Disulfide-constrained peptide scaffolds enable a robust peptide-therapeutic discovery platform.

Peptides present an alternative modality to immunoglobulin domains or small molecules for developing therapeutics to either agonize or antagonize cellular pathways associated with diseases. However, peptides often suffer from poor chemical and physical stability, limiting their therapeutic potential. Disulfide-constrained peptides (DCP) are naturally occurring and possess numerous desirable properties, such as high stability, that qualify them as drug-like scaffolds for peptide therapeutics. DCPs contain loop regions protruding from the core of the molecule that are amenable to peptide engineering via direct evolution by use of phage display technology. In this study, we have established a robust platform for the discovery of peptide therapeutics using various DCPs as scaffolds. We created diverse libraries comprising seven different DCP scaffolds, resulting in an overall diversity of 2 x 1011. The effectiveness of this platform for functional hit discovery has been extensively evaluated, demonstrating a hit rate comparable to that of synthetic antibody libraries. By utilizing chemically synthesized and in vitro folded peptides derived from selections of phage displayed DCP libraries, we have successfully generated functional inhibitors targeting the HtrA1 protease. Through affinity maturation strategies, we have transformed initially weak binders against Notch2 with micromolar Kd values to high-affinity ligands in the nanomolar range. This process highlights a viable hit-to-lead progression. Overall, our platform holds significant potential to greatly enhance the discovery of peptide therapeutics.

[Carbon Emission Characteristics and Influencing Factors of Typical Processes in Drinking Water Treatment Plant].

Based on the actual operating conditions and data monitoring, the carbon emission characteristics of typical processes of a drinking water treatment plant (DWTP) in Tianjin were studied. The total carbon emission intensity measured by CO2-eq was 0.254 kg·m-3, and the proportion of carbon emissions from electricity consumption and reagent consumption was 81.76% and 9.15%, respectively. The key carbon emission sectors of electricity consumption were the water supply pump house, ultrafiltration membrane process, and inlet pump house, which accounted for 50.99%-73.51%, 17.64%-20.70%, and 17.97%-22.40% of the total carbon emission from electricity consumption in the DWTP, respectively. The contribution of sodium hypochlorite to the carbon emission of reagent consumption was 89.12%-90.30%, followed by ferric chloride, PAC, and ammonium sulfate. In the traditional water purification process, the carbon emission intensity of the process unit was in the order of inlet pump house > rapid filter > sedimentation tank. The order in the ultrafiltration membrane advanced treatment process was inlet pump house > ultrafiltration membrane > mechanical coagulation > clarification tank. The carbon emission intensity of the rapid filter process and the ultrafiltration membrane process were 0.070 9 kg·m-3 and 0.109 0 kg·m-3, respectively. The ultrafiltration membrane process could save 23% of the reagent consumption, and its carbon emission of electricity consumption was twice that of the traditional treatment process. The analysis of factors affecting carbon emission in key sectors showed that the raw water quality parameters such as turbidity, pH, ammonia nitrogen, temperature, etc., were significantly correlated with the carbon emission intensity of sodium hypochlorite. There was a significant linear regression relationship between ex-factory water pressure, daily water supply, and carbon emission intensity of the water supply pump house. The control measures of water quality and water pressure can effectively reduce the carbon emissions of the DWTP.

Improved Thermal Anisotropy of Multi-Layer Tungsten Telluride on Silicon Substrate.

WTe2, a low-symmetry transition metal dichalcogenide, has broad prospects in functional device applications due to its excellent physical properties. When WTe2 flake is integrated into practical device structures, its anisotropic thermal transport could be affected greatly by the substrate, which matters a lot to the energy efficiency and functional performance of the device. To investigate the effect of SiO2/Si substrate, we carried out a comparative Raman thermometry study on a 50 nm-thick supported WTe2 flake (with κzigzag = 62.17 W·m-1·K-1 and κarmchair = 32.93 W·m-1·K-1), and a suspended WTe2 flake of similar thickness (with κzigzag = 4.45 W·m-1·K-1, κarmchair = 4.10 W·m-1·K-1). The results show that the thermal anisotropy ratio of supported WTe2 flake (κzigzag/κarmchair ≈ 1.89) is about 1.7 times that of suspended WTe2 flake (κzigzag/κarmchair ≈ 1.09). Based on the low symmetry nature of the WTe2 structure, it is speculated that the factors contributing to thermal conductivity (mechanical properties and anisotropic low-frequency phonons) may have affected the thermal conductivity of WTe2 flake in an uneven manner when supported on a substrate. Our findings could contribute to the 2D anisotropy physics and thermal transport study of functional devices based on WTe2 and other low-symmetry materials, which helps solve the heat dissipation problem and optimize thermal/thermoelectric performance for practical electronic devices.

