NUDT21 limits CD19 levels through alternative mRNA polyadenylation in B cell acute lymphoblastic leukemia.

B cell progenitor acute lymphoblastic leukemia (B-ALL) treatment has been revolutionized by T cell-based immunotherapies-including chimeric antigen receptor T cell therapy (CAR-T) and the bispecific T cell engager therapeutic, blinatumomab-targeting surface glycoprotein CD19. Unfortunately, many patients with B-ALL will fail immunotherapy due to 'antigen escape'-the loss or absence of leukemic CD19 targeted by anti-leukemic T cells. In the present study, we utilized a genome-wide CRISPR-Cas9 screening approach to identify modulators of CD19 abundance on human B-ALL blasts. These studies identified a critical role for the transcriptional activator ZNF143 in CD19 promoter activation. Conversely, the RNA-binding protein, NUDT21, limited expression of CD19 by regulating CD19 messenger RNA polyadenylation and stability. NUDT21 deletion in B-ALL cells increased the expression of CD19 and the sensitivity to CD19-specific CAR-T and blinatumomab. In human B-ALL patients treated with CAR-T and blinatumomab, upregulation of NUDT21 mRNA coincided with CD19 loss at disease relapse. Together, these studies identify new CD19 modulators in human B-ALL.

Transplacental SARS-CoV-2 protein ORF8 binds to complement C1q to trigger fetal inflammation.

Prenatal SARS-CoV-2 infection is associated with higher rates of pregnancy and birth complications, despite that vertical transmission rates are thought to be low. Here, multi-omics analyses of human placental tissues, cord tissues/plasma, and amniotic fluid from 23 COVID-19 mother-infant pairs revealed robust inflammatory responses in both maternal and fetal compartments. Pronounced expression of complement proteins (C1q, C3, C3b, C4, C5) and inflammatory cytokines (TNF, IL-1α, and IL-17A/E) was detected in the fetal compartment of COVID-19-affected pregnancies. While ~26% of fetal tissues were positive for SARS-CoV-2 RNA, more than 60% of fetal tissues contained SARS-CoV-2 ORF8 proteins, suggesting transplacental transfer of this viral accessory protein. ORF8-positive fetal compartments exhibited increased inflammation and complement activation compared to ORF8-negative COVID-19 pregnancies. In human placental trophoblasts in vitro, exogenous ORF8 exposure resulted in complement activation and inflammatory responses. Co-immunoprecipitation analysis demonstrated that ORF8 binds to C1q specifically by interacting with a 15-peptide region on ORF8 (C37-A51) and the globular domain of C1q subunit A. In conclusion, an ORF8-C1q-dependent complement activation pathway was identified in COVID-19-affected pregnancies, likely contributing to fetal inflammation independently of fetal virus exposure.

The legacy environmental footprints of manufactured capital.

The foundations of today's societies are provided by manufactured capital accumulation driven by investment decisions through time. Reconceiving how the manufactured assets are harnessed in the production-consumption system is at the heart of the paradigm shifts necessary for long-term sustainability. Our research integrates 50 years of economic and environmental data to provide the global legacy environmental footprint (LEF) and unveil the historical material extractions, greenhouse gas emissions, and health impacts accrued in today's manufactured capital. We show that between 1995 and 2019, global LEF growth outpaced GDP and population growth, and the current high level of national capital stocks has been heavily relying on global supply chains in metals. The LEF shows a larger or growing gap between developed economies (DEs) and less-developed economies (LDEs) while economic returns from global asset supply chains disproportionately flow to DEs, resulting in a double burden for LDEs. Our results show that ensuring best practice in asset production while prioritizing well-being outcomes is essential in addressing global inequalities and protecting the environment. Achieving this requires a paradigm shift in sustainability science and policy, as well as in green finance decision-making, to move beyond the focus on the resource use and emissions of daily operations of the assets and instead take into account the long-term environmental footprints of capital accumulation.

Unexpected Alliance of WHIP-TRIM14-PPP6C to Combat Viruses.

