How can China achieve its goal of peaking carbon emissions at minimal cost? A research perspective from shadow price and optimal allocation of carbon emissions.

The Chinese government has declared a determination at the 75th United Nations General Assembly that China will improve its independent contribution and adopt more powerful measures to peak the carbon emissions before 2030. However, such strict implementation of carbon reduction policies is bound to bring the cost of sacrificing economic development. In such a context, this paper tries to use shadow price to measure the average social cost of emission reduction, marginal abatement cost to depict the pressure to reduce carbon emissions based on non-radial distance function, and provides an optimal scheme for provincial emission reduction to minimize the national cost of emission reduction based on variable-coefficient model. Results show that: First, the average value of shadow price is 15.91 and varies widely among regions, which means on average reducing one unit of carbon emissions will sacrifice 15.914 yuan RMB of economic output, and there exists possibility of carbon transactions across regions; Second, on the one hand, marginal abatement cost of carbon emission for most regions presents an upward tendency over time, which means greater economic costs have to be sacrificed with economic development in the future; On the other hand, marginal abatement cost is much higher in regions with high economic level than that in the economically undeveloped areas, which indicates reducing carbon emissions is becoming increasingly difficult and would pay more economical cost in economically developed regions; Third, the optional allocation scheme of CO2 reduction derived from this research is better than administrative ways of Grandfathering and Benchmarking in terms of minimizing emission reduction cost. Results of this paper indicate that larger carbon trading market can be implemented in China to economically fulfill the commitment of peaking carbon emissions.

Crosstalk of FGFR1 signaling and choline metabolism promotes cell proliferation and survival in prostate cancer cells.

The acquisition of ectopic type I fibroblast growth factor receptor (FGFR1) is a common feature of prostate cancer (PCa), the most frequently diagnostic cancer in men. However, how ectopic FGFR1 contributes to PCa progression is not well understood. In our study we showed that ablation of FGFR1 in DU145 human PCa cells changed the cell metabolite profile. Among the changes, the choline metabolism profile was the most significantly altered by FGFR1 ablation. Detailed characterization revealed that ablation of FGFR1 altered expression of multiple choline metabolism enzymes. Among the changes of FGFR1-regulated choline metabolic enzymes, downregulation of choline kinase α (CHKA) is the most prominent changes, which phosphorylates free choline to phosphocholine. Ablation of FGFR1 blunted the activity of choline to promote cell proliferation and survival. Furthermore, depletion of CHKA compromised FGF signaling activity in DU145 cells. We also first time demonstrated that FGFR1 formed complex with CHKA, suggesting that FGFR1 regulated CHKA at the posttranslational level. Together with the previous report that ectopic FGFR1 contributes to PCa progression and metastasis, our results here unravel a novel mechanism by which FGFR1 promotes PCa progression by dysregulating choline metabolism, and that the crosstalk between FGFR1-choline metabolism can be a potential target for managing PCa progression.

Zebrafish Xenograft Model for Studying Pancreatic Cancer-Instructed Innate Immune Microenvironment.

Pancreatic ductal adenocarcinoma (PDAC) has up to half the tumor mass of tumor-associated myeloid cells. Myeloid innate immune cells play important roles in regulating cancer cell recognition and tumor growth. PDAC cells often mold myeloid cells into pro-tumoral state to fuel cancer growth and induce immune suppression. However, how tumor cells educate the innate immune responses remains largely unknown. In this study, we used four different human PDAC cell lines (PANC1, BxPC3, AsPC1, and CFPAC1) to establish the zebrafish xenograft model and investigated the interaction between pancreatic cancer and innate immune cells. The primary tumor-derived cancer cells PANC1 and BxPC3 activated innate immune anti-tumoral responses efficiently, while cancer cells from metastatic tissues AsPC1 and CFPAC1 induced an innate immune suppression and educated innate immune cells towards pro-tumoral state. Chemical conversion of innate immune cells to anti-tumoral state inhibited tumor growth for AsPC1 and CFPAC1. Moreover, genetic and pharmacological inhibition of macrophages also significantly reduced tumor growth, supporting the important roles of macrophages in innate immune suppression. REG4 expression is high in AsPC1 and CFPAC1. Knockdown of REG4 induced innate immune activation and reduced tumor growth in the xenografts, indicating that REG4 is a beneficial target for PDAC therapy. Our study provides a fast in-vivo model to study PDAC-innate immune interaction and their plasticity that could be used to study the related mechanism as well as identify new drugs to enhance immunotherapy.