Accounting for the importance of psychological distance in assessing public preferences for air quality improvement policies: an application of the integrated choice and latent variable model.

Assessing public preferences for air pollution control is essential to achieving effective air quality improvement, but the internal psychological factors affecting public preferences, especially psychological distance (PD), have only received limited attention. Therefore, this paper explores the role of PD in assessing public preferences for air quality improvement policies. Compared with previous studies that consider psychological factors in the choice model, this study incorporates PD into the choice model as a latent variable by considering both individual responses to measurement questions and socio-economic characteristics in the integrated choice and latent variable model. The results of this study clearly show that PD significantly affects public preferences for air quality improvement policies. Respondents with close PD had obvious preferences for air quality improvement, while those with distant PD were satisfied with the current situation and reluctant to improve it. After considering PD in the analysis, respondents' willingness to pay for one-unit level change of attributes "heavily polluted days," "good air days," "mortality," and "policy postponement" were respectively 10.3791CNY, 10.9005CNY, 11.0427CNY, 28.3412CNY per year. In addition, the paper also found men and respondents with lower levels of education and higher monthly incomes tended to view air pollution as psychologically distant and thus less willing to improve air quality. It is suggested that policy makers should reduce the PD of air pollution among these people by increasing publicity about the hazards of air pollution. This study not only contributes to the literature on the importance of PD in assessing individual preferences, but also provides constructive guidance for policy makers to assess the public's acceptability of air quality improvement.

Will information interventions affect public preferences and willingness to pay for air quality improvement? An empirical study based on deliberative choice experiment.

Environmental information is a prerequisite for public participation in air quality improvement, and the choice of such participation behavior is influenced by the intervention of environmental information. Nonetheless, there has been insufficient analysis of how information interventions affect public preferences and willingness to pay for air quality improvement. The combination of deliberative and choice experiment is used to explore the importance of information interventions for public participation in air quality improvement, and the changes in public preferences and willingness to pay for air quality improvement before and after information interventions are compared to analyze the impact of information interventions on evaluation results of air quality value. The results suggest that information interventions do alter the preferences and willingness of the public to pay for air quality improvement, significantly increasing the choice certainty of respondents and decreasing the protest response. In addition, women and high-income groups showed a stronger willingness to improve air quality after the information interventions, with 35.15 CNY, 44.07 CNY and 46.75 CNY increases in willingness to pay for improved urban green coverage rate, fewer haze days and reduced morbidity. The combination of deliberative information interventions and choice experiment will help improve the effectiveness of air quality value evaluation, stimulate public environmental awareness and willingness to participate, and the results will aid government environmental management.

Energy Dissipation and Electrical Breakdown in Multilayer PtSe2 Electronics.

Investigating the energy dissipation in micro- and nanoscale is fundamental to improve the performance and reliability of two-dimensional (2D) electronics. Recently, 2D platinum selenide (PtSe2) has drawn extensive attention in developing next-generation functional devices due to its distinctive fusion of versatile properties. Toward practical applications of PtSe2 devices, it is essential to understand the interfacial thermal properties between PtSe2 and its substrate. Among them, the thermal boundary conductance (TBC) has played a critical role for out-of-plane heat dissipation of PtSe2 devices. Here, we identify the energy dissipation behavior of multilayer PtSe2 devices and extract the actual TBC value of the PtSe2/SiO2 interface by Raman thermometry with electrical bias. The obtained TBC value is about 8.6 MW m-2 K-1, and it belongs to the low end of as-known solid-solid interfaces, suggesting possible applications regarding thermoelectric devices or others reliant on a large temperature gradient. Furthermore, the maximum current density of the PtSe2 device determines its threshold power, which is crucial for improving device design and guiding future applications. Therefore, we explore the electrical breakdown profile of the multilayer PtSe2 device, revealing the breakdown current density of 17.7 MA cm-2 and threshold power density of 0.2 MW cm-2, which are larger than typical values for commonly used aluminum and copper. These results provide key insights into the energy dissipation of PtSe2 devices and make PtSe2 an excellent candidate for thermal confinement applications and nanometer-thin interconnects, which will benefit the development of energy-efficient functional 2D devices.