In this issue of Molecular Cell, Tan et al. (2017) provide novel perspectives into the regulatory role of WHIP-TRIM14-PPP6C signalosome in enhancing RIG-I-mediated viral RNA sensing pathway.

RNS2 is required for the biogenesis of a wounding responsive 16 nts tsRNA in Arabidopsis thaliana.

tRNA-derived small RNAs (tsRNAs), a new category of regulatory small non-coding RNA existing in almost all branches of life, have recently attracted broad attention. Increasing evidence has shown that tsRNAs are not random degradation debris of tRNAs, but products cleaved by specific endoribonucleases, with versatile functions in response to various developmental and environmental cues. However, it is still unclear about the diversity, biogenesis and function of tsRNAs in plants. In this study, we comprehensively profiled 10-60 nts small RNAs in Arabidopsis thaliana leaf with or without wounding stress and identified four 16 nts tiny tRFs (tRNA-derived fragments) sharply increased after wounding, namely tRF5'Ala. Notably, genetic, biochemical and bioinformatic data indicated that RNS2, a member of class II RNase T2 enzymes, was the main endoribonuclease responsible for the biogenesis of tRF5'Ala. Moreover, tRF5'Ala was highly abundant and conserved in Arabidopsis and rice pollen. However, tRF5'Ala did not associate with AGO 1 in vivo or display any inhibitory effect on the translation of a luciferase mRNA in vitro. Altogether, our study highlights the discovery of a novel class of tiny tsRNAs drastically increased under wounding stress as well as their generation by RNS2, which provides a new insight into tsRNAs research in plants.

Quantum Criticality with Emergent Symmetry in the Extended Shastry-Sutherland Model.

Motivated by the novel phenomena observed in the layered material SrCu_{2}(BO_{3})_{2}, the Shastry-Sutherland model (SSM) has been extensively studied as the minimal model for SrCu_{2}(BO_{3})_{2}. However, the nature of its quantum phase transition from the plaquette valence-bond solid to antiferromagnetic phase is under fierce debate, posing a challenge to understand the underlying quantum criticality. Via the state-of-the-art tensor network simulations, we study the ground state of the SSM on large-scale size up to 20×20 sites. We identify the continuous transition nature accompanied by an emergent O(4) symmetry between the plaquette valence-bond solid and antiferromagnetic phase, which strongly suggests a deconfined quantum critical point (DQCP). Furthermore, we map out the phase diagram of an extended SSM that can be continuously tuned to the SSM, which demonstrates the same DQCP phenomena along a whole critical line. Our results indicate a compelling scenario for understanding the origin of the proposed proximate DQCP in recent experiments of SrCu_{2}(BO_{3})_{2}.

Direct, Embedded, and Embodied Trade of Arsenic: 1990-2019.

International arsenic trade, physical and virtual, has resulted in considerable transfer of arsenic pollution across regions. However, no study has systematically captured, estimated, and compared physical and virtual arsenic trade and its relevant impacts. This study combines material flow analysis and embodied emission factors to estimate embedded (including direct and indirect trade) and embodied arsenic trade during 1990-2019, encompassing 18 arsenic-containing products among 244 countries. Global embedded arsenic trade increased considerably from 47 ± 7.3 to 450 ± 68 kilotonnes (kt) during this time and was dominated by indirect arsenic trade, contributing 94 and 90% to global arsenic trade in 1990 and 2019, respectively. Since the 1990s, global arsenic trade centers and the main flows have shifted from European and American markets to developing countries. The mass of arsenic involved in embodied trade increased from 87.5 ± 26 kt in 1990 to 800 ± 236 kt in 2019. Direct trade and indirect trade aggravate arsenic environmental emissions in major importing countries, like China, while embodied trade aggravates arsenic environmental emissions in major exporting countries, like Peru and Chile. The trade-related arsenic pollution transfer calls for a rational arsenic emission responsibility-sharing mechanism and corresponding policy recommendations for different trading countries.

Toward More Realistic Estimates of Product Displacement in Life Cycle Assessment.

