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The construction of neuronal membranes is a dynamic process involving the biogenesis, vesicular packaging, transport, insertion and recycling of membrane proteins. Optical imaging is well suited for the study of protein spatial organization and transport. However, various shortcomings of existing imaging techniques have prevented the study of specific types of proteins and cellular processes. Here we describe strategies for protein tagging and labeling, cell culture and microscopy that enable the real-time imaging of axonal membrane protein trafficking and subcellular distribution as they progress through some stages of their life cycle. First, we describe a process for engineering membrane proteins with extracellular self-labeling tags (either HaloTag or SNAPTag), which can be labeled with fluorescent ligands of various colors and cell permeability, providing flexibility for investigating the trafficking and spatiotemporal regulation of multiple membrane proteins in neuronal compartments. Next, we detail the dissection, transfection and culture of dorsal root ganglion sensory neurons in microfluidic chambers, which physically compartmentalizes cell bodies and distal axons. Finally, we describe four labeling and imaging procedures that utilize these enzymatically tagged proteins, flexible fluorescent labels and compartmentalized neuronal cultures to study axonal membrane protein anterograde and retrograde transport, the cotransport of multiple proteins, protein subcellular localization, exocytosis and endocytosis. Additionally, we generated open-source software for analyzing the imaging data in a high throughput manner. The experimental and analysis workflows provide an approach for studying the dynamics of neuronal membrane protein homeostasis, addressing longstanding challenges in this area. The protocol requires 5–7 days and expertise in cell culture and microscopy.

Dissecting the photochemical reactivity of metal ions is a significant contribution to understanding secondary pollutant formation, as they have a role to be reckoned with atmospheric chemistry. However, their photochemical reactivity has received limited attention within the active nitrogen cycle, particularly at the gas–solid interface. In this study, we delve into the contribution of magnesium ion (Mg2+) and ferric ion (Fe3+) to nitrate decomposition on the surface of photoactive mineral dust. Under simulated sunlight irradiation, the observed NOXproduction rate differs by an order of magnitude in the presence of Mg2+(6.02 × 10–10mol s–1) and Fe3+(2.07 × 10–11mol s–1). The markedly decreased fluorescence lifetime induced by Mg2+and the change in the valence of Fe3+revealed that Mg2+and Fe3+significantly affect the concentration of nitrate decomposition products by distinct photochemical reactivity with photogenerated electrons. Mg2+promotes NOXproduction by accelerating charge transfer, while Fe3+hinders nitrate decomposition by engaging in a redox cyclic reaction with Fe2+to consume photogenerated carriers continuously. Furthermore, when Fe3+coexists with other metal ions (e.g., Mg2+, Ca2+, Na+, and K+) and surpasses a proportion of approximately 12%, the photochemical reactivity of Fe3+tends to be dominant in depleting photogenerated electrons and suppressing nitrate decomposition. Conversely, below this threshold, the released NOXconcentration increases sharply as the proportion of Fe3+decreases. This research offers valuable insights into the role of metal ions in nitrate transformation and the generation of reactive nitrogen species, contributing to a deep understanding of atmospheric photochemical reactions.

One-pot catalysis of olefins and CO2provides an economical and energy-efficient way for the fixation of CO2and the production of cyclic carbonates. In this work, a two-dimensional Co-1,4-benzenedicarboxylate MOF (2D CoBDC) was synthesized via a facile solvothermal reflux method and further examined in the one-pot synthesis of cyclic carbonates. The results of activity evaluations and detailed kinetics showed that 2D CoBDC exhibited enhanced catalytic performance (92% of styrene conversion and 85% of styrene carbonate yield) under cocatalyst-free conditions of 100 °C, 1 bar, and 12 h, compared with the 3D counterpart. The results from effectiveness factors and Thiele modulus revealed the full utilization and negligible mass transfer limitations of the 2D CoBDC catalyst. A further recycle experiment confirmed the excellent reusability of 2D CoBDC with little loss in catalytic activity after at least 5 runs. Finally, a possible mechanism of the one-pot reaction catalyzed by 2D CoBDC was proposed.

Osteoarthritis (OA) is the most common joint disease. Currently there are no effective methods that simultaneously prevent joint degeneration and reduce pain1. Although limited evidence suggests the existence of voltage-gated sodium channels (VGSCs) in chondrocytes2, their expression and function in chondrocytes and in OA remain essentially unknown. Here we identify Nav1.7 as an OA-associated VGSC and demonstrate that human OA chondrocytes express functional Nav1.7 channels, with a density of 0.1 to 0.15 channels per µm2and 350 to 525 channels per cell. Serial genetic ablation of Nav1.7 in multiple mouse models demonstrates that Nav1.7 expressed in dorsal root ganglia neurons is involved in pain, whereas Nav1.7 in chondrocytes regulates OA progression. Pharmacological blockade of Nav1.7 with selective or clinically used pan-Navchannel blockers significantly ameliorates the progression of structural joint damage, and reduces OA pain behaviour. Mechanistically, Nav1.7 blockers regulate intracellular Ca2+signalling and the chondrocyte secretome, which in turn affects chondrocyte biology and OA progression. Identification of Nav1.7 as a novel chondrocyte-expressed, OA-associated channel uncovers a dual target for the development of disease-modifying and non-opioid pain relief treatment for OA.

Optical signal processing has been playing a crucial part as powerful engine for various information systems in the practical applications. In particular, achieving large-scale programmable chips for signal processing are highly desirable for high flexibility, low cost and powerful processing. Silicon photonics, which has been developed successfully in the past decade, provides a promising option due to its unique advantages. Here, recent progress of large-scale programmable silicon photonic chip for signal processing in microwave photonics, optical communications, optical computing, quantum photonics as well as dispersion controlling are reviewed. Particularly, we give a discussion about the realization of high-performance building-blocks, including ultra-low-loss silicon photonic waveguides, 2 × 2 Mach–Zehnder switches and microring resonator switches. The methods for configuring large-scale programmable silicon photonic chips are also discussed. The representative examples are summarized for the applications of beam steering, optical switching, optical computing, quantum photonic processing as well as optical dispersion controlling. Finally, we give an outlook for the challenges of further developing large-scale programmable silicon photonic chips.

The application of Automated Writing Evaluation (AWE) has recently gained researchers’ attention worldwide. However, the impact of AWE feedback on student writing, particularly in languages other than English, remains controversial. This study aimed to compare the impacts of Chinese AWE feedback and teacher feedback on Chinese writing revision, writing quality, and writing motivation among 7th grade students. Using an experimental design, the study found the following results: (1) compared to students receiving teacher feedback, those receiving Chinese AWE feedback conducted fewer revisions, showed a higher proportion of low-level revisions, exhibited a higher frequency of “deleting” behavior, and had a lower success rate of revisions. (2) Both Chinese AWE feedback and teacher feedback could significantly improve students’ writing quality from the first to the final draft. However, the effect sizes in the AWE group were smaller than those in the teacher feedback group. (3) Chinese AWE feedback positively impacted students’ writing motivation. Students receiving Chinese AWE feedback exhibited significantly higher writing confidence and persistence in the post-test compared to those receiving teaching feedback. Chinese AWE has the potential to facilitate personalized writing instruction and evaluation. The trend toward human–computer collaboration in writing education is expected to gain popularity in the future.