Negative Elongation Factor (NELF) Inhibits Premature Granulocytic Development in Zebrafish.

Gene expression is tightly regulated during hematopoiesis. Recent studies have suggested that RNA polymerase II (Pol II) promoter proximal pausing, a temporary stalling downstream of the promoter region after initiation, plays a critical role in regulating the expression of various genes in metazoans. However, the function of proximal pausing in hematopoietic gene regulation remains largely unknown. The negative elongation factor (NELF) complex is a key factor important for this proximal pausing. Previous studies have suggested that NELF regulates granulocytic differentiation in vitro, but its in vivo function during hematopoiesis remains uncharacterized. Here, we generated the zebrafish mutant for one NELF complex subunit Nelfb using the CRISPR-Cas9 technology. We found that the loss of nelfb selectively induced excessive granulocytic development during primitive and definitive hematopoiesis. The loss of nelfb reduced hematopoietic progenitor cell formation and did not affect erythroid development. Moreover, the accelerated granulocytic differentiation and reduced progenitor cell development could be reversed by inhibiting Pol II elongation. Further experiments demonstrated that the other NELF complex subunits (Nelfa and Nelfe) played similar roles in controlling granulocytic development. Together, our studies suggested that NELF is critical in controlling the proper granulocytic development in vivo, and that promoter proximal pausing might help maintain the undifferentiated state of hematopoietic progenitor cells.

The Protective Effect of Basic Fibroblast Growth Factor in Intestine of db/db Mice: A 1H NMR-Based Metabolomics Investigation.

Diabetic enteropathy (DE) is a diabetic complication and affects the quality of life for which there are limited therapies. In this study, db/db mice were administered with a basic fibroblast growth factor (bFGF) to explore its therapeutic effect on the intestine. 1H NMR-based metabolomics was applied to investigate the metabolic pattern. H&E and PAS staining were used to observe the morphological phenotypes related to intestinal barrier function. Tight junction proteins such as Zo-1 and Occluding were successively tested by immunofluorescence and real-time PCR. We found that bFGF treatment significantly restored intestinal barrier function. In addition, the administration of bFGF decreased the levels of inflammatory cytokines in the cecum. Metabolomic results show that bFGF remodeled metabolic phenotypes of the colon, cecum, and small intestine in db/db mice, including energy metabolism, short chain fatty acid metabolism, amino acid metabolism, and choline metabolism. Hence, this study indicates that the bFGF has a protective effect in diabetic bowel disease by restoring intestinal barrier function, reducing inflammatory infiltration, and remodeling metabolic function.

A new aminoglycoside etimicin shows low nephrotoxicity and ototoxicity in zebrafish embryos.

Aminoglycoside antibiotics are widely used for many life-threatening infections. The use of aminoglycosides is often comprised by their deleterious side effects to the kidney and inner ear. A novel semisynthetic antibiotic, etimicin, has good antimicrobial activity against both gram-positive and gram-negative bacteria. But its toxicity profile analysis is still lacking. In the present study, we compared the in vivo toxic effects of three aminoglycosides, gentamicin, amikacin, and etimicin, in zebrafish embryos. We examined the embryotoxicity, nephrotoxicity, and the damage to the neuromast hair cells. Our results revealed that etimicin and amikacin exhibit more developmental toxicities to the young embryos than gentamicin. But at subtoxic doses, etimicin and amikacin show significantly reduced toxicities towards kidney and neuromast hair cells. We further demonstrated that fluorescently conjugated aminoglycosides (gentamicin-Texas red [GTTR], amikacin-Texas red [AMTR], and etimicin-Texas red [ETTR]) all enter the hair cells properly. Inside the hair cells, gentamicin, not etimicin and amikacin, displays robust reactive oxygen species generation and induces apoptosis. Our data support that the different intracellular cytotoxicity underlies the different ototoxicity of the three aminoglycosides and that etimicin is a new aminoglycoside with reduced risk of nephrotoxicity and ototoxicity.

