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Rational provincial allocation of carbon quotas serves as the foundational premise for attaining China’s carbon peak. Yet, prevailing strategies often overlook the holistic integration of trade-induced carbon transfers and ecological carbon sequestration, resulting in equity and scientific robustness deficiencies. This study addresses these shortcomings by examining historical carbon sources and sinks across China’s provinces and proposing a novel provincial allocation scheme based on the ‘equal consumption-based cumulative per capita net emission’ principle. Our findings reveal significant disparities in the carbon quotas between provinces, ranging from ‒98 Mt in Shanghai to 1016 Mt in Sichuan, primarily influenced by factors such as population size, historical emissions, and carbon sinks. The proposed scheme, integrating considerations of carbon transfers and sinks, safeguards the interests of less developed provinces (e.g., Hebei and Inner Mongolia) and those with valuable ecosystems (e.g., Yunnan and Inner Mongolia). Furthermore, the impact of carbon transfers on provincial carbon allocation quotas is more pronounced than that of carbon sinks. For instance, the inclusion of carbon transfers has increased Inner Mongolia’s quotas by 238 Mt, compared to 125 Mt attributed to carbon sinks. Considering the disparities in emissions reduction pressure and capacity across different provinces, combining fair carbon quota allocation with a nationwide carbon market can achieve cost-effective emissions reduction while ensuring the attainment of carbon peak. [ABSTRACT FROM AUTHOR]

Monkeypox was declared a global health emergency by the World Health Organization, and as of March 2023, 86,000 confirmed cases and 111 deaths across 110 countries have been reported. Its causal agent, monkeypox virus (MPV) belongs to a large family of double-stranded DNA viruses, Orthopoxviridae, that also includes vaccinia virus (VACV) and others. MPV produces two distinct forms of viral particles during its replication cycles: the enveloped viron (EV) that is released via exocytosis, and the mature viron (MV) that is discharged through lysis of host cells. This study was designed to develop multi-valent mRNA vaccines against monkeypox EV and MV surface proteins, and examine their efficacy and mechanism of action. Four mRNA vaccines were produced with different combinations of surface proteins from EV (A35R and B6R), MV (A29L, E8L, H3L and M1R), or EV and MV, and were administered in Balb/c mice to assess their immunogenicity potentials. A dynamic immune response was observed as soon as seven days after initial immunization, while a strong IgG response to all immunogens was detected with ELISA after two vaccinations. The higher number of immunogens contributed to a more robust total IgG response and correlating neutralizing activity against VACV, indicating the additive potential of each immunogen in generating immune response and nullifying VACV infection. Further, the mRNA vaccines elicited an antigen-specific CD4+ T cell response that is biased towards Th1. The mRNA vaccines with different combinations of EV and MV surface antigens protected a mouse model from a lethal dose VACV challenge, with the EV and MV antigens-combined vaccine offering the strongest protection. These findings provide insight into the protective mechanism of multi-valent mRNA vaccines against MPV, and also the foundation for further development of effective and safe mRNA vaccines for enhanced protection against monkeypox virus outbreak. [ABSTRACT FROM AUTHOR]

Recent evidence shows that carbon emissions in China are likely to peak ahead of 2030. However, the social and economic impacts of such an early carbon peak have rarely been assessed. Here we focus on the economic costs and health benefits of different carbon mitigation pathways, considering both possible socio-economic futures and varying ambitions of climate policies. We find that an early peak before 2030 in line with the 1.5 °C target could avoid ~118,000 and ~614,000 PM2.5 attributable deaths under the Shared Socioeconomic Pathway 1, in 2030 and 2050, respectively. Under the 2 °C target, carbon mitigation costs could be more than offset by health co-benefits in 2050, bringing a net benefit of $393–$3,017 billion (in 2017 USD value). This study not only provides insight into potential health benefits of an early peak in China, but also suggests that similar benefits may result from more ambitious climate targets in other countries. Understanding benefits of carbon mitigation is an important impetus for governments to adopt more ambitious climate targets. Here, the authors show positive air quality and health co-benefits are possible if China's CO2 emissions peak before 2030. [ABSTRACT FROM AUTHOR]