Life-cycle assessment (LCA) is one of the most widely applied methods for sustainability assessment. A main application of LCA is to compare alternative products to identify and promote those that are more environmentally friendly. Such comparative LCA studies often rest on, explicitly or implicitly, an idealized assumption, namely, 1:1 displacement between functionally equivalent products. However, product displacement in the real world is much more complicated, affected by various factors such as the rebound effect and policy schemes. Here, we quantitatively review studies that have considered these aspects to evaluate the magnitude and distribution of realistic displacement estimates across several major product categories (biofuels, electricity, electric vehicles, and recycled products). Results show that displacement ratios concentrate around 40-60%, suggesting considerable overestimation of the benefits of alternative products if the 1:1 displacement assumption was used. Overall, there have been a small number of modeling studies on realistic product displacement and their scopes were limited. Additional research is needed to cover more product categories and geographies and improve the modeling of market and policy complexities. As such research accumulates, their displacement estimates can form a database that can be drawn upon by comparative LCA studies to more accurately determine the environmental impacts of alternative products.

A Comprehensive Accounting of Construction Materials in Belt and Road Initiative Projects.

The Belt and Road Initiative (BRI) stands as the most ambitious infrastructure project in history, marked by its scale of investment, extensive geographical reach across continents and countries, and a diverse array of projects from roads to digital networks. While the BRI's environmental sustainability has raised concerns, the impacts of construction materials used in these projects have been overlooked, especially in developing countries. Here, we map and account for the materials embodied in the BRI by integrating, for the first time, official governmental project reports, geographical information, and material flow analysis. We pinpoint and analyze the BRI material stocks in each individual project by material types, countries, regions, and sectors. Between 2008 and 2023, 328 million tons of construction materials have accumulated in 540 BRI projects around the world, mostly in Asia and Africa. Aggregates (sand and gravel) constitute the largest share (82%), followed by cement, steel, and other materials. Most of the materials are used in transportation infrastructure. Our work further highlights some limitations in terms of data quality for such sustainability assessments. By shedding light on the significant impact of BRI projects on raw material usage across the globe, this study sets the stage for further investigations into environmental impacts of BRI and material stock-flow-nexus from perspective of an initiative.

The effect of dietary oxidation balance scores and volatile organic compounds exposures on inflammation.

BACKGROUND: Inflammation is a significant factor in adverse health outcomes, but the combined effects of diets with varying oxidation levels and exposure to volatile organic compounds (VOCs) on inflammation are not well understood. This study aimed to elucidate the effects of the recognized Dietary Oxidative Balance Score (DOBS) and five VOCs on the systemic immune-inflammation index (SII) and C-reactive protein (CRP). METHODS: This cross-sectional study included data from participants in three cycles (2003-2004, 2005-2006, 2009-2010) of the National Health and Nutrition Examination Survey (NHANES). We used Spearman correlation, logistic regression, and trend tests to explore the associations between DOBS, VOCs, SII, and CRP. Additionally, we conducted restricted cubic spline (RCS) analysis to assess dose-response relationships between exposure and effect. G-computation and stratified analyses were performed to further elucidate these associations. RESULTS: We included 7033 eligible participants, with 48.8 % males and 51.2 % females. Spearman correlation revealed that DOBS was negatively correlated with SII and CRP, while the five VOCs were positively correlated with SII and CRP. Although fully adjusted logistic regression models did not yield statistically significant results, trend tests indicated a gradual decrease in SII and CRP with increasing DOBS, a finding validated by RCS analysis. G-computation results demonstrated that the combined effect of DOBS and VOCs on inflammation was positive, with DOBS exerting a negative effect and benzene, ethylbenzene, and 1,4-dichlorobenzene exerting positive effects. Stratified analysis showed that maintaining physical activity significantly influenced the effects of DOBS and VOCs on inflammation. CONCLUSION: This study suggests that adjusting dietary structure and reducing daily exposure to VOCs can effectively reduce inflammation in the body.

Liquiritin Carbomer Gel Cold Paste Promotes Healing of Solar Dermatitis in Mice.

