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INTRODUCTION: The tumor microenvironment is mainly flooded with immunosuppressive cells and inhibitory cytokines, resulting in the inability of effective immune cells to infiltrate and recognize tumors and even the loss of anti-cancer ability. OBJECTIVES: We propose a novel HDAC6/HSP90 dual inhibitory strategy as well as a chemoimmunotherapeutic agent that does not only kill tumor cells but also destroys the tumor microenvironment and enhances anti-cancer immunity. METHODS: A hybrid scaffold construction approach was leveraged to furnish a series of rationally designed resorcinol-based hydroxamates as dual selective HDAC6/HSP90 inhibitors. The drug design campaign commenced with a fragment recruitment process to pinpoint validated structural units to inhibit HDAC6 and HSP90, followed by their installation in flexible HDAC inhibitory templates via an efficient and facile multistep synthetic route. Subsequent evaluations identified a strikingly potent selective HDAC6/HSP90 dual inhibitor (compound 17) via molecular and biological analysis in vitro and in vivo. RESULTS: Compound 17 exhibited not only direct cytotoxicity to cancer cells but also downregulated immune checkpoints (PD-L1 and IDO) expression in tumors via the inhibition of STAT1 pathway and degradation of oncogene proteins (Src, AKT, Rb, and FAK), leading to in vivo tumor growth inhibition. These multiple effects enabled the effector T cells to largely infiltrate into the tumor region and release granzyme B to kill cancer cells. In addition, compound 17 also decreased TGF-β secretion from normal cells, resulting in the systemic reduction of immunosuppressive regulatory T cells. Delightfully, a cocktail treatment of compound 17 and anti-PD-1 antibodies demonstrated synergistic efficacy to eliminate solid tumors with 83.9% of tumor growth inhibition. CONCLUSION: In summary, the impressive activity profile of compound 17, as an effective anticancer agent and a potential immunosensitizer, forecasts the application of HDAC6/HSP90 dual inhibitory strategy to overcome the immunosuppressive tumor microenvironment.

Three new isopimaric acid diterpenoids, 6-oxoisopimaric acid (1), 6α-hydroxyisopimaric acid (2), and isopimara-7,9(11),15-trien-18-oic acid (4), together with two known isopimaric acid diterpenoids, isopimaric acid (3), and 8(14),15-isopimaradien-18-oic acid (5), were isolated from the bark of Cryptomeria japonica D. Don. Their structures were determined by analysis of spectroscopic data and comparison with the spectral data of known analogues. At the concentration of 50 μM, compounds 1–5 inhibited xanthine oxidase activity by 17.3, 16.5, 2.6, 30.5, and 24.5 %, respectively.

Summary Mechanoreceptors are essential components of the somatosensory system that convert received mechanical signals into electrical signals that can be sent to the brain. These receptors provide the ability to sense a variety of stimuli from the external environment, including touch, vibration, and heat. Mechanoreceptors do not convert signals monotonically; in addition, several fundamental characteristics are embedded in mechanoreceptors, including thresholds and adaptation properties. In this study, we proposed and experimentally demonstrated a van der Waals stacking field-effect transistor (VS-FET), which was inspired by an FET with a floating gate structure, to realize the important characteristics of mechanoreceptors. The VS-FET can not only demonstrate the fundamental biological functions but also produce other unique properties such as fatigue and accommodation. We also integrated an artificial touch receptor with an array of the proposed VS-FET to demonstrate the feasibility of these devices experimentally in artificial humanoid systems.