Polyelectrolyte-micelle coacervates: intrapolymer-dominant vs. interpolymer-dominant association, solute uptake and rheological properties.

The effects of polyelectrolyte charge density, polyelectrolyte-to-surfactant ratio, and micelle species on coacervation were studied by turbidity, dynamic light scattering, and zeta potential measurements to examine the coacervation of the weak polyelectrolyte branched polyethylenimine (BPEI) and oppositely charged sodium dodecyl sulfate (SDS) micelles as well as BPEI and mixed micelles composed of SDS and poly(ethylene glycol) 4-nonylphenyl 3-sulfopropyl ether potassium salt (PENS). The results of dynamic light scattering and zeta potential measurements are discussed in terms of pH and BPEI-to-surfactant ratio. An intrapolymer-dominant to interpolymer-dominant association model for the BPEI-micelle coacervates was proposed based on the variation of size and zeta potential of coacervate particles by their BPEI-to-surfactant ratio. The partition coefficient of solutes into BPEI-micelle coacervates was determined using UV-vis measurements as a function of pH, BPEI-to-surfactant ratio, and mixed micelle composition. Both the hydrophobicity of solutes and micelles, as well as the association mode of coacervates, impact the solute uptake efficiency. Dynamic rheological measurements on the coacervates suggest that the rheological properties of the complex coacervates are impacted by the association mode of the coacervates as well as the charge density on BPEI chains during coacervation.

On-chip second-harmonic generation and broadband parametric down-conversion in a lithium niobate microresonator.

Nonlinear wavelength conversion is essential for many classical and quantum pho-tonic applications. The underlying second-order nonlinear optical processes, however, generally exhibit limited spectral bandwidths that impact their application potential. Here we use a high-Q X-cut lithium niobate microdisk resonator to demonstrate both second-harmonic generation and spontaneous parametric down-conversion on chip. In particular, our lithium niobate microresonator, with its wide-range cyclic phase matching and rich optical mode structures, is able to achieve ultra-broadband spontaneous parametric down-conversion, with a bandwidth over 400 nm, inferred from recorded spectra of the down-converted photons. The produced biphoton pairs exhibit strong temporal correlation, with a coincidence-to-accidental ratio measured to be 43.1. Our device is promising for integrated quantum photonics where optical frequency could be used as a degree of freedom for signal processing.

Broadband sum-frequency generation using d33 in periodically poled LiNbO3 thin film in the telecommunications band.

We demonstrate the first, to the best of our knowledge, type-0 broadband sum-frequency generation (SFG) based on single-crystal periodically poled LiNbO3 (PPLN) thin film. The broad bandwidth property was largely tuned from mid-infrared region to the telecommunications band by engineering the thickness of PPLN from bulk crystal to nanoscale. It provides SFG a solution with both broadband and high efficiency by using the highest nonlinear coefficient d33 instead of d31 in type-I broadband SFG or second-harmonic generation. The measured 3 dB upconversion bandwidth is about 15.5 nm for a 4 cm long single crystal at 1530 nm wavelength. It can find applications in chip-scale spectroscopy, quantum information processing, LiNbO3-thin-film-based microresonator and optical nonreciprocity devices, etc.

Self-referenced temperature sensing with a lithium niobate microdisk resonator.

Self-referenced temperature sensing based on thermo-optic birefringence is demonstrated on a Z-cut lithium niobate microdisk resonator. Due to the significant difference between thermo-optic coefficients of ordinary and extraordinary light, quasi-transverse magnetic (quasi-TM) and quasi-transverse electric (quasi-TE) modes in the microdisk show relative cavity resonance shift upon temperature change, which acts as a robust self-reference for temperature sensing. A temperature sensitivity of 0.834 GHz/K and a measurement uncertainty of 0.8 mK are demonstrated with an optical input power of only 1.5 µW.