A compact silicon photonic wavelength-selective switch (WSS) based on an array of elliptical microrings with adiabatically varied radii and widths is proposed and demonstrated experimentally. A 1 × 4 WSS is designed and realized by integrating four cells sharing the same bus waveguide. Particularly each cell contains four elliptical microring units corresponding to four wavelength-channels. For the fabricated WSS, the average excess loss at the output port of all the channels is measured to be less than 1 dB, while the crosstalk between adjacent channels is less than −20 dB. Leveraging the thermo-optic effect and fine wavelength-tuning linearity, precise alignment of the resonance peak can be implemented, enabling the selection of arbitrary wavelength-channel for any port. The fabricated WSS is used for realizing wavelength-selective data routing with 30 Gbps non-return-to-zero signals and open eye diagrams are obtained. The proposed architecture has excellent scalability, which can facilitate the development of reconfigurable optical add/drop multiplexers in wavelength-division-multiplexing systems, and is suitable for building large-scale optical data center interconnects.

The cancer-associated fibroblast (CAF) barrier in pancreatic ductal adenocarcinoma (PDAC) greatly restricts clinical outcomes. Major obstacles to PDAC treatment include restricted immune cell infiltration and drug penetration and the immunosuppressive microenvironment. Here, we reported a “shooting fish in a barrel” strategy by preparing a lipid–polymer hybrid drug delivery system (PI/JGC/L-A) that could overcome the CAF barrier by turning it into a “barrel” with antitumor drug depot properties to alleviate the immunosuppressive microenvironment and increase immune cell infiltration. PI/JGC/L-A is composed of a pIL-12-loaded polymeric core (PI) and a JQ1 and gemcitabine elaidate coloaded liposomal shell (JGC/L-A) that has the ability to stimulate exosome secretion. By normalizing the CAF barrier to create a CAF “barrel” with JQ1, stimulating the secretion of gemcitabine-loaded exosomes from the CAF “barrel” to the deep tumor site, and leveraging the CAF “barrel” to secrete IL-12, PI/JGC/L-A realized effective drug delivery to the deep tumor site, activated antitumor immunity at the tumor site, and produced significant antitumor effects. In summary, our strategy of transforming the CAF barrier into antitumor drug depots represents a promising strategy against PDAC and might benefit the treatment of any tumors facing a drug delivery barrier.

The optimal control problem with a long run average cost is investigated for unknown linear discrete-time systems with additive noise. The authors propose a value iteration-based stochastic adaptive dynamic programming (VI-based SADP) algorithm, based on which the optimal controller is obtained. Different from the existing relevant work, the algorithm does not need to estimate the expectation (conditional expectation) and variance (conditional variance) of states or other relevant variables, and the convergence of the algorithm can be proved rigorously. A simulation example is given to verify the effectiveness of the proposed approach.

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has affected more than 600 million people worldwide. Several organs including lung, intestine, and brain are infected by SARS-CoV-2. It has been reported that SARS-CoV-2 receptor angiotensin-converting enzyme-2 (ACE2) is expressed in human testis. However, whether testis is also affected by SARS-CoV-2 is still unclear. In this study, we generate a human ACE2 (hACE2) transgenic mouse model in which the expression of hACE2gene is regulated by hACE2promoter. Sertoli and Leydig cells from hACE2 transgenic mice can be infected by SARS-CoV-2 pseudovirus in vitro, and severe pathological changes are observed after injecting the SARS-CoV-2 pseudovirus into the seminiferous tubules. Further studies reveal that Sertoli and Leydig cells from hACE2 transgenic mice are also infected by authentic SARS-CoV-2 virus in vitro. After testis interstitium injection, authentic SARS-CoV-2 viruses are first disseminated to the interstitial cells, and then detected inside the seminiferous tubules which in turn cause germ cell loss and disruption of seminiferous tubules. Our study demonstrates that testis is most likely a target of SARS-CoV-2 virus. Attention should be paid to the reproductive function in SARS-CoV-2 patients.

The design and fabrication of novel two-dimensional (2D) metal-organic framework (MOF) nanosheets with excellent electrochemical performance are significant in the field of energy storage. Herein, a series of 2D bimetallic nickel‑cobalt MOFs (NiCo-MOFs) nanosheets based on thiophene ligand with adjustable components are synthesized using an in situapproach and a facile one-step hydrothermal reaction in DMF/H2O mixed solvent. These thienyl based NiCo-MOF nanosheets, grown directly on nickel foam (NF), function as electrodes for supercapacitors. The optimal NiCo-MOF/NF-3-2 (Ni/Co = 3:2) obtained by modulating the Ni/Co molar ratio demonstrates an ultrahigh specific capacity of 615.7 C g−1(1243 F g−1) at the current density of 1 A g−1and an excellent rate capacity (63.9% retention at 10 A g−1). DFT calculations indicate that adjustable bimetallic composition can modulate the electronic structure of metal centers and improve conductivity of MOF materials. The exceptional electrochemical performance of the NiCo-MOF/NF-3-2 electrode can be attributed to regular 2D nanosheet arrays on a conductive substrate, which provides open spaces and short transport distance between abundance active sites and electrolyte ions. Moreover, an asymmetric supercapacitor device composed of NiCo-MOF/NF-3-2 and active carbon exhibits a high energy density of 54.6 Wh kg−1at a power density of 800 W kg−1and an outstanding cycle life with a capacitance retention of 84.7% after 5000 cycles. This study demonstrates the remarkable potential of novel 2D bimetallic NiCo-MOF nanosheets for energy storage and conversion applications.

Popularization of lithium-sulfur batteries (LSBs) is still hindered by shuttle effect and volume expansion. Herein, a new modularized sulfur storage strategy is proposed to solve above problems and accomplished viaemploying 100% space utilization host material of cobalt loaded carbon nanoparticles derived from ZIF-67. The modular dispersed storage of sulfur not only greatly increases the proportion of active sulfur, but also inhibits the occurrence of volume expansion. Meanwhile, 100% space utilization host material can greatly improve the conductivity of the cathode, provide a larger electrolyte wetting interface and effectively suppress the shuttle effect. Moreover, loaded cobalt particles have high catalytic activity for electrochemical reaction and can effectively improve the redox kinetics. The cell with new cathode host material carbonized at 650 °C (ZIF-67 (650 °C)) exhibits superior rate performance and can maintain a high specific capacity of 950 mAh/g after 100 cycles at 0.2 C, showing a good cycle stability.