Ultraviolet radiation (UVR) has various effects on human cells and tissues, which can lead to a variety of skin diseases and cause inconvenience to people's lives. Among them, solar dermatitis is one of the important risk factors for malignant melanoma, so prevention and treatment of solar dermatitis is very necessary. Additionally, liquiritin (LQ) has anti-inflammatory effects. In this study, we aimed to evaluate the anti-inflammatory and pro-wound healing effects of liquiritin carbomer gel cold paste (LQ-CG-CP) in vitro and in vivo. The results of MTT experiments showed no cytotoxicity of LQ at concentrations of 40 µg/mL and below and cell damage at UVB irradiation doses above 60 mJ/cm2. Moreover, LQ can promote cell migration. ELISA results also showed that LQ inhibited the elevation of the inflammatory factors tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), and interleukin-6 (IL-6) after UVB irradiation. In the mouse model of solar dermatitis, 2% LQ-CG-CP showed the best therapeutic efficacy for wound healing and relief of itching compared to MEIBAO moist burn moisturizer (MEBO). What is more, the results of skin histopathological examination show that LQ-CG-CP promotes re-epithelialization, shrinks wounds, and promotes collagen production, thus promoting wound healing. Simultaneously, LQ-CG-CP reduced TNF-α, IL-1ß, and IL-6 expression. In addition, LQ-CG-CP was not observed to cause histopathological changes and blood biochemical abnormalities in mice. Overall, LQ-CG-CP has great potential for the treatment of solar dermatitis.

Material resource decoupling dilemma: Convergence and traps of in-use stock productivity in national economy development.

Various studies have suggested decoupling material stock from economic output as an important measure for promoting sustainable development. Here, we develop three theoretical hypotheses to describe the evolution features and economic effects of material stock intensity, and predict in theory that (1) Countries with higher material stock intensity are more likely to decouple economic growth from material stock. (2) Material stock intensity follows convergence trends. (3) Higher material stock intensity leads to higher long-run economic growth rates. To examine the adaptability of these hypotheses, we choose steel in-use stock as the proxy for the material capital stock and use panel data in 85 countries from 1950 to 2018 to conduct empirical analysis. Our empirical results in most countries support the theoretical predictions of the hypotheses. In particular, a 0.1t/k$ increase in steel stock intensity leads to a 2.12% increase in the probability of decoupling between steel stock and economic output next year and a 0.34% increase in the long-run GDP per capita growth rate annually. Moreover, steel stock intensity converges to approximately 0.25t/k$ to 0.35t/k$ at mature development stages. We predict that, except China, which is expected to follow decoupling trends, other large developing economies will couple economic output with steel stock. However, the shape of intensity curves is still uncertain for highly developed countries in the future.

Influence of mandatory waste classification on environmental and economic impacts of residual waste treatment in Xiamen, China.

Mandatory waste classification has been widely considered as an effective solution for reducing the production and treatment amount of municipal solid waste. However, there is limited evidence regarding whether and how waste classification can affect the composition of residual waste (RW) and its environmental economic impacts. Here, an accounting method recommended by the Intergovernmental Panel on Climate Change, field surveys and cost-benefit analysis was utilized to investigate the changes in RW composition, environmental impacts and economic benefits under the waste classification policies implementation in Xiamen, China. This study found that: (1) The implementation of waste classification policies led to a significant increase in recyclable content from 17% to 51% and a decrease in organic content from 56% to 32%. (2) Waste classification effectively reduces greenhouse gas emissions from landfilling and incineration by an additional 0.34 tCO2-eq t-1 RW. (3) The introduction of mechanical recycling achieves a saving of 0.47 tCO2-eq t-1 RW at 40% recycling efficiency, a 4.5-fold increase compared to business as usual (BAU). (4) The operational benefits (900 yuan t-1 RW) from the recyclables sorting system offset the total expenses of investment, operation and waste disposal. The study successfully demonstrated that RW source-classified management can optimize the structure of waste composition, reduce environmental emissions and offer detailed guidance for the development of solid waste management systems in other cities in China.

Depletion of endogenously biotinylated carboxylases enhances the sensitivity of TurboID-mediated proximity labeling in Caenorhabditis elegans.

