The projected impact of the inflation reduction act's climate provisions on cardiovascular and respiratory outcomes.

Onjective: Climate change and environmental pollution have known health effects. The recently introduced inflation reduction act (IRA) by the United States government includes funding initiatives to curb climate change, and reduce environmental pollution, in line with the nationally determined contribution (NDC) plan (40-50 % reduction in greenhouse gas [GHG] emissions by 2030, as compared with 2005). The projected cardiovascular health benefits of the IRA driven climate actions to achieve the NDC goals are not known. Methods: We used the Energy Policy Simulator (EPS), a simulation algorithm based on systems dynamics modelling estimating the impact of various energy policies, to model the impact of achieving NDC targets in the United States on health outcomes by 2050. We further investigated race-specific impact on mortality (absolute and relative) by 2050.We estimated the projected reduction in six adverse health outcomes between 2022 and 2050: asthma attacks, non-fatal heart attacks, hospital admissions, respiratory symptoms and bronchitis, lost workdays, and deaths. Results: Achievement of NDC targets by 2050 will result in 987,415 avoided asthma attacks, 41,565 avoided nonfatal heart attacks, 18,993 avoided hospital admissions, 1,493,010 avoided respiratory symptoms and bronchitis, 3,317,250 avoided lost workdays, and 32,659 avoided deaths (22,839 among white individuals, 4993 among Black individuals, 2801 among Asian individuals, and 2026 among other/multirace individuals). By 2050, minority racial groups had higher relative change in avoided deaths (white -0.74 %, Black -1.01 %, Asian -1.24 %, and other/multirace -1.75 %). Similarly, Hispanics/latinos higher relative reductions in deaths (-1.4 %) compared with non-Hispanic/Latinos (-0.7 %) by 2050. Conclusion: The IRA facilitated achievement of NDC GHG reduction goals by 2050 would result in substantial number of avoided adverse health outcomes and death. Racial and ethnic minorities are expected to have the largest relative reductions in deaths by 2050. The current report underscores the importance of continued climate action investment irrespective of political differences. The appreciation of this aspect of the IRA may be more important to overall preservation of health, beyond the reduction in medication costs.

Biallelic NDC1 variants that interfere with ALADIN binding are associated with neuropathy and triple A-like syndrome.

Nuclear pore complexes (NPCs) regulate nucleocytoplasmic transport and are anchored in the nuclear envelope by the transmembrane nucleoporin NDC1. NDC1 is essential for post-mitotic NPC assembly and the recruitment of ALADIN to the nuclear envelope. While no human disorder has been associated to one of the three transmembrane nucleoporins, biallelic variants in AAAS, encoding ALADIN, cause triple A syndrome (Allgrove syndrome). Triple A syndrome, characterized by alacrima, achalasia, and adrenal insufficiency, often includes progressive demyelinating polyneuropathy and other neurological complaints. In this report, diagnostic exome and/or RNA sequencing was performed in seven individuals from four unrelated consanguineous families with AAAS-negative triple A syndrome. Molecular and clinical studies followed to elucidate the pathogenic mechanism. The affected individuals presented with intellectual disability, motor impairment, severe demyelinating with secondary axonal polyneuropathy, alacrima, and achalasia. None of the affected individuals has adrenal insufficiency. All individuals presented with biallelic NDC1 in-frame deletions or missense variants that affect amino acids and protein domains required for ALADIN binding. No other significant variants associated with the phenotypic features were reported. Skin fibroblasts derived from affected individuals show decreased recruitment of ALADIN to the NE and decreased post-mitotic NPC insertion, confirming pathogenicity of the variants. Taken together, our results implicate biallelic NDC1 variants in the pathogenesis of polyneuropathy and a triple A-like disorder without adrenal insufficiency, by interfering with physiological NDC1 functions, including the recruitment of ALADIN to the NPC.

Naringin dihydrochalcone alleviates sepsis-induced acute lung injury via improving gut microbial homeostasis and activating GPR18 receptor.