Gut bacteria-derived enzymes play important roles in the metabolism of dietary fiber through enabling the hydrolysis of polysaccharides. In this study, we identified and characterized a 29 kDa novel acetyl xylan esterase, BTAxe1, from Bacteroides thetaiotaomicronVPI5482. Then, we solved the structure of BTAxe1 and performed the rational design. Mutants N65S and N65A increased the activities toward short-chain (pNPA, pNPB) to near four-fold, and gained the activities toward longer-chain substrate (pNPO). Molecular docking analysis showed that the mutant N65S had a larger substrate binding pocket than the wild type. Hydrolysis studies using natural substrates showed that either N65S or N65A showed higher activity of that of wild-type, yielding 131.31 and 136.09 mM of acetic acid from xylan. This is the first study on the rational design of gut bacteria-derived Axes with broadened substrate specificity and enhanced activity, which can be referenced by other acetyl esterases or gut-derived enzymes.

Tumor necrosis factor α (TNF-α) is a major pro-inflammatory cytokine, important in many diseases, that sensitizes nociceptors through its action on a variety of ion channels, including voltage-gated sodium (NaV) channels. We show here that TNF-α acutely upregulates sensory neuron excitability and current density of threshold channel NaV1.7. Using electrophysiological recordings and live imaging, we demonstrate that this effect on NaV1.7 is mediated by p38 MAPK and identify serine 110 in the channel’s N terminus as the phospho-acceptor site, which triggers NaV1.7 channel insertion into the somatic membrane. We also show that the N terminus of NaV1.7 is sufficient to mediate this effect. Although acute TNF-α treatment increases NaV1.7-carrying vesicle accumulation at axonal endings, we did not observe increased channel insertion into the axonal membrane. These results identify molecular determinants of TNF-α-mediated regulation of NaV1.7 in sensory neurons and demonstrate compartment-specific effects of TNF-α on channel insertion in the neuronal plasma membrane.

The development of functional films with both antibacterial and preservative properties is crucial to ensure food safety. Herein, porous carbon nitride-chitosan/zein (PCN-CS/ZN) bilayer active films were developed via layer-by-layer deposition method. The incorporation of PCN into the inner CS layer imparted the bilayer films with efficient photocatalytic antibacterial activity. The bilayer structure featuring a moisture absorption inner layer (PCN-CS) and a moisture barrier outer layer (ZN), allowed tuning of the water barrier performance. The addition of the ZN layer increased the tensile strength (TS) and elongation at break (EAB) and decreased the water vapor permeability (WVP, CS side), moisture content (MC), water solubility (WS) and swelling degree (SD) of the CS film. Addition an appropriate amount of PCN was able to further increase the TS and decrease the WVP (CS side), MC, WS, and SD of the bilayer films. Antibacterial experiments confirmed that the addition of PCN photocatalyst significantly increased the antibacterial activity of the bilayer films against Escherichia coli(E. coli) and Staphylococcus aureus(S. aureus). The banana fruits covered with 10% PCN-CS/ZN bilayer films had a long shelf life, with no obvious deterioration observed over 10 days under visible light at room temperature (about 32 °C). Therefore, PCN-CS/ZN bilayer films represent a promising low-cost food packaging material with good functional properties.

Drawing from agenda building theory, this study explores the impact of factors like journalistic culture, national stance and conflict periods on the similarity and dissimilarity of network agendas in China-U.S. trade conflict news across China, the United States, Singapore and Ireland. Findings revealed significant correlations in network agendas across countries, albeit with disparities between China and the United States. Notably, the correlation weakened in both Chinese and U.S. news following the trade war’s eruption.

Aiming at the problem of poor processing performance and difficult processing in the process of aluminum-based diamond composites for electronic packaging, this paper uses electrolytic in-process dressing (ELID) grinding technology to grind the aluminum-based diamond composites. The quadratic orthogonal rotation combination method was used to investigate the influence law and degree of grinding depth, grinding wheel linear velocity, duty cycle and electrolysis current on surface roughness. The ELID grinding optimization process parameters of aluminum-based diamond composites obtained by LINGO software are: grinding depth 9.3μm, grinding wheel linear speed 36m/s, duty cycle 63.7%, electrolysis current 11.5A. The surface of the aluminum-based diamond composite with a surface roughness of 125 nm was machined by this optimized process parameter combination.

N6-methyladenosine (m6A) on mRNAs is critical for various biological processes, yet whether m6A regulates drug resistance remains unknown. Here we show that developing resistant phenotypes during tyrosine kinase inhibitor (TKI) therapy depends on m6A reduction resulting from FTOoverexpression in leukemia cells. This deregulated FTO-m6A axis pre-exists in naïve cell populations that are genetically homogeneous and is inducible/reversible in response to TKI treatment. Cells with mRNA m6A hypomethylation and FTOupregulation demonstrate more TKI tolerance and higher growth rates in mice. Either genetic or pharmacological restoration of m6A methylation through FTO deactivation renders resistant cells sensitive to TKIs. Mechanistically, the FTO-dependent m6A demethylation enhances mRNA stability of proliferation/survival transcripts bearing m6A and subsequently leads to increased protein synthesis. Our findings identify a novel function for the m6A methylation in regulating cell fate decision and demonstrate that dynamic m6A methylome is an additional epigenetic driver of reversible TKI-tolerance state, providing a mechanistic paradigm for drug resistance in cancer.

Compressed sensing MRI (CS-MRI) significantly accelerates scanning time via accurate reconstruction of the image from undersampled k-space data. In this work, combining two priors of sparsity and nonlocal similarity, an algorithm of group sparsity with an orthogonal dictionary (GSOD) is proposed to realize CS-MRI reconstruction within an optimization framework. To efficiently solve the resultant non-convex optimization, a lower bound of the original problem is derived, and generalized soft-thresholding is then applied to obtain the solution from that lower bound in a fast and accurate manner. Moreover, considering the important role of the dictionary in sparse representation, a modified GSOD (M-GSOD) approach is also developed in which the orthogonal dictionary is adaptively learned from the group. It is proven that the proposed sparse coding model in the M-GSOD is equivalent to the low-rank model, and the connection between the two independent models is established for the first time. Finally, a fast and accurate algorithm to solve M-GSOD is provided. Compared with the current methods, the proposed methods demonstrate a state-of-the-art performance, which shows the correctness of the non-convex regularization and optimal dictionary learning. [ABSTRACT FROM AUTHOR]