Breaking the Cut-Off Wavelength Limit of GaTe through Self-Driven Oxygen Intercalation in Air.

Low symmetric two dimensional (2D) semiconductors are of great significance for their potential applications in polarization-sensitive photodetection and quantum information devices. However, their real applications are limited by their photo-detecting wavelength ranges, which are restricted by their fundamental optical bandgaps. Recently, intercalation has been demonstrated to be a powerful strategy to modulate the optical bandgaps of 2D semiconductors. Here, the authors report the self-driven oxygen (O2 ) intercalation induced bandgap reduction from 1.75 to 1.19 eV in gallium telluride (GaTe) in air. This bandgap shrinkage provides the long-wavelength detection threshold above ≈1100 nm for O2 intercalated GaTe (referred to as GaTeO2 ), well beyond the cut-off wavelength at ≈708 nm for pristine GaTe. The GaTeO2 photodetectors have a high photoresponsivity, and highly anisotropic photodetection behavior to even sub-waveband radiation. The dichroic ratio (Imax /Imin ) of photocurrent is about 1.39 and 2.9 for 600 nm and 1100 nm, respectively. This findings demonstrates a broadband photodetector utilizing GaTe after breaking through its bandgap limitation by self-driven O2 intercalation in air and further reveal its photoconductivity anisotropic nature. This provides design strategies of 2D materials-based high-performance broadband photodetectors for the exploration of polarized state information.

Stress Effects on Temperature-Dependent In-Plane Raman Modes of Supported Monolayer Graphene Induced by Thermal Annealing.

The coupling strength between two-dimensional (2D) materials and substrate plays a vital role on thermal transport properties of 2D materials. Here we systematically investigate the influence of vacuum thermal annealing on the temperature-dependence of in-plane Raman phonon modes in monolayer graphene supported on silicon dioxide substrate via Raman spectroscopy. Intriguingly, raising the thermal annealing temperature can significantly enlarge the temperature coefficient of supported monolayer graphene. The derived temperature coefficient of G band remains mostly unchanged with thermal annealing temperature below 473 K, while it increases from -0.030 cm-1/K to -0.0602 cm-1/K with thermal annealing temperature ranging from 473 K to 773 K, suggesting the great impact of thermal annealing on thermal transport in supported monolayer graphene. Such an impact might reveal the vital role of coupling strength on phonon scattering and on the thermal transport property of supported monolayer graphene. To further interpret the thermal annealing mechanism, the compressive stress in supported monolayer graphene, which is closely related to coupling strength and is studied through the temperature-dependent Raman spectra. It is found that the variation tendency for compressive stress induced by thermal annealing is the same as that for temperature coefficient, implying the intense connection between compressive stress and thermal transport. Actually, 773 K thermal annealing can result in 2.02 GPa compressive stress on supported monolayer graphene due to the lattice mismatch of graphene and substrate. This study proposes thermal annealing as a feasible path to modulate the thermal transport in supported graphene and to design future graphene-based devices.

ATF5, a putative therapeutic target for the mitochondrial DNA 3243A > G mutation-related disease.

The mitochondrial DNA m.3243A > G mutation is well-known to cause a variety of clinical phenotypes, including diabetes, deafness, and osteoporosis. Here, we report isolation and expansion of urine-derived stem cells (USCs) from patients carrying the m.3243A > G mutation, which demonstrate bimodal heteroplasmy. USCs with high levels of m.3243A > G mutation displayed abnormal mitochondrial morphology and function, as well as elevated ATF5-dependent mitochondrial unfolded protein response (UPRmt), together with reduced Wnt/ß-catenin signaling and osteogenic potentials. Knockdown of ATF5 in mutant USCs suppressed UPRmt, improved mitochondrial function, restored expression of GSK3B and WNT7B, and rescued osteogenic potentials. These results suggest that ATF5-dependent UPRmt could be a core disease mechanism underlying mitochondrial dysfunction and osteoporosis related to the m.3243A > G mutation, and therefore could be a novel putative therapeutic target for this genetic disorder.

