Creation of bladder assembloids mimicking tissue regeneration and cancer.

Current organoid models are limited by their inability to mimic mature organ architecture and associated tissue microenvironments1,2. Here we create multilayer bladder 'assembloids' by reconstituting tissue stem cells with stromal components to represent an organized architecture with an epithelium surrounding stroma and an outer muscle layer. These assembloids exhibit characteristics of mature adult bladders in cell composition and gene expression at the single-cell transcriptome level, and recapitulate in vivo tissue dynamics of regenerative responses to injury. We also develop malignant counterpart tumour assembloids to recapitulate the in vivo pathophysiological features of urothelial carcinoma. Using the genetically manipulated tumour-assembloid platform, we identify tumoural FOXA1, induced by stromal bone morphogenetic protein (BMP), as a master pioneer factor that drives enhancer reprogramming for the determination of tumour phenotype, suggesting the importance of the FOXA1-BMP-hedgehog signalling feedback axis between tumour and stroma in the control of tumour plasticity.

ARBM101 (Methanobactin SB2) Drains Excess Liver Copper via Biliary Excretion in Wilson's Disease Rats.

BACKGROUND & AIMS: Excess copper causes hepatocyte death in hereditary Wilson's disease (WD). Current WD treatments by copper-binding chelators may gradually reduce copper overload; they fail, however, to bring hepatic copper close to normal physiological levels. Consequently, lifelong daily dose regimens are required to hinder disease progression. This may result in severe issues due to nonadherence or unwanted adverse drug reactions and also due to drug switching and ultimate treatment failures. This study comparatively tested bacteria-derived copper binding agents-methanobactins (MBs)-for efficient liver copper depletion in WD rats as well as their safety and effect duration. METHODS: Copper chelators were tested in vitro and in vivo in WD rats. Metabolic cage housing allowed the accurate assessment of animal copper balances and long-term experiments related to the determination of minimal treatment phases. RESULTS: We found that copper-binding ARBM101 (previously known as MB-SB2) depletes WD rat liver copper dose dependently via fecal excretion down to normal physiological levels within 8 days, superseding the need for continuous treatment. Consequently, we developed a new treatment consisting of repetitive cycles, each of ∼1 week of ARBM101 applications, followed by months of in-between treatment pauses to ensure a healthy long-term survival in WD rats. CONCLUSIONS: ARBM101 safely and efficiently depletes excess liver copper from WD rats, thus allowing for short treatment periods as well as prolonged in-between rest periods.

Anti-pollutant effect of oleic acid against urban particulate matter is mediated via regulation of AhR- and TRPV1-mediated signaling in vitro.

Urban Particulate Matter (UPM) induces skin aging and inflammatory responses by regulating skin cells through the transient receptor potential vanilloid 1 (TRPV1). Although oleic acid, an unsaturated free fatty acid (FFA), has some functional activities, its effect on UPM-induced skin damage has not been elucidated. Here, we investigated signaling pathways on how oleic acid is involved in attenuating UPM induced cell damage. UPM treatment increased XRE-promoter luciferase activity and increased translocation of AhR to the nucleus, resulting in the upregulation of CYP1A1 gene. However, oleic acid treatment attenuated the UPM effects on AhR signaling. Furthermore, while UPM induced activation of TRPV1 and MAPKs signaling which activated the downstream molecules NFκB and AP-1, these effects were reduced by cotreatment with oleic acid. UPM-dependent generation of reactive oxygen species (ROS) and reduction of cellular proliferation were also attenuated by the treatment of oleic acid. These data reveal that cell damage induced by UPM treatment occurs through AhR signaling and TRPV1 activation which in turn activates ERK and JNK, ultimately inducing NFκB and AP-1 activation. These effects were reduced by the cotreatment of oleic acid on HaCaT cells. These suggest that oleic acid reduces UPM-induced cell damage through inhibiting both the AhR signaling and activation of TRPV1 and its downstream molecules, leading to a reduction of pro-inflammatory cytokine and recovery of cell proliferation.

Anti-Pollutant Activity of Porphyra yezoensis Water Extract and Its Active Compound, Porphyra 334, against Urban Particulate Matter-Induced Keratinocyte Cell Damage.

