Nanomaterials promote the fast development of electrochemical MiRNA biosensors.

Cancer has become the leading cause of death worldwide. In recent years, molecular diagnosis has demonstrated great potential in the prediction and diagnosis of cancer. MicroRNAs (miRNAs) are short oligonucleotides that regulate gene expression and cell function and are considered ideal biomarkers for cancer detection, diagnosis, and patient prognosis. Therefore, the specific and sensitive detection of ultra-low quantities of miRNA is of great significance. MiRNA biosensors based on electrochemical technology have advantages of high sensitivity, low cost and fast response. Nanomaterials show great potential in miRNA electrochemical detection and promote the rapid development of electrochemical miRNA biosensors. Some methods and signal amplification strategies for miRNA detection in recent years are reviewed herein, followed by a discussion of the latest progress in electrochemical miRNA detection based on different types of nanomaterial. Future perspectives and challenges are also proposed for further exploration of nanomaterials to bring breakthroughs in electrochemical miRNA detection.

Construction of thermally stable Tb3+-activated green-emitting phosphors: dual driving strategy of doping concentration and excitation wavelength.

The realization of thermally stable Tb3+-doped green emission at high temperatures in solid-state lighting is still a crucial challenge. Nevertheless, the study on modulating the thermally stable luminescence at high temperatures is seldom reported. The position of the intervalence charge transfer (IVCT) energy level is used to systematically investigate the thermal quenching performance of Tb3+-activated green-emitting phosphors with varying concentration gradients of Gd1-xTaO4:xTb3+ (x = 0.1%, 0.5%, and 2%) in this study. The IVCT energy levels were determined according to the empirical formula to show a decreasing trend, consistent with the position of the IVCT energy levels measured in the excitation and diffuse reflectance spectra. Moreover, the thermal quenching performance of different wavelength excitation positions (host absorption, 4f-5d of Tb3+, and Tb3+-Ta5+ IVCT band) is quite different. The modulation of thermal quenching performance among distinct phosphors when subjected to host excitation or IVCT excitation can be elucidated through optimal positions within the energy levels associated with IVCT. The diverse concentration gradient samples exhibit varying degrees of thermal quenching performance in the variable-temperature spectra. The fluorescence lifetimes of the samples are generally comparable but slightly lower. The quantum efficiency rapidly improves as the Tb concentration increases. The underlying mechanism governing this phenomenon is elucidated by constructing a model that encapsulates the interplay between the compensating and quenching channels, in addition to the energy conversion of Tb3+ into Gd3+. The abovementioned results indicate that the dual driving scheme of the doping concentration and excitation wavelength is an effective means to regulate the thermal quenching performance of Tb-activated green-emitting tantalate phosphors.

All-optical self-manipulation of light flow in on-chip topological waveguides based on synthetic dimension.

Topological photonic crystals provide a new platform for designing nanophotonic devices with robustness. Especially, all-optical devices, which use the light controlling light, based on nonlinear topological photonic crystals, have not been reported yet. In this article, we numerically investigate the robust self-manipulation of light flow in silicon topological photonic crystal waveguides based on the Kerr nonlinearity of silicon and topological edge states of photonic crystal waveguides. By adjusting the intensity of incident light at a communication wavelength of 1550 nm, the transmission path of the light flow in waveguides can be effectively controlled, and such manipulation is immune to some disturbances of nanostructures and thus shows the robustness. The results indicate that nonlinear topological photonic crystals have potential applications in on-chip integrated all-optical photonic devices.

Pt Nanodot Inlaid Mesoporous NaBiOF Nanoblackberry for Remarkable Signal Amplification Toward Biomarker Detection.

