Circadian clock genes REV-ERBα regulates the secretion of IL-1ß in deciduous tooth pulp stem cells by regulating autophagy in the process of physiological root resorption of deciduous teeth.

Physiological root resorption is a common occurrence during the development of deciduous teeth in children. Previous research has shown that the regulation of the inflammatory microenvironment through autophagy in DDPSCs is a significant factor in this process. However, it remains unclear why there are variations in the autophagic status of DDPSCs at different stages of physiological root resorption. To address this gap in knowledge, this study examines the relationship between the circadian clock of DDPSCs, the autophagic status, and the periodicity of masticatory behavior. Samples were collected from deciduous teeth at various stages of physiological root resorption, and DDPSCs were isolated and cultured for analysis. The results indicate that the circadian rhythm of important autophagy genes, such as Beclin-1 and LC3, and the clock gene REV-ERBα in DDPSCs, disappears under mechanical stress. Additionally, the study found that REV-ERBα can regulate Beclin-1 and LC3. Evidence suggests that mechanical stress is a trigger for the regulation of autophagy via REV-ERBα. Overall, this study highlights the importance of mechanical stress in regulating autophagy of DDPSCs via REV-ERBα, which affects the formation of the inflammatory microenvironment and plays a critical role in physiological root resorption in deciduous teeth.

Two-photon absorption flexible photodetector responsive to femtosecond laser.

Integrated on-chip femtosecond (fs) laser optoelectronic system, with photodetector as a critical component for light-electrical signal conversion, is a long-sought-after goal for a wide range of frontier applications. However, the high laser peak intensity and complicated nanophotonic waveguide structure of on-chip fs laser are beyond the detectability and integrability of conventional photodetectors. Therefore, flexible photodetector with the response on intense fs laser is in urgent needs. Herein, we demonstrate the first (to our knowledge) two-photon absorption (TPA) flexible photodetector based on the strong TPA nonlinearity of layered hybrid perovskite (IA)2(MA)2Pb3Br10, exhibiting efficient sub-bandgap response on the infrared fs laser at 700-1000 nm. High saturation intensity up to ∼3.8 MW/cm2 is achieved. The device also shows superior current stability even after bending for 1000 cycles. This work may pave the new way for the application of flexible optoelectronics specialized in integrated fs-laser detection.

[UPLC-Q-TOF-MS-based metabolomics reveals mechanism of Morinda officinalis iridoid glycosides in treating rheumatoid arthritis and bone loss].

This study aimed to investigate the therapeutic effects of Morinda officinalis iridoid glycosides(MOIG) on paw edema and bone loss of rheumatoid arthritis(RA) rats, and analyze its potential mechanism based on ultra-high performance liguid chromatography-guadrupole time-of-flight tandem mass spectrometry(UPLC-Q-TOF-MS) serum metabolomics. RA rats were established by injecting bovin type Ⅱ collagen. The collagen-induced arthritis(CIA) rats were administered drug by gavage for 8 weeks, the arthritic score were used to evaluate the severity of paw edem, serum bone metabolism biochemical parameters were measured by ELISA kits, Masson staining was used to observe the bone microstructure of the femur in CIA rats. UPLC-Q-TOF-MS was used to analyze the alteration of serum metabolite of CIA rats, principal component analysis(PCA) and partial least squares-discriminant analysis(PLS-DA) were used to screen the potential biomarkers, KEGG database analysis were used to construct related metabolic pathways. The results demonstrated that the arthritic score, serum levels of IL-6 and parameters related with bone metabolism including OCN, CTX-Ⅰ, DPD and TRAP were significantly increased, and the ratio of OPG and RANKL was significantly decreased, the microstructure of bone tissue and cartilage were destructed in CIA rats, while MOIG treatments could significantly reduce arthritis score, mitigate the paw edema, reverse the changes of serum biochemical indicators related with bone metabolism, and improve the microstructure of bone tissue and cartilage of CIA rats. The non-targeted metabolomics results showed that 24 altered metabolites were identified in serum of CIA rats; compared with normal group, 13 significantly altered metabolites related to RA were identified in serum of CIA rats, mainly involving alanine, aspartate and glutamate metabolism; compared with CIA model group, MOIG treatment reversed the alteration of 15 differential metabolites, mainly involving into alanine, aspartate and glutamate metabolism, D-glutamine and D-glutamate metabolism, taurine and hypotaurine metabolism, valine, leucine and isoleucine biosynthesis. Therefore, MOIG significantly alleviated paw edema, improved the destruction of microstructure of bone and cartilage in CIA rats maybe through involving into the regulation of amino acid metabolism.