The Long Non-coding RNA NEAT1/miR-224-5p/IL-33 Axis Modulates Macrophage M2a Polarization and A1 Astrocyte Activation.

To identify potential regulators and investigate the molecular mechanism of macrophage polarization affecting astrocyte activation from the perspective of non-coding RNA regulation, we isolated mouse bone marrow mononuclear cells (BMMNCs)-induced macrophages toward M1 or M2a polarization. Long non-coding RNA NEAT1 and IL-33 expression levels were significantly upregulated in M2a macrophages; NEAT1 knockdown in M2a macrophages markedly reduced the protein levels of IL-33 and M2a markers, IL-4 and IL-13 concentrations, and the bacterial killing capacity of M2a macrophages. NEAT1 acted as a competing endogenous RNA (ceRNA) to regulate IL-33 expression by sponging miR-224-5p in M2a macrophages; NEAT1 knockdown upregulated miR-224-5p expression, while miR-224-5p inhibition increased the protein content and concentration of IL-33. miR-224-5p inhibition exerted the opposite effects on the protein levels of IL-33 and M2a markers, IL-4 and IL-13 concentrations, and the bacterial killing capacity of M2a macrophages compared to NEAT1 knockdown; the effects of NEAT1 knockdown were significantly reversed by miR-224-5p inhibition. M2a macrophage conditioned medium (CM) significantly suppressed the activation of A1 astrocytes. NEAT1 knockdown M2a macrophage CM led to enhanced A1 astrocyte activation while miR-224-5p-silenced M2a macrophage CM led to a blockade of A1 astrocyte activation; the effects of NEAT1 knockdown M2a macrophage CM on A1 astrocyte activation were significantly reversed by miR-224-5p inhibition in M2a macrophages. The NEAT1/miR-224-5p/IL-33 axis modulates macrophage M2a polarization, therefore affecting A1 astrocyte activation.

PLAP -CAR T cells mediate high specific cytotoxicity against colon cancer cells.

Placental alkaline phosphatase, PLAP encoded by ALPP gene in humans is mainly expressed in placenta and testis, and not expressed in any other normal tissues. PLAP is overexpressed in colorectal cancers which makes it an attractive target for CAR (chimeric antigen receptor)-T cell therapy. PLAP mRNA expression was detected in 21.5% (25 out of 116) of colorectal cancer cell lines and this expression was confirmed by FACS at the protein level. In addition, IHC staining on primary colorectal cancer tumors demonstrated PLAP expression in >20% of colorectal cancer tumors. We generated mouse and humanized PLAP ScFv-CAR-T cells and demonstrated high specificity against PLAP-positive colon cancer cells using RTCA (real-time cytotoxicity assay) and IFN-gamma secretion. In addition, humanized-CAR-T cells significantly decreased Lovo xenograft tumor growth in vivo. The combination of hPLAP-CAR-T cells with PD-1, PD-L1 or LAG-3 checkpoint inhibitors significantly increased the activity of hPLAP-CAR-T cells. This study demonstrates ability of novel PLAP-CAR-T cells to kill colorectal cancers and that the extent of killing can be increased by combination with checkpoint inhibitors.

Thickness-Independent Energy Dissipation in Graphene Electronics.

The energy dissipation issue has become one of the greatest challenges of the modern electronic industry. Incorporating graphene into the electronic devices has been widely accepted as a promising approach to solve this issue, due to its superior carrier mobility and thermal conductivity. Here, using Raman spectroscopy and infrared thermal microscopy, we identify the energy dissipation behavior of graphene device with different thicknesses. Surprisingly, the monolayer graphene device is demonstrated to have a comparable energy dissipation efficiency per unit volume with that of a few-layer graphene device. This has overturned the traditional understanding that the energy dissipation efficiency will reduce with the decrease of functional materials dimensions. Additionally, the energy dissipation speed of the monolayer graphene device is very fast, promising for devices with high operating frequency. Our finding provides a new insight into the energy dissipation issue of two-dimensional materials devices, which will have a global effect on the development of the electronic industry.

