Corynoxine B targets at HMGB1/2 to enhance autophagy forα-synuclein clearance in fly and rodent models of Parkinson's disease

Parkinson's disease(PD)is the most common neurodegenerative movement disease.It is featured by abnormal alphα-synuclein(α-syn)aggregation in dopaminergic neurons in the substantia nigra.Macroautophagy(autophagy)is an evolutionarily conserved cellular process for degradation of cellular contents,including protein aggregates,to maintain cellular homeostasis.Corynoxine B(Cory B),a natural alkaloid isolated from Uncaria rhynchophylla(Miq.)Jacks.,has been reported to promote the clearance ofα-syn in cell models by inducing autophagy.However,the molecular mechanism by which Cory B induces autophagy is not known,and theα-syn-lowering activity of Cory B has not been verified in animal models.Here,we report that Cory B enhanced the activity of Beclin 1/VPS34 complex and increased autophagy by promoting the interaction between Beclin 1 and HMGB1/2.Depletion of HMGB1/2 impaired Cory B-induced autophagy.We showed for the first time that,similar to HMGB1,HMGB2 is also required for autophagy and depletion of HMGB2 decreased autophagy levels and phosphatidylinositol 3-kinaseⅢactivity both under basal and stimulated conditions.By applying cellular thermal shift assay,surface plasmon resonance,and molecular docking,we confirmed that Cory B directly binds to HMGB1/2 near the C106 site.Furthermore,in vivo studies with a wild-typeα-syn transgenic drosophila model of PD and an A53Tα-syn transgenic mouse model of PD,Cory B enhanced autophagy,promotedα-syn clearance and improved behavioral abnormalities.Taken together,the results of this study reveal that Cory B enhances phosphatidylinositol 3-kinaseⅢactivity/autophagy by binding to HMGB1/2 and that this enhancement is neuroprotective against PD.

800 Gbit/s transmission over 1 km single-mode fiber using a four-channel silicon photonic transmitter

We demonstrate the optical transmission of an 800 Gbit/s(4×200 Gbit/s)pulse amplitude modulation-4(PAM-4)signal and a 480 Gbit/s(4×120 Gbit/s)on–off-keying(OOK)signal by using a high-bandwidth(BW)silicon photonic(SiP)transmitter with the aid of digital signal processing(DSP).In this transmitter,a four-channel SiP modulator chip is co-packaged with a four-channel driver chip,with a measured 3 dB BW of 40 GHz.DSP is applied in both the transmitter and receiver sides for pre-/post-compensation and bit error rate(BER)calculation.Back-to-back(B2B)BERs of the PAM-4 signal and OOK signal are first measured for each channel of the transmitter with respect to a variety of data rates.Similar BER performance of four channels shows good uniformity of the transmitter between different channels.The BER penalty of the PAM-4 and OOK signals for 500 m and 1 km standard single-mode fiber(SSMF)transmission is then experimentally tested by using one channel of the transmitter.For a 200 Gbit/s PAM-4 signal,the BER is below the hard-decision forward error correction(HD-FEC)threshold for B2B and below the soft-decision FEC(SD-FEC)threshold after 1 km transmission.For a 120 Gbit/s OOK signal,the BER is below SD-FEC threshold for B2B.After 500 m and 1 km transmission,the data rate of the OOK signal shrinks to 119 Gbit/s and 118 Gbit/s with the SD-FEC threshold,respectively.Finally,the 800 Gbit/s PAM-4 signal with 1 km transmission is achieved with the BER of all four channels below the SD-FEC threshold.