Evidence suggests that the long noncoding RNA (lncRNA) metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is upregulated in cancer tissues, and its elevated expression is associated with hyperproliferation. However, the underlying mechanisms regarding the role of MALAT1 in retinoblastoma (RB) remain unclear. This study aimed to explore the functional role of MALAT1 in RB by targeting miR-124. The results showed that the expression of MALAT1 was significantly higher in the Y79 cell line than in the ARPE-19 cell line (p < 0.01). Moreover, MALAT1 silence inhibited cell viability, migration, and invasion and promoted apoptosis in Y79 cells (p < 0.05, p < 0.01, or p < 0.001). miR-124 was upregulated by MALAT1 silence and hence was identified as a target of MALAT1 (p < 0.05 or p < 0.001). In addition, miR-124 suppression inhibited cell apoptosis and remarkably abolished the inhibitory effects of MALAT1 silence on cell viability, migration, and invasion (p < 0.05, p < 0.01, or p < 0.001). In addition, Slug was a target of miR-124 and regulated cell viability, migration, invasion, and apoptosis in Y79 cells (p < 0.05, p < 0.01, or p < 0.001). Further, Slug silence abolished miR-124 suppression-induced inactivation of the ERK/MAPK and Wnt/β-catenin pathways. Taken together, our data highlight the pivotal role of MALAT1 in RB. Moreover, the present study elucidated the MALAT1‐miR-124‐ERK/MAPK and Wnt/β-catenin signaling pathways in RB, which might provide a new approach for the treatment of RB.

In this article, we give the existence of global L∞bounded entropy solutions to the Cauchy problem of a generalized n × nhyperbolic system of LeRoux type. The main difficulty lies in establishing some compactness estimates of the viscosity solutions because the system has been generalized from 2 × 2 to n × nand more linearly degenerate characteristic fields emerged, and the emergence of singularity in the region {v1=0} is another difficulty. We obtain the existence of the global weak solutions using the compensated compactness method coupled with the construction of entropy-entropy flux and BV estimates on viscous solutions.

Gold nanoparticles (AuNPs) with adsorbed high-density lipoprotein (HDL) have been utilized to deliver oligonucleotides, yet HDL-AuNPs functionalized with small-molecule inhibitors have not been systematically explored. Here, we report an AuNP-based therapeutic system (HDL-AuNPs-BMS) for acute myeloid leukemia (AML) by delivering BMS309403 (BMS), a small molecule that selectively inhibits AML-promoting factor fatty acid-binding protein 4. To synthesize HDL-AuNPs-BMS, we use AuNP as a template to control conjugate size ensuring a spherical shape to engineer HDL-like nanoparticles containing BMS. The zeta potential and size of the HDL-AuNPs obtained from transmission electron microscopy demonstrate that the HDL-AuNPs-BMS are electrostatically stable and 25 nm in diameter. Functionally, compared to free drug, HDL-AuNPs-BMS conjugates are more readily internalized by AML cells and have more pronounced effects on downregulation of DNA methyltransferase 1 (DNMT1), induction of DNA hypomethylation, and restoration of epigenetically silenced tumor suppressor p15INK4Bcoupled with AML growth arrest. Importantly, systemic administration of HDL-AuNPs-BMS conjugates into AML-bearing mice inhibits DNMT1-dependent DNA methylation, induces AML cell differentiation, and diminishes AML disease progression without obvious side effects. In summary, these data, for the first time, demonstrate HDL-AuNPs as an effective delivery platform with great potential to attach distinct inhibitors and HDL-AuNPs-BMS conjugates as a promising therapeutic platform to treat leukemia.

In this work, the effect of additive noise is studied in order to reduce the mean squared error (MSE) between the input parameter and its linear estimator constructed by the nonlinear system output. To improve the estimation performance, the optimal additive noise that minimizes the MSE of the noise enhanced linear minimum mean squared error (LMMSE) estimator is explored and determined. In addition, in the presence of prior information uncertainty, the estimation performances of the noise enhanced LMMSE are investigated under a constant constraint of the expected value of the output, and the corresponding algorithms are developed to find the optimal additive noise. Finally, two illustrative examples are provided to verify the theoretical results. The performance comparisons conducted between the LMMSE estimator without noise excitation and the optimal noise modified LMMSE estimator demonstrate that noise indeed improves the estimation accuracy under certain conditions. [ABSTRACT FROM AUTHOR]

Image restoration is a crucial problem in image processing and a necessary step before the image segmentation and recognition. A new framework for image restoration in 3D transform domain terms as joint sparse representation (JSR) is proposed in this work. The proposed JSR is able to represent image more sparsely and more precisely in the transform domain by performing 3D transform on each set of similar blocks. In addition to that, in order to overcome the issues of defective block matching and spurious artifact in the 3D sparse representation, JSR introduces a new nonlocal regularization term which characterizes the statistics of the nonlocal image to improve the accuracy of the estimated coefficients. The parameters of regularization terms are calculated based on Bayesian philosophy, and a split Bregman-based technique is developed to obtain the solution in a tractable and robust manner. Extensive experiments on image denoising, image inpainting and image deblurring demonstrate that the proposed JSR algorithm outperforms current state-of-the-art approaches in terms of peak signal-to-noise ratio and visual quality. [ABSTRACT FROM AUTHOR]

2D magnetic resonance spectroscopy (MRS) is extensively used to analyze the components, structures, and interactions of substances in chemistry and bioengineering. To reduce data acquisition time, the spatiotemporally encoded ultrafast (STEU) MRS employs a fast means to acquire data in the hybrid time and frequency (HTF) plane, but relies on non-uniform sampling (NUS) technique. After that, a proper reconstruction method is essential to recover a high quality 2D MRS from undersampled HTF data. In this work, each column and row of 2D MRS are converted into Hankel matrices, by which a simultaneous low rank regularization model is proposed to exploit the bivariate exponential structure of 2D MRS signal. Additionally, a non-convex surrogate function for rank is integrated in the proposed model to more precisely enforce the low rank property of Hankel matrices. To ensure computational accuracy and convergence, an efficient numerical algorithm is further deduced based on alternating direction method of multipliers (ADMM) iteration. The experimental results have shown that the proposed method significantly outperforms existing 2D MRS reconstruction methods, and presents a strong robustness to low sampling rates, various sampling patterns, and measurement noise with a favorable complexity. [ABSTRACT FROM AUTHOR]

We present an effective way to generate the suitable or the optimal additive noises which can achieve the three goals of the noise enhanced detectability, i.e., the maximum detection probability ( P D ), the minimum false alarm probability ( P FA ) and the maximum overall improvement of P D and P FA , without increasing P FA and decreasing P D in a binary hypothesis testing problem. The mechanism of our method is that we divide the discrete vectors into six intervals and choose the useful or partial useful vectors from these intervals to form the additive noise according to different requirements. The form of the optimal noise is derived and proven as a randomization of no more than two discrete vectors in our way. Moreover, how to choose suitable and optimal noises from the six intervals are given. Finally, numerous examples are presented to illustrate the theoretical analysis, where the background noises are Gaussian, symmetric and asymmetric Gaussian mixture noise, respectively. [ABSTRACT FROM AUTHOR]