A new ultrasensitive sandwich-type electrochemical immunosensor has been successfully constructed to quantitatively detect carcinoembryonic antigen (CEA) using blackberry-like mesoporous bismuth-based nanospheres NaBiOF (NBOF NSs) inlaid with Pt nanodots (NDs) (BiPt NSs) as the antibody capture and signal-amplifying probe. The growth of Pt NDs inside the holes of NBOF NSs formed the nanozyme inlay outside NBOF NSs, greatly increasing the specific surface area and exposure of the catalytic active sites by minimizing the particle size of the Pt to nanodot scale. Such a blackberry-shaped heterojunction structure of BiPt NSs was well-suited to antibody capture and improved the catalytic performance of BiPt NSs in reducing H2O2, amplifying the signal, and yielding highly sensitive detection of CEA. The use of Au nanoparticle-modified multi-walled carbon nanotubes (Au@MWCNTs) as the electrode substrates significantly enhanced the electron transfer behavior over the electrode surface, further increasing the conductivity and sensitivity of the immunosensor. Remarkably, good compatibility with human body fluid was achieved using the newly developed BiPt-based immunosensor resulting from the favorable biocompatibility and stability of both BiPt NSs and Au@MWCNTs. Benefiting from the double signal amplification strategy and the high biocompatibility, the immunosensor responded linearly to CEA in a wide range from 50 fg/mL to 100 ng/ml with an extremely low detection limit of 3.52 fg/mL (S/N = 3). The excellent detection properties of this new immunosensor were evidenced by the satisfactory selectivity, reproducibility, and stability obtained, as well as the reliable and precise determination  of CEA in actual human blood samples. This work provides a new strategy for the early clinical diagnosis of cancer. Novel blackberry-like mesoporous NaBiOF nanospheres with Pt nanodot inlay were successfully usedto construct a sandwich-type electrochemical immunosensor for the ultra-sensitive detection ofcarcinoembryonic antigen in human blood plasma based on a remarkable signal amplification strategy.

Potent saccharinate-containing palladium(II) complexes for sensitization to cancer therapy.

Palladium(II) (PdII) complexes are among the most promising anticancer compounds. Both 2`-benzoylpyridine thiosemicarbazone (BpT) and saccharinate (Sac) are efficient metal chelators with potent anticancer activity. To explore a more effective new anticancer drug, we synthesized a series of Sac and BpT-containing PdII complexes coordinated with thiosemicarbazone (TSC)-derived ligands, and characterized them through nuclear magnetic resonance (NMR), Fourier transformed infrared spectroscopy (FT-IR), elemental analysis, ultraviolet-visible spectroscopy (UV-Vis) and thermogravimetric analysis (TGA). Each target complex was composed of PdII, BpT, and one or two Sac molecules. Both the in vitro and in vivo anti-growth effects of those ligands and the obtained PdII complexes were investigated in the human lung adenocarcinoma cell lines A549 and Spc-A1. The coordination of PdII with the TSC-derivatives and Sac resulted in clearly greater anticancer activity than single ligands. These compounds were demonstrated to be safe for 293 T normal human kidney epithelial cells. The introduction of Sac into the TSC-derived PdII complex significantly enhanced anti-growth effects, and induced apoptosis of human lung cancer cells in vitro and in vivo in a dose dependent manner. Moreover, the PdII complex containing two Sac molecules showed the most promising therapeutic effects, thereby confirming that Sac increases the cancer therapeutic efficacy of PdII complexes and providing a new strategy for exploring anticancer drugs for potential clinical treatment.

Ti3C2@Bi2O3 nanoaccordion for electrochemical determination of miRNA-21.

Based on a dual signal amplification strategy of novel accordion-like Bi2O3-decorated Ti3C2 (Ti3C2@Bi2O3) nanocomposites and hybridization chain reaction (HCR), an ultra-sensitive electrochemical biosensor was constructed for miRNA-21 detection. By etching Ti3AlC2 with HF, Ti3C2 with an accordion-like structure was first obtained and subsequently covered by Bi2O3 nanoparticles (NPs), forming Ti3C2@Bi2O3. A layer of Au NPs was electrodeposited on the glassy carbon electrode coated with Ti3C2@Bi2O3, which not only significantly improved the electron transport capacity of the electrode but also greatly increased its surface active area. Upon the immobilization of the thiolated capture probe (SH-CP) on the electrode, the target miRNA-21 specifically hybridized with SH-CP and thus opened its hairpin structure, triggering HCR to form a long double strand with the primers H1 and H2. A large number of the electrochemical indicator molecules were thus embedded inside the long double strands to produce the desirable electrochemical signal at a potential of - 0.19 V (vs. Ag/AgCl). Such dual signal amplification strategy successfully endowed the biosensor with ultra-high sensitivity for miRNA-21 detection in a wide linear range from 1 fM to 100 pM with a detection limit as low as 0.16 fM. The excellent detection of miRNA-21 in human blood plasma displayed a broad prospect in clinical diagnosis. An ultra-sensitive electrochemical biosensor was successfully constructed for miRNA-21 detection in human blood plasma based on the dual signal amplification strategy of novel accordion-like Bi2O3 decorated Ti3C2 (Ti3C2@Bi2O3) nanocomposites and hybridization chain reaction.

