in the angular field of view between the two instruments. The aspect ratios showed that the Optos® California had more symmetrical images than the Optos® 200Tx at the center (0.98 vs 0.89, P

This study aimed to clarify the health-related quality of life (HRQOL) of patients with oral cancer and elucidate the factors that affect HRQOL. The participants were 14 male and 10 female patients who underwent definitive surgery. The patients' mean age was 68.2 years. A total of 21 oral cancer cases (87.5%) were in the early stages (stages 0-II), and 15 (62.5%) to tongue cancer. This study's assessments were conducted using HRQOL questionnaires (e.g., the SF-8 and EORTC QLQ Head&Neck35(QLQ-H&N35)) and the Beck Depression Inventory—second edition (BDI-II) along with evaluations of speech, mastication, and swallowing function. The evaluations were performed before surgery and one month, three months, and six months after surgery. There was no significant change in the SF-8 and BDI-II scores during the study period. However, the scores for pain, speech problems, social contact, and coughing within the QLQ-H&N35 significantly increased post-surgery. Furthermore, significant correlations were observed between almost all SF-8 scores and some QLQ-H&N35 scores. Speech intelligibility and masticatory and swallowing functions were significantly correlated with speech problems, social eating, and swallowing within the QLQ-H&N35. These results indicate that disease-specific and site-specific HRQOL decline as a result of oral dysfunction.

Cryptococcus-associated immune reconstitution inflammatory syndrome (C-IRIS) is identified upon immune reconstitution in immunocompromised patients, who have previously contracted an infection of Cryptococcus neoformans (Cn). C-IRIS can be lethal but how the immune system triggers life-threatening outcomes in patients is still poorly understood. Here, we establish a mouse model for C-IRIS with Cn serotype A strain H99, which is highly virulent and the most intensively studied. C-IRIS in mice is induced by the adoptive transfer of CD4+ T cells in immunocompromised Rag1-deficient mice infected with a low inoculum of Cn. The mice with C-IRIS exhibit symptoms which mimic clinical presentations of C-IRIS. This C-IRIS model is Th1-dependent and shows host mortality. This model is characterized with minimal lung injury, but infiltration of Th1 cells in the brain. C-IRIS mice also exhibited brain swelling with resemblance to edema and upregulation of aquaporin-4, a critical protein that regulates water flux in the brain in a Th1-dependent fashion. Our C-IRIS model may be used to advance our understanding of the paradoxical inflammatory phenomenon of C-IRIS in the context of neuroinflammation.

Coughing, huffing and swallowing protect the airway from aspiration. This study was conducted to compare the physical properties of voluntary coughing, huffing and swallowing in healthy subjects. Ten healthy men were asked to huff, cough and swallow repeatedly. Electromyograms (EMGs) were recorded from the left side of the external oblique (EO), sternocleidomastoid, suprahyoid (SH) and thyrohyoid muscles. Airflow was recorded using a face mask with two-way non-rebreathing valves. The expiratory velocity of huffing and coughing and the SH EMG of all actions presented high intraclass correlation coefficients (> 0.8). The inspiratory and expiratory velocities did not differ significantly between coughing and huffing. The expiratory acceleration of coughing was significantly higher than that of huffing, whereas the expiratory volume of coughing was significantly smaller than that of huffing. The EO EMG of coughing and huffing were significantly larger than that of swallowing. The EO EMG activity during the expiratory phase was significantly higher than that of the other phases of both coughing and huffing. The SH EMG of coughing and huffing were significantly smaller than that of swallowing. Correlation analysis revealed that the expiratory velocity of coughing was strongly positively correlated with that of huffing. The expiratory volume of huffing was significantly positively correlated with hand grip strength. These results suggest that EO and SH muscle activities during huffing or coughing differ those during swallowing, and huffing and coughing may work similarly in expiratory function.

Purpose: To report the findings and surgical techniques on two cases of severe tilting of an intraocular lens (IOL) that had been implanted with intrascleral fixation and the tilting was detected by anterior segment optical coherence tomography (AS-OCT). Observations: Two patients underwent flanged intrascleral fixation of an IOL with the double needle technique. AS-OCT showed that the tilt of IOL was 25.3° in Case 1 and was 38.1° in Case 2, and a second surgery was planned to reduce the IOL tilt. Both edges of the flanged haptics were externalized and shortened by 2–3 mm. Then, the haptics edges were inserted intrasclerally. The tilt of the IOLs was reduced to 7.7° and 5.7°, and the myopia-shifted refraction was reduced from −2.75 diopters (D) and −4.50 D to −0.13 D and −0.50 D of the approximate planned refraction in the two cases. Conclusions and importance: An excessive tilt of an intrasclerally fixed IOL can be corrected by shortening the length of the haptics. AS-OCT was useful in not only detecting the tilted IOL but also in monitoring the degree of tilt after adjustment surgery. Keywords: Intraocular lens, Intrascleral fixation, Optical coherence tomography, Tilt

This study was conducted using a drone with advanced mobility to develop a unified sensor and communication system as a new platform for in situ atmospheric measurements. As a major cause of air pollution, particulate matter (PM) has been attracting attention globally. We developed a small, lightweight, simple, and cost-effective multi-sensor system for multiple measurements of atmospheric phenomena and related environmental information. For in situ local area measurements, we used a long-range wireless communication module with real-time monitoring and visualizing software applications. Moreover, we developed four prototype brackets with optimal assignment of sensors, devices, and a camera for mounting on a drone as a unified system platform. Results of calibration experiments, when compared to data from two upper-grade PM2.5 sensors, demonstrated that our sensor system followed the overall tendencies and changes. We obtained original datasets after conducting flight measurement experiments at three sites with differing surrounding environments. The experimentally obtained prediction results matched regional PM2.5 trends obtained using long short-term memory (LSTM) networks trained using the respective datasets.