In this paper, the stochastic resonance (SR) effects of the fixed linear–quadratic (L–Q) detector in binary hypothesis testing problems is investigated. The effects include the improvement of the overall performance of the detector wherein the output signal-to-noise ratio (SNR) of receiver and the detection probability ( P D ) are increased and the false-alarm probability ( P FA ) is reduced at the same time. The SNR of a noise modified detector is derived. Since the improvement of the SNR does not mean the improvement of detection performance, the noise enhanced detection performance in terms of P FA and P D are discussed graphically and elaborated through an example of Gaussian background noise. Furthermore, the conditions are deduced to determine whether the overall performance of the detector can be improved or not. In addition, the form of the suitable noise probability distribution function (PDF) is determined and the PDF of noise that satisfies the conditions to improve the overall performance of detector are derived. Finally, an illustrative example is presented to verify the theoretical results. [ABSTRACT FROM AUTHOR]

In this paper, the noise enhanced system performance in a binary hypothesis testing problem is investigated when the additive noise is a convex combination of the optimal noise probability density functions (PDFs) obtained in two limit cases, which are the minimization of false-alarm probability ( P FA ) without decreasing detection probability ( P D ) and the maximization of P D without increasing P FA , respectively. Existing algorithms do not fully consider the relationship between the two limit cases and the optimal noise is often deduced according to only one limit case or Bayes criterion. We propose a new optimal noise framework which utilizes the two limit cases and deduce the PDFs of the new optimal noise. Furthermore, the sufficient conditions are derived to determine whether the performance of the detector can be improved or not via the new noise. In addition, the effects of the new noise are analyzed according to Bayes criterion. Rather than adjusting the additive noise again as shown in other algorithms, we just tune one parameter of the new optimal noise PDF to meet the different requirements under the Bayes criterion. Finally, an illustrative example is presented to study the theoretical results. [ABSTRACT FROM AUTHOR]

CD33-targeted lipid nanoparticles (aCD33LNs) were synthesized for delivery of GTI-2040, an antisense oligonucleotide (ASO) against the R2 subunit of ribonucleotide reductase, to acute myelogenous leukemia (AML). These LNs incorporated a deoxycholate-polyethylenimine (DOC-PEI) conjugate, which has shown significant activity to facilitate oligonucleotide delivery. Anti-CD33 scFv (aCD33) was added as a targeting ligand. The delivery efficiency of this system was investigated both in vitroand in vivo. When cells were treated with aCD33LN/GTI-2040, significant uptake was observed in CD33 positive Kasumi-1 cells. aCD33LNs loaded with GTI-2040 induced significant down-regulation of R2 mRNA and protein levels in AML cells. Moreover, aCD33LN/GTI-2040 showed a 15-fold reduction in the IC50of antileukemic drug Ara-C in Kasumi-1 cells. In Kasumi-1 xenograft model, aCD33LN/GTI-2040 showed significant R2 downregulation compared to LN/GTI-2040. Furthermore, aCD33LN/GTI-2040 coadministered with Ara-C was shown to be highly effective in tumor growth inhibition and to greatly increase survival time of mice bearing Kasumi-1 xenograft tumors. The conjugate DOC-PEI has shown an ability to include calcein release from lipid nanoparticles, suggesting a potential mechanism contributing to efficient endosome release by DOC-PEI2K. These results indicate that aCD33LNs are a highly effective vehicle for the therapeutic delivery of antisense agents to AML.

Astrocytes actively participate in the response of the central nervous system to injury, including in multiple sclerosis. Astrocytes can play both beneficial and detrimental roles in response to neuroinflammation; however, in extreme cases, astrogliosis can result in the formation of a glial scar, which can impede the regeneration of injured neurons. Although astrocytes do not express the voltage-gated sodium channel Nav1.5 in the nonpathological human brain, they exhibit robust upregulation of Nav1.5 within acute and chronic multiple sclerosis lesions. Recent work has indicated that Nav1.5 contributes to the pathways that regulate glial scar formation in vitrothrough modulation of intracellular Ca2levels. However, the temporal dynamics of astrocytic Nav1.5 channel expression in response to neuroinflammatory pathologies has not been investigated. We examined astrocytes from mice with monophasic and chronic-relapsing (CR) experimental autoimmune encephalomyelitis (EAE) by immunohistochemical analysis to determine whether Nav1.5 is expressed in these cells, and whether the expression correlates with the severity of disease andor phases of relapse and remission. Our results demonstrate that Nav1.5 is upregulated in astrocytes in situin a temporal manner that correlates with disease severity in both monophasic and CR EAE. Further, in CR EAE, Nav1.5 expression is upregulated during relapses and subsequently attenuated during periods of remission. These observations are consistent with the suggestion that Nav1.5 can play a role in the response of astrocytes to inflammatory pathologies in the central nervous system and suggest Nav1.5 may be a potential therapeutic target to modulate reactive astrogliosis in vivo.

The coexpression of the MLL partial tandem duplication (PTD) and the FLT3 internal tandem duplication (ITD) mutations associate with a poor outcome in cytogenetically normal acute myeloid leukemia (AML). In mice, a double knock-in (dKI) of MllPTD/wt and Flt3ITD/wt mutations induces spontaneous AML with an increase in DNA methyltransferases (Dnmt1, 3a, and 3b) and global DNA methylation index, thereby recapitulating its human AML counterpart. We determined that a regulator of Dnmts, miR-29b, is downregulated in bone marrow of dKI AML mice. Bortezomib exerted a dose-dependent increase in miR-29b expression in AML blasts ex vivo, followed by decreased Dnmts, reduced proliferation, and increased apoptosis. In vivo, bortezomib was not active against dKI AML, yet liposomal-encapsulated bortezomib, as a single agent, reversed downregulation of miR-29b in vivo and induced a long-term (90-day) disease-free remission in 80% of dKI AML mice that exhibited high leukemic burden at the start of therapy, yet showed no signs of relapse at autopsy. Taken together, these data support that liposomal bortezomib, as a single agent, eradicates MllPTD/wt:Flt3ITD/wt AML in mouse and may represent a powerful and potentially curative approach to high-risk human disease.

The coexpression of the MLLpartial tandem duplication (PTD) and the FLT3internal tandem duplication (ITD) mutations associate with a poor outcome in cytogenetically normal acute myeloid leukemia (AML). In mice, a double knock-in (dKI) of MllPTD/wtand Flt3ITD/wtmutations induces spontaneous AML with an increase in DNA methyltransferases (Dnmt1, 3a, and 3b) and global DNA methylation index, thereby recapitulating its human AML counterpart. We determined that a regulator of Dnmts, miR-29b, is downregulated in bone marrow of dKI AML mice. Bortezomib exerted a dose-dependent increase in miR-29bexpression in AML blasts ex vivo, followed by decreased Dnmts, reduced proliferation, and increased apoptosis. In vivo, bortezomib was not active against dKI AML, yet liposomal-encapsulated bortezomib, as a single agent, reversed downregulation of miR-29bin vivo and induced a long-term (90-day) disease-free remission in 80% of dKI AML mice that exhibited high leukemic burden at the start of therapy, yet showed no signs of relapse at autopsy. Taken together, these data support that liposomal bortezomib, as a single agent, eradicates MllPTD/wt:Flt3ITD/wtAML in mouse and may represent a powerful and potentially curative approach to high-risk human disease.