Efficient improvement in chemo/photothermal synergistic therapy against lung cancer using Bi@Au nano-acanthospheres.

Novel highly hydrophilic and biocompatible bismuth nanospheres with gold nanoparticles growing outside (Bi@Au nano-acanthospheres, Bi@Au NASs) were synthesized through a simple procedure, which demonstrated to be a promising photothermal agent owing to the ultrahigh photothermal conversion efficiency (η = 46.6 %). The as-prepared Bi@Au NASs showed excellent blood compatibility and fairly low cytotoxicity to human lung cancer A549 cells, as well as efficient photothermal ablation (PTA) therapy induced by a near-infrared laser. Under the 808 nm laser radiation, the tumour temperature could be elevated by ∼25 °C high enough to kill the cancer cells. Moreover, the anticancer drug doxorubicin hydrochloride (DOX) was successfully loaded in Bi@Au NASs with a loading content as high as 16.78 % and released under a pH sensitive release profile, a characteristic beneficial for intravenous delivery of DOX into cancer cells for chemotherapy. The presence of the Bi element enabled Bi@Au NASs to act as a favourable computed tomography (CT) contrast medium for CT imaging-guided tumour treatment. Compared with cancer treatment through either photothermal therapy or chemotherapy, the chemo-photothermal synergistic therapy using Bi@Au NASs as both a photothermal agent and a drug carrier has efficiently enhanced the in vitro and in vivo therapeutic effects in cancer treatment.

Free-space remote detection of a spinning object using the combined vortex beam.

The rotational Doppler effect (RDE) associated with orbital angular momentum (OAM) has been used for remote sensing of a spinning object. However, one of the challenges of long-range detection stems from the low echo signal power. In this paper, we propose a new detection scheme that uses the combined vortex beam (CVB) generated by coherent beam combining (CBC) technology as the probe beam to enhance the echo signal power. Furthermore, we establish a rotational speed remote sensing model based on RDE, the emitted power and emission diameter of the probe beam are investigated in detail. The results show that, compared with the superposition vortex beam (SVB) generated by a single laser beam, the CVB detection scheme can significantly enhance the echo signal intensity and detection distance. The measuring range and accuracy of rotational speed are also studied in detail. And finally, we present the first experimental demonstration of the RDE arising directly from the interaction of the CVB with a rotating rough surface. The scheme proposed in our paper offers a good reference for practical application of the remote detection based on RDE.

METTL3 promotes non-small cell lung cancer (NSCLC) cell proliferation and colony formation in a m6A-YTHDF1 dependent way.

BACKGROUND: N6-methyladenosine (m6A) is the most common RNA modification, which plays a pivotal role in tumor development and progression. In this study, we assessed the role of m6A methyltransferase METTL3 in FRAS1-involved cell proliferation and colony formation of non-small cell lung cancer (NSCLC) cell lines. METHODS: Cell viability was analyzed by Cell Counting Kit (CCK-8) and colony formation. M6A RNA immunoprecipitation (IP), Ribosomal immunoprecipitation, RNA immunoprecipitation (RIP) were performed to verify the relationship between METTL3, FRAS1 and YTHDF1. Rescue experiments to confirm the regulatory mechanism of METTL3-FRAS1 promoted NSCLC cell proliferation through CDON by cooperating YTHDF1. RESULTS: We found that FRAS1 was correlated with poor prognosis in NSCLC patients, of which the transcript undergoes m6A modification regulated by METTL3. METTL3 silence reduced cell viability of NSCLC cells HCC827 and NCI-H1975, which could be restored by FRAS1 overexpression. The m6A modification of FRAS1 could be recognized by YTHDF1. FRAS1 silence or YTHDF1 silence could rescue the elevated NSCLC cell proliferation, colony formation, and tumor growth induced by METTL3 overexpression in vitro and in vivo. CONCLUSIONS: Our study reveals that METTL3-FRAS1 plays a crucial role in NSCLC cell proliferation, colony formation, and tumor growth through the regulation of CDON by cooperating YTHDF1.