Broadly conserved roles of TMEM131 family proteins in intracellular collagen assembly and secretory cargo trafficking.

Collagen is the most abundant protein in animals. Its dysregulation contributes to aging and many human disorders, including pathological tissue fibrosis in major organs. How premature collagen proteins in the endoplasmic reticulum (ER) assemble and route for secretion remains molecularly undefined. From an RNA interference screen, we identified an uncharacterized Caenorhabditis elegans gene tmem-131, deficiency of which impairs collagen production and activates ER stress response. We find that amino termini of human TMEM131 contain bacterial PapD chaperone-like domains, which recruit premature collagen monomers for proper assembly and secretion. Carboxy termini of TMEM131 interact with TRAPPC8, a component of the TRAPP tethering complex, to drive collagen cargo trafficking from ER to the Golgi. We provide evidence that previously undescribed roles of TMEM131 in collagen recruitment and secretion are evolutionarily conserved in C. elegans, Drosophila, and humans.

Methionine increases yolk production to offset the negative effect of caloric restriction on reproduction without affecting longevity in C. elegans.

Caloric restriction (CR) or Dietary restriction (DR) is known to improve health and in many cases increases lifespan. However, its negative effect on reproduction has not been fully studied. Practicing CR/DR without adequate knowledge on its side effect may risk complications such as infertility, birth defect, or malnutrition. In this study, by using several CR strategies in C. elegans, we examine key functions of reproduction including embryonic development and larvae growth. We find that CR significantly decreases the survival of embryos and slows the growth of the offspring. We further determine that defect in oocyte but not sperm is responsible for the compromised reproduction under CR. Interestingly, adding methionine to the medium reverses the reproduction defects, but does not affect the long lifespan resulted from CR. The beneficial effect of methionine on reproduction requires the yolk protein vitellogenin. CR down-regulates vitellogenin expression, which can be reversed by supplementing methionine in the food. Lacking the yolk protein transport due to rme-2 mutation blocks methionine's beneficial effects. Our study has revealed a novel, methionine-mediated genetic pathway linking nutrient sensing to reproduction and suggested methionine as a potential food supplement to mitigate the side effect of CR.

Synthesis of oxygen-doped graphitic carbon nitride and its application for the degradation of organic pollutants via dark Fenton-like reactions.

Graphitic carbon nitride (g-C3N4) is a promising photocatalyst for environmental protection but its development is greatly limited for its application in dark Fenton-like reactions due to its extremely low specific surface area and lack of suitable active sites. Herein, for the first time, graphitic carbon nitride with large surface area and abundant defect sites was developed by tailoring oxygen via a simple and green method without any templates, namely, the calcination-hydrothermal-calcination successive treatment of melamine. The structure of the catalyst was characterized using several technologies, including XRD, SEM, TEM, N2-physisorption, FT-IR, Raman spectroscopy and XPS. The results revealed that it possessed a large specific surface area (ca. 236 m2 g-1), while changes in its structural properties such as the formation of new defect sites and change in the content of nitrogen atoms were observed. These properties were beneficial for the in situ activation of H2O2 toward reactive oxygen species, as confirmed by the reactive oxygen species capturing experiments. Furthermore, various influencing factors were systemically investigated. The results clearly showed that the oxygen-doped g-C3N4 was light-independent and metal-free Fenton-like catalyst for the enhanced degradation of organic pollutants in wastewater. Compared to the pristine g-C3N4, the oxygen-doped g-C3N4 showed superior performance under various conditions such as broad pH range and excellent stability. Thus, this study provides a novel pathway for the treatment of organic pollutants in water.

A Real-time Potency Assay for Chimeric Antigen Receptor T Cells Targeting Solid and Hematological Cancer Cells.