Massive production of efficacious SARS-CoV-2 vaccines is essential for controlling the ongoing COVID-19 pandemic. We report here the preclinical development of yeast-produced receptor-binding domain (RBD)-based recombinant protein SARS-CoV-2 vaccines. We found that monomeric RBD of SARS-CoV-2 could be efficiently produced as a secreted protein from transformed Pichia pastoris (P. pastoris) yeast. Yeast-derived RBD-monomer possessed functional conformation and was able to elicit protective level of neutralizing antibodies in mice. We further designed and expressed a genetically linked dimeric RBD protein in yeast. The engineered dimeric RBD was more potent than the monomeric RBD in inducing long-lasting neutralizing antibodies. Mice immunized with either monomeric RBD or dimeric RBD were effectively protected from live SARS-CoV-2 virus challenge even at 18 weeks after the last vaccine dose. Importantly, we found that the antisera raised against the RBD of a single SARS-CoV-2 prototype strain could effectively neutralize the two predominant circulating variants B.1.1.7 and B.1.351, implying broad-spectrum protective potential of the RBD-based vaccines. Our data demonstrate that yeast-derived RBD-based recombinant SARS-CoV-2 vaccines are feasible and efficacious, opening up a new avenue for rapid and cost-effective production of SARS-CoV-2 vaccines to achieve global immunization. [ABSTRACT FROM AUTHOR]

This randomized controlled study used corneal confocal microscopy (CCM) to compare the efficacy of Mecobalamin intramuscular injections vs oral tablets in treating mild to moderate diabetic peripheral neuropathy (DPN) by detecting early nerve fiber repair. Enrolled patients were randomized approximately 1:1 to receive Mecobalamin intramuscular injections (0.5 mg/day, 3 times/week) or Mecobalamin oral tablets (1.5 mg/day) for 8 weeks. Primary outcome was change of inferior whorl length (IWL) from baseline. Secondary outcomes included changes of corneal nerve fibre length (CNFL), corneal nerve fibre density (CNFD), corneal nerve branch density (CNBD) and the Survey of Autonomic Symptoms (SAS). 15 (93.75%) patients in the injection group and 17 (89.47%) patients in the tablet group completed the study. The injection treatment significantly improved patients' IWL from baseline (21.64 ± 3.00 mm/mm2 vs 17.64 ± 4.83 mm/mm2, P < 0.01) while the tablet treatment didn't. Additionally, the injection treatment led to significantly improved CNFL, CNBD and SAS from baseline (all P < 0.05) while the tablet treatment did not. No patient experienced any adverse events. In conclusion, CCM is sensitive enough to detect the superior efficacy of 8-week Mecobalamin intramuscular injection treatment for DPN compared to the oral tablet treatment. ClinicalTrials.gov registration number: NCT04372316 (30/04/2020). [ABSTRACT FROM AUTHOR]

Human FOXP3+ regulatory T (Treg) cells are central to immune tolerance. However, their heterogeneity and differentiation remain incompletely understood. Here we use single-cell RNA and T cell receptor sequencing to resolve Treg cells from healthy individuals and patients with or without acute graft-versus-host disease (aGVHD) who undergo stem cell transplantation. These analyses, combined with functional assays, separate Treg cells into naïve, activated, and effector stages, and resolve the HLA-DRhi, LIMS1hi, highly suppressive FOXP3hi, and highly proliferative MKI67hi effector subsets. Trajectory analysis assembles Treg subsets into two differentiation paths (I/II) with distinctive phenotypic and functional programs, ending with the FOXP3hi and MKI67hi subsets, respectively. Transcription factors FOXP3 and SUB1 contribute to some Path I and Path II phenotypes, respectively. These FOXP3hi and MKI67hi subsets and two differentiation pathways are conserved in transplanted patients, despite having functional and migratory impairments under aGVHD. These findings expand the understanding of Treg cell heterogeneity and differentiation and provide a single-cell atlas for the dissection of Treg complexity in health and disease. Human Treg cells are central to immune tolerance, yet their heterogeneity and differentiation remain incompletely understood. Here the authors perform single-cell RNA and T cell receptor sequencing to resolve Treg cells from healthy individuals and patients with or without acute graft-versus-host disease revealing Treg complexity in health and disease. [ABSTRACT FROM AUTHOR]