Exciton-induced mid-infrared optical nonlinearity of wide bandgap hexagon boron nitride.

In this Letter, an exciton absorption assumption is made to explain the mid-infrared saturable absorption performance of the 2D h-BN nanosheet. The exciton binding energy of ∼0.4 eV corresponds to the light wavelength around 3 µm, matching well with the experimental results. Experimentally, the h-BN saturable absorber (SA) shows a modulation depth of 5.3% in the wavelength region of 3 µm. By employing the h-BN SA in an Er:Lu2O3 laser, laser pulses with a pulse duration of 252 ns are realized at a repetition rate of 169 kHz, corresponding to a pulse energy of 3.55 µJ and peak power of 14 W. The exciton absorption assumption will help obtain a better understanding of the nonlinear optical dynamics in 2D materials from a new perspective.

Multi-Object Positioning and Imaging Based on Single-Pixel Imaging Using Binary Patterns.

Single-pixel imaging (SPI) is a new type of imaging technology that uses a non-scanning single-pixel detector to image objects and has important application prospects and value in many fields. Most of the modulators currently used in SPI systems are digital micromirror device (DMD) modulators, which use a higher frequency for binary modulation than other alternatives. When modulating grayscale information, the modulation frequency is significantly reduced. This paper conducts research on multiple discrete objects in a scene and proposes using binary patterns to locate and image these objects. Compared with the existing methods of using gray patterns to locate and image multiple objects, the method proposed in this paper is more suitable for DMD-type SPI systems and has wider applicability and greater prospects. The principle of the proposed method is introduced, and the effectiveness of the method is experimentally verified. The experimental results show that, compared to traditional SPI methods, the number of patterns required by the proposed method is reduced by more than 85%.

Rapid electrochemical detection of MiRNA-21 facilitated by the excellent catalytic ability of Pt@CeO2 nanospheres.

Pt@CeO2 nanospheres (NSs) were first synthesized by simply mixing Ce(NO3)3 and K2PtCl4 under the protection of pure argon at 70 °C for 1 h, which exhibited excellent catalytic ability toward hydrogen peroxide (H2O2). An electrochemical biosensor was successfully developed using Pt@CeO2 NSs as a capture probe for the ultra-sensitive and fast detection of miRNA-21, a new type of biomarker for disease diagnostics, especially for cancer. During the step-by-step construction process of the RNA sensor, Pt@CeO2 NSs were functionalized with streptavidin (SA) to obtain SA-Pt@CeO2 NSs through amide bonds. Gold nanoparticles (Au NPs) were electrodeposited on the surface of the glassy carbon electrode to improve the transmission capacity of electrons and provided Au atoms for fixing the thiolated capture probe (SH-CP) with a hairpin structure on the electrode via forming Au-S bonds. The target miRNA-21 specifically hybridized with SH-CP and opened the hairpin structure to form a rigid duplex so as to activate the biotin at the end of the capture probe. SA-Pt@CeO2 NSs were thus specially attached to the electrode surface through the biotin-streptavidin affinity interaction, finally leading to the significant signal amplification. The ultra-sensitive and rapid detection of miRNA-21 was finally realized as expected benefiting from the excellent catalytic ability of Pt@CeO2 NSs toward H2O2 in a wide linear concentration range from 10 fM to 1 nM with the detection limit as low as 1.41 fM. The results achieved with this new RNA sensor were quite satisfactory during the blood sample analysis.

Lanthanide-doped bismuth-based nanophosphors for ratiometric upconversion optical thermometry.

Nanothermometry could realize stable, efficient, and noninvasive temperature detection at the nanoscale. Unfortunately, most applications of nanothermometers are still limited due to their intricate synthetic process and low-temperature sensitivity. Herein, we reported a kind of novel bismuth-based upconversion nanomaterial with a fast and facile preparation strategy. The bismuth-based upconversion luminophore was synthesized by the co-precipitation method within 1 minute. By optimizing the doping ratio of the sensitizer Yb ion and the activator Er ion and adjusting the synthetic solvent strategy, the crystallinity of the nanomaterials was increased and the upconversion luminescence intensity was improved. Ratiometric upconversion optical measurements of temperature in the range of 278 K to 358 K can be achieved by ratiometric characteristic emission peaks of thermally sensitive Er ion. This method of rapidly constructing nanometer temperature probes provides a feasible strategy for the construction of novel fluorescent temperature probes.