•RT3D-STE and exosome miRNAs can be used as a hierarchical diagnostic system in AMI.•Exosomal miR-152-5p and miR-3681-5p function as potential biomarkers for ST-segment elevation myocardial infarction.

MicroRNAs (miRs) are deregulated in cancer and leukemia. Restoring aberrantly downregulated tumor suppressor miRs or antagonizing overexpressed oncogenic miRs in malignant cells by synthetic RNA oligonucleotides represents a potentially novel therapeutic approach in cancer and leukemia. However, given the complex networking and concurrent deregulation of miRs in malignant cells, an effective approach may require concurrent targeting of multiple miRs. Cassette dosing involves simultaneous administration of a mixture of oligonucleotides from the same or different structural classes. However, information on cassette dosing pharmacokinetics, tissue distribution and bioactivity of synthetic miRs is lacking. In this study, three synthetic 2′-methoxyphosphorothioate-miRs (2′-MeOPSmiR16-1, 2′-MeOPSmiR29b and 2′-MeOPSantagomiR155) were administered iv to C57BL/6 mice as a mixture, each at 7.5 mg/kg. Analysis of concentrations of individual miR in plasma and major organ tissues (bone marrow, spleen, liver, brain, heart, kidney and lung) was performed. The mRNA and protein levels of miR’s biotargets were monitored sequentially after dosing up to 24 h. Our results demonstrated that these synthetic miRs retain their different individual pharmacokinetic properties and all display three-compartmental pharmacokinetics. 2′-MeOPSmiR16-1 has the longest plasma gamma half-life of 2508 min and lowest total body clearance of 0.0054 L/min·kg, whereas 2′-MeOPSmiR29b has the shortest gamma half-life of 510.6 min and highest total body clearance of 0.042 L/min·kg. The tissue concentrations of all three 2′-MeOPS-modified miR(s)/antagomiR were measurable from 5 min to at least 24 h after dosing, indicating that these concurrently delivered oligonucleotides can reach organ tissues. Importantly, there were biological activities of the concurrently administered miRs which persisted, as shown by the downregulation of specific targets in tested tissues, albeit with variations. Brain was one of the most sensitive tissues with respect to downregulation of mRNA and protein levels of four measured biotargets (e.g., Bcl-2, Mcl-1, DNMT3a and DNMT3b) despite its relatively low miR/antagomiRs levels. We conclude that cassette dosing is applicable to 2′-MeOPS-modified synthetic miRs that are tissue-deliverable and biofunctional without any additional formulation requirement. This study supports future exploration of miR-involved combination therapies.

5-Azacytidine (5-azaC) is an azanucleoside approved for myelodysplastic syndrome. Approximately 80%-90% of 5-azaC is believed to be incorporated into RNA, which disrupts nucleic acid and protein metabolism leading to apoptosis. A smaller fraction (10%-20%) of 5-azaC inhibits DNA methylation and synthesis through conversion to decitabine triphosphate and subsequent DNA incorporation. However, its precise mechanism of action remains unclear. Ribonucleotide reductase (RR) is a highly regulated enzyme comprising 2 subunits, RRM1 and RRM2, that provides the deoxyribonucleotides required for DNA synthesis/repair. In the present study, we found for the first time that 5-azaC is a potent inhibitor of RRM2 in leukemia cell lines, in a mouse model, and in BM mononuclear cells from acute myeloid leukemia (AML) patients. 5-azaC–induced RRM2 gene expression inhibition involves its direct RNA incorporation and an attenuated RRM2 mRNA stability. Therefore, 5-azaC causes a major perturbation of deoxyribonucleotide pools. We also demonstrate herein that the initial RR-mediated 5-azaC conversion to decitabine is terminated through its own inhibition. In conclusion, we identify RRM2 as a novel molecular target of 5-azaC in AML. Our findings provide a basis for its more widespread clinical use either alone or in combination.

Therapeutic use of oligodeoxynucleotides (ODNs) that hybridize to and downregulate target mRNAs encoding proteins that contribute to malignant transformation has a sound rationale, but has had an overall limited clinical success in cancer due to insufficient intracellular delivery. Here we report a development of formulations capable of promoting targeted delivery and enhanced pharmacologic activity of ODNs in acute myeloid leukemia (AML) cell lines and patient primary cells. In this study, transferrin (Tf) conjugated pH-sensitive lipopolyplex nanoparticles (LPs) were prepared to deliver GTI-2040, an antisense ODN against the R2 subunit of ribonucleotide reductase that has been shown to contribute to chemoresistance in AML. LPs had an average particle size around 110 nm and a moderately positive zeta potential at ∼ 10 mV. The ODN encapsulation efficiency of LPs was >90%. These nanoparticles could release ODNs at acidic endosomal pH and facilitate the cytoplasmic delivery of ODNs after endocytosis. In addition, Tf-mediated targeted delivery of GTI-2040 was achieved. R2 downregulation at both mRNA and protein levels was improved by 8-fold in Kasumi-1 cells and 2- to 20-fold in AML patient primary cells treated with GTI-2040-Tf-LPs, compared to free GTI-2040 treatment. Moreover, Tf-LPs were more effective than nontargeted LPs, with 10 to 100% improvement at various concentrations in Kasumi-1 cells and an average of 45% improvement at 3 μM concentration in AML patient primary cells. Treatment with 1 μM GTI-2040-Tf-LPs sensitized AML cells to the chemotherapy agent cytarabine, by decreasing its IC50value from 47.69 nM to 9.05 nM. This study suggests that the combination of pH sensitive LP formulation and Tf mediated targeting is a promising strategy for antisense ODN delivery in leukemia therapy.

Human CD56bright natural killer (NK) cells possess little or no killer immunoglobulin-like receptors (KIRs), high interferon-γ (IFN-γ) production, but little cytotoxicity. CD56dim NK cells have high KIR expression, produce little IFN-γ, yet display high cytotoxicity. We hypothesized that, if human NK maturation progresses from a CD56bright to a CD56dim phenotype, an intermediary NK cell must exist, which demonstrates more functional overlap than these 2 subsets, and we used CD94 expression to test our hypothesis. CD94highCD56dim NK cells express CD62L, CD2, and KIR at levels between CD56bright and CD94lowCD56dim NK cells. CD94highCD56dim NK cells produce less monokine-induced IFN-γ than CD56bright NK cells but much more than CD94lowCD56dim NK cells because of differential interleukin-12–mediated STAT4 phosphorylation. CD94highCD56dim NK cells possess a higher level of granzyme B and perforin expression and CD94-mediated redirected killing than CD56bright NK cells but lower than CD94lowCD56dim NK cells. Collectively, our data suggest that the density of CD94 surface expression on CD56dim NK cells identifies a functional and likely developmental intermediary between CD56bright and CD94lowCD56dim NK cells. This supports the notion that, in vivo, human CD56bright NK cells progress through a continuum of differentiation that ends with a CD94lowCD56dim phenotype.

