Streamlined Synthesis of C(sp3)-Rich N-Heterospirocycles Enabled by Visible-Light-Mediated Photocatalysis

We report a general visible-light-mediated strategy that enables the construction of complex C(sp3)-rich N-heterospirocycles from feedstock aliphatic ketones and aldehydes with a broad selection of alkene-containing secondary amines. Key to the success of this approach was the utilization of a highly reducing Ir-photocatalyst and orchestration of the intrinsic reactivities of 1,4-cyclohexadiene and Hantzsch ester. This methodology provides streamlined access to complex C(sp3)-rich N-heterospirocycles displaying structural and functional features relevant to fragment-based lead identification programs.We are grateful to the Gates Cambridge Trust (N.J.F.) and Herchel Smith Scholarship Scheme (A.T.) for studentships, the EPSRC (EP/S020292/1 and EP/N031792/1), Ambitious Leader’s Program, Hokkaido University, Japan (Y.K.), and the Royal Society for a Wolfson Merit Award (M.J.G.). S.M.W. is a Fellow of the AstraZeneca Postdoctoral program. We are grateful to the EPSRC UK National Mass Spectrometry Facility at Swansea University for HRMS analysis

Streamlined Synthesis of C(sp3)-Rich N-Heterospirocycles Enabled by Visible-Light-Mediated Photocatalysis

We report a general visible-light-mediated strategy that enables the construction of complex C(sp3)-rich N-heterospirocycles from feedstock aliphatic ketones and aldehydes with a broad selection of alkene-containing secondary amines. Key to the success of this approach was the utilization of a highly reducing Ir-photocatalyst and orchestration of the intrinsic reactivities of 1,4-cyclohexadiene and Hantzsch ester. This methodology provides streamlined access to complex C(sp3)-rich N-heterospirocycles displaying structural and functional features relevant to fragment-based lead identification programs.We are grateful to the Gates Cambridge Trust (N.J.F.) and Herchel Smith Scholarship Scheme (A.T.) for studentships, the EPSRC (EP/S020292/1 and EP/N031792/1), Ambitious Leader’s Program, Hokkaido University, Japan (Y.K.), and the Royal Society for a Wolfson Merit Award (M.J.G.). S.M.W. is a Fellow of the AstraZeneca Postdoctoral program. We are grateful to the EPSRC UK National Mass Spectrometry Facility at Swansea University for HRMS analysis

Titanium dioxide induces apoptotic cell death through reactive oxygen species-mediated Fas upregulation and Bax activation

Background: Titanium dioxide (TiO2) has been widely used in many areas, including biomedicine, cosmetics, and environmental engineering. Recently, it has become evident that some TiO2 particles have a considerable cytotoxic effect in normal human cells. However, the molecular basis for the cytotoxicity of TiO2 has yet to be defined.Methods and results: In this study, we demonstrated that combined treatment with TiO2 nanoparticles sized less than 100 nm and ultraviolet A irradiation induces apoptotic cell death through reactive oxygen species-dependent upregulation of Fas and conformational activation of Bax in normal human cells. Treatment with P25 TiO2 nanoparticles with a hydrodynamic size distribution centered around 70 nm (TiO2P25-70) together with ultraviolet A irradiation-induced caspase-dependent apoptotic cell death, accompanied by transcriptional upregulation of the death receptor, Fas, and conformational activation of Bax. In line with these results, knockdown of either Fas or Bax with specific siRNA significantly inhibited TiO2-induced apoptotic cell death. Moreover, inhibition of reactive oxygen species with an antioxidant, N-acetyl-L-cysteine, clearly suppressed upregulation of Fas, conformational activation of Bax, and subsequent apoptotic cell death in response to combination treatment using TiO2P25-70 and ultraviolet A irradiation.Conclusion: These results indicate that sub-100 nm sized TiO2 treatment under ultraviolet A irradiation induces apoptotic cell death through reactive oxygen species-mediated upregulation of the death receptor, Fas, and activation of the preapoptotic protein, Bax. Elucidating the molecular mechanisms by which nanosized particles induce activation of cell death signaling pathways would be critical for the development of prevention strategies to minimize the cytotoxicity of nanomaterials.This work was supported by the Korea Ministry of Environment and The Eco-Technopia 21 Project (091-091-081)