Sequential CD19 and CD22 chimeric antigen receptor T-cell therapy for childhood refractory or relapsed B-cell acute lymphocytic leukaemia: a single-arm, phase 2 study.

BACKGROUND: Relapses frequently occur following CD19-directed chimeric antigen receptor (CAR) T-cell treatment for relapsed or refractory B-cell acute lymphocytic leukaemia in children. We aimed to assess the activity and safety of sequential CD19-directed and CD22-directed CAR T-cell treatments. METHODS: This single-centre, single-arm, phase 2 trial, done at Beijing GoBroad Boren Hospital, Beijing, China, included patients aged 1-18 years who had relapsed or refractory B-cell acute lymphocytic leukaemia with CD19 and CD22 positivity greater than 95% and an Eastern Cooperative Oncology Group performance status of 0-2. Patients were initially infused with CD19-directed CAR T cells intravenously, followed by CD22-directed CAR T-cell infusion after minimal residual disease-negative complete remission (or complete remission with incomplete haematological recovery) was reached and all adverse events (except haematological adverse events) were grade 2 or better. The target dose for each infusion was 0·5 × 106 to 5·0 × 106 cells per kg. The primary endpoint was objective response rate at 3 months after the first infusion. Secondary endpoints were duration of remission, event-free survival, disease-free survival, overall survival, safety, pharmacokinetics, and B-cell quantification. The prespecified activity analysis included patients who received the target dose and the safety analysis included all treated patients. This study is registered with ClinicalTrials.gov, NCT04340154, and enrolment has ended. FINDINGS: Between May 28, 2020, and Aug 16, 2022, 81 participants were enrolled, of whom 31 (38%) were female and 50 (62%) were male. Median age was 8 years (IQR 6-10), all patients were Asian. All 81 patients received the first infusion and 79 (98%) patients received sequential infusions, CD19-directed CAR T cells at a median dose of 2·7 × 106 per kg (IQR 1·1 × 106 to 3·7 × 106) and CD22-directed CAR T cells at a median dose of 2·2 × 106 per kg (1·1 × 106 to 3·7 × 106), with a median interval of 39 days (37-41) between the two infusions. 62 (77%) patients received the target dose, including two patients who did not receive CD22 CAR T cells. At 3 months, 60 (97%, 95% CI 89-100) of the 62 patients who received the target dose had an objective response. Median follow-up was 17·7 months (IQR 11·4-20·9). 18-month event-free survival for patients who received the target dose was 79% (95% CI 66-91), duration of remission was 80% (68-92), and disease-free survival was 80% (68-92) with transplantation censoring; overall survival was 96% (91-100). Common adverse events of grade 3 or 4 between CD19-directed CAR T-cell infusion and 30 days after CD22-directed CAR T-cell infusion included cytopenias (64 [79%] of 81 patients), cytokine release syndrome (15 [19%]), neurotoxicity (four [5%]), and infections (five [6%]). Non-haematological adverse events of grade 3 or worse more than 30 days after CD22-directed CAR T-cell infusion occurred in six (8%) of 79 patients. No treatment-related deaths occurred. CAR T-cell expansion was observed in all patients, with a median peak at 9 days (IQR 7-14) after CD19-directed and 12 days (10-15) after CD22-directed CAR T-cell infusion. At data cutoff, 35 (45%) of 77 evaluable patients had CAR transgenes and 59 (77%) had B-cell aplasia. INTERPRETATION: This sequential strategy induced deep and sustained responses with an acceptable toxicity profile, and thus potentially provides long-term benefits for children with this condition. FUNDING: The National Key Research & Development Program of China, the CAMS Innovation Fund for Medical Sciences (CIFMS), and the Non-Profit Central Research Institute Fund of Chinese Academy of Medical Sciences. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

UV-VIS-NIR broadband flexible photodetector based on layered lead-free organic-inorganic hybrid perovskite.