Abstract Background To evaluate the quality of the images obtained by an ultra-widefield device in gas-filled eyes after vitrectomy for a retinal detachment. Methods Retrospective case series. The ultra-widefield scanning laser ophthalmoscopic images (Optos 200Tx imaging system) of 40 eyes that were gas-filled with 40 to 90% of the vitreous cavity after vitrectomy for a rhegmatogenous retinal detachment were studied. The rates of detecting the rates of reattachments and the causative retinal tears that were treated and were in the superior or inferior areas in eyes with intravitreal gas of ≥60% were compared to that to eyes with intravitreal gas of

Abstract Background Intrascleral fixation of an intraocular lens (IOL) is used in eyes that lack capsular support. The aim of the study is to determine whether a larger optical diameter IOL will decrease the higher-order aberrations (HOAs) when the haptics are extended for intrascleral fixation than a smaller diameter IOL. Methods Three-piece acrylic IOLs with 6.0 mm optics (X-60, VA-60BBR) and 7.0 mm optics (X-70, VA-70 AD) were fixed at lengths of 13, 14, 15, 16, or 17 mm. A wavefront analyzer was used to measure the HOAs within the central 3.0 and 5.2 mm optic diameter. Results The astigmatic aberration within the central 5.2 mm was greater than that within the central 3.0 mm for all IOLs. The HOAs increased significantly with an extension of the IOLs with both optical diameters (P

Amyotrophic lateral sclerosis (ALS) is a progressive and fatal degenerative disorder of motor neurons (MNs). Embryonic stem cells (ESCs)/induced pluripotent stem cells (iPSCs) now help us to understand the pathomechanisms of ALS via disease modeling. Various methods to differentiate ESCs/iPSCs into MNs by the addition of signaling molecules have been reported. However, classical methods require multiple steps, and newer simple methods using the transduction of transcription factors run the risk of genomic integration of the vector genes. Heterogeneity of the expression levels of the transcription factors also remains an issue. Here we describe a novel approach for differentiating human and mouse ESCs/iPSCs into MNs using a single Sendai virus vector encoding three transcription factors, LIM/homeobox protein 3, neurogenin 2, and islet-1, which are integration free. This single-vector method, generating HB9-positive cells on day 2 from human iPSCs, increases the ratio of MNs to neurons compared to the use of three separate Sendai virus vectors. In addition, the MNs derived via this method from iPSCs of ALS patients and model mice display disease phenotypes. This simple approach significantly reduces the efforts required to generate MNs, and it provides a useful tool for disease modeling.

In this study, we investigated the effects of the Tibetan High near the tropopause and the North Pacific High in the troposphere on occurrences of hot or cool summers in Japan. We first classified Japan into six regions and identified hot and cool summer years in these regions from a 38-year sample (1980–2017) based on the monthly air temperature. To investigate the features of circulation fields over Asia during hot and cool summers in Japan, we calculated the composite differences (hot summer years minus cool summer years) of several variables such as geopotential height, which indicated significant high-pressure anomalies in the troposphere and lower stratosphere. These results suggest that both the North Pacific and the Tibetan Highs tend to extend to Japan during hot summer years, while cool summers seem to be associated with the weakening of these highs. We found that extension of the Tibetan High to the Japanese mainland can lead to hot summers in Northern, Eastern, and Western Japan. On the other hand, hot summers in the Southwestern Islands may be due to extension of the Tibetan High to the south. Similarly, the latitudinal direction of extension of the North Pacific High is profoundly connected with the summer climate in respective regions.

Aberrant Wnt/β-catenin signaling is implicated in tumorigenesis and the progression of human colorectal cancers, and mutations in the components of the Wnt/β-catenin signaling pathway are observed in the majority of patients. Therefore, extensive studies on the Wnt signaling pathway and its target genes are crucial to understand the molecular events of tumorigenesis and develop an efficacious therapy. In this study, we showed that the stress response gene ATF3 is transcriptionally activated by the binding of β-catenin and TCF4 to the redundant TCF4 site at the proximal promoter region of the ATF3 gene, indicating that ATF3 is a direct target of the Wnt/β-catenin pathway. The loss of function or overexpression studies showed that ATF3 inhibited the migration or invasion of HCT116 cells. The expression of some MMP and TIMP genes and the ratio of MMP2/9 to TIMP3/4 mRNAs was differentially regulated by ATF3. Therefore, though ATF3 is activated downstream of the Wnt/β-catenin pathway, it acts as a negative regulator of the migration and invasion of HCT116 human colon cancer cells exhibiting aberrant Wnt/β-catenin activity. ATF3 is a candidate biomarker and target for human colorectal cancer treatment and prevention.