Urban particulate matter (UPM) causes skin aging and inflammatory reactions by influencing skin cells through the aryl hydrocarbon receptor (AhR) signaling pathway. Porphyra yezoensis (also known as Pyropia yezoensis), a red alga belonging to the Bangiaceae family, is an edible red seaweed. Here, we examined the anti-pollutant effect of P. yezoensis water extract. While UPM treatment induced xenobiotic response element (XRE) promoter luciferase activity, P. yezoensis water extract reduced UPM-induced XRE activity. Next, we isolated an active compound from P. yezoensis and identified it as porphyra 334. Similar to the P. yezoensis water extract, porphyra 334 attenuated UPM-induced XRE activity. Moreover, although UPM augmented AhR nuclear translocation, which led to an increase in cytochrome P450 1A1 (CYP1A1) mRNA levels, these effects were reduced by porphyra 334. Moreover, UPM induced the production of reactive oxygen species (ROS) and reduced cell proliferation. These effects were attenuated in response to porphyra 334 treatment. Furthermore, our results revealed that the increased ROS levels induced by UPM treatment induced transient receptor potential vanilloid 1 (TRPV1) activity, which is related to skin aging and inflammatory responses. However, porphyra 334 treatment reduced this reaction by inhibiting ROS production induced by CYP1A1 activation. This indicates that porphyra 334, an active compound of P. yezoensis, attenuates UP-induced cell damage by inhibiting AhR-induced ROS production, which results in a reduction in TRPV1 activation, leading to cell proliferation. This also suggests that porphyra 334 could protect the epidermis from harmful pollutants.

Restoring natural upper limb movement through a wrist prosthetic module for partial hand amputees.

BACKGROUND: Most partial hand amputees experience limited wrist movement. The limited rotational wrist movement deteriorates natural upper limb system related to hand use and the usability of the prosthetic hand, which may cause secondary damage to the musculoskeletal system due to overuse of the upper limb affected by repetitive compensatory movement patterns. Nevertheless, partial hand prosthetics, in common, have only been proposed without rotational wrist movement because patients have various hand shapes, and a prosthetic hand should be attached to a narrow space. METHODS: We hypothesized that partial hand amputees, when using a prosthetic hand with a wrist rotation module, would achieve natural upper limb movement muscle synergy and motion analysis comparable to a control group. To validate the proposed prototype design with the wrist rotation module and verify our hypothesis, we compared a control group with partial hand amputees wearing hand prostheses, both with and without the wrist rotation module prototype. The study contained muscle synergy analysis through non-negative matrix factorization (NMF) using surface electromyography (sEMG) and motion analyses employing a motion capture system during the reach-to-grasp task. Additionally, we assessed the usability of the prototype design for partial hand amputees using the Jebsen-Taylor hand function test (JHFT). RESULTS: The results showed that the number of muscle synergies identified through NMF remained consistent at 3 for both the control group and amputees using a hand prosthesis with a wrist rotation module. In the motion analysis, a statistically significant difference was observed between the control group and the prosthetic hand without the wrist rotation module, indicating the presence of compensatory movements when utilizing a prosthetic hand lacking this module. Furthermore, among the amputees, the JHFT demonstrated a greater improvement in total score when using the prosthetic hand equipped with a wrist rotation module compared to the prosthetic hand without this module. CONCLUSION: In conclusion, integrating a wrist rotation module in prosthetic hand designs for partial hand amputees restores natural upper limb movement patterns, reduces compensatory movements, and prevent the secondary musculoskeletal. This highlights the importance of this module in enhancing overall functionality and quality of life.

Transient Vestibular Symptoms Preceding Posterior Circulation Stroke: A Prospective Multicenter Study.