Enterovirus D68 (EV-D68) is an emerging pathogen associated with respiratory diseases and/or acute flaccid myelitis. Here, two MAbs, 2H12 and 8F12, raised against EV-D68 virus-like particle (VLP), show distinct preference in binding VLP and virion and in neutralizing different EV-D68 strains. A combination of 2H12 and 8F12 exhibits balanced and potent neutralization effects and confers broader protection in mice than single MAbs when given at onset of symptoms. Cryo-EM structures of EV-D68 virion complexed with 2H12 or 8F12 show that both antibodies bind to the canyon region of the virion, creating steric hindrance for sialic acid receptor binding. Additionally, 2H12 binding can impair virion integrity and trigger premature viral uncoating. We also capture an uncoating intermediate induced by 2H12 binding, not previously described for picornaviruses. Our study elucidates the structural basis and neutralizing mechanisms of the 2H12 and 8F12 MAbs and supports further development of the 2H12/8F12 cocktail as a broad-spectrum therapeutic agent against EV-D68 infections in humans. Although enterovirus D68 poses a major global threat to children, neither vaccines nor therapeutics are currently available. Using Cryo-EM, Zhang et al. show that two murine-derived monoclonal antibodies with therapeutic efficacy neutralize virions via binding to the canyon region, creating steric hindrance for sialic acid receptor binding. [ABSTRACT FROM AUTHOR]

Express delivery services are booming in both developed and emerging economies due to their low cost, convenience, and the fast growth in online shopping. The increasing environmental impacts of express delivery services and mitigation potentials, however, remain largely unexplored. Here we addressed such a gap for China, a country which is expanding online retail sales and express delivery rapidly. We found a total of 8.8 Mt of scrap packaging materials were generated by the express delivery sector in China in 2018. Its transportation-related GHG emissions surged from 0.3 Mt in 2007 to 13.7 Mt of CO2-equivalent (CO2e) in 2018, with an average of 0.27 kgCO2e per piece. Over 80% from online shopping deliveries. We predict these emissions will reach 75 MtCO2e by 2035. Nevertheless, it is possible to mitigate such GHG emissions by 102~134 MtCO2e between 2020 and 2035 if a suite of policies is adopted, including a slowdown of delivery speed, fuel system upgrades, packaging materials reduction, logistics optimization, and carbon pricing. Online shopping deliveries are booming, but the environmental cost is not always accounted. Here, the authors examine the impact of delivery services in China from 2007 to 2018 and find that Greenhouse gas emissions surged from 0.3 Mt in 2007 to 13.7 Mt of CO2-equivalent in 2018, they predict that emissions could reach 75 MtCO2e by 2035 if no mitigation measures are adopted. [ABSTRACT FROM AUTHOR]

Anthropogenic heat emission (AHE) is an important contributor to regional climate change, and may affect air quality in many ways. To gain a complete picture of global AHEs and lay a basis for modeling, in this study, global and regional AHEs from energy consumption are estimated for the past nearly five decades, and projected for the future through the year 2100. From 1965 to 2013, global AHE increased from 148 to 485 EJ/year, and the anthropogenic heat flux (AHF) over land increased from 0.03 to 0.10 W/m. Meanwhile, AHE per capita increased from 44.6 to 68.1 GJ. Regional differences are remarkable. In 2013, AHFs in Asia Pacific (AP), the Middle East (ME), North America (NA), Europe and Eurasia (EE), South and Central America (SCA), and Africa (AF) were 0.23, 0.22, 0.09, 0.08, 0.04, and 0.02 W/m, respectively. During the past 50 years, AHFs in ME, AP, AF, and SCA have increased by factors of 15.3, 10.8, 5.6, and 4.0. However, growth in NA and EE has been relatively slow. In the high, moderate, and low scenarios, by 2100, the terrestrial AHFs are projected to be 0.28, 0.24, and 0.19 W/m, respectively. The largest increase would occur in Asia and ME. Although the mean AHF is small compared to the forcing of GHGs, it may exert quite distinctive effects on the climate and the environment because of the surface-based emissions and uneven geographical distribution. [ABSTRACT FROM AUTHOR]