Comparison of two internal fixation systems in lumbar spondylolysis by finite element methods.

BACKGROUND AND PURPOSE: Internal fixation surgeries are currently the most effective treatments for lumbar spondylolysis, but the optimal fixation method is still on debate. This study was designed to compare the biomechanical characteristics of two fixation methods for lumbar spondylolysis, the pedicle screw-U shape rod (PSUSR) internal fixation system, and the pedicle screw-vertebral plate hook (PSVPH) internal fixation system, through three-dimensional finite element analysis, expecting to provide clinical guidance. METHODS: Four finite element models (A, B, C, D) of L4-S1 vertebral body of a female patient were reconstructed by CT image segmentation. (A: intact model. B: spondylolysis model. C: spondylolysis model with PSUSR internal fixation. D: spondylolysis model with PSVPH internal fixation). Six physiological motion states were simulated by applying 500N concentrated force and 10Nm moment load to four models. The biomechanical advantages of the two internal fixation systems were evaluated by comparing the range of motion (ROM), maximum stress, maximum strain, and maximum displacement of the models. RESULTS: Compared to model B, the ROM decreased by 35.7%-57.1% in model C and 39.7%-64.8% in model D. The maximum displacements of model C and D both decreased. The maximum stresses in both vertebral and the internal fixation system are greater in model C than those in model D. The maximum stress and strain reduction of L5-S1 intervertebral disc in model D was greater than that in model C. Model D restores the articular cartilage stresses to the normal levels of model A. The maximum stress and maximum displacement of the bone graft in model C are greater than those in model D. CONCLUSIONS: The PSVPH internal fixation system has better biomechanical properties than PSUSR internal fixation system in several mechanical comparisons. Experimental results suggest that PSVPH internal fixation system can effectively treat lumbar spondylolysis while preserving segmental mobility, and can be the treatment of choice.

Sensitive detection of radio-frequency field phase with interacting dark states in Rydberg atoms.

An efficient scheme of phase measurement of a radio-frequency (RF) field is proposed by interacting dark states. Under the condition of electromagnetically induced transparency (EIT), the four-level Rydberg atom exhibits two windows. Compared with the transmission spectrum on resonance, the linewidths of absorption peaks off resonance are very narrow due to the interaction of double dark states. It is interesting to find that the distance of absorption peaks shifts approximately linearly with the phase of an RF field, which can be used to measure the RF field phase. Simulation results show that the linewidth of an absorption peak can be narrowed by more than one order of magnitude, and a narrow linewidth improves the detectable minimum phase difference by more than six times. It helps to reduce analyzation complexity and increase sensing resilience. The dependence of phase measurement on the control field and RF field is also investigated.

Enhanced fiber-coupling efficiency via high-order partially coherent flat-topped beams for free-space optical communications.

The fiber-coupling efficiency of signal beams is crucial in free space optical (FSO) communications. Herein, we derived an analytical expression for the fiber-coupling efficiency of partially coherent flat-topped beams propagating through atmospheric turbulence based on the cross-spectral density function. Our numerical calculation results showed that the fiber-coupling efficiency of partially coherent flat-topped beams in a turbulent atmosphere could be enhanced by increasing the beam order. Under the same conditions, the fiber-coupling efficiency of the high-order partially coherent flat-topped beams was larger than those connected to the Gaussian and Gaussian Schell-model (GSM) beams. Our results will improve the quality of partially coherent beams used in FSO communications.

Protocatechuic acid as an inhibitor of the JNK/CXCL1/CXCR2 pathway relieves neuropathic pain in CCI rats.