Chimeric antigen receptor (CAR) T-cell therapy for cancer has achieved significant clinical benefit for resistant and refractory hematological malignancies such as childhood acute lymphocytic leukemia. Efforts are currently underway to extend this promising therapy to solid tumors in addition to other hematological cancers. Here, we describe the development and production of potent CAR T cells targeting antigens with unique or preferential expression on solid and liquid tumor cells. The in vitro potency of these CAR T cells is then evaluated in real-time using the highly sensitive impedance-based xCELLigence assay. Specifically, the impact of different costimulatory signaling domains, such as glucocorticoid-induced tumor necrosis factor receptor (TNFR)-related protein (GITR), on the in vitro potency of CAR T cells is examined. This report includes protocols for: generating CAR T cells for preclinical studies using lentiviral gene transduction, expanding CAR T cells, validating CAR expression, and running and analyzing xCELLigence potency assays.

Conserved roles of glucose in suppressing reactive oxygen species-induced cell death and animal survival.

Carbohydrate overconsumption increases blood glucose levels, which contributes to the development of various diseases including obesity and diabetes. It is generally believed that high glucose metabolism increases cellular reactive oxygen species (ROS) levels, damages insulin-secreting cells and leads to age-associated diabetic phenotypes. Here we find that in contrast, high glucose suppresses ROS production induced by paraquat in both mammalian cells and the round worm C. elegans. The role of glucose in suppressing ROS is further supported by glucose's ability to alleviate paraquat's toxicity on C. elegans development. Consistently, we find that the ROS-regulated transcription factor SKN-1 is inactivated by glucose. As a result, the ROS/SKN-1-dependent lifespan extension observed in paraquat-treated animals, mitochondrial respiration mutant isp-1 and germline-less mutant glp-1 are all suppressed by glucose. Our study reveals an unprecedented interaction of glucose with ROS, which could have significant impact on our current understanding of glucose- and ROS-related diseases.

A homogeneous p-n junction diode by selective doping of few layer MoSe2 using ultraviolet ozone for high-performance photovoltaic devices.

The realization of p-n homojunctions, which can be achieved via spatially controlled carrier-type modulation, remains a challenge for two-dimensional transition metal dichalcogenides. Here, we report an effective method to tune intrinsic n-type few-layer MoSe2 to p-type through controlling precisely the ultraviolet-ozone treatment time, which can be attributed to the surface charge transfer from the underlying MoSe2 to MoOx (x < 3). The resulting hole mobility and concentration are ∼20.1 cm2 V-1 s-1 and ∼1.9 × 1012 cm-2, respectively, and the on-off ratio is ∼105, which are comparable to the values of pristine n-type MoSe2. Moreover, the lateral p-n homojunction prepared by partially treating MoSe2 displays a high rectification ratio of 2.4 × 104, an ideality factor of 1.1, and a high photoresponsivity of 0.23 A W-1 to the 633 nm laser at Vd = 0 V and Vg = 0 V due to the built-in potential in the p-n homojunction area. Our findings ensure the MoSe2 p-n diode as a promising candidate for future low-power operating photodevices.

CAR-T Cells Based on Novel BCMA Monoclonal Antibody Block Multiple Myeloma Cell Growth.

The cell-surface protein B cell maturation antigen (BCMA, CD269) has emerged as a promising target for CAR-T cell therapy for multiple myeloma. In order to create a novel BCMA CAR, we generated a new BCMA monoclonal antibody, clone 4C8A. This antibody exhibited strong and selective binding to human BCMA. BCMA CAR-T cells containing the 4C8A scFv were readily detected with recombinant BCMA protein by flow cytometry. The cells were cytolytic for RPMI8226, H929, and MM1S multiple myeloma cells and secreted high levels of IFN-γ in vitro. BCMA-dependent cytotoxicity and IFN-γ secretion were also observed in response to CHO (Chinese Hamster Ovary)-BCMA cells but not to parental CHO cells. In a mouse subcutaneous tumor model, BCMA CAR-T cells significantly blocked RPMI8226 tumor formation. When BCMA CAR-T cells were given to mice with established RPMI8226 tumors, the tumors experienced significant shrinkage due to CAR-T cell activity and tumor cell apoptosis. The same effect was observed with 3 humanized BCMA-CAR-T cells in vivo. These data indicate that novel CAR-T cells utilizing the BCMA 4C8A scFv are effective against multiple myeloma and warrant future clinical development.