Intraperitoneal radioimmunotherapy in treating peritoneal carcinomatosis of colon cancer in mice compared with systemic radioimmunotherapy

医薬保健研究域医学系Peritoneal spread is one of major causes of mortality in colorectal cancer patients. In the current investigation, the efficacy of radio-immunotherapy (RIT) with i.p. administration of an anti-colorectal cancer IgG1, 131 I-A7, was compared to that with i.v. administration in BALB/c female mice bearing peritoneal nodules of LS180 human colon cancer cells, at the same toxicity level. Distribution of either i.p. or i.v. administered 131 I-A7 and i.p. administered irrelevant 131 I-HPMS-1 was assessed. Based on the results of toxicity determination at increments of 2 MBq and estimated dosimetry, an i.p. dose of 11 MBq and an i.v. dose of 9 MBq were chosen for treatment. Mice were monitored for long-term survival: untreated mice (n=11), mice undergoing i.p. RIT with 131 I-A7 (n=11), mice undergoing i.v. RIT with 131 I-A7 (n=11) and mice undergoing non-specific i.p. RIT with 131 I-HPMS-1 (n=5). Intraperitoneal injection of 131 I-A7 produced faster and greater tumor accumulation than i.v. injection: 34.2±16.5% of the injected dose per g (% ID/ g) and 11.1±3.6% ID/g at 2 h, respectively (P<0.0001). Consequently, cumulative radioactivity in tumors was 1.73-fold higher with i.p. injection. 131 I-HPMS-1 did not show specific accumulation. Non-specific RIT with 131 I-HPMS-1 (mean survival, 26.0±2.5 days) did not affect the survival as compared to no treatment (26.7±1.9 days). Intravenous RIT with 131 I-A7 prolonged the survival of mice to 32.8±1.8 days (P<0.01). Intraperitoneal RIT with 131 I-A7 improved the survival more significantly and attained cure in 2 of 11 mice (P<0.05 vs. i.v. RIT). In conclusion, i.p. RIT is more beneficial in treating peritoneal carcinomatosis of colon cancer than i.v. RIT in a murine model

PTER is a N-acetyltaurine hydrolase that regulates feeding and obesity.

Taurine is a conditionally essential micronutrient and one of the most abundant amino acids in humans1-3. In endogenous taurine metabolism, dedicated enzymes are involved in the biosynthesis of taurine from cysteine and in the downstream metabolism of secondary taurine metabolites4,5. One taurine metabolite is N-acetyltaurine6. Levels of N-acetyltaurine are dynamically regulated by stimuli that alter taurine or acetate flux, including endurance exercise7, dietary taurine supplementation8 and alcohol consumption6,9. So far, the identities of the enzymes involved in N-acetyltaurine metabolism, and the potential functions of N-acetyltaurine itself, have remained unknown. Here we show that the body&nbsp;mass&nbsp;index&nbsp;associated orphan enzyme phosphotriesterase-related (PTER)10 is a physiological N-acetyltaurine hydrolase. In vitro, PTER catalyses the hydrolysis of N-acetyltaurine to taurine and acetate. In mice, PTER is expressed in the kidney, liver and brainstem. Genetic ablation of Pter in mice results in complete loss of tissue N-acetyltaurine hydrolysis activity and a systemic increase in N-acetyltaurine levels. After stimuli that increase taurine levels, Pter knockout mice exhibit reduced food intake, resistance to diet-induced obesity and improved glucose homeostasis. Administration of N-acetyltaurine to obese wild-type mice also reduces food intake and body weight in a GFRAL-dependent manner. These data place PTER into a central enzymatic node of secondary taurine metabolism and uncover a role for PTER and N-acetyltaurine in body weight control and energy balance

Burden of disease scenarios for 204 countries and territories, 2022–2050: a forecasting analysis for the Global Burden of Disease Study 2021