BACKGROUND AND PURPOSE: The recognition of clinical features of transient vestibular symptoms (TVSs) preceding posterior circulation stroke (PCOS) would be informative to discriminate dizziness/vertigo due to vertebrobasilar transient ischemic attack from the acute transient vestibular syndrome. We sought to determine the prevalence and characteristics of TVSs preceding PCOS. METHODS: We performed a prospective multicenter observational study that had recruited 447 patients with PCOS from referral-based 4 university hospitals in Korea. We investigated the timing, pattern, frequency, duration, and accompanying neurological symptoms of TVSs during the 3 months preceding PCOS. RESULTS: The prevalence of TVSs preceding PCOS was 12% (55/447) during the previous 3 months. The TVSs preceding PCOS occurred within 1 week (33%), between 1 week and 1 month (16%), or between 1 and 3 months (51%). The TVSs were mostly dizziness/vertigo with (36%) or without (60%) imbalance, while the remaining 4% had an isolated imbalance. The dizziness/vertigo was spinning in 38% and was aggravated during head position in 45%. The duration of TVSs was mostly a few seconds (55%) or minutes (38%). Approximately 72% of the patients with PCOS had TVSs 1 to 5 times, while 16% had >10 times. Accompanying neurological symptoms, including headache, tinnitus, limb weakness, sensory change, dysarthria, visual field defect, and diplopia, were reported in 11%. CONCLUSIONS: Preceding TVSs can occur in 12% of PCOS during the previous 3 months. Isolated dizziness/vertigo of unknown cause needs to be considered as a vertebrobasilar transient ischemic attack symptom, especially in patients with vascular risk factors. The characteristics of isolated vestibular symptom in vertebrobasilar transient ischemic attacks is highly variable and atypical compared with other transient ischemic symptoms.

A Novel Simplified System to Estimate Lower-Limb Joint Moments during Sit-to-Stand.

To provide effective diagnosis and rehabilitation, the evaluation of joint moments during sit-to-stand is essential. The conventional systems for the evaluation, which use motion capture cameras, are quite accurate. However, the systems are not widely used in clinics due to their high cost, inconvenience, and the fact they require lots of space. To solve these problems, some studies have attempted to use inertial sensors only, but they were still inconvenient and inaccurate with asymmetric weight-bearing. We propose a novel joint moment estimation system that can evaluate both symmetric and asymmetric sit-to-stands. To make a simplified system, the proposal is based on a kinematic model that estimates segment angles using a single inertial sensor attached to the shank and a force plate. The system was evaluated with 16 healthy people through symmetric and asymmetric weight-bearing sit-to-stand. The results showed that the proposed system (1) has good accuracy in estimating joint moments (root mean square error < 0.110 Nm/kg) with high correlation (correlation coefficient > 0.99) and (2) is clinically relevant due to its simplicity and applicability of asymmetric sit-to-stand.

Olfactory Receptor OR7A17 Expression Correlates with All-Trans Retinoic Acid (ATRA)-Induced Suppression of Proliferation in Human Keratinocyte Cells.

Olfactory receptors (ORs), which belong to the G-protein-coupled receptor family, have been widely studied as ectopically expressed receptors in various human tissues, including the skin. However, the physiological functions of only a few OR types have been elucidated in skin cells. All-trans retinoic acid (ATRA) is a well-known medication for various skin diseases. However, many studies have shown that ATRA can have adverse effects, resulting from the suppression of cell proliferation. Here, we investigated the involvement of OR7A17 in the ATRA-induced suppression of human keratinocyte (HaCaT) proliferation. We demonstrated that OR7A17 is expressed in HaCaT keratinocytes, and its expression was downregulated by ATRA. The ATRA-induced downregulation of OR7A17 was attenuated via RAR α or RAR γ antagonist treatment, indicating that the effects of ATRA on OR7A17 expression were mediated through nuclear retinoic acid receptor signaling. Moreover, we found that the overexpression of OR7A17 induced the proliferation of HaCaT cells while counteracting the antiproliferative effect of ATRA. Mechanistically, OR7A17 overexpression reversed the ATRA-induced attenuation of Ca2+ entry. Our findings indicated that ATRA suppresses cell proliferation through the downregulation of OR7A17 via RAR α- and γ-mediated retinoid signaling. Taken together, OR7A17 is a potential therapeutic target for ameliorating the anti-proliferative effects of ATRA.

Atypical clinical manifestations of Miller Fisher syndrome.

