A logical network-based drug-screening platform for Alzheimer's disease representing pathological features of human brain organoids.

Developing effective drugs for Alzheimer's disease (AD), the most common cause of dementia, has been difficult because of complicated pathogenesis. Here, we report an efficient, network-based drug-screening platform developed by integrating mathematical modeling and the pathological features of AD with human iPSC-derived cerebral organoids (iCOs), including CRISPR-Cas9-edited isogenic lines. We use 1300 organoids from 11 participants to build a high-content screening (HCS) system and test blood-brain barrier-permeable FDA-approved drugs. Our study provides a strategy for precision medicine through the convergence of mathematical modeling and a miniature pathological brain model using iCOs.

Inhibitory Basal Ganglia Inputs Induce Excitatory Motor Signals in the Thalamus.

Basal ganglia (BG) circuits orchestrate complex motor behaviors predominantly via inhibitory synaptic outputs. Although these inhibitory BG outputs are known to reduce the excitability of postsynaptic target neurons, precisely how this change impairs motor performance remains poorly understood. Here, we show that optogenetic photostimulation of inhibitory BG inputs from the globus pallidus induces a surge of action potentials in the ventrolateral thalamic (VL) neurons and muscle contractions during the post-inhibitory period. Reduction of the neuronal population with this post-inhibitory rebound firing by knockout of T-type Ca2+ channels or photoinhibition abolishes multiple motor responses induced by the inhibitory BG input. In a low dopamine state, the number of VL neurons showing post-inhibitory firing increases, while reducing the number of active VL neurons via photoinhibition of BG input, effectively prevents Parkinson disease (PD)-like motor symptoms. Thus, BG inhibitory input generates excitatory motor signals in the thalamus and, in excess, promotes PD-like motor abnormalities. VIDEO ABSTRACT.

An MEG study of alpha modulation in patients with schizophrenia and in subjects at high risk of developing psychosis.

BACKGROUND: Selective attention involves a dynamic interaction between attentional control systems and brain oscillations. In auditory processing, selective attention toward task-relevant stimuli and the inhibition of irrelevant information can be considered as aspects of top-down attentional control. Oscillatory rhythms in the alpha band have been found to play an important role during top-down processing. Because attention deficits have been noted in patients with schizophrenia, we examined alpha oscillations in schizophrenia and in the prodromal phase of psychosis. METHODS: The present study compared alpha oscillations using measures of both spectral power and inter-trial coherence in 17 subjects at ultra-high-risk, 10 patients with schizophrenia, and 18 matched normal control subjects. Whole-head magnetoencephalography (MEG) was conducted during an auditory oddball task to investigate alpha brain activity related to selective attention to target stimuli and selective inhibition of irrelevant stimuli. RESULTS: Patients with schizophrenia showed diminished alpha event-related desynchronization compared with the control subjects, while the ultra-high-risk subjects had values intermediate between the control subjects and schizophrenia patients. Similarly, alpha inter-trial phase coherence was lower in the schizophrenia patients than the ultra-high-risk subjects, and lower in the ultra-high-risk subjects than the normal control subjects. Furthermore, alpha band activity in the parieto-occipital region was more severely depressed in the schizophrenia patients than the ultra-high-risk subjects. CONCLUSIONS: The altered alpha band activity in the ultra-high-risk group indicates that a deficit in top-down attentional control exists before the onset of psychosis. The alpha event-related desynchronization and inter-trial coherence may reflect a functional decline in the prodromal phase of schizophrenia.

Full-spectrum light phototherapy for atopic dermatitis.

BACKGROUND: Atopic dermatitis (AD) is a chronic skin disease resulting in a profound deterioration in quality of life. The FSL® is a newly developed phototherapy device generating full-spectrum light (FSL) with a continuous wavelength (320-5000 nm). This study aimed to evaluate the efficacy and safety of FSL® phototherapy in AD. METHODS: We enrolled 38 patients with moderate to severe AD in this open, randomized, controlled, prospective study. In the FSL-irradiated group (20 patients), irradiation was conducted twice per week for 4 consecutive weeks. In the control group (18 patients), only emollient application was allowed. SCORing Atopic Dermatis (SCORAD) values were obtained at baseline, week 4 and 8. Patients were asked to give subjective assessments of improvement and laboratory tests including serum eosinophil counts, ECP levels, IgE levels and 22 cytokine levels were performed. RESULTS: In the FSL-irradiated group, the mean SCORAD value decreased significantly after 4 weeks of phototherapy and remained reduced for a further 4 weeks after the cessation of treatment. In the control group, the mean SCORAD value did not change significantly over the study period. Patients' subjective assessments indicated good to excellent responses in 75% of the FSL-irradiated group, by contrast with 50% of the control group. The mean values for serum eosinophil counts, IL-4 and IL-5 levels decreased significantly after FLS phototherapy. No serious adverse effects were reported. CONCLUSIONS: In this study, we showed that FSL® phototherapy can be an effective and safe treatment option in AD.