Background: Future trends in disease burden and drivers of health are of great interest to policy makers and the public at large. This information can be used for policy and long-term health investment, planning, and prioritisation. We have expanded and improved upon previous forecasts produced as part of the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) and provide a reference forecast (the most likely future), and alternative scenarios assessing disease burden trajectories if selected sets of risk factors were eliminated from current levels by 2050. Methods: Using forecasts of major drivers of health such as the Socio-demographic Index (SDI; a composite measure of lag-distributed income per capita, mean years of education, and total fertility under 25 years of age) and the full set of risk factor exposures captured by GBD, we provide cause-specific forecasts of mortality, years of life lost (YLLs), years lived with disability (YLDs), and disability-adjusted life-years (DALYs) by age and sex from 2022 to 2050 for 204 countries and territories, 21 GBD regions, seven super-regions, and the world. All analyses were done at the cause-specific level so that only risk factors deemed causal by the GBD comparative risk assessment influenced future trajectories of mortality for each disease. Cause-specific mortality was modelled using mixed-effects models with SDI and time as the main covariates, and the combined impact of causal risk factors as an offset in the model. At the all-cause mortality level, we captured unexplained variation by modelling residuals with an autoregressive integrated moving average model with drift attenuation. These all-cause forecasts constrained the cause-specific forecasts at successively deeper levels of the GBD cause hierarchy using cascading mortality models, thus ensuring a robust estimate of cause-specific mortality. For non-fatal measures (eg, low back pain), incidence and prevalence were forecasted from mixed-effects models with SDI as the main covariate, and YLDs were computed from the resulting prevalence forecasts and average disability weights from GBD. Alternative future scenarios were constructed by replacing appropriate reference trajectories for risk factors with hypothetical trajectories of gradual elimination of risk factor exposure from current levels to 2050. The scenarios were constructed from various sets of risk factors: environmental risks (Safer Environment scenario), risks associated with communicable, maternal, neonatal, and nutritional diseases (CMNNs; Improved Childhood Nutrition and Vaccination scenario), risks associated with major non-communicable diseases (NCDs; Improved Behavioural and Metabolic Risks scenario), and the combined effects of these three scenarios. Using the Shared Socioeconomic Pathways climate scenarios SSP2-4.5 as reference and SSP1-1.9 as an optimistic alternative in the Safer Environment scenario, we accounted for climate change impact on health by using the most recent Intergovernmental Panel on Climate Change temperature forecasts and published trajectories of ambient air pollution for the same two scenarios. Life expectancy and healthy life expectancy were computed using standard methods. The forecasting framework includes computing the age-sex-specific future population for each location and separately for each scenario. 95% uncertainty intervals (UIs) for each individual future estimate were derived from the 2·5th and 97·5th percentiles of distributions generated from propagating 500 draws through the multistage computational pipeline. Findings: In the reference scenario forecast, global and super-regional life expectancy increased from 2022 to 2050, but improvement was at a slower pace than in the three decades preceding the COVID-19 pandemic (beginning in 2020). Gains in future life expectancy were forecasted to be greatest in super-regions with comparatively low life expectancies (such as sub-Saharan Africa) compared with super-regions with higher life expectancies (such as the high-income super-region), leading to a trend towards convergence in life expectancy across locations between now and 2050. At the super-region level, forecasted healthy life expectancy patterns were similar to those of life expectancies. Forecasts for the reference scenario found that health will improve in the coming decades, with all-cause age-standardised DALY rates decreasing in every GBD super-region. The total DALY burden measured in counts, however, will increase in every super-region, largely a function of population ageing and growth. We also forecasted that both DALY counts and age-standardised DALY rates will continue to shift from CMNNs to NCDs, with the most pronounced shifts occurring in sub-Saharan Africa (60·1% [95% UI 56·8–63·1] of DALYs were from CMNNs in 2022 compared with 35·8% [31·0–45·0] in 2050) and south Asia (31·7% [29·2–34·1] to 15·5% [13·7–17·5]). This shift is reflected in the leading global causes of DALYs, with the top four causes in 2050 being ischaemic heart disease, stroke, diabetes, and chronic obstructive pulmonary disease, compared with 2022, with ischaemic heart disease, neonatal disorders, stroke, and lower respiratory infections at the top. The global proportion of DALYs due to YLDs likewise increased from 33·8% (27·4–40·3) to 41·1% (33·9–48·1) from 2022 to 2050, demonstrating an important shift in overall disease burden towards morbidity and away from premature death. The largest shift of this kind was forecasted for sub-Saharan Africa, from 20·1% (15·6–25·3) of DALYs due to YLDs in 2022 to 35·6% (26·5–43·0) in 2050. In the assessment of alternative future scenarios, the combined effects of the scenarios (Safer Environment, Improved Childhood Nutrition and Vaccination, and Improved Behavioural and Metabolic Risks scenarios) demonstrated an important decrease in the global burden of DALYs in 2050 of 15·4% (13·5–17·5) compared with the reference scenario, with decreases across super-regions ranging from 10·4% (9·7–11·3) in the high-income super-region to 23·9% (20·7–27·3) in north Africa and the Middle East. The Safer Environment scenario had its largest decrease in sub-Saharan Africa (5·2% [3·5–6·8]), the Improved Behavioural and Metabolic Risks scenario in north Africa and the Middle East (23·2% [20·2–26·5]), and the Improved Nutrition and Vaccination scenario in sub-Saharan Africa (2·0% [–0·6 to 3·6]). Interpretation: Globally, life expectancy and age-standardised disease burden were forecasted to improve between 2022 and 2050, with the majority of the burden continuing to shift from CMNNs to NCDs. That said, continued progress on reducing the CMNN disease burden will be dependent on maintaining investment in and policy emphasis on CMNN disease prevention and treatment. Mostly due to growth and ageing of populations, the number of deaths and DALYs due to all causes combined will generally increase. By constructing alternative future scenarios wherein certain risk exposures are eliminated by 2050, we have shown that opportunities exist to substantially improve health outcomes in the future through concerted efforts to prevent exposure to well established risk factors and to expand access to key health interventions