The flexible photodetector is viewed as a research hotspot for numerous advanced optoelectronic applications. Recent progress has manifested that lead-free layered organic-inorganic hybrid perovskites (OIHPs) are highly attractive to engineering flexible photodetectors due to the effective overlapping of several unique properties, including efficient optoelectronic characteristics, exceptional structural flexibility, and the absence of Pb toxicity to humans and the environment. The narrow spectral response of most flexible photodetectors with lead-free perovskites is still a big challenge to practical applications. In this work, we demonstrate the flexible photodetector based on a novel (to our knowledge) narrow-bandgap OIHP of (BA)2(MA)Sn2I7, with achieving a broadband response across an ultraviolet-visible-near infrared (UV-VIS-NIR) region as 365-1064 nm. The high responsivities of 28.4 and 2.0 × 10-2 A/W are obtained at 365 and 1064 nm, respectively, corresponding to detectives of 2.3 × 1010 and 1.8 × 107 Jones. This device also shows remarkable photocurrent stability after 1000 bending cycles. Our work indicates the huge application prospect of Sn-based lead-free perovskites in high-performance and eco-friendly flexible devices.

Multifunctional Half-Floating-Gate Field-Effect Transistor Based on MoS2-BN-Graphene van der Waals Heterostructures.

Multifunctional electronic devices that combine logic operation and data storage functions are of great importance in developing next-generation computation. The recent development of van der Waals (vdW) heterostructures based on various two-dimensional (2D) materials have brought exceptional opportunities in designing novel electronic devices. Although various 2D-heterostructure-based electronic devices have been reported, multifunctional devices that can combine logic operations and data storage functions are still quite rare. In this work, we design and fabricate a half-floating-gate field-effect transistor based on MoS2-BN-graphene vdW heterostuctures, which can be used for logic operations as a MOSFET, nonvolatile memory as a floating-gate MOSFET (FG-MOSFET), and rectification as a diode. These results could lay the foundation for various applications based on 2D vdW heterostuctures and inspire the design of next-generation computation beyond the von Neumann architecture.

GaInSn liquid nanospheres as a saturable absorber for Q-switched pulse generation at 639 nm.

Liquid metals, which possess the superiority of low cost, shape-reconfigurability, and excellent optoelectronic properties, have been applied in various fields, such as flexible electronics, superconductivity, and coolants. In this paper, high-quality GaInSn liquid nanospheres synthesized by the ultrasonic method are applied for nonlinear optics and laser switches. The saturation absorption property derived from localized surface plasmon resonance at 639 nm is studied based on the open-aperture Z-scan technique, exhibiting a modulation depth of ∼35.5% and a saturation fluence of ∼21.75 mJ/cm2, respectively. The as-prepared GaInSn liquid nanospheres are also successfully utilized as a saturable absorber to achieve a stable Q-switched Pr:YLF laser at 639 nm. The output pulse width can reach ∼280 ns with a pulse repetition rate of ∼174.8 kHz. Our results suggest that GaInSn liquid nanospheres are a candidate material for generating visible laser pulses, which is of great interest for potential applications in visible nonlinear optics.

Enhanced photothermoelectric detection in Co:BiCuSeO crystals with tunable Seebeck effect.

BiCuSeO is a widely-used thermoelectric material recently proved to be an appealing candidate for broadband photothermoelectric (PTE) detection. Developing a simple and scalable route for advancing PTE properties is therefore essential to explore the full potential of BiCuSeO. Here we systematically demonstrated that Co3+ atomic doping strategies in BiCuSeO single crystals (Co concentration of 1%, 2% and 4%) could modulate the Seebeck coefficient and thus strongly improve the performance of BiCuSeO PTE photodetectors across visible to infrared spectral regions. Benefiting from these strategies, a large enhancement on photovoltage responsivity is achieved and the response time of a 4% Co:BiCuSeO PTE photodetector is one order of magnitude faster than those in most of PTE photodetectors. Also, Co:BiCuSeO PTE photodetectors show good stability with changeless photoresponse after being exposed to air for three months. Therefore, the controllable atomic doping of BiCuSeO with tunable PTE properties as well as fast and broadband photodetection provides the feasibility for facilitating ongoing research toward PTE devices.