Effect of CYP2C9 and VKORC1 genotypes on early-phase and steady-state warfarin dosing in Korean patients with mechanical heart valve replacement.

OBJECTIVES: The effect of CYP2C9 and vitamin K epoxide reductase complex subunit 1 (VKORC1) genotypes was evaluated for the early-phase and steady-state warfarin dosing in Korean patients with mechanical heart valve replacement. METHODS: The genotypes of CYP2C9 variants including CYP2C9*3, CYP2C9*13, and CYP2C9*14, and VKORC1 1173C>T were assessed for the association with warfarin dosing in 265 patients whose data were collected for warfarin dose; international normalized ratio (INR), comedication, comorbidity, and other clinical characteristics. RESULTS: In the early phase of warfarin therapy, the combined genotypes of CYP2C9 and VKORC1 caused statistically significant difference in warfarin dose from day 7 of warfarin dosing and the subsequent time course of dose increase showed significant difference among the three different genotypes (P<0.001). Compared with patients with CYP2C9 wild type, the patients with heterozygous CYP2C9 variants have delayed time to reach stable dose [adjusted hazard ratio (HRadj): 0.48; 95% confidence interval (CI): 0.27-0.85] and tended to have high risk for the first INR greater than 3.5 (HRadj: 1.64; 95% CI: 0.98-2.75). The patients with the VKORC1 CT genotype showed no significant difference in the time to reach stable dose but statistically significant low HR for time to first INR greater than 3.5 compared with those with VKORC1 TT genotype (HRadj: 0.25; 95% CI: 0.13-0.51). The observed warfarin maintenance dose was best explained by a model including covariates of age, weight, concurrent congestive heart failure/cardiomyopathy, INR-increasing drugs, aspirin, dietary supplements, and CYP2C9 and VKORC1 genotypes (R=0.56). CONCLUSION: The heterozygous CYP2C9 and VKORC1 genotypes influence warfarin dosing in an early phase as well as steady state of warfarin therapy in Korean patients with mechanical heart valve replacement.

Berberine inhibits TPA-induced MMP-9 and IL-6 expression in normal human keratinocytes.

Berberine is a plant ingredient that has anti-inflammatory and anti-oxidative effects. Matrix metalloproteinase-9 (MMP-9) and interleukin-6 (IL-6) are known to be highly induced by ultraviolet (UV) light and may play important roles in UV-induced skin inflammation and the skin aging process. In this study, we investigated the effects of berberine on MMP-9 and IL-6 expression in normal human keratinocytes (NHK). Our results demonstrated that berberine dose-dependently inhibited basal and TPA-induced expression and activity of MMP-9, and also suppressed TPA-induced IL-6 expression. Berberine prevented TPA-induced ERK activation and AP-1 DNA binding activity. Therefore, berberine may be used as an effective ingredient for anti-skin aging products, which can prevent skin inflammation and the degradation of extracellular matrix proteins, including collagen, by MMPs.

Bee venom injection significantly reduces nociceptive behavior in the mouse formalin test via capsaicin-insensitive afferents.

UNLABELLED: Peripheral bee venom (BV) administration produces 2 contrasting effects, nociception and antinociception. This study was designed to evaluate whether the initial nociceptive effect induced by BV injection into the Zusanli acupoint is involved in producing the more prolonged antinociceptive effect observed in the mouse formalin test, and whether capsaicin-sensitive primary afferents are involved in these effects. BV injection into the Zusanli point increased spinal Fos expression but not spontaneous nociceptive behavior. BV pretreatment 10 minutes before intraplantar formalin injection dose-dependently attenuated nociceptive behavior associated with the second phase of the formalin test. The destruction of capsaicin-sensitive primary afferents by resiniferatoxin (RTX) pretreatment selectively decreased BV-induced spinal Fos expression but did not affect BV-induced antinociception. Furthermore, BV injection increased Fos expression in tyrosine hydroxylase immunoreactive neurons in the locus caeruleus, and this expression was unaltered by RTX pretreatment. Finally, BV's antinociception was blocked by intrathecal injection of 10 microg idazoxan, and this effect was not modified by RTX pretreatment. These findings suggest that subcutaneous BV stimulation of the Zusanli point activates central catecholaminergic neurons via capsaicin-insensitive afferent fibers without induction of nociceptive behavior. This in turn leads to the activation of spinal alpha2-adrenoceptors, which ultimately reduces formalin-evoked nociceptive behaviors. PERSPECTIVE: This study demonstrates that BV acupuncture produces a significant antinociception without nociceptive behavior in rodents, which is mediated by capsaicin-insensitive afferents and involves activation of central adrenergic circuits. These results further suggest that BV stimulation into this acupuncture point might be a valuable alternative to traditional electrical or mechanical acupoint stimulation.