Little is known about the impact of fronto-temporal transcranial direct current stimulation (tDCS) on attitudes toward mental illness, psychosocial and autonomic functioning, life quality, and medication adherence among schizophrenia patients.Sixty schizophrenia patients were randomly allocated to receive 10 sessions of active (2 mA, 20 min, 2 sessions/day for five weekdays) or sham fronto-temporal tDCS. Self-Appraisal of Illness Questionnaire (SAIQ), Medication Adherence Rating Scale (MARS), World Health Organization Quality of Life-BREF (WHOQOL-BREF) and indices of heart rate variability (HRV) were measured at baseline, immediately after tDCS and at one-month follow-up visit.There were significant group-by-time interactions for scores of SAIQ presence/outcome subscale, total MARS and its subscale of subjective response to taking medication, WHOQOL-BREF psychological domain. Relative to sham, tDCS significantly improved self-awareness of presence/outcome of schizophrenia (Cohen's d = 0.465, p = 0.0011), subjective response to taking medication (Cohen's d = 0.639, p 0.001) and psychological domain of life quality (Cohen's d = 0.459, p = 0.00114). These effects lasted for less than one month. The group-by-time interactions were non-significant for clinician-rated psychosocial functioning, mean RR intervals, and all HRV indices.Fronto-temporal tDCS briefly optimizes self-reported insight levels, beliefs about treatment adherence, and psychological domain of life quality in patients with schizophrenia. Further studies are required to confirm whether patients treated with 5-day, 10-session tDCS in combination with multisession "maintenance" stimulation every month would attain favourable outcomes.We provide novel evidence for the potential utility of tDCS in schizophrenia.

The exploitation of high-quality borophosphate-based phosphor products is currently garnering a significant research focus in solid-state light source. The interest is due to its low-cost and environment-friendly synthesis. In this paper, a new La7O6(BO3)(PO4)2 (LBP):Dy phosphor was developed via sintering at 1673 K for 3 h under an air atmosphere. Structural characterization indicates that all of the prepared products are the monoclinic phases with the space group P21/n. A comparison of the surface chemical states of the elemental compositions for the LBP host versus optimal LBP:13%Dy product was conducted via X-ray photoelectron spectroscopy. Optical characterization shows that the Dy-doped products exhibited visible light emissions of Dy3+ from 4F9/2 to 6H15/2, 6H13/2, and 6H11/2 upon exposure to 348 nm near-ultra violet irradiation. The dominant emission (yellow, 576 nm) belongs to the 4F9/2 → 6H13/2 transition. The best Dy content for doping was 13 mol%, and content quenching occurred due to dipole – dipole interaction. The measured decay lifetime and calculated chromatic properties together manifest that the optimal LBP:13%Dy phosphor shows potential as a yellow ingredient in solid-state lighting.

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This investigation reports the nanostructural evolution and associated encapsulation and elution of a hydrophobic drug, demethoxycurcumin (DMC), as a molecular probe, with the carboxymethyl-hexanoyl chitosan (CHC), which has been a technically interesting amphiphilic chitosan-based polymer successfully developed in this lab for years. The self-assembly nature of the CHC in neutral aqueous solutions allowed efficient encapsulation of various drugs without deteriorating or changing drugs' activity. However, its self-assembly behavior associated with nanostructural stability or variation, in terms of residence time in aqueous solution has not been well characterized and how the CHC nanostructure may be altered upon entrapping a drug, followed releasing out of the nanostructure. In this study, the CHC/DMC assembled model was used to evaluate entrapping efficiency, CHC-DMC interaction, and nanostructural variation while the drug being encapsulated and released from the CHC nanoparticles. Experimental outcomes showed a fractal transition between nanoparticulate and short fiber-like network evolution of the CHC as time elapsed, with the presence or absence of the DMC probe. This entrapment of DMC is relatively efficient upon CHC assembly and the associated DMC arrangement inside the helical CHC macromolecule gave largely increasing space over the resulting CHC/DMC assembly. Its excellent colloidal and nanostructural stability over a reasonably long period of time in testing environment suggests that this CHC/DMC assembly not only provides a crucial advantage for drug delivery application but also considers as a nanostructural model for better understanding of the mechanism upon drug encapsulation and elution which may be applicable to alternative amphiphilic polysaccharide-based macromolecules.