Acute lung injury (ALI) is a life-threatening disease characterized by severe lung inflammation and intestinal microbiota disorder. The GPR18 receptor has been demonstrated to be a potential therapeutic target against ALI. Extracting Naringin dihydrochalcone (NDC) from the life-sustaining orange peel is known for its diverse anti-inflammatory properties, yet the specific action target remains uncertain. In the present study, we identified NDC as a potential agonist of the GPR18 receptor using virtual screening and investigated the pharmacological effects of NDC on sepsis-induced acute lung injury in rats and explored underlying mechanisms. In in vivo experiments, CLP-induced ALI model was established by cecum puncture and treated with NDC gavage one hour prior to drug administration, lung histopathology and inflammatory cytokines were evaluated, and feces were subjected to 16s rRNA sequencing and untargeted metabolomics analysis. In in vitro experiments, the anti-inflammatory properties were exerted by evaluating NDC targeting the GPR18 receptor to inhibit lipopolysaccharide (LPS)-induced secretion of TNF-α, IL-6, IL-1ß and activation of inflammatory signaling pathways in MH-S cells. Our findings showed that NDC significantly ameliorated lung damage and pro-inflammatory cytokine levels (TNF-α, IL-6, IL-1ß) in both cells and lung tissues via inhibiting the activation of STAT3, NF-κB, and NLRP3 inflammatory signaling pathways through GRP18 receptor activation. In addition, NDC can also partly reverse the imbalance of gut microbiota composition caused by CLP via increasing the proportion of Firmicutes/Bacteroidetes and Lactobacillus and decreasing the relative abundance of Proteobacteria. Meanwhile, the fecal metabolites in the NDC treatment group also significantly were changed, including decreased secretion of Phenylalanin, Glycine, and bile secretion, and increased secretion of Lysine. In conclusion, these findings suggest that NDC can alleviate sepsis-induced ALI via improving gut microbial homeostasis and metabolism and mitigate inflammation via activating GPR18 receptor. In conclusion, the results indicate that NDC, derived from the typical orange peel of food, could significantly contribute to development by enhancing intestinal microbial balance and metabolic processes, and reducing inflammation by activating the GPR18 receptor, thus mitigating sepsis-induced ALI and expanding the range of functional foods.

A conserved site on Ndc80 complex facilitates dynamic recruitment of Mps1 to yeast kinetochores to promote accurate chromosome segregation.

Accurate chromosome segregation relies on kinetochores carrying out multiple functions, including establishing and maintaining microtubule attachments, forming precise bi-oriented attachments between sister chromatids, and activating the spindle assembly checkpoint. Central to these processes is the highly conserved Ndc80 complex. This kinetochore subcomplex interacts directly with microtubules but also serves as a critical platform for recruiting kinetochore-associated factors and as a key substrate for error correction kinases. The precise manner in which these kinetochore factors interact and regulate each other's function remains unknown, considerably hindering our understanding of how Ndc80 complex-dependent processes function together to orchestrate accurate chromosome segregation. Here, we aimed to uncover the role of Nuf2's CH domain, a component of the Ndc80 complex, in ensuring these processes. Through extensive mutational analysis, we identified a conserved interaction domain composed of two segments in Nuf2's CH domain that form the binding site for Mps1 within the yeast Ndc80 complex. Interestingly, this site also associates with the Dam1 complex, suggesting Mps1 recruitment may be subject to regulation by competitive binding with other factors. Mutants disrupting this "interaction hub" exhibit defects in spindle assembly checkpoint function and severe chromosome segregation errors. Significantly, specifically restoring Mps1-Ndc80 complex association rescues these defects. Our findings shed light on the intricate regulation of Ndc80 complex-dependent functions and highlight the essential role of Mps1 in kinetochore bi-orientation and accurate chromosome segregation.

NDC80 Kinetochore Complex Serves as a Potential Prognostic Predictor and Correlates with Immune Infiltrates in Epithelial Ovarian Cancer Patients.

Purpose: This study focuses on evaluating the prognostic value of the NDC80 kinetochore complex in ovarian cancer (OC) using the Gene Expression Omnibus (GEO) database and the Cancer Genome Atlas (TCGA) database and reveals the relationship between the NDC80 complex and immune infiltrates in OC. Methods: We collected data on NDC80 complex expression levels in both OC tissues and non-OC ovarian tissues from the University of California Santa Cruz Xena and GEO databases. The clinicopathological characteristics correlated with overall survival were analyzed using Cox regression and the Kaplan-Meier method. Gene Ontology analysis, Kyoto Encyclopedia of Genes and Genomes analysis, gene set enrichment analysis and CIBERSORT were performed using data from TCGA database. Immunohistochemical staining was used to verify the higher expression