A Long Wave-Infrared Miniatured Quantum Dot Spectrometer.

In this work, a long-wave infrared (LWIR) quantum dot (QD) spectrometer was constructed for the first time by integrating a 255-element HgSe QD filter array with an LWIR array detector. The filter array was fabricated using a combination inkjet printing strategy with eight types of T-dodecyl mercaptan-terminated HgSe QD inks. The stability and morphology of the QDs were improved by optimizing the purification methodology and ligand modification. Combined with the compressive-sensing-based least-squares linear regression (CS-LS) algorithm, the LWIR QD spectrometer achieved a spectral resolution of 5.4 cm-1 over a wide spectral range of 8 to 14 µm, enabling the detection of the chemical warfare agent simulant dimethyl methylphosphonate. This technology is expected to facilitate the development of smaller volumes and more accurate identification of various targets in the future. This paper offers an approach to fabricating low-cost LWIR spectrometers and promoting the scale-up applications of QD devices.

Interleukin-1ß inhibits normal hematopoietic expansion and promotes acute myeloid leukemia progression via the bone marrow niche.

Enhanced interleukin-1ß (IL-1ß) signaling is a common event in patients with acute myeloid leukemia (AML). It was previously demonstrated that chronic IL-1ß exposure severely impaired hematopoietic stem cell (HSC) self-renewal capability in mice and promoted leukemia cell growth in primary AML cells. However, the role of IL-1ß in the murine bone marrow (BM) niche remains unclear. Here, we explored the role of IL-1ß in the BM niche in Il-1r1-/- mice, chronic IL-1ß exposure mice and mixed lineage leukemia-AF9 fusion gene (MLL-AF9)-induced AML mice models. We demonstrated that IL-1R1 deficiency did not affect the function of HSCs or niche cells under steady-state conditions or during transplantation. Chronic exposure to IL-1ß decreased the expansion of Il-1r1-/- hematopoietic cells in Il-1r1+/+ recipient mice. These results indicated that IL-1ß exposure impaired the ability of niche cells to support hematopoietic cells. Furthermore, we revealed that IL-1R1 deficiency in niche cells prolonged the survival of MLL-AF9-induced AML mice. The results of our study suggest that inhibition of the IL-1ß/IL-1R1 signaling pathway in the niche might be a non-cell-autonomous therapy strategy for AML.

Model-Based Practically Precise Fabrication of HgSe Quantum Dots toward Their Application in a Long-Wave Infrared Micro Spectrometer.

Quantum dot (QD) passive filters present a simple and low-cost strategy for the micromation of spectrometers. In this field, the consistency between ultranarrow band gap QD fabrication and the precise control of its absorption characteristics is the key-challenge to extend QD spectrometers into the long-wave infrared (LWIR) region. Here, we show the model-based, practically precise fabrication of HgSe QDs as well as their specific spectral responses. Both the theoretical and experimental models of the HgSe QDs r-λ are formulated, which reveals the variation of transmission spectrum with the size of HgSe QDs. Then, the HgSe QDs synthesis parameter-spectral response hyperplane model and neural network model were obtained by using traditional polynomial fitting and machine learning, respectively. We also demonstrate the model-based precise fabrication of HgSe QDs with transmission characteristic peaks within 14 µm. The further simulation also shows that the 255─element QD filter array has the signal-to-noise ratio up to 14.57 dB with detection resolution about 5 cm-1.

Synthesis and Application of Polymer SXFA in the Detection of Organophosphine Agents with a SAW Sensor.

The effective detection of isopropyl methylfluorophosphonate (GB, sarin), a type of organophosphine poisoning agent, is an urgent issue to address to maintain public safety. In this research, a gas-sensitive film material, poly (4-hydroxy-4,4-bis trifluoromethyl)-butyl-1-enyl)-siloxane (SXFA), with a structure of hexafluoroisopropyl (HFIP) functional group was synthesized by using methyl vinylpropyl dichlorosilane and hexafluoroacetone trihydrate as initial materials. The synthesis process products were characterized using FTIR. SXFA was prepared on a 200 MHz shear surface wave delay line using the spin-coating method for GB detection. A detection limit of <0.1 mg/m3 was achieved through conditional experiments. Meanwhile, we also obtained a maximum response of 2.168 mV at a 0.1 mg/m3 concentration, indicating the much lower detection limit of the SAW-SXFA sensor. Additionally, a maximum response standard deviation of 0.11 mV with a coefficient of variation of 0.01 and a maximum recovery standard deviation of 0.22 mV with a coefficient of variation of 0.02 were also obtained through five repeated experiments. The results show that the SAW-SXFA sensor has strong selectivity and reproducibility, good selectivity, positive detection ability, high sensitivity, and fast alarm performance for sarin detection.