Proximity-dependent protein labeling provides a powerful in vivo strategy to characterize the interactomes of specific proteins. We previously optimized a proximity labeling protocol for Caenorhabditis elegans using the highly active biotin ligase TurboID. A significant constraint on the sensitivity of TurboID is the presence of abundant endogenously biotinylated proteins that take up bandwidth in the mass spectrometer, notably carboxylases that use biotin as a cofactor. In C. elegans, these comprise POD-2/acetyl-CoA carboxylase alpha, PCCA-1/propionyl-CoA carboxylase alpha, PYC-1/pyruvate carboxylase, and MCCC-1/methylcrotonyl-CoA carboxylase alpha. Here, we developed ways to remove these carboxylases prior to streptavidin purification and mass spectrometry by engineering their corresponding genes to add a C-terminal His10 tag. This allows us to deplete them from C. elegans lysates using immobilized metal affinity chromatography. To demonstrate the method's efficacy, we use it to expand the interactome map of the presynaptic active zone protein ELKS-1. We identify many known active zone proteins, including UNC-10/RIM, SYD-2/liprin-alpha, SAD-1/BRSK1, CLA-1/CLArinet, C16E9.2/Sentryn, as well as previously uncharacterized potentially synaptic proteins such as the ortholog of human angiomotin, F59C12.3 and the uncharacterized protein R148.3. Our approach provides a quick and inexpensive solution to a common contaminant problem in biotin-dependent proximity labeling. The approach may be applicable to other model organisms and will enable deeper and more complete analysis of interactors for proteins of interest.

Permissive HLA-DPB1 mismatches in HCT depend on immunopeptidome divergence and editing by HLA-DM.

In hematopoietic cell transplantation (HCT), permissive HLA-DPB1 mismatches between patients and their unrelated donors are associated with improved outcomes compared with nonpermissive mismatches, but the underlying mechanism is incompletely understood. Here, we used mass spectrometry, T-cell receptor-ß (TCRß) deep sequencing, and cellular in vitro models of alloreactivity to interrogate the HLA-DP immunopeptidome and its role in alloreactive T-cell responses. We find that permissive HLA-DPB1 mismatches display significantly higher peptide repertoire overlaps compared with their nonpermissive counterparts, resulting in lower frequency and diversity of alloreactive TCRß clonotypes in healthy individuals and transplanted patients. Permissiveness can be reversed by the absence of the peptide editor HLA-DM or the presence of its antagonist, HLA-DO, through significant broadening of the peptide repertoire. Our data establish the degree of immunopeptidome divergence between donor and recipient as the mechanistic basis for the clinically relevant permissive HLA-DPB1 mismatches in HCT and show that permissiveness is dependent on HLA-DM-mediated peptide editing. Its key role for harnessing T-cell alloreactivity to HLA-DP highlights HLA-DM as a potential novel target for cellular and immunotherapy of leukemia.

s

Recently, the bilayer perovskite nickelate La_{3}Ni_{2}O_{7} has been reported to show evidence of high-temperature superconductivity (SC) under a moderate pressure of about 14 GPa. To investigate the superconducting mechanism, pairing symmetry, and the role of apical-oxygen deficiencies in this material, we perform a random-phase approximation based study on a bilayer model consisting of the d_{x^{2}-y^{2}} and d_{3z^{2}-r^{2}} orbitals of Ni atoms in both the pristine crystal and the crystal with apical-oxygen deficiencies. Our analysis reveals an s^{±}-wave pairing symmetry driven by spin fluctuations. The crucial role of pressure lies in that it induces the emergence of the γ pocket, which is involved in the strongest Fermi-surface nesting. We further found the emergence of local moments in the vicinity of apical-oxygen deficiencies, which significantly suppresses the T_{c}. Therefore, it is possible to significantly enhance the T_{c} by eliminating oxygen deficiencies during the synthesis of the samples.

Ultrasensitive detection of thiram based on surface-enhanced Raman scattering via Au@Ag@Ag core/shell/shell bimetallic nanorods.

