High-Temperature Superconducting YBa_(2)Cu_(3)O_(7-δ)Josephson Junction Fabricated with a Focused Helium Ion Beam

As a newly developed method for fabricating Josephson junctions,a focused helium ion beam has the advantage of producing reliable and reproducible junctions.We fabricated Josephson junctions with a focused helium ion beam on our 50 nm YBa_(2)Cu_(3)O_(7-δ)(YBCO)thin films.We focused on the junction with irradiation doses ranging from 100 to 300 ions/nm and demonstrated that the junction barrier can be modulated by the ion dose and that within this dose range,the junctions behave like superconductor–normal conductor–superconductor junctions.The measurements of the I–V characteristics,Fraunhofer diffraction pattern,and Shapiro steps of the junctions clearly show AC and DC Josephson effects.Our findings demonstrate high reproducibility of junction fabrication using a focused helium ion beam and suggest that commercial devices based on this nanotechnology could operate at liquid nitrogen temperatures.

A novel S1P1 modulator IMMH002 ameliorates psoriasis in multiple animal models

Psoriasis is characterized by abnormal proliferation of keratinocytes,as well as infiltration of immune cells into the dermis and epidermis,causing itchy,scaly and erythematous plaques of skin.The understanding of this chronic inflammatory skin disease remains unclear and all available treatments have their limitations currently.Here,we showed that IMMH002,a novel orally active S1 P1 modulator,desensitized peripheral pathogenic lymphocytes to egress signal from secondary lymphoid organs and thymus.Using different psoriasis animal models,we demonstrated that IMMH002 could significantly relieve skin damage as revealed by PAS I score and pathological injure evaluation.Mechanistically,IMMH002 regulated CD3+T lymphocytes re-distribution by inducing lymphocytes’homing,thus decreased T lymphocytes allocation in the peripheral blood and skin but increased in the thymus.Our results suggest that the novel SIP1 agonist,IMMH002,exert extraordinary capacity to rapidly modulate T lymphocytes distribution,representing a promising drug candidate for psoriasis treatment.

A Bioorthogonal-Activated Fluorescence Turn-On Probe Based on Nitrone-Modified 1,8-Naphthalimide for Live-Cell Imaging

A nitrone-modified 1,8-naphthalimide was desig ned as a novel bioorthog on alactivated turn-on probe based on strain-promoted alkyne-nitrone cycloadditio n(SPANC).The bioorthog onal cycloadducts were subseque ntly tran sformed into fluoresce nt rearra nge-ment products by photo-accelerati on,which exhibited sign ificant fluoresce nee enhan ceme nt,large stokes shift,and high fluores-cence qua ntum yield.DFT calculati ons were performed to elucidate the fluoresce nee OFF-ON mecha nism.This fluoroge nic strategy was successfully applied to labeling of proteins and visualizing mitochondria in live cells in real time.

Synthesis of tetrahydroisoquinolines through TiCl4-mediated cyclization and Et3SiH reduction

A versatile and efficient telescoped reaction sequence for the synthesis of tetrahydroisoquinolines(THIQs)is reported that uses TiCl4 to promote cyclization of a benzylaminoacetal derivative and Et3SiH for reduction of the intermediate 4-hydroxy-THIQ.This method is complimentary to the classical Pomeranz-Fritsch and related reactions since it tolerates electron-withdrawing substituents and allows access to 8-substituted THIQs.

A general strategy for in situ assembly of light-up fluorophores via bioorthogonal Suzuki-Miyaura cross-coupling

Herein we presented a general strategy for in situ assembly of intramolecular charge-transfer(ICT)-based light-up fluorophores via bioorthogonal Suzuki-Miyaura cross-coupling reaction.By introducing iodo group at the appropriate position,five fluorophores with different scaffolds including naphthalimide,coumarin,naphthalene sulfonate,nitrobenzoxadiazole,and acetonaphthone,were designed as bioorthogonal multicolor fluorogenic probes,which could produce significant fluorescence enhancement and high fluorescence quantum yield after Suzuki-Miyaura reaction with aryl boronic acid or boronate.Manipulating the substituents andπscaffold in the fluorophores allows fine-tuning of their photophysical properties.With this strategy,we succeeded in peptide conjugation,no-wash fluorogenic protein labeling,and mitochondria-selective bioorthogonal imaging in live cells.

Design and synthesis of selective sphingosine-1-phosphate receptor 1 agonists with increased phosphorylation rates

FTY720 and IMMH002,prodrugs for sphingosine-1-phosphate receptor 1(S1P1)agonists,show inadequate and inconsistent levels of phosphorylation in humans compared to that in rats.In this study,FTY720 or IMMH002 analogues(21-24)were designed and synthesized with modified head pieces to improve the biotransformation of the prodrugs to the active phosphorylated forms.Target compounds were synthesized via a convergent route using the key and optically pure building block 9,which was first synthesized via asymmetrically catalyzed amination.The phosphorylation rates of these analogues in rat or human blood were compared.The new methyl-substituted analogue compound 21 showed higher phosphorylation rates in both rats and humans than the parent compound,whereas compound 23 showed improvements in rats,but not in humans.In pharmacokinetics studies of rats,compounds 21 and 23 both had higher levels of phosphorylation than FTY720 and IMMH002.Thus,our study not only yielded new compounds with therapeutic potential,but also showed species differences between rats and humans in response to the structural modifications,which might be useful for predicting the biotransformation behavior and efficacy of this class of prodrugs in the clinic.