A passive wireless surface acoustic wave (SAW) sensor system for detecting warfare agents based on fluoroalcohol polysiloxane film.

Long-term monitoring of environmental warfare agengts is a challenge for chemical gas sensors. To address this issue, we developed a 433 MHz passive wireless surface acoustic wave (WSAW) gas sensor for dimethyl methylphosphonate (DMMP) detection. This WSAW gas sensor includes a YZ lithium niobate (LiNbO3) substrate with metallic interdigital transducers (IDTs) etched on it, and an antenna was placed near the IDT. A DMMP-sensitive viscoelastic polymer fluoroalcoholpolysiloxane (SXFA) film was prepared on a LiNbO3 substrate, and mode modeling coupling was used to optimize the design parameters. The sensor can function properly in an environments between -30 °C and 100 °C with humidity less than 60% RH. When the wireless transmission distance was within the range of 0-90 cm, the sensor noise increased with distance, and the stability was less than 32°/h. While optimizing the film thickness of SXFA, a relationship was observed between sensor sensitivity and film thickness. When the film thickness of SXFA reached 450 nm, the optimal value was reached. At a distance of 20 cm between the transmitting and receiving antennas, DMMP was detected at different concentrations with the developed WSAW gas sensor. The lower detection limit of DMMP was 0.48 mg/m3, the sensitivity of the sensor was 4.63°/(mg/m3), and repeatable performance of the sensor was confirmed.

Loss of RNA-binding protein CELF2 promotes acute leukemia development via FAT10-mTORC1.

RNA-binding proteins (RBPs) are critical regulators for RNA transcription and translation. As a key member of RBPs, ELAV-like family protein 2 (CELF2) has been shown to regulate RNA splicing and embryonic hematopoietic development and was frequently seen dysregulated in acute myeloid leukemia (AML). However, the functional role(s) of CELF2 in hematopoiesis and leukemogenesis has not been fully elucidated. In the current study, we showed that Celf2 deficiency in hematopoietic system led to enhanced HSCs self-renewal and differentiation toward myeloid cells in mice. Loss of Celf2 accelerated myeloid cell transformation and AML development in MLL-AF9-induced AML murine models. Gene expression profiling integrated with RNA immunoprecipitation sequencing (RIP-Seq), together with biochemical experiments revealed that CELF2 deficiency stabilizes FAT10 mRNA, promotes FAT10 translation, thereby increases AKT phosphorylation and mTORC1 signaling pathway activation. Notably, combination therapy with a mTORC1 inhibitor (Rapamycin) and a MA9/DOTL1 inhibitor (EPZ-5676) reduced the leukemia burden in MLL-AF9 mice lacking Celf2 in vivo. Our study elucidated a novel mechanism by which the CELF2/FAT10-AKT/mTORC1 axis regulates the proliferation of normal blood cells and the development of AML, thus providing potential therapeutic targets for myeloid leukemia suppression.

The Influence of Synthetic Parameters on HgSe QDs.

HgSe quantum dots (QDs) were synthesized by a thermal injection method. The effects of material ratio, growth time, and reaction temperature on the growth and spectral properties of the QDs have been studied. The experimental results show that the QDs had the highest yield of 53.04% when the molar ratio of Se source to Hg source was 1.5. Also, the excess source of SeS2 was reduced to Se. In addition, the critical radius and spectral red-shift rate of QDs can be increased with the reaction temperature. When the reaction temperature was increased to 100 °C, the spectrum reached far-infrared and the growth rate was increased to 10 times and reached 0.63 nm/min. Differing particle morphologies can be obtained by increasing the growth time to 40 min. Moreover, the growth rate reached the minimum at 30 min and the maximum at 80 min of the growth time. This study can provide guidance for the synthesis of long-wave infrared QD materials.

High Expression of Microtubule-associated Protein TBCB Predicts Adverse Outcome and Immunosuppression in Acute Myeloid Leukemia.