ELECTRIFIED HIGH-TEMPERATURE MANUFACTURING AND APPLICATIONS IN ENVIRONMENTAL SCIENCE

High temperature processes hold great potential for material and chemical manufacturing.On the one hand, high temperature can help overcome energy barriers and thus effectively convert precursors to desired products. On the other hand, high temperature can also boost the reaction rate and improve synthesis efficiency. Recent development of electrified high temperature technologies by our group further revealed the important role played by non-equilibrium conditions on nanomaterial and chemical syntheses. For example, Joule-heating of carbon-based materials through a programmable electrical signal can offer spatial and temporal temperature profiles, which can be used to manipulate the chemical reaction pathways. For another example, tunable heating duration and quenching rates can be used to achieve a range of compositions and structures of nanoparticles. In this dissertation, two specific applications of the electrified high temperature technology will be explored, including: (1) Thermal shock synthesis of multielemental nanoparticles as selective and stable catalysts; and (2) Efficient biomass upgrading via pulsed electrical heating. Supported nanoparticle (NP) catalysts are widely used for various reactions. However, it remains challenging to synthesize high quality NPs with accurate morphologically and structure control. In this part of the research, NP catalysts with morphology or structural design were prepared by high temperature thermal shock methods. Ultra-small and high-loading carbon supported Pt3Ni NPs: Strong electrostatic effect was introduced between metal salts and carbon particles that can largely improve anchoring and dispersion of the precursors, thereby achieving high NP loading (40 wt%) as well as small NP size and good distribution (1.66 ± 0.56 nm). This method is not only limited to bimetallic NPs synthesis or NPs on carbon black but can be extended to a range of NP compositions on various substrate materials, thus providing a general strategy for developing ultrafine and high-loading NPs as electrocatalysts for various reactions. Sustainable aviation fuels (SAFs) are essential to meet future air travel demand while reducing the carbon footprint. Among many potential feedstocks to produce SAFs, lignin stands out as it is an abundant and renewable aromatic biopolymer that is usually treated as a waste material from the paper industry. However, converting lignin to SAFs by conventional thermochemical processes has been challenging due to poor control on the reaction pathway which leads to undesired product distribution. In this study, a programmed electrified heating method was designed and used to break down large lignin molecule to small aromatic molecules with targeted product distribution. A controlled heating step offers sufficient energy input to break down lignin molecules to smaller fragments without excessive secondary reactions toward undesired species such as coke. The lignin thermal decomposition products were evaluated as potential precursor for SAFs generation. This process can be further extended to process other biomass materials such as algae and sawdust to value-added chemicals

DESIGN OF FREE-STANDING POLYMER MEMBRANES FOR OVER-LIMITING CURRENT SUPPRESSION

Rough electrodeposition and dendrite-induced short-circuits have hindered development of advanced energy storage technologies based on metallic lithium, sodium and aluminum electrodes. Electroconvection and associated over-limiting conductance plays an important role in producing rough, dendritic deposition of metals at planar electrodes. Solid polymer electrolytes have shown great potential to suppress lithium dendrite growth, but the dual challenges of maintaining good mechanical properties and high ionic conductivity at room temperature have hindered progress towards commercial systems. In this thesis, we designed a solid-state polymer electrolyte composed of cross-linked polymer networks containing dangling ionic liquid moieties. We show that a simple UV synthesis can be used to create free- standing membranes with controlled structure. The membranes preserve these traits when soaked with a liquid electrolyte, but also exhibit good ionic conductivity at room temperature. Application of the materials as separators in lithium metal batteries show that they are able to completely eliminate over-limiting conductance up to potentials as high as 5V, where the liquid electrolyte component itself becomes electrochemically unstable