Human serum albumin (HSA)-coated liposomal formulations were synthesized and evaluated for the delivery of antisense oligodeoxyribonucleotide (ODN) G3139 in KB human oral carcinoma cells. Liposomes composed of dimethyldioctadecyl ammonium bromide/egg phosphatidylcholine/α-tocopheryl polyethylene glycol 1000 succinate (58:40:2 molar ratio) complexed with G3139 and coated with HSA were investigated for Bcl-2downregulating activity. Cellular uptake of HSA-coated liposome−ODN complexes was more efficient than the uncoated liposome−ODN complexes. Treatment of the cells with HSA-coated liposome−ODN complexes resulted in efficient Bcl-2mRNA downregulation that was approximately 3-fold greater than with uncoated liposomes (p< 0.05) and 6-fold greater than with free ODN. The transfection efficiency of liposome−ODN complexes coated with HSA was dependent on the concentration of HSA used and on the contents of α-helix and β-strand in HSA. HSA-coated liposomes are effective delivery vehicles for antisense ODN.

Aberrant DNA hypermethylation contributes to myeloid leukemogenesis by silencing structurally normal genes involved in hematopoiesis. MicroRNAs (miRNAs) are noncoding RNAs that regulate gene expression by targeting protein-coding mRNAs. Recently, miRNAs have been shown to play a role as both targets and effectors in gene hypermethylation and silencing in malignant cells. In the current study, we showed that enforced expression of miR-29bin acute myeloid leukemia cells resulted in marked reduction of the expression of DNA methyltransferases DNMT1, DNMT3A, and DNMT3Bat both RNA and protein levels. This in turn led to decrease in global DNA methylation and reexpression of p15INK4band ESR1via promoter DNA hypomethylation. Although down-regulation of DNMT3Aand DNMT3Bwas the result of a direct interaction of miR-29bwith the 3′ untranslated regions of these genes, no predicted miR-29binteraction sites were found in the DNMT13′ untranslated regions. Further experiments revealed that miR-29bdown-regulates DNMT1indirectly by targeting Sp1, a transactivator of the DNMT1gene. Altogether, these data provide novel functional links between miRNAs and aberrant DNA hypermethylation in acute myeloid leukemia and suggest a potentially therapeutic use of synthetic miR-29boligonucleotides as effective hypomethylating compounds.

Aberrant DNA hypermethylation contributes to myeloid leukemogenesis by silencing structurally normal genes involved in hematopoiesis. MicroRNAs (miRNAs) are noncoding RNAs that regulate gene expression by targeting protein-coding mRNAs. Recently, miRNAs have been shown to play a role as both targets and effectors in gene hypermethylation and silencing in malignant cells. In the current study, we showed that enforced expression of miR-29b in acute myeloid leukemia cells resulted in marked reduction of the expression of DNA methyltransferases DNMT1, DNMT3A, and DNMT3B at both RNA and protein levels. This in turn led to decrease in global DNA methylation and reexpression of p15INK4b and ESR1 via promoter DNA hypomethylation. Although down-regulation of DNMT3A and DNMT3B was the result of a direct interaction of miR-29b with the 3′ untranslated regions of these genes, no predicted miR-29b interaction sites were found in the DNMT1 3′ untranslated regions. Further experiments revealed that miR-29b down-regulates DNMT1 indirectly by targeting Sp1, a transactivator of the DNMT1 gene. Altogether, these data provide novel functional links between miRNAs and aberrant DNA hypermethylation in acute myeloid leukemia and suggest a potentially therapeutic use of synthetic miR-29b oligonucleotides as effective hypomethylating compounds.

Aberrant methylation of tumor suppressor genes can lead to their silencing in many cancers. TSC-22is a gene silenced in several solid tumors, but its function and the mechanism(s) responsible for its silencing are largely unknown. Here we demonstrate that the TSC-22promoter is methylated in primary mouse T or natural killer (NK) large granular lymphocyte (LGL) leukemia and this is associated with down-regulation or silencing of TSC-22expression. The TSC-22deregulation was reversed in vivo by a 5-aza-2′-deoxycytidine therapy of T or NK LGL leukemia, which significantly increased survival of the mice bearing this disease. Ectopic expression of TSC-22 in mouse leukemia or lymphoma cell lines resulted in delayed in vivo tumor formation. Targeted disruption of TSC-22in wild-type mice enhanced proliferation and in vivo repopulation efficiency of hematopoietic precursor cells (HPCs). Collectively, our data suggest that TSC-22normally contributes to the regulation of HPC function and is a putative tumor suppressor gene that is hypermethylated and silenced in T or NK LGL leukemia.

Hypermethylation of 5'-cytosine-guanosine islands of tumor suppressor genes resulting in their silencing has been proposed to be a hallmark of various tumors. Modulation of DNA methylation with DNA methylation inhibitors has been shown to result in cancer cell differentiation or apoptosis and represents a novel strategy for chemotherapy. Currently, effective DNA methylation inhibitors are mainly limited to decitabine and 5-azacytidine, which still show unfavorable toxicity profiles in the clinical setting. Thus, discovery and development of novel hypomethylating agents, with a more favorable toxicity profile, is essential to broaden the spectrum of epigenetic therapy. Parthenolide, the principal bioactive sesquiterpene lactone of feverfew, has been shown to alkylate Cys(38) of p65 to inhibit nuclear factor-kappaB activation and exhibit anti-tumor activity in human malignancies. In this article, we report that parthenolide 1) inhibits DNA methyltransferase 1 (DNMT1) with an IC(50) of 3.5 microM, possibly through alkylation of the proximal thiolate of Cys(1226) of the catalytic domain by its gamma-methylene lactone, and 2) down-regulates DNMT1 expression possibly associated with its SubG(1) cell-cycle arrest or the interruption of transcriptional factor Sp1 binding to the promoter of DNMT1. These dual functions of parthenolide result in the observed in vitro and in vivo global DNA hypomethylation. Furthermore, parthenolide has been shown to reactivate tumor suppressor HIN-1 gene in vitro possibly associated with its promoter hypomethylation. Hence, our study established parthenolide as an effective DNA methylation inhibitor, representing a novel prototype for DNMT1 inhibitor discovery and development from natural structural-diversified sesquiterpene lactones.