Ruxolitinib mitigates steroid-refractory CRS during CAR T therapy.

Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity are two major CAR T related toxicities. With the interventions of Tocilizumab and steroids, many patients can recover from severe CRS. However, some patients are refractory to steroids and develop life-threatening consequences. Ruxolitinib is an oral JAKs inhibitor and promising drug in inflammatory diseases. In this pilot study, we evaluate the efficacy of Ruxolitinib in CRS. Of 14 r/r B-ALL children who received CD19 or CD22 CAR T cell therapies, 4 patients developed severe (≥grade 3) CRS with symptoms that were not alleviated with high-dose steroids and thus received ruxolitinib. Rapid resolution of CRS symptoms was observed in 4 patients after ruxolitinib treatment. Serum cytokines significantly decreased after ruxolitinib intervention. All patients achieved complete remission on day 30 after infusion, and we could still detect CAR T expansion in vivo despite usage of ruxolitinib. There were no obvious adverse events related to ruxolitinib. In vitro assays revealed that ruxolitinib could dampen CAR T expansion and cytotoxicity, suggesting that the timing and dosage of ruxolitinib should be carefully considered to avoid dampening anti-leukaemia response. Our results suggest that ruxolitinib is active and well tolerated in steroid-refractory and even life-threatening CRS.

Toxicity and effectiveness of CD19 CAR T therapy in children with high-burden central nervous system refractory B-ALL.

INTRODUCTION: Although recent clinical trials have demonstrated the efficacy of CD19-directed chimeric antigen receptor (CAR) T-cell therapy for refractory or relapsed B acute lymphoblastic leukemia (r/r B-ALL), most trials exclude patients with high-burden CNS leukemia (CNSL) to avoid the risk of severe neurotoxicity. There were only sparse cases describing the effect of CAR T cells on low-burden CNSL, and the safety and effectiveness of CAR T cells in high-burden CNSL remains unknown. METHODS: Here, we retrospectively analyzed the results of CD19 CAR T-cell therapy in 12 pediatric patients that had low (Blasts < 20/µL in CSF) or high-burdens (Blasts or intracranial solid mass) of CNS B-ALL, that are enrolled in three clinical trials and one pilot study at Beijing Boren Hospital RESULTS: Eleven patients (91.7%) achieved complete remission (CR) on day 30, and one patient got CR on day 90 after infusion. Most patient experienced mild cytokine-release syndrome. However, of the five patients who retained > 5/µL blasts in CSF or a solid mass before CAR T-cell expansion, four developed severe (grade 3-4) neurotoxicity featured by persistent cerebral edema and seizure, and they fully recovered after intensive managements. Sustained remission was achieved in 9 of the 12 patients, resulted in a 6-month leukemia-free survival rate of 81.8% (95% CI 59.0-100). Only one patient has CNS relapse again. CONCLUSION: Our study demonstrates that CAR T cells are effective in clearing both low- and high-burden CNSL, but a high CNSL burden before CAR T-cell expansion may cause severe neurotoxicity requiring intense intervention.

A Plasmon-Enhanced SnSe2 Photodetector by Non-Contact Ag Nanoparticles.

The 2D layered materials are promising candidates for broadband, low-cost photodetectors. One deficiency of 2D materials is the relatively low absorbance of light, limiting the applications of the 2D photodetectors. Doping of plasmonic nanoparticles into 2D materials may enhance the optical absorbance owing to the localized surface plasmonic resonance (LSPR) effect; however, considerable defects may be introduced into the 2D materials at the same time, resulting in certain degradation of device performance. Here, a novel design of 2D photodetectors with enhanced photoresponsivity by non-contact plasmonic nanoparticles (NPs) is proposed, consisting of a hybrid structure of few-layer SnSe2 transferred a fused silica (SiO2 ) plate with embedded Ag NPs. The system of Ag NPs-in-SiO2 shows strong LSPR effect with significantly enhanced optical absorption, acting on SnSe2 in a non-contact configuration. Benefiting from well-preserved intrinsic features of SnSe2 and LSPR effect, the responsivity of the photodetector is enhanced by 881 times with the bias voltage of 0.1 V, which is superior to previously reported results of plasmon-enhanced 2D photodetectors. Moreover, the SiO2 with embedded Ag NPs is recyclable and can be easy to be recombined with different 2D materials. This work offers additional strategy for development of efficient, low-cost 2D photodetectors by using plasmonic NPs.