The cellular and molecular events that drive the early development of innate lymphoid cells (ILCs) remain poorly understood. We show that the transcription factor TCF-1 is required for the efficient generation of all known adult ILC subsets and their precursors. Using novel reporter mice, we identified a new subset of early ILC progenitors (EILPs) expressing high amounts of TCF-1. EILPs lacked efficient T and B lymphocyte potential but efficiently gave rise to NK cells and all known adult helper ILC lineages, indicating that they are the earliest ILC-committed progenitors identified so far. Our results suggest that upregulation of TCF-1 expression denotes the earliest stage of ILC fate specification. The discovery of EILPs provides a basis for deciphering additional signals that specify ILC fate. [ABSTRACT FROM AUTHOR]

CD4+ follicular helper T cells (TFH cells) are essential for germinal center (GC) responses and long-lived antibody responses. Here we report that naive CD4+ T cells deficient in the transcription factor Foxp1 'preferentially' differentiated into TFH cells, which resulted in substantially enhanced GC and antibody responses. We found that Foxp1 used both constitutive Foxp1A and Foxp1D induced by stimulation of the T cell antigen receptor (TCR) to inhibit the generation of TFH cells. Mechanistically, Foxp1 directly and negatively regulated interleukin 21 (IL-21); Foxp1 also dampened expression of the costimulatory molecule ICOS and its downstream signaling at early stages of T cell activation, which rendered Foxp1-deficient CD4+ T cells partially resistant to blockade of the ICOS ligand (ICOSL) during TFH cell development. Our findings demonstrate that Foxp1 is a critical negative regulator of TFH cell differentiation. [ABSTRACT FROM AUTHOR]

In the 21st Conference of the Parties held in Paris in December 2015, China pledged to peak its carbon emissions and increase non-fossil energy to 20% by 2030 or earlier. Expanding renewable capacity, especially wind power, is a central strategy to achieve these climate goals. Despite greater capacity for wind installation in China compared to the US (114.7 vs. 65.9 GW), less wind electricity is generated in China (153.4 vs. 181.8 TWh). Here, we quantify the relative importance of the key factors accounting for the unsatisfactory performance of Chinese wind farms. Different from qualitative studies, we find that the difference in wind resources explains only a small fraction of the current US-China difference in wind power output (-17.9% in 2012); the curtailment of wind power, differences in turbine quality and delayed connection to the grid are identified as the three primary factors (respectively -49.3%, -50.2%, and -50.3% in 2012). Improvements in both technology choices and the policy environment are critical in addressing these challenges., Engineering and Applied Sciences

The molecular mechanisms that underlie T cell quiescence are poorly understood. Here we report that mature naive CD8+ T cells lacking the transcription factor Foxp1 gained effector phenotype and function and proliferated directly in response to interleukin 7 (IL-7) in vitro. Foxp1 repressed expression of the IL-7 receptor ?-chain (IL-7R?) by antagonizing Foxo1 and negatively regulated signaling by the kinases MEK and Erk. Acute deletion of Foxp1 induced naive T cells to gain an effector phenotype and proliferate in lympho-replete mice. Foxp1-deficient naive CD8+ T cells proliferated even in lymphopenic mice deficient in major histocompatibility complex class I. Our results demonstrate that Foxp1 exerts essential cell-intrinsic regulation of naive T cell quiescence, providing direct evidence that lymphocyte quiescence is achieved through actively maintained mechanisms that include transcriptional regulation. [ABSTRACT FROM AUTHOR]

Several neurotransmitters act through G-protein-coupled receptors to evoke a ‘slow’ excitation of neurons. These include peptides, such as substance P and neurotensin, as well as acetylcholine and noradrenaline. Unlike the fast (approximately millisecond) ionotropic actions of small-molecule neurotransmitters, the slow excitation is not well understood at the molecular level, but can be mainly attributed to suppressing K+ currents and/or activating a non-selective cation channel. The molecular identity of this cation channel has yet to be determined; similarly, how the channel is activated and its relative contribution to neuronal excitability induced by the neuropeptides are unknown. Here we show that, in the mouse hippocampal and ventral tegmental area neurons, substance P and neurotensin activate a channel complex containing NALCN and a large previously unknown protein UNC-80. The activation by substance P through TACR1 (a G-protein-coupled receptor for substance P) occurs by means of a unique mechanism: it does not require G-protein activation but is dependent on Src family kinases. These findings identify NALCN as the cation channel activated by substance P receptor, and suggest that UNC-80 and Src family kinases, rather than a G protein, are involved in the coupling from receptor to channel. [ABSTRACT FROM AUTHOR]