Emerging evidence has shown that protocatechuic acid (PCA) has antioxidant and anti-inflammatory effects. It can alleviate the injury of sciatic nerve, while the mechanism of its therapeutic effect on neuralgia remains unknown . In vivo, chromium bowel ligation was used to establish a chronic constriction injury (CCI) rat model to induce sciatic nerve pain, then two doses of PCA were used to treat CCI rats. In vitro, 10 ng/mL TNF-α was used to stimulate glial satellite cells derived from the dorsal root ganglia (DRG) L4-L6 of the sciatic nerve to simulate sciatic nerve pain. PCA relieved mechanical allodynia and thermal hyperalgesia in CCI rats. CCK-8 assay revealed that PCA inhibited the proliferation of glial satellite cells induced by TNF-α. Moreover, ELISA demonstrated that PCA could improve the inflammatory response of rats caused by CCI and cells induced by TNF-α. Next, RT-qPCR and Western blot assays testified that PCA blocked the c-Jun N-terminal kinase/the chemokine ligand 1/CXC chemokine receptor 2 (JNK/CXCL1/CXCR2) pathway by inhibiting CXCL1 levels in cells induced by TNF-α and DRG of CCI rats. In conclusion, PCA can alleviate neuropathic pain of CCI rats, improve oxidative stress by inhibiting the JNK/CXCL1/CXCR2 signaling pathway, which provides a new perspective for the treatment of neuropathic pain caused by CCI.

Investigation on the optical nonlinearity of the layered magnesium-mediated metal organic framework (Mg-MOF-74).

The wavelength-related optical nonlinearities of few-layer Mg-MOF-74 nanosheets were investigated in the wavelength region around 1.08, 1.94, and 2.85 µm by the closed aperture Z-scan, open aperture Z-scan and I-scan method. Under the excitation of 100-µJ laser pulses, the nonlinear refractive index (n2) of -7.7 ± 2.6, -131 ± 5 and 4.9 ± 0.2 cm2/W were obtained, respectively. The wavelength-related optical nonlinearity of the Mg-MOF-74 nanosheet was also investigated. In 2.85 µm wavelength region, the Mg-MOF-74 nanosheets shows a stable saturable absorption property with a modulation depth of 8% and a saturation intensity of 170 mJ/cm2. In the 1.08 and 1.94 µm wavelength regions, we can observe that the Mg-MOF-74 transits from saturable absorption regime to reverse saturable absorption regime with the increasing incident laser intensity. Employed as a saturable absorber in a Er:Lu2O3 laser, Mg-MOF-74 nanosheet shows a thickness-related laser modulation performance. The shortest laser pulse of 284-ns was achieved under a repetition rate of 116 kHz with a 6-nm-thick Mg-MOF-74 nanosheet, which corresponds to a pulse energy of 3.2 µJ and a peak power of 11.4 W.

Differences in patterns of metabolic abnormality and metabolic syndrome between early-onset and adult-onset first-episode drug-naive schizophrenia patients.

Although metabolic abnormalities and metabolic syndrome (MetS) often occur in schizophrenia, few studies have investigated them in early-onset schizophrenia (EOS) patients. To our knowledge, this was the first to compare clinical correlates of metabolic abnormalities between first-episode drug-naïve (FEDN) EOS and adult-onset schizophrenia (AOS) patients. A total of 489 Chinese FEDN schizophrenia patients (116 EOS and 373 AOS) and 451 healthy controls were recruited in this cross-sectional study. Blood pressure, waist circumference (WC), Body mass index (BMI), total cholesterol (TC), triglycerides (TG), high density lipoprotein cholesterol (HDLC), low density lipoprotein cholesterol (LDLC), glucose, hemoglobin A1c (HbA1c), insulin and insulin resistance were measured. The Positive and Negative Syndrome Scale (PANSS) was applied to evaluate the clinical symptoms of schizophrenia patients, and higher scores on PANSS indicate increased severity. EOS patients had lower rates of: MetS, elevated WC, hypertriglyceridemia, hypercholesterolemia, and hyper-LDLC than EOS patients (all p < 0.05). In EOS patients, WC was positively associated with PANSS general psychopathology score (p = 0.04). In AOS patients, WC (p = 0.01; p = 0.02) and glucose (p < 0.001; p < 0.001) were positively associated with PANSS general psychopathology and total score. HOMA-IR was positively associated with PANSS total score (p = 0.04). Systolic BP, triglycerides and HDLC were main contributors to MetS in AOS (all p < 0.05), but not in EOS. BMI was a risk factor of MetS in EOS, while BMI and HOMA-IR were risk factors of MetS in AOS (all p < 0.05). Our results indicate differences in metabolic abnormalities patterns, risk factors and their association with clinical characteristics between Chinese EOS and AOS patients. DATA AVAILABILITY STATEMENT: The datasets that support the findings of this study are not publically available due to ongoing analyses for further publications, but are available from the corresponding author X.Z. upon reasonable request.