No studies have examined the effects of fronto-temporal transcranial direct current stimulation (tDCS) on cognitive insight and neurocognitive function in schizophrenia patients and the dynamic interplay between tDCS-induced changes in these two outcomes. In this double-blind, randomized, sham-controlled study, we investigated the effects of fronto-temporal tDCS [anode corresponding to left dorsolateral prefrontal cortex and cathode to left temporo-parietal junction; 2-mA, twice-daily sessions for 5 days] on illness severity, psychosocial functioning, cognitive insight and neurocognitive function in schizophrenia patients (N = 60). The authors observed significant trends that tDCS ameliorated the severity of total and general psychopathology as measured by the Positive and Negative Syndrome Scale. No significant effects were observed for other psychopathological symptoms and psychosocial functioning. Cognitive insight as measured by the Beck Cognitive Insight Scale (BCIS) was rapidly enhanced by 10-session tDCS (F = 10.80, Cohen's d = 0.44, p = 0.002) but the beneficial effect became borderline significant 1 month after stimulation. A trend-level improvement with tDCS of planning ability (F = 6.40, Cohen's d = 0.339, p = 0.014) as measured by the accuracy in Tower of London task was also observed. In the active tDCS group, the change in cognitive insight from baseline to immediately after tDCS assessment was positively correlated with that in planning ability (r = 0.46, p = 0.015), which was independent of the corresponding change in illness severity. The promising results regarding the fast-acting beneficial effects of tDCS on cognitive insight and planning ability in schizophrenia require confirmation in future replication studies.

The exploration of appropriate inorganic phosphors with high color purity (CP) and low correlated color temperature (CCT) has always been a hot issue for solid state light applications. In this work, we have developed series of Sm3+ doped Li2NaBP2O8 (abbreviated as: LNBP) phosphors by means of the solid state synthesis route. The crystalline phase compositions, micromorphology, valence state of elements as well as photoluminescence properties were systematically illustrated. Upon the excitation wavelength at 400 nm, emission peaks are located at 561，597，643 and 699 nm, corresponding to the 4G5/2 → 6H5/2, 6H7/2, 6H9/2 and 6H11/2 transitions of Sm3+ in the same order. The optimal doping amount of Sm3+ ions is 2 mol% for the reddish-orange photoluminescence of the LNBP:Sm3+ phosphor system. The critical energy transfer distance, mechanism of concentration quenching, CIE chromaticity coordinate, CP, CCT and internal quantum efficiency were extensively investigated. The title product might be considered as a promising candidate of phosphor in near UV-based warm white LEDs.

Three new 7-oxoabietane-type diterpenoids, 3-oxosugiol methyl ether (1), 18-hydroxysugiol (2), and 1β-hydroxysugiol (3), as well as two known 7-oxoabietane-type diterpenoids, 6α-hydroxysugiol (4) and 6α-acetoxysugiol (5), were isolated from the bark of Cryptomeria japonica D. Don. Their structures were elucidated mainly by NMR and HREIMS, as well as on comparison with the data of known analogues. At the concentration of 75 μM, compounds 2 and 5 exhibited 11.9 and 21.7% xanthine oxidase inhibitory activity, respectively.

OBJECTIVE Tracheostomy in children is a surgical procedure with considerable morbidity and mortality. However, there is still a lack of population-based survey in pediatric tracheostomy. This study analyses population-based data in pediatric tracheostomy among different ages in Taiwan. METHODS This study used National Health Insurance Research Database in Taiwan. All children (aged

Neuromorphic electronics with two-dimensional van der Waals materials meet the ever-increasing demands of both the semiconductor industry and biological engineering, such as miniaturization, structure flexibility, multifunctionality, and low power consumption. However, the majority of reported electronic devices achieve multifarious memory storage states or synaptic plasticity through regulation of an electrical or an optical signal. Herein, we propose an innovative touch-modulated device based on an indium selenide/hexagonal boron nitride/graphene van der Waals heterostructure coupled with a triboelectric nanogenerator. The device is prepared utilizing a simple copper grid shadow mask instead of the expensive and cumbersome electron beam lithography process, exhibits high mobility of 829 cm2 V−1 s−1, low voltage, and low power consumption. Nonvolatile memory with self-writing power, durability and multibit data storage is achieved through mechanical modulation without an additional gate-voltage supply. Moreover, by adjusting the distance between the two friction layers, essential synaptic plasticity, including short-term and long-term potentiation/depression and paired-pulse facilitation/depression, are successfully imitated in the device. Most importantly, we achieve ultralow power consumption of 165 aJ in tribotronic synapses owing to the ultra-high mobility of InSe. Our tribotronic synapse with self-writing power has great potential to simulate the low-power-consuming neuromorphic bioelectronic devices with multiple functions and lays the foundation for future advanced neuromorphic systems and artificial intelligence.