2D van der Waals Layered [C(NH2)3]2SO3S Exhibits Desirable UV Nonlinear-Optical Trade-Off.

It remains a challenge to develop UV nonlinear optical (NLO) crystals that can achieve a desirable trade-off on UV absorption edge, second harmonic generation (SHG), and birefringence. Here we report a thiosulfate UV NLO crystal of a 2D van der Waals layered structure, [C(NH2)3]2SO3S. Remarkably, this thiosulfate realizes the desired trade-off, with a short absorption edge of 254 nm, a strong SHG response of approximately 2.8 times that of the benchmark KH2PO4, and a sufficient birefringence of 0.073 at the wavelength of 546 nm. In addition, it exhibits strong in-plane anisotropy of the SHG intensity. According to the first-principles calculations, the non-π-conjugated [SO3S]2- anion is the dominant SHG functional gene, while the π-conjugated [C(NH2)3]+ cation serves as the functional gene of birefringence. This is different from common UV NLO materials whose functionals of SHG and birefringence are the same. These findings indicate that combining different function genes may be an effective strategy to develop outstanding NLO materials with the desirable property trade-off.

Structural Crack Detection Using DPP-BOTDA and Crack-Induced Features of the Brillouin Gain Spectrum.

Structural damage generally initiates in the form of structural cracks. Thus, developing efficient crack detection techniques is of great importance for the structural health monitoring. In this paper, a new crack identification method is proposed, which is based on the differential pulse-width pair Brillouin optical time domain analysis (DPP-BOTDA) technology and the irregular features of Brillouin gain spectrum (BGS) in the fiber due to structural cracks. The proposed method provides a new way to detect and quantify structural cracks without knowing the strain in the structure. First, the working mechanism of DPP-BOTDA is introduced to illustrate the reason that the DPP-BOTDA, compared to traditional BOTDA technique, can significantly improve the spatial resolution of distributed strain sensing, which is critical for structural crack detection. Then, the BGSs in the fiber with the presence of structural cracks, measured by the DPP-BOTDA, are numerically simulated, from which the crack-induced irregular features of the BGS are summarized. Based these irregular features, new structural crack detection and quantification methods are proposed, which are found to be independent of structural stain. Finally, an experiment is conducted on a simple supported reinforced concrete (RC) beam. The results demonstrate that by using the BGS measured by the DPP-BOTDA, the proposed structural crack identification method successfully detects the occurrence of structural cracks and relatively accurately predicts the crack widths.

High performance of a passively Q-switched mid-infrared laser with Bi2Te3/graphene composite SA.

We report passively Q-switched ∼2 and ∼3 µm mid-infrared (MIR) solid-state lasers with a self-assembly solvothermal-synthesized Bi2Te3/graphene heterostructure saturable absorber (SA) for the first time. Based on the oxidation resistance and high thermal conductivity of graphene, and large modulation depth of Bi2Te3 nanosheets, two high-performance Q-switching lasers were realized. One is a Tm:YAP laser with a maximum average output power of 2.34 W and a pulse width of 238 ns at ∼2 µm. The corresponding maximum pulse peak power was 91 W, which was much improved in comparison with the pure graphene-based Tm laser. The other one is an Er:YSGG laser producing a pulse width of 243 ns, which is the shortest among the 2D SAs-based ∼3 µm solid-state lasers, as far as we know. Our results indicate that such a composite Bi2Te3/graphene material is a promising SA for generating high-performance mid-infrared pulse lasers.

Dual function of Nd3+ in Nd,Er:LuYSGG crystal for LD pumped ~3.0 µm mid-infrared laser.