Photo-epilation results of axillary hair in dark-skinned patients by intense pulsed light: comparison between different wavelengths and pulse width.

BACKGROUND: Recently, intense pulsed light (IPL) sources have been shown to provide long-term hair removal. OBJECTIVE: This study examined the photo-epilatory effects of different wavelengths and pulse width application in the same IPL device and compared their efficiencies in Asian skin. METHODS: Twenty-eight Korean women were treated using hair removal (HR) (600-950 nm filter) and 27 using HR-D (645-950 nm filter) in the axillary area. Four treatments were carried out at intervals of 4 to 6 weeks; follow-ups were conducted 8 months after the last treatment. Mean energy settings were 14.9 6 2.0 J/cm2 for HR and 17.1 6 0.6 J/cm2 for HR-D. Longer pulse widths were applied in case of HR-D treatment. Hair counts and photographic evaluation of skin sites were made at baseline and at the last follow-up. Final overall evaluations were performed by patients and clinicians. RESULTS: Average clearances of 52.8% and 83.4% were achieved by HR and HR-D, respectively. No significant adverse effects were reported after HR-D treatment. One case each of hypopigmentation and hyperpigmentation was reported for HR. CONCLUSION: An IPL source removing 45 nm of the emitted spectra and applying a longer pulse width was found to provide a safer and more effective means of photo-epilation in Asian patients.

Erythrodiol-3-acetate, pentacyclic triterpenoid from Styrax japonica, expressions of matrix metalloproteinase-1,2 in cultured human skin fibroblasts.

Although many studies have been performed to elucidate the molecular consequences of ultraviolet irradiation, little is known about the effect of natural products. Ultraviolet irradiation is widely considered to be an environmental stress. Here we investigated the effect of erythrodiol-3-acetate on the expressions of MMP-1,2 in cultured human skin fibroblasts. Erythrodiol-3-acetate was isolated from the stems of Styrax japonica (Styracaceae). Erythrodiol-3-acetate reduced the expression of MMP-1 but not MMP-2, at the mRNA and protein levels in a dose-dependent manner by ultraviolet irradiation. Taken together, our results suggest that erythrodiol-3-acetate an important role in the reduction of MMP-1 induction by ultraviolet irradiation.

Modulation of collagen metabolism by the topical application of dehydroepiandrosterone to human skin.

Dehydroepiandrosterone (DHEA) and its sulfate conjugate (DHEA-S) are the most abundantly produced human adrenal steroids to be reduced with age. DHEA may be related to the process of skin aging through the regulation and degradation of extracelluar matrix protein. In this study, we demonstrate that DHEA can increase procollagen synthesis and inhibit collagen degradation by decreasing matrix metalloproteinases (MMP)-1 synthesis and increasing tisuue inhibitor of matrix metalloprotease (TIMP-1) production in cultured dermal fibroblasts. DHEA was found to inhibit ultraviolet (UV)-induced MMP-1 production and the UV-induced decrease of procollagen synthesis, probably due to the inhibition of UV-induced AP-1 activity. DHEA (5%) in ethanol:olive oil (1:2) was topically applied to buttock skin of volunteers 12 times over 4 weeks, and was found to significantly increase the expression of procollagen alpha1(I) mRNA and protein in both aged and young skin. On the other hand, topical DHEA significantly decreased the basal expression of MMP-1 mRNA and protein, but increased the expression of TIMP-1 protein in aged skin. We also found that DHEA induced the expressions of transforming growth factor-beta1 and connective tissue growth factor mRNA in cultured fibroblasts and aged skin, which may play a role in the DHEA-induced changes of procollagen and MMP-1 expression. Our results suggest the possibility of using DHEA as an anti-skin aging agent.