Thymoma is the most common tumor of the anterior mediastinum. Routine imaging methods such as computed tomography or magnetic resonance imaging often lead to misdiagnosis between thymoma and other thymic abnormalities. Therefore, urgently needed is to develop a new diagnostic strategy. Here we identify interleukin-8 (IL-8) as a biomarker for auxiliary diagnosis of thymoma. We find that IL-8 levels in naïve T cells are markedly elevated in patients with thymoma compared to those with other thymic tumors. IL-8 levels in naive T cells are significantly decreased after surgical resection in thymoma patients, and rise again when thymoma recurs. A receiver operating characteristic curve analysis shows that IL-8 evaluation performs well in thymoma identification, with high specificities and sensitivities. We also observe significant clinical relevance between IL-8 levels in naïve T cells and clinicopathological features. In conclusion, our study suggests that IL-8 is a biomarker for thymoma identification and recurrence surveillance. Imaging methods, such as CT or MRI, cannot provide accurate diagnosis between malignant thymomas and other thymic abnormalities. Here the authors show that the levels of IL-8 in circulating naive T cells are elevated in patients with thymoma compared with other thymic masses, proposing IL-8 as a candidate biomarker for thymoma diagnosis and recurrence surveillance. [ABSTRACT FROM AUTHOR]

The ubiquitination status of RIPK1 is considered to be critical for cell fate determination. However, the in vivo role for RIPK1 ubiquitination remains undefined. Here we show that mice expressing RIPK1K376R which is defective in RIPK1 ubiquitination die during embryogenesis. This lethality is fully rescued by concomitant deletion of Fadd and Ripk3 or Mlkl. Mechanistically, cells expressing RIPK1K376R are more susceptible to TNF-α induced apoptosis and necroptosis with more complex II formation and increased RIPK1 activation, which is consistent with the observation that Ripk1K376R/K376R lethality is effectively prevented by treatment of RIPK1 kinase inhibitor and is rescued by deletion of Tnfr1. However, Tnfr1−/−Ripk1K376R/K376R mice display systemic inflammation and die within 2 weeks. Significantly, this lethal inflammation is rescued by deletion of Ripk3. Taken together, these findings reveal a critical role of Lys376-mediated ubiquitination of RIPK1 in suppressing RIPK1 kinase activity–dependent lethal pathways during embryogenesis and RIPK3-dependent inflammation postnatally. RIPK1 integrates signals that drive both NF-κB activation and cell death pathways. Here Zhang et al. generate RIPK1 knock-in mice lacking a major ubiquitination site and demonstrate that this modification is important to suppress cell death during embryogenesis and inflammation postnatally. [ABSTRACT FROM AUTHOR]

Induction of long-lived antibody responses during infection or vaccination is often essential for subsequent protection, but the relative contributions of T follicular helper (Tfh) cells and T helper 1 (Th1) cells for induction of antigen specific antibody responses to viruses are unclear. Here, we establish an acute Zika virus (ZIKV) infection model in immunocompetent mice, and show that ZIKV infection elicits robust Th1-like Tfh cell and protective antibody responses. While these Th1-like Tfh cells share phenotypic and transcriptomic profiles with both Tfh and Th1 cells, they also have unique surface markers and gene expression characteristics, and are dependent on T-bet for their development. Th1-like Tfh cells, but not Th1 cells, are essential for class switching of ZIKV-specific IgG2c antibodies and maintenance of long-term neutralizing antibody responses. Our study suggests that specific modulation of the Th1-like Tfh cell response during infection or vaccination may augment the induction of antiviral antibody response to ZIKV and other viruses. Here, the authors show that Zika virus (ZIKV) infection induces Th1-like Tfh cells that depend on T-bet for their development and are essential for class switching of ZIKV-specific IgG2c antibodies and maintenance of long-term neutralizing antibody responses. [ABSTRACT FROM AUTHOR]