We developed a highly sensitive and stable SERS-active substrate of Au@Ag@Ag core/shell/shell nanorods, formed by encapsulating Au nanorods (Au NRs) into a bilayer silver shell with Raman reporter molecules (4-mercaptobenzoic acid (4-MBA) and thiram) in the shell-shell gap. The core/shell/shell nanostructures demonstrated a high SERS enhancement and easy assembly. The important role of the bilayer silver shell in boosting the SERS intensity and detection sensitivity was revealed by comparing the performances of the Au@Ag@4-MBA@Ag NRs, Au@Ag@4-MBA NRs, and Au@4-MBA NRs. The obtained Au@Ag@4-MBA@Ag NRs exhibited a significantly promoted SERS intensity, which could reach around 2.6 times and 240 times that of the Au@Ag@4-MBA NRs and Au@4-MBA NRs, where the enhancement factor was found to be strongly correlated with the shell thickness. The controllable plasma properties and SERS effect of the Au@Ag@4-MBA@Ag NRs could be optimized by adjusting the dose of silver nitrate. The SERS substrate comprising core/shell/shell nanorods was highly reproducible and stable (retaining 83% SERS intensity after one month). Moreover, the highly sensitive detection of the pesticide thiram with a detection limit as low as 1.74 × 10-9 M was achieved by taking advantage of the great SERS response of the core/shell/shell nanostructures, which was 1-2 orders of magnitude lower than for other SERS substrates. The developed SERS substrate could be readily extended to embed other target analytes into the core/shell/shell nanostructure for novel and sensitive detection. This study could enable fresh approaches toward next-generation ultrasensitive analyte detection.

Material Flow Analysis of Dysprosium in the United States.

Dysprosium (Dy) is increasingly being adopted in various clean energy products around the world, intriguing many nations' interests in its availability. However, since data are inaccessible, crucial information about Dy supplies and demands across products and countries remains incomplete. To fill these knowledge gaps, we performed a dynamic bottom-up material flow analysis of Dy, taking the United States (1987-2018) as a case. The results show that the United States (US) domestic demands experienced a growing trend (by 45-fold) with fluctuation and several shifts among applications, primarily owing to technological advancement. A large imbalance (80 times) exists between domestic mineral supplies and market demands, resulting in significant import dependency, with the net import reliance of alloys, chemicals, finished products, and concentrates being 97, 44, 40, and 31%, respectively. Dy is mainly imported as finished products (55.7%) and alloys (43.2%), with concentrates (0.4%) and chemicals (0.7%) accounting for less than 2%. This import dependency may result from fragmentation of the US supply chains because of the stricter environmental regulations on upstream industries and reshoring of the downstream industries. These findings suggest that rare-earth mineral production in the US is about to restart, and it is important for industries to seek international collaboration to boost product competition.

Unlocking Dysprosium Constraints for China's 1.5 °C Climate Target.

Some key low-carbon technologies, ranging from wind turbines to electric vehicles, are underpinned by the strong rare-earth-based permanent magnets of the Nd, Pr (Dy)-Fe-Nb type (NdFeB). These NdFeB magnets, which are sensitive to demagnetization with temperature elevation (the Curie point), require the addition of variable amounts of dysprosium (Dy), where an elevation of the Curie point is needed to meet operational conditions. Given that China is the world's largest REE supplier with abundant REE reserves, the impact of an ambitious 1.5 °C climate target on China's Dy supply chain has sparked widespread concern. Here, we explore future trends and innovation strategies associated with the linkage between Dy and NdFeBs under various climate scenarios in China. We find China alone is expected to exhaust the global present Dy reserve within the next 2-3 decades to facilitate the 1.5 °C climate target. By implementing global available innovation strategies, such as material substitution, reduction, and recycling, it is possible to avoid 48%-68% of China's cumulative demand for Dy. Nevertheless, ongoing efforts in REE exploration and production are still required to meet China's growing Dy demand, which will face competition from the United States, European Union, and other countries with ambitious climate targets. Thus, our analysis urges China and those nations to form wider cooperation in REE supply chains as well as in NdFeB innovation for the realization of a global climate-safe future.

Intracranial Rosai-Dorfman disease: a case report and review of the literature.

RDD involving the central nervous system is rarely reported. To better understand the disease and explore the treatments, we reported this case and review the literature.