Miller Fisher syndrome (MFS) is characterized by a clinical triad of ophthalmoplegia, ataxia, and areflexia, and is closely associated with serum anti-GQ1b antibody. Although the clinical triad is the cardinal diagnostic clue, a variety of other symptoms and signs beyond the triad have been reported. To elucidate the frequency and characteristics of atypical clinical manifestations of MFS, we recruited 38 patients with MFS and evaluated the symptoms or signs beyond the classic triad. Eleven (29%) of 38 patients had atypical clinical manifestations of MFS such as headache (n = 6), delayed facial palsy (n = 3), divergence insufficiency (n = 2), and taste impairment (n = 2). Headache was localized to the periorbital (n = 3), temporal (n = 2), or whole (n = 1) area. Only one of them showed bilateral papilledema and an elevated opening pressure in cerebrospinal fluid analysis. Delayed facial palsy developed after the other signs have reached nadir (n = 1) or started to improve (n = 2), and did not follow a pattern of descending paralysis with other cranial neuropathies. Two patients showed divergence insufficiency without external ophthalmoplegia, and another two had taste impairment over the entire tongue without the other signs of facial and glossopharyngeal nerve involvements. Our study shows that approximately 30% of MFS patients can have atypical clinical manifestations beyond the classic triad. These results reflect the broad clinical spectrum of MFS, and might be associated with the presence of additional antiganglioside antibodies besides anti-GQ1b in patients with MFS.

A novel sensor-based assessment of lower limb spasticity in children with cerebral palsy.

BACKGROUND: To provide effective interventions for spasticity, accurate and reliable spasticity assessment is essential. For the assessment, the Modified Tardieu Scale (MTS) has been widely used owing to its simplicity and convenience. However, it has poor or moderate accuracy and reliability. METHODS: We proposed a novel inertial measurement unit (IMU)-based MTS assessment system to improve the accuracy and reliability of the MTS itself. The proposed system consists of a joint angle calculation algorithm, a function to detect abnormal muscle reaction (a catch and clonus), and a visual biofeedback mechanism. Through spastic knee and ankle joint assessment, the proposed IMU-based MTS assessment system was compared with the conventional MTS assessment system in 28 children with cerebral palsy by two raters. RESULTS: The results showed that the proposed system has good accuracy (root mean square error < 3.2°) and test-retest and inter-rater reliabilities (ICC > 0.8), while the conventional MTS system has poor or moderate reliability. Moreover, we found that the deteriorated reliability of the conventional MTS system comes from its goniometric measurement as well as from irregular passive stretch velocity. CONCLUSIONS: The proposed system, which is clinically relevant, can significantly improve the accuracy and reliability of the MTS in lower limbs for children with cerebral palsy.

Diabetic retinopathy is associated with diastolic dysfunction in type 2 diabetic patients with non-ischemic dilated cardiomyopathy.

BACKGROUND: To investigate the association between diabetic retinopathy (DR) and myocardial dysfunction in patients with type 2 diabetes and dilated cardiomyopathy (dCMP). METHODS: Data were collected retrospectively from 89 patients with dCMP (46 with type 2 diabetes and 43 without diabetes) and no evidence of coronary artery disease. Echocardiographic parameters and laboratory data, including lipid profiles and fundus findings, were obtained from medical records. A left ventricular ejection fraction (LVEF) less than 40% was considered impaired systolic function, while an E/E' ratio greater than 15 was considered elevated left ventricular (LV) filling pressure. RESULTS: Baseline characteristics show that LVEF was not significantly different between patients with and without diabetes or between diabetic patients with and without DR. Among the diastolic function parameters, patients with DR exhibited higher E/E' ratios (left ventricular filling pressures) than patients without DR (23.75 ± 13.37 vs 11.71 ± 3.50, P = 0.022). Logistic regression analysis revealed that statin use lowered the risk of impaired systolic dysfunction in all patients (odds ratio (OR) 0.33, 95% confidence interval (CI) 0.12-0.92, P = 0.034) and in patients with diabetes (OR 0.273, 95% CI 0.08-0.99, P = 0.049), while the presence of DR was associated with a higher risk of elevated LV filling filling pressure in patients with diabetes (OR 18.00, 95% CI 1.50-216.62, P = 0.023). CONCLUSIONS: In conclusion, DR was associated with elevated LV filling pressure in patients with dCMP. DR may not only represent microvascular long-term complications in patients with diabetes but may also be associated with more advanced form of diastolic dysfunction among diabetic patients with cardiomyopathy.

Isolated optic neuritis associated with Mycoplasma pneumoniae infection: report of two cases and literature review.