We design a novel ABA type triblock copolymer (triBCP) by performing efficient synthetic methods of chain-growth condensation polymerization (CGCP), supplemental activator and reducing agent atom transfer radical polymerization (SARA ATRP), and styrenics-assisted atom transfer radical coupling (SA ATRC). A well-defined poly(3-(N-(octyloxy)benzyl benzamide) having a 2-bromo-2-phenylacetate effective ATRP initiating site (i.e., POOBBA-BrPA) through CGCP following quantitative chain end modifications, was firstly synthesized. The POOBBA-BrPA macroinitiator then conducted chain extension with lauryl methacrylate (LMA) via SARA ATRP to obtain the POOBBA-b-PLMA-Br diBCP (Mn = 8800 and Mw/Mn = 1.15). This was followed by SA ATRC of POOBBA-b-PLMA-Br with a high extent of coupling (xc = 0.85, Mn = 15300, and Mw/Mn = 1.26). The obtained triBCP was further purified and the selective removal of the protecting group yielded poly(N-H benzamide)-b-poly(lauryl methacrylate)-b-poly(N-H benzamide) (i.e., PNHBA-b-PLMA-b-PNHBA) was conducted. The characterization of these copolymers was performed using 1H NMR, GPC, FT-IR, TGA, DSC, AFM and SAXS.

Visualization has been extensively applied in many areas, especially for the management of massive data and the display interface area. However, the complexity of grid connections in a large-scale power system is a challenging issue. For an efficient power system operation, it is necessary for electrical engineers and operators to analyze huge amount of data. Additionally, providing real-time operating status and visualization to system operators is also significant. This work reviews different types of power system visualization techniques, including power-flow visualization, trend charts, pie chart, area chart, and warnings in colors. This work also developed a visualization interface that displays the transmission system congestions for N-0 steady state and N-1 contingency analyses. The developed visualization interface has been applied to the Taiwan power system by considering real system parameters and operating conditions, and the developed visualization techniques include the plot for displaying real-time transmission system operation, status warning, and N-1 system contingencies. The developed visualization interface helps system operators understand the real-time operating conditions and determine the potential schedules for generation and transmission systems.

To assess outcomes of pediatric tracheotomy and duration of associated hospital stay according to indications.In this retrospective study, subjects were 142 consecutive pediatric patients (18 years old) who underwent tracheotomy at a tertiary referral medical center, National Taiwan University Hospital, in 1997-2012. Age, sex, indications, pre-operative status (oxygen demand, number of repeated intubations), and post-operative status (duration of weaning, length of hospital stay, mortality) were analyzed.The indications included craniofacial anomalies (n = 19, 13.4%), upper airway obstruction (n = 41, 28.9%), neurological deficit (n = 58, 40.8%), prolonged ventilation (n = 15, 10.6%), and trauma (n = 9, 6.3%). Ninety-one patients (64.1%) were successfully weaned off ventilation after tracheotomy (40% in the prolonged ventilation group). Total hospital stay and duration of ventilation before tracheotomy were longest in patients with craniofacial anomalies (150.9 ± 98.8 days, p = 0.004; 108.8 ± 88.2, p 0.001). The early tracheotomy group had a shorter duration of post-tracheotomy mechanical ventilation support than the late tracheotomy group (14.4 ± 19.0, n = 49 vs. 34.9 ± 58.6, n = 80, p = 0.004). Decannulation was successful in 20 patients (14.1%), with the highest rate in the upper airway obstruction group (n = 14, 34.1%) and lowest in the prolonged ventilation group (none). Thirteen patients (9.2%) died during admission from causes unrelated to tracheotomy.Outcomes of pediatric tracheotomy and duration of hospitalization depend on indications. Children with craniofacial anomalies had earlier tracheotomy age and longer mechanical ventilation before tracheotomy resulted in longer hospitalization. Earlier tracheotomy can shorten the duration of post-tracheotomy mechanical ventilation in several conditions.