Interactions between subjective memory complaint and objective cognitive deficit on memory performances

Background Subjective memory complaint (SMCs) is a common trait amongst older population. The subjective cognition about their memory could depend on objective cognition. The aim of the current study was to examine the interaction between subjective memory cognition (i.e., SMC) and objective cognition on cognitive functions in participants from older generation. Methods A total of 219 patients, 181 normal control (NC) patients and 38 patients with mild cognitive impairment (MCI), were examined through standardized and comprehensive clinical evaluation and neuropsychological assessment. The Subjective Memory Complaints Questionnaire was used to assess SMCs along with five cognitive tasks were used to evaluate cognitive decline over following areas: verbal memory, visuospatial memory, attention, fluency, and language. Results The results of 2 × 2 two-way analysis of variance (ANOVA) showed that there were significant interactions between SMCs and cognitive status (NC, MCI) on memory performances. NC with SMCs showed significantly lower performance in verbal memory and visuospatial memory compared to NCs without SMCs. Conversely, no effect was observed in the MCI group. Conclusion There are interactions between subjective cognition (i.e., SMC) and objective cognition (i.e., cognitive status) on memory performances in older adults. The roles of SMCs on memory performances should be interpreted with older adults objective cognitive status.This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (No. NRF-2017R1D1A1A02018479). This funding source had no role in the design of this study and will not have any role during its execution, analyses, interpretation of the data, or decision to submit result

Estimating the Damage Function of Disease and Insect Pest of Ginseng Considering Spatial Autocorrelation

The increasing trend in disease and insect pest (DIP) outbreaks is expected to continue due to climate change and become one of the major risks for the agricultural sector. Many researchers tried to construct a flexible control system of the DIP outbreaks that have intensified with climate change. This study estimated a DIP damage function for ginseng that is incorporating spatial autocorrelation and weather variables. We find that major DIP of ginseng such as anthracnose and gray mold has statistically significant spatial autocorrelation effects within the effective distance. Our estimation result also shows that there exists a significant relationship between DIP outbreaks and weather variables except for Pseudococcus Comstock. And anthracnose outbreaks show a strong spatial autocorrelation especially when the effective distance is considered

The Role of American Sign Language(ASL) in Paired Deaf Signers' Mathematics Learning through Computer Games

2015Many researchers have investigated how hearing kindergarteners explore technology-based tools (e.g., mathematics computer games) and interact with each other while playing computer games. However, we still know very little about how deaf kindergarteners interact and sign with each other while using technology-based tools. We conducted a case study of paired deaf signers learning number concepts playing mathematics computer games. We observed three different pairs for five months and videotaped sessions between two signers working on on-line mathematics computer games. The paired students American Sign Language competency was found to be critical for deaf kindergartners interaction to solve mathematical questions such as number concepts. Our findings also indicate that mathematics computer games can be a tool which can motivate deaf signers to communicate with each other and that in technology-based learning environments pairing would be a strategy to encourage deaf signers to interact with each other

A Sub-1 ppm/degrees C CMOS Bandgap Voltage Reference With Process Tolerant Piecewise Second-Order Curvature Compensation

This paper presents a CMOS high-precision bandgap voltage reference. To obtain low temperature coefficient (TC) regardless of process variation, piecewise second-order curvature compensation method is proposed. Curvature compensation current is generated through current subtraction and current squaring operation with two currents with different dependence on temperature. Also, several circuit techniques are adopted to achieve compensate error sources. Chopping technique is utilized to cancel 1/f noise and DC offset of the error amplifier. Trimming resistor is used to compensate process variation. The bandgap reference is designed in a 0.13 mu m CMOS process. Post layout simulation shows that TC of the bandgap reference is 0.64ppm/degrees C over a wide temperature range of -40 degrees C to 125 degrees C. Moreover, sub-1 ppm/degrees C TC is achieved irrespective of process variation after two-point temperature trimming. The bandgap reference consumes 44 mu A at 27 degrees C and layout size is 0.0534mm(2).N