G3139, an antisense oligodeoxyribonucleotide (ODN) against Bcl-2, contains two CpG dinucleotides and has shown immunostimulatory activities in preclinical studies. It has been suggested that immunoactivation, rather than antisense activity, is primarily responsible for the therapeutic efficacy of G3139. Nanoparticle formulations naturally target phagocytic antigen presenting cells and therefore might enhance the immunological effects of G3139. In this study, a novel formulation of lipid nanoparticles (LNPs) encapsulating G3139 was synthesized and evaluated in mice bearing L1210 subcutaneous tumors. Intravenous injection of G3139-LNPs into mice led to increased serum levels of IL-6 and IFN-γ, promoted proliferation of natural killer (NK) cells and dendritic cells (DCs), and triggered a strong antitumor immune response in mice. The observed effects were much greater than those induced by free G3139. Correspondingly, the G3139-LNPs more effectively inhibited tumor growth and induced complete tumor regression in some mice. In contrast, free G3139 was ineffective in tumor growth inhibition and did not prolong survival of the tumor-bearing mice. These results suggest that G3139-LNPs are a potential immunomodulatory agent and may have applications in cancer therapy.

Antisense oligonucleotide G3139-mediated down-regulation of Bcl-2 is a potential strategy for overcoming chemoresistance in leukemia. However, the limited efficacy shown in recent clinical trials calls attention to the need for further development of novel and more efficient delivery systems. In order to address this issue, transferrin receptor (TfR)-targeted, protamine-containing lipid nanoparticles (Tf-LNs) were synthesized as delivery vehicles for G3139. The LNs were produced by an ethanol dilution method, and lipid-conjugated Tf ligand was then incorporated by a postinsertion method. The resulting Tf-LNs had a mean particle diameter of ∼90 nm and G3139 loading efficiency of 90.4%. Antisense delivery efficiency of Tf-LNs was evaluated in K562, MV4-11, and Raji leukemia cell lines. The results showed that Tf-LNs were more effective than nontargeted LNs and free G3139 (p< 0.05) in decreasing Bcl-2 expression (by up to 62% at the mRNA level in K562 cells) and in inducing caspase-dependent apoptosis. In addition, Bcl-2 down-regulation and apoptosis induced by Tf-LN G3139 were shown to be blocked by excess free Tf and thus were TfR-dependent. Cell lines with higher TfR expression also showed greater Bcl-2 down-regulation. Furthermore, up-regulation of TfR expression in leukemia cells by iron chelator deferoxamine resulted in a further increase in antisense effect (up to 79% Bcl-2 reduction in K562 at the mRNA level) and in caspase-dependent apoptosis (by ∼3-fold) by Tf-LN. Tf-LN-mediated delivery combined with TfR up-regulation by deferoxamine appears to be a potentially promising strategy for enhancing the delivery efficiency and therapeutic efficacy of antisense oligonucleotides.

In teleost fish, sex steroids are involved in sex determination, sex differentiation, and fertility. Cyp17a1 (Cytochrome P450 family 17 subfamily A member 1) is thought to play essential roles in fish steroidogenesis. Therefore, to further understand its roles in steroidogenesis, sex determination, and fertility in fish, we constructed a cyp17a1gene mutant in Nile tilapia (Oreochromis niloticus). In XX fish, mutation of the cyp17a1gene led to a female-to-male sex reversal with a significant decline in 17β-estradiol (E2) and testosterone (T) production, and ectopic expression of male-biased markers (Dmrt1 and Gsdf) in gonads from the critical window of sex determination. Sex reversal was successfully rescued via T or E2 administration, and ovarian characteristics were maintained after termination of E2 supplementation in the absence of endogenous estrogen production in cyp17a1–/–XX fish. Likewise, deficiencies in T and 11-ketotestosterone (11-KT) production in both cyp17a1–/–XX sex-reversed males and cyp17a1–/–XY mutants resulted in meiotic initiation delays, vas deferens obstruction and sterility due to excessive apoptosis and abnormal mitochondrial morphology. However, 11-KT treatment successfully rescued the dysspermia to produce normal sperm in cyp17a1–/–male fish. Significant increases in gonadotropic hormone (gth) and gthreceptors in cyp17a1–/–mutants may excessively upregulate steroidogenic gene expression in Leydig cells through a feedback loop. Taken together, our findings demonstrate that Cyp17a1 is indispensable for E2 production, which is fundamental for female sex determination and differentiation in XX tilapia. Additionally, Cyp17a1 is essential for T and 11-KT production, which further promotes spermatogenesis and fertility in XY males.

• Improvability of the noise modified MAP signal detection system is discussed. • Noise enhanced signal detection models under MAP criterion considering various constraint conditions are formulated. • Pairs of optimal additive noise and the corresponding noise modified MAP decision rule that satisfy different constraints are explored. In this paper, a noise enhanced hypothesis testing framework for a general nonlinear system is established under the Maximum A Posteriori (MAP) criterion, where an additive noise is added to the nonlinear system input and then the optimal MAP test for the discrimination between two hypotheses is made based on the noise modified nonlinear system output. The improvability of the noise modified MAP detection system is presented first, and then the noise enhanced decision solutions for the performance optimization are explored under three kinds of different cases. In opt SR case, the minimization of the average error probability is studied, and the optimal additive noise is proved as a constant vector, i.e. its probability distribution function is expressed by Dirac type δ(n-n o). Furthermore, constraints on detection and false-alarm probabilities are considered in the minimization problem in UCSR and CSR cases. The difference is that no randomization between different detectors is allowed in UCSR case, while the randomization between detectors is feasible in CSR case. Finally, numerical results for sine transform and amplitude limit systems are given to confirm the theoretical results. The performance comparisons of no SR (i.e., in the absence of additive noise), opt SR, CSR and UCSR cases demonstrate that the SR phenomenon could occur to improve the optimal MAP decision under certain conditions. [ABSTRACT FROM AUTHOR]

The partial tandem duplication of MLL (MLL-PTD) is found in 5% to 10% of patients with acute myeloid leukemia (AML) and normal cytogenetics. Its expression in leukemic blasts is coincident with a silenced wild-type (WT) MLL allele. We therefore generated mice expressing the Mll-PTD in the absence of Mll-WT. These MllPTD/− mice die at birth unlike the normal life expectancy of MllPTD/WT, MllWT/−, and MllWT/WT mice. Using MllWT/WT fetal liver cells (FLC) as baseline, we compared MllPTD/− with MllPTD/WT FLC and found both had increased HoxA gene expression and granulocyte-macrophage colony-forming progenitor cells (CFU-GM); in contrast, only MllPTD/WT FLC had increased pluripotent hemopoietic progenitors (CFU-GEMM). The similarities between MllPTD/WT and MllPTD/− mice suggest that the Mll-PTD mutation can up-regulate target genes in a dominant, gain-of-function fashion. The differences between these 2 genotypes suggest that in select tissues the Mll-PTD requires cooperation with the Mll-WT in the genesis of the observed abnormality.