Fast response of photorefraction in lithium niobate microresonators.

We present a detailed characterization of photorefraction in on-chip high-Q lithium niobate (LN) microresonators. We show that the photorefractive effect in these devices exhibits very distinctive temporal relaxation dynamics compared with those in bulk crystals and in mm-sized LN resonators. The relaxation of photorefraction is dominated by a fast time response with a time constant as small as 20.85 ms that is more than three-orders of magnitude faster than those observed in macroscopic devices. The observed fast response of photorefraction is of great potential as a convenient and energy-efficient approach for on-chip all-optical functionalities.

An Audio Jack-Based Electrochemical Impedance Spectroscopy Sensor for Point-of-Care Diagnostics.

Portable and easy-to-use point-of-care (POC) diagnostic devices hold high promise for dramatically improving public health and wellness. In this paper, we present a mobile health (mHealth) immunoassay platform based on audio jack embedded devices, such as smartphones and laptops, that uses electrochemical impedance spectroscopy (EIS) to detect binding of target biomolecules. Compared to other biomolecular detection tools, this platform is intended to be used as a plug-and-play peripheral that reuses existing hardware in the mobile device and does not require an external battery, thereby improving upon its convenience and portability. Experimental data using a passive circuit network to mimic an electrochemical cell demonstrate that the device performs comparably to laboratory grade instrumentation with 0.3% and 0.5° magnitude and phase error, respectively, over a 17 Hz to 17 kHz frequency range. The measured power consumption is 2.5 mW with a dynamic range of 60 dB. This platform was verified by monitoring the real-time formation of a NeutrAvidin self-assembled monolayer (SAM) on a gold electrode demonstrating the potential for POC diagnostics.

Optical half-adder and half-subtracter employing the Pockels effect.

The Pockels effect in periodically poled lithium niobate made it possible to switch optical signals between two orthogonal optical linear polarizations of the vertical and horizontal polarization states. Based on this effect, we demonstrated polarization-based binary optical logic gates: AND, and OR gates. By combining these basic gates with other polarization-based optical logic gates such as XOR gate accomplished in our previous researches, half-adder and half-subtracter of digital signals with a high extinction ratio of about 10dB have been demonstrated in our experiment, which made it possible to run more complex logical calculus.

Tunable temporal gap based on simultaneous fast and slow light in electro-optic photonic crystals.

We demonstrated a tunable temporal gap based on simultaneous fast and slow light in electro-optic photonic crystals. The light experiences an anomalous dispersion near the transmission center and a normal dispersion away from the center, where it can be accelerated and slowed down, respectively. We also obtained the switch between fast and slow light by adjusting the external electric filed. The observed largest temporal gap is 541 ps, which is crucial in practical event operation inside the gap. The results offer a new solution for temporal cloak.

Measures of insulin resistance and beta cell function before and after treatment of HCV infection.

The association between chronic HCV infection and type 2 diabetes mellitus (T2DM) has been established; however, there is limited research on ß-cell function particularly in the pre-diabetic population. Here, we evaluated indices of ß-cell function and insulin sensitivity across the spectrum from normal glucose tolerance to T2DM in individuals with and without chronic hepatitis C (CHC), and the effects of antiviral treatments on these variables. A total of 153 non-cirrhotic, non-fibrotic CHC patients with a BMI < 25 were enrolled in the study. Among them, 119 were successfully treated with either direct acting antiviral (DAA) drugs or pegylated interferon/ribavirin (IFN/RBV) anti-HCV therapy. Fasting state- and oral glucose tolerance test (OGTT)-derived indexes were used to evaluate ß-cell function and insulin sensitivity. Among all subjects, 19 (13%) had T2DM and 21% exhibited pre-diabetes including 8% isolated impaired fasting glucose (IFG) and 13% combined IFG and impaired glucose tolerance (IGT). Early and total insulin secretion adjusted for the degree of insulin resistance were decreased in prediabetic CHC patients compared to HCV-uninfected individuals. Viral eradication through DAA or IFN/RBV therapy demonstrated positive impacts on insulin sensitivity and ß-cell function in CHC patients who achieved sustained virologic response (SVR), regardless of fasting or OGTT state. These findings emphasize the role of HCV in the development of ß-cell dysfunction, while also suggesting that viral eradication can improve insulin secretion, reverse insulin resistance, and ameliorates glycemic control. These results have important implications for managing prediabetic CHC patients and could prevent diabetes-related clinical manifestations and complications.