Enhanced ~3.0 µm emission corresponding to Er3+:4I11/2→4I13/2 was achieved in Nd3+/Er3+ co-doped Lu0.15Y2.85Sc2Ga3O12 (abbr. as Nd,Er:LuYSGG) crystal under 808 nm pumping. As compared with Er:YSGG crystal, the absorption pump efficiency of Nd,Er:LuYSGG crystal is greatly improved and thus ~3.0 µm emission is enhanced by 2.2 times owing to the sensitization of Nd3+, at the same time, Nd3+ as deactivator quenches ~1.5 µm emission from Er3+:4I13/2 level and thus inhibit the self-termination effect successfully. The energy transfer efficiencies of Nd: 4F3/2→Er: 4I11/2 and Er: 4I13/2→Nd:4I15/2 are estimated to be 91.6% and nearly 100%, respectively. These results indicate that the introduction of Nd3+ is very helpful for achieving ~3.0 µm laser in Nd,Er:LuYSGG crystal.

Bend-insensitive distributed sensing in singlemode-multimode-singlemode optical fiber structure by using Brillouin optical time-domain analysis.

We propose a bend-insensitive distributed Brillouin optical fiber sensing by using a singlemode-multimode-singlemode optical fiber structure for the first time to the best of our knowledge. The sensing fiber is a graded-index multimode fiber (GI-MMF) sandwiched by two standard single-mode fibers (SMFs) with central-alignment splicing at the interface between GI-MMF and SMF to excite the fundamental mode in GI-MMF. The sensing system can resist a minimal bend radius of 1.25mm while maintain the measurement performance, with which the measured coefficients of strain and temperature are 421.6MHz/% and 0.826MHz/°C, respectively. We also demonstrate that the higher-order modes excited in GI-MMF can be easily influenced by bending, so that exciting the fundamental mode is essential for bend-insensitive distributed sensing.

Single-longitudinal-mode Er:GGG microchip laser operating at 2.7 µm.

We reported on a diode-end-pumped single-longitudinal-mode microchip laser using a 600-µm-thick Er:GGG crystal at ∼2.7 µm, generating a maximum output power of 50.8 mW and the maximum pulsed energy of 0.306 mJ, with repetition rates of pumping light of 300, 200, and 100 Hz, respectively. The maximum slope efficiency of the laser was 20.1%. The laser was operated in a single-longitudinal mode centered at about 2704 nm with a FWHM of 0.42 nm. The laser had a fundamental beam profile and the beam quality parameter M(2) was measured as 1.46. These results indicate that the Er:GGG microchip laser is a potential compact mid-infrared laser source.

New pregnane glycosides from Gymnema sylvestre.

Four new pregnane glycosides 1-4 were isolated from the ethanol extract of the stem of Gymnema sylvestre and named gymsylvestrosides A-D. Hydrolysis of compound 1 under the catalysis of Aspergilus niger ß-glucosidase afforded compound 5 (gymsylvestroside E). Their structures were determined by spectroscopic methods such as HRESIMS, 1D and 2D NMR, as well as HMQC-TOCSY experiment. Compounds 1-4 were screened for Saccharomyces cerevisiae α-glucosidase inhibitory activity.

Self-Q-switched, orthogonally polarized, dual-wavelength laser using long-lifetime Yb³âº crystal as both gain medium and saturable absorber.

A novel self-Q-switched and orthogonally polarized dual-wavelength laser has been investigated with Yb³âº-doped CGB disordered crystals. By slightly inclining output coupler to introduce the Fresnel loss, we realized simultaneously dual-wavelength laser operation at 1052.6 nm in E//b polarization and 1057.7 nm in E//c polarization with a frequency difference of 1.38 THz. Self-Q-switched pulse generation was observed in this free-running laser, originating from the nonlinear reabsorption effect of Yb:CGB as well as the strong storage of inversion population induced by the long excited-state lifetime (~1 ms). Pulse duration of 287 ns was obtained with an output average power of 416 mW and a repetition rate of 35 kHz. The self-Q-switching effect increased the peak power by 100 times the average power. This very simple laser, free from the complexity and high-cost of additional intracavity polarization modulator and Q-switcher, may be applied for constructing miniature, integrated and portable laser system.