Mycoplasma pneumonia is a major pathogen of primary atypical pneumonia and has been known to cause various kinds of extrapulmonary manifestations involving almost all organs of the human body. Optic neuritis associated with M. pneumoniae infection has rarely been described and mostly, it combined other neurological complications including meningitis, meningoencephalitis, myelitis, and peripheral neuropathy. We report two patients who presented with isolated optic neuritis due to M. pneumoniae infection, and reviewed the literatures on five additional patients. All patients are child or young adults, and optic neuritis was unilateral (n = 3) or bilateral (n = 4). Remarkably, four patients did not have preceding history of respiratory M. pneumonia infection, and ocular pain or headache was accompanied in only three. Although initial visual acuities were severely reduced in most cases, visual outcome was excellent after systemic steroid and/or antibiotics treatment. M. pneumonia infection should be considered in the differential diagnosis of isolated optic neuritis, especially when occurring in a child or young adults, even though there was no preceding pneumonia, accompanying ocular pain, or headache. Various mechanisms including direct local inflammation, vascular occlusion, or indirect immune modulation due to M. pneumonia infection can lead to isolated neurological manifestations without pneumonia.

Clinical and Oculographic Analysis of Inferior Oblique Myokymia.

A 63-year-old man experienced transient vertical oscillopsia lasting several seconds for 2 months. Examination disclosed paroxysmal excyclotorsion of the right eye, spontaneously or triggered by adduction. Eye movements using 3D video-oculography showed intermittent, monocular phasic movements which consisted of excyclotorsion of the right eye mixed with a small amount of supraduction and abduction, and a tonic movement with excyclotorsion and slight elevation. Orbital and brain MRI was unremarkable. Administration of oxcarbazepine markedly decreased the severity and frequency of the episodes. The oculographic characteristics in our patient may indicate that inferior oblique myokymia may be attributed to aberrant, spontaneous discharges in the inferior oblique motor unit.

Transition-Metal-Free Regioselective Alkylation of Pyridine N-Oxides Using 1,1-Diborylalkanes as Alkylating Reagents.

Reported herein is an unprecedented base-promoted deborylative alkylation of pyridine N-oxides using 1,1-diborylalkanes as alkyl sources. The reaction proceeds efficiently for a wide range of pyridine N-oxides and 1,1-diborylalkanes with excellent regioselectivity. The utility of the developed method is demonstrated by the sequential C-H arylation and methylation of pyridine N-oxides. The reaction also can be applied for the direct introduction of a methyl group to 9-O-methylquinine N-oxide, thus it can serve as a powerful method for late-stage functionalization.

Ophthalmoplegia Due to Scrub Typhus.

Scrub typhus is an acute febrile infectious disease caused by Orientia tsutsugamushi. The illness is usually characterized by fever, rash, and lymphadenopathy, but severe cases progress to pulmonary and neurological involvement. We report a 69-year-old man who developed ptosis and ophthalmoplegia with a focal nodular lesion in the anterior cavernous sinus detected with magnetic resonance imaging. Found to have scrub typhus, the ptosis and ophthalmoplegia resolved after treatment with doxycycline.

Abnormal vestibular-evoked myogenic potentials as a risk factor for unpredicted falls in spinocerebellar ataxia: a preliminary study.

OBJECTIVE: This study aimed to correlate the symptoms and signs with the findings of laboratory vestibular function tests in patients with spinocerebellar ataxia (SCA). METHOD: We retrospectively recruited 26 patients with SCA (9 men, median age: 52, age range: 21-67). Assessments included Dizziness Handicap Inventory, EuroQoL Five-Dimension, symptom questionnaires manifesting during walking in daily life, the Scale for the Assessment and Rating of Ataxia (SARA), and vestibular function tests including 3D video-oculography, video head impulse test, subjective visual vertical, and cervical and ocular vestibular evoked myogenic potentials (VEMP). RESULTS: Cross-analyses revealed that the patients with VEMP abnormalities showed higher SARA (p = 0.014) and prevalence of unpredictable falls (p = 0.046). The patients with SCA1 more frequently had unpredictable falls (75%, p = 0.038) and VEMP abnormalities (88%, p = 0.001) compared to SCA2 (29% falls, 17% VEMP abnormalities) and SCA6 (no falls or VEMP abnormalities). CONCLUSION: Abnormal VEMPs are strongly associated with unpredicted falls in patients with SCA, particularly in those with SCA1. Impaired processing of otolithic information may contribute to falls in SCAs, and VEMP may help identifying the patients with a risk for unpredicted falls and preventing fall-related injuries in SCA. Limited number of patients with lower SARA scores warrant further confirmatory studies.