Self-poled piezoelectric polymer composites via melt-state energy implantation.

Lightweight flexible piezoelectric polymers are demanded for various applications. However, the low instinctively piezoelectric coefficient (i.e. d33) and complex poling process greatly resist their applications. Herein, we show that introducing dynamic pressure during fabrication is capable for poling polyvinylidene difluoride/barium titanate (PVDF/BTO) composites with d33 of ~51.20 pC/N at low density of ~0.64 g/cm3. The melt-state dynamic pressure driven energy implantation induces structure evolutions of both PVDF and BTO are demonstrated as reasons for self-poling. Then, the porous material is employed as pressure sensor with a high output of ~20.0 V and sensitivity of ~132.87 mV/kPa. Besides, the energy harvesting experiment suggests power density of ~58.7 mW/m2 can be achieved for 10 N pressure with a long-term durability. In summary, we not only provide a high performance lightweight, flexible piezoelectric polymer composite towards sustainable self-powered sensing and energy harvesting, but also pave an avenue for electrical-free fabrication of piezoelectric polymers.

The microbiota regulates hematopoietic stem and progenitor cell development by mediating inflammatory signals in the niche.

The commensal microbiota regulates the self-renewal and differentiation of hematopoietic stem and progenitor cells (HSPCs) in bone marrow. Whether and how the microbiota influences HSPC development during embryogenesis is unclear. Using gnotobiotic zebrafish, we show that the microbiota is necessary for HSPC development and differentiation. Individual bacterial strains differentially affect HSPC formation, independent of their effects on myeloid cells. Early-life dysbiosis in chd8-/- zebrafish impairs HSPC development. Wild-type microbiota promote HSPC development by controlling basal inflammatory cytokine expression in kidney niche, and chd8-/- commensals elicit elevated inflammatory cytokines that reduce HSPCs and enhance myeloid differentiation. We identify an Aeromonas veronii strain with immuno-modulatory activities that fails to induce HSPC development in wild-type fish but selectively inhibits kidney cytokine expression and rebalances HSPC development in chd8-/- zebrafish. Our studies highlight the important roles of a balanced microbiome during early HSPC development that ensure proper establishment of lineal precursor for adult hematopoietic system.

A combined metabolomics and molecular biology approach to reveal hepatic injury and underlying mechanisms after chronic l-lactate exposure in mice.

This study aimed to explore whether chronic l-lactate exposure could affect the peripheral tissues of mice and to determine the underlying pathogenesis. Herein, male C57BL/6 mice were divided into control and l-lactate groups. After l-lactate treatment for eight weeks (1 g/kg), metabolic changes in liver, kidney, muscle, and serum samples were determined by 1H nuclear magnetic resonance (1H NMR)-based metabolomics. Additionally, organ function was evaluated by serum biochemical and histopathological examinations. Reactive oxygen species (ROS) levels were measured using dihydroethidium staining; levels of signals involved in lactate metabolism and ROS-related pathways were detected using western blotting or polymerase chain reaction. Apoptosis was detected by TUNEL-fluorescence staining. Metabolomic analysis revealed that l-lactate mice showed decreased levels of glutathione (GSH), taurine, ATP, and increased glucose content, compared to control mice. Furthermore, l-lactate mice presented significantly higher serum levels of alanine aminotransferase and aspartate aminotransferase and increased glycogen content in hepatic tissues, compared to control mice. l-lactate mice also had a greater number of apoptotic nuclei in the livers than controls. Moreover, l-lactate exposure reduced mRNA and protein levels of superoxide dismutase-2 and c-glutamylcysteine ligase, elevated levels of cytochrome P450 2E1 and NADPH oxidase-2, and increased the protein expressions of LDHB, Bax/Bcl-2, cleaved caspase-3, and sirtuin-1 in hepatic tissues. Together, these results indicate that chronic l-lactate exposure increases oxidative stress and apoptosis in hepatocytes via upregulation of Bax/Bcl-2 expression and the consequent mitochondrial cytochrome-C release and caspase-3 activation, which contributes to the pathogenesis of hepatic dysfunction.