Acute myeloid leukemia (AML) is a devastating blood cancer with high heterogeneity and ill-fated outcome. Despite numerous advances in AML treatment, the prognosis remains poor for a significant proportion of patients. Consequently, it is necessary to accurately and comprehensively identify biomarkers as soon as possible to enhance the efficacy of diagnosis, prognosis and treatment of AML. In this study, we aimed to identify prognostic markers of AML by analyzing the cohorts from TCGA-LAML database and GEO microarray datasets. Interestingly, the transcriptional level of microtubule-associated protein TBCB in AML patients was noticeably increased when compared with normal individuals, and this was verified in two independent cohorts (GSE9476 and GSE13159) and with our AML patients. Furthermore, univariate and multivariate regression analysis revealed that high TBCB expression was an independent poor prognostic factor for AML. GO and GSEA enrichment analysis hinted that immune-related signaling pathways were enriched in up-regulated DEGs between two populations separated by the median expression level of TBCB. By constructing a protein-protein interaction network, we obtained six hub genes, all of which are immune-related molecules, and their expression levels were positively linked to that of TBCB. In addition, the high expression of three hub genes was significantly associated with a poor prognosis in AML. Moreover, we found that the tumor microenvironment in AML with high TBCB expression tended to be infiltrated by NK cells, especially CD56bright NK cells. The transcriptional levels of NK cell inhibitory receptors and their ligands were positively related to that of TBCB, and their high expression levels also predicted poor prognosis in AML. Notably, we found that the down-regulation of TBCB suppressed cell proliferation in AML cell lines by enhancing the apoptosis and cell cycle arrest. Finally, drug sensitivity prediction illustrated that cells with high TBCB expression were more responsive to ATRA and midostaurin but resistant to cytarabine, dasatinib, and imatinib. In conclusion, our findings shed light on the feasibility of TBCB as a potential predictor of poor outcome and to be an alternative target of treatment in AML.

R274X-mutated Phf6 increased the self-renewal and skewed T cell differentiation of hematopoietic stem cells.

The PHD finger protein 6 (PHF6) mutations frequently occurred in hematopoietic malignancies. Although the R274X mutation in PHF6 (PHF6R274X) is one of the most common mutations identified in T cell acute lymphoblastic leukemia (T-ALL) and acute myeloid leukemia (AML) patients, the specific role of PHF6R274X in hematopoiesis remains unexplored. Here, we engineered a knock-in mouse line with conditional expression of Phf6R274X-mutated protein in the hematopoietic system (Phf6R274X mouse). The Phf6R274X mice displayed an enlargement of hematopoietic stem cells (HSCs) compartment and increased proportion of T cells in bone marrow. More Phf6R274X T cells were in activated status than control. Moreover, Phf6R274X mutation led to enhanced self-renewal and biased T cells differentiation of HSCs as assessed by competitive transplantation assays. RNA-sequencing analysis confirmed that Phf6R274X mutation altered the expression of key genes involved in HSC self-renewal and T cell activation. Our study demonstrated that Phf6R274X plays a critical role in fine-tuning T cells and HSC homeostasis.

PHF6 maintains acute myeloid leukemia via regulating NF-κB signaling pathway.

Acute myeloid leukemia (AML) is a major hematopoietic malignancy characterized by the accumulation of immature and abnormally differentiated myeloid cells in bone marrow. Here with in vivo and in vitro models, we demonstrate that the Plant homeodomain finger gene 6 (PHF6) plays an important role in apoptosis and proliferation in myeloid leukemia. Phf6 deficiency could delay the progression of RUNX1-ETO9a and MLL-AF9-induced AML in mice. PHF6 depletion inhibited the NF-κB signaling pathways by disrupting the PHF6-p50 complex and partially inhibiting the nuclear translocation of p50 to suppress the expression of BCL2. Treating PHF6 over-expressed myeloid leukemia cells with NF-κB inhibitor (BAY11-7082) significantly increased their apoptosis and decreased their proliferation. Taken together, in contrast to PHF6 as a tumor suppressor in T-ALL as reported, we found that PHF6 also plays a pro-oncogenic role in myeloid leukemia, and thus potentially to be a therapeutic target for treating myeloid leukemia patients.

Performance of feature extraction method for classification and identification of proteins based on three-dimensional fluorescence spectrometry.