Risk Evaluation of Qinghai–Tibet Power Grid Interconnection Project for Sustainability

The Qinghai–Tibet power grid interconnection project is the first power transmission project with the highest altitude, longest transmission lines, longest distance running across the plateau frozen ground, and highest iron tower in the world. The risk evaluation on it can identify the overall risk level and key risk factors, which can reduce risk-induced loss and promote sustainable construction. In this paper, the risk of the Qinghai–Tibet power grid interconnection project was evaluated by employing a matter-element extension model under a fuzzy environment. After building the risk evaluation index system, the performances and weights of criteria were qualitatively judged by three groups of experts in different fields, and then the risk of the Qinghai–Tibet power grid interconnection project was rated by employing matter-element extension model. Meanwhile, the sensitivity analysis was performed to identify key risk criteria. The empirical results indicate the risk of the Qinghai–Tibet power grid interconnection project belongs to the “stronger” grade, tending to the “strongest” grade. “Social stability risk”, “altitude sickness seizure risk”, “permafrost-induced risk”, “severe weather-induced risk”, and “ecological destruction risk” are key sub-criteria, which should be paid more attention to when taking risk management measures. Finally, some countermeasures for key risks of the Qinghai–Tibet power grid interconnection project were given. The findings in this paper can provide references for engineering managers and related stakeholders

Enantioselective Cascade Biocatalysis via Epoxide Hydrolysis and Alcohol Oxidation: One-Pot Synthesis of (R)-?-Hydroxy Ketones from Meso- or Racemic Epoxides

ACS Catalysis5151-5

The Impact of High-Speed Rail on the Service-Sector Agglomeration in China

High-speed rail (HSR) can potentially influence various economic activities across space. Estimating the impacts of HSR on service-sector agglomeration (SSA) was proven to be difficult but meaningful. In this paper, prefectural-level data from 1998 to 2016 and a panel data program evaluation method are employed to evaluate the effect of the Wuhan&ndash;Guangzhou HSR (WGHSR) on the SSA along the route. In this way, we construct hypothetical counterfactuals for SSA index of the WGHSR cities in the absence of the HSR projects using the SSA index in selected non-HSR cities. By comparing the counterfactual index and the actual index, the evaluation of the WGHSR&rsquo;s impact on the SSA along the route can be obtained. The results show that: (a) the WGHSR has increased the SSA by 9.44% on average for cities along the WGHSR, and (b) the impacts of the WGHSR on the SSA are heterogeneous. The WGHSR has brought about both spillover effect and &ldquo;siphon&rdquo; effect. In addition, whether the HSR influences and how much it could influence the SSA requires other supplementary conditions to be met. As a national strategy in China, the construction plan of HSR should fully consider its heterogeneity of impact on regional development. Policies should be formulated to drive the HSR&rsquo;s spillover effect to promote regional sustainable development

Biocatalytic Formal Anti-Markovnikov Hydroamination and Hydration of Aryl Alkenes

Biocatalytic anti-Markovnikov alkene hydroamination and hydration were achieved based on two concepts involving enzyme cascades: epoxidation–isomerization–amination for hydroamination and epoxidation–isomerization–reduction for hydration. An <i>Escherichia coli</i> strain coexpressing styrene monooxygenase (SMO), styrene oxide isomerase (SOI), ω-transaminase (CvTA), and alanine dehydrogenase (AlaDH) catalyzed the hydroamination of 12 aryl alkenes to give the corresponding valuable terminal amines in high conversion (many ≥86%) and exclusive anti-Markovnikov selectivity (>99:1). Another <i>E. coli</i> strain coexpressing SMO, SOI, and phenylacetaldehyde reductase (PAR) catalyzed the hydration of 12 aryl alkenes to the corresponding useful terminal alcohols in high conversion (many ≥80%) and very high anti-Markovnikov selectivity (>99:1). Importantly, SOI was discovered for stereoselective isomerization of a chiral epoxide to a chiral aldehyde, providing some insights on enzymatic epoxide rearrangement. Harnessing this stereoselective rearrangement, highly enantioselective anti-Markovnikov hydroamination and hydration were demonstrated to convert α-methylstyrene to the corresponding (<i>S</i>)-amine and (<i>S</i>)-alcohol in 84–81% conversion with 97–92% <i>ee</i>, respectively. The biocatalytic anti-Markovnikov hydroamination and hydration of alkenes, utilizing cheap and nontoxic chemicals (O₂, NH₃, and glucose) and cells, provide an environmentally friendly, highly selective, and high-yielding synthesis of terminal amines and alcohols