Effects of Fibroblast Growth Factor 21 on Lactate Uptake and Usage in Mice with Diabetes-Associated Cognitive Decline.

Fibroblast growth factor 21 (FGF21) is an endocrine hormone that exerts beneficial effects on glucose and lipid metabolic homeostasis. However, the impact of FGF21 on type 1 diabetes-associated cognitive decline (DACD) and its mechanisms of action remain unclear. In this study, we aimed to evaluate the effects of FGF21 on lactate uptake and usage in a mouse model of streptozotocin-induced DACD. Six-week-old male C57BL/6 mice were divided into the control, diabetic, and FGF21 (which received 2 mg/kg recombinant human FGF21) groups. At the end of the treatment period, learning and memory performance, nuclear magnetic resonance-based metabonomics, and expressions of various hippocampal protein were analyzed to determine the efficacy of FGF21. The results showed that compared to the control mice, the diabetic mice had reduced long-term memory performance after the hyperglycemic insult; decreased hippocampal levels of lactate dehydrogenase-B (LDH-B) activity, bioenergy metabolites, and monocarboxylate transporter 2 (MCT2); and increased lactate levels. Impaired phosphoinositide 3-kinase (PI3K) signaling was also observed in the diabetic mice. However, FGF21 treatment improved LDH-B activity, ß-nicotinamide adenine dinucleotide, and ATP levels, and increased MCT2 expression and PI3K signaling pathway, which in turn improved the learning and memory defects. These findings demonstrated that the effects of FGF21 on DACD were associated with its ability to improve LDH-B-mediated lactate usage and MCT2-dependent lactate uptake. Further, these beneficial effects of FGF21 in the hippocampus were mediated by the PI3K signaling pathways.

Unilateral biportal endoscopic discectomy versus percutaneous endoscopic lumbar discectomy in the treatment of lumbar disc herniation: a retrospective study.

BACKGROUND: Unilateral biportal endoscopic discectomy (UBE) is a rapidly growing surgical method that uses arthroscopic system for treatment of lumbar disc herniation (LDH), while percutaneous endoscopic lumbar discectomy (PELD) has been standardized as a representative minimally invasive spine surgical technique for LDH. The purpose of this study was to compare the clinical outcomes between UBE and PELD for treatment of patients with LDH. METHODS: The subjects consisted of 54 patients who underwent UBE (24 cases) and PELD (30 cases) who were followed up for at least 6 months. All patients had lumber disc herniation for 1 level. Outcomes of the patients were assessed with operation time, incision length, hospital stay, total blood loss (TBL), intraoperative blood loss (IBL), hidden blood loss (HBL), complications, total hospitalization costs, visual analogue scale (VAS) for back and leg pain, the Oswestry disability index (ODI) and modified MacNab criteria. RESULTS: The VAS scores and ODI decreased significantly in two groups after operation. Preoperative and 1 day, 1 month, 6 months after operation VAS and ODI scores were not significantly different between the two groups. Compared with PELD group, UBE group was associated with higher TBL, higher IBL, higher HBL, longer operation time, longer hospital stay, longer incision length, and more total hospitalization costs. However, a dural tear occurred in one patient of the UBE group. There was no significant difference in the rate of complications between the two groups. CONCLUSIONS: Application of UBE for treatment of lumbar disc herniation yielded similar clinical outcomes to PELD, including pain control and patient satisfaction. However, UBE was associated with various disadvantages relative to PELD, including increased total, intraoperative and hidden blood loss, longer operation times, longer hospital stays, and more total hospitalization costs.