Three-dimensional excitation emission matrix (EEM) fluorescence spectroscopy was employed to discriminate protein samples comprising bovine serum albumin, neurotensin, ovalbumin, ricin, trypsin from bovine pancreas and trypsin from porcine pancreas. Two methods of feature extraction with and without parameterization were applied to the spectral data in order to evaluate their performance of discrimination between protein samples. The discrimination of protein samples was conducted by k-means clustering algorithm and eigenvalue extracting procedure based on principal component analysis (PCA). It was found that the method of feature extraction without parameterization performed best, correctly attributing 100% of the spectral data in the condition of two principal components (PCs) captured. Features extracted with spectral parameterization failed to separate ricin and trypsin from bovine pancreas in same condition. Without spectral parameterization, less dimensionality and unique principal components captured by PCA indicates the spectrally-resolved features of corresponding protein samples. By clustering using each spectrum at fixed excitation wavelength, excitation wavelengths matched with common intrinsic fluorophores were found to be more sensitive to the classification accuracy. Contributions of spectral features extracted from EEM to the principal components were discussed and demonstrated their feature differentiation capabilities among six protein samples. These results reveal that appropriate extraction approach of features in combination with PCA analysis could be used in discrimination of protein samples at species level as a spectroscopic diagnostic tool. Our study provides fundamental references about computational strategies when EEM are used to explore proteins in ambient environment.

Influence of Ink Properties on the Morphology of Long-Wave Infrared HgSe Quantum Dot Films.

As the core device of the miniature quantum dot (QD) spectrometer, the morphology control of the filter film array cannot be ignored. We eliminated strong interference from additives on the spectrum of a long-wave infrared (LWIR) QD filter film by selecting volatile additives. This work is significant for detecting targets by spectroscopic methods. In this work, a filter film with characteristic spectral bands located in the LWIR was obtained by the natural evaporation of QD ink, which was prepared by mixing various volatile organic solvents with HgSe QD-toluene solution. The factors affecting the morphology of HgSe LWIR films, including ink surface tension, particle size, and solute volume fraction, were the main focus of the analysis. The experimental results suggested that the film slipped in the evaporation process, and the multilayer annular deposition formed when the surface tension of the ink was no more than 24.86 mN/m. The "coffee ring" and the multilayer annular deposition essentially disappeared when the solute particles were larger than 188.11 nm. QDs in the film were accumulated, and a "gully" morphology appeared when the solute volume fraction was greater than 0.1. In addition, both the increase rate of the film height and the decrease rate of the transmission slowed down. The relationship between film height and transmission was obtained by fitting, and the curve conformed to the Lambert-Beer law. Therefore, a uniform and flat film without "coffee rings" can be prepared by adjusting the surface tension, particle size, and volume fraction. This method could provide an empirical method for the preparation of LWIR QD filter film arrays.

Development of a SAW poly(epichlorohydrin) gas sensor for detection of harmful chemicals.

The uniformity and compactness of the surface of a viscoelastic sensitive film are among the most important factors that influence the characteristics of a surface acoustic wave (SAW) gas sensor, directly affecting the detection sensitivity of a SAW sensor on a target gas. In this paper, poly(epichlorohydrin) (PECH) with viscoelastic properties was used as sensitive film for the detection of 2-chloroethyl ethyl sulfide (CEES), a common simulant of the chemical agent mustard gas. Nanoscale films were prepared using a spin coating technology on a SAW delay line of 200 MHz. Films were evaluated using polarizing microscopy and atomic force microscopy and observed with uniform surface states and particle diameter in the cluster region of 4.52-5.22 µm. The interface parameters, including contact angle, surface tension, Gibbs free energy, work of adhesion, work of immersion, and spreading coefficient values were 9.31° to 39.63°, 22.475 to 29.945 mN m-1, -85.70 to -78.08 J m-2, 78.08 to 85.70 J m-2, -42.62 to -35.00 J m-2, and 0.46 to 8.08 J m-1, respectively. These values were obtained by experiments combined with the Young T equation and Gibbs adsorption isotherm, and the surface analysis was carried out theoretically. The glass transition temperature (-22.4 °C), viscosity, pyrolysis, and other physical characteristics of the prepared PECH were discussed. Five SAW sensors prepared at the same time were used to test the repeatability of CEES measurements at one concentration, where the consistency of the sensor preparation was confirmed. At a concentration of 13.6 mg m-3 for CEES, 10 consecutive detection results showed good repeatability (i.e., standard deviation = 0.295, coefficient of variance = 0.021, and population mean deviation = 0.364). At room temperature (20 °C ± 5 °C), different concentrations of CEES were detected using the developed sensor, which showed good linearity in the concentration range of 1.9-19.6 mg m-3 (y = 0.0309 + 1.13x, r = 0.99478). The limit of detection was 0.85 mg m-3, the limit of quantitation was 1.91 mg m-3, and the sensitivity of the SAW sensor was 1.13 mV (mg m-3). The adsorption mechanism related to PECH in the detection of CEES was also discussed.

Rapamycin Promotes the Expansion of Myeloid Cells by Increasing G-CSF Expression in Mesenchymal Stem Cells.

Rapamycin, also known as sirolimus, an inhibitor of mammalian target of rapamycin (mTOR), is a regulatory kinase responsible for multiple signal transduction pathways. Although rapamycin has been widely used in treating various hematologic diseases, the effects of rapamycin are still not fully understood. Here we found that both oral and intraperitoneal administration of rapamycin led to the expansion of myeloid lineage, while intraperitoneal administration of rapamycin impaired granulocyte differentiation in mice. Rapamycin induced bone marrow mesenchymal stem cells to produce more G-CSF in vitro and in vivo, and promoted the myeloid cells expansion. Our results thus demonstrated that intraperitoneal administration of rapamycin might promote the expansion of myeloid lineage while impair myeloid cell differentiation in vivo.

PHF6 and JAK3 mutations cooperate to drive T-cell acute lymphoblastic leukemia progression.

T-cell acute lymphoblastic leukemia (T-ALL) is a malignant hematologic disease caused by gene mutations in T-cell progenitors. As an important epigenetic regulator, PHF6 mutations frequently coexist with JAK3 mutations in T-ALL patients. However, the role(s) of PHF6 mutations in JAK3-driven leukemia remain unclear. Here, the cooperation between JAK3 activation and PHF6 inactivation is examined in leukemia patients and in mice models. We found that the average survival time is shorter in patients with JAK/STAT and PHF6 comutation than that in other patients, suggesting a potential role of PHF6 in leukemia progression. We subsequently found that Phf6 deficiency promotes JAK3M511I-induced T-ALL progression in mice by inhibiting the Bai1-Mdm2-P53 signaling pathway, which is independent of the JAK3/STAT5 signaling pathway. Furthermore, combination therapy with a JAK3 inhibitor (tofacitinib) and a MDM2 inhibitor (idasanutlin) reduces the Phf6 KO and JAK3M511I leukemia burden in vivo. Taken together, our study suggests that combined treatment with JAK3 and MDM2 inhibitors may potentially increase the drug benefit for T-ALL patients with PHF6 and JAK3 comutation.

Ultra-Fast Computation of Excited-States Spectra for Large Systems: Ultraviolet and Fluorescence Spectra of Proteins.

A workable approach named xTB-sTDDFT was selected to investigate the excited-state spectra of oxytocin (135 atoms), GHRP-6 (120 atoms) and insulin (793 atoms). Three different Hartree-Fock components functionals (wB97XD3: 51%, LC-BLYP: 53%, wB97X: 57%) were used to calculate the excitation spectra, and the results calculated by wB97XD3 functional well agree with the experiments. It's a deep impression that computed time cost reduced by more than 80%. For polypeptide (oxytocin and GHRP-6), both UV and fluorescence spectra were obtained, and the errors between the calculated and experimental values approximately were 20 nm. For Insulin, the errors are within 15 nm. UV spectrum peak is λcal = 262 nm (λexp = 277 nm, Δλ = 15 nm), and fluorescence spectrum peak is λcal = 294 nm (λexp = 304 nm, Δλ = 10 nm). In summary, a suitable theoretical model is established to ultra-fast calculate the electronic excitation spectra of large systems, such as proteins and biomacromolecules, with good calculation accuracy, fast calculation speed and low cost.

Theoretical Research on Excited States: Ultraviolet and Fluorescence Spectra of Aromatic Amino Acids.

Using Gaussian and Orca, UV and fluorescence spectra of three amino acids (Tyr: Tyrosine, Trp: Tryptophan, Phe: Phenylalanine) were calculated by different functionals (B3LYP, BP86, wB97X). The spectra calculated by BP86 are consistent with the experiments. UV spectra peak of Tyr is 255 nm (Exp. 275 nm, Δλ = 20 nm), Trp is 279 nm (Exp. 277 nm, Δλ = 2 nm), and Phe is 275 nm (Exp. 257 nm, Δλ = 18 nm). Fluorescence spectra peak of Trp is 341 nm (Exp. 350 nm, Δλ = 9 nm), Tyr is 295 nm (Exp. 306 nm, Δλ = 11 nm), and Phe is 285 nm (Exp. 302 nm, Δλ = 17 nm). Moreover, a theoretical model for calculating the excited states of biomolecules is established. Compared with Gaussian's results, Orca is more quickly and effectively for calculating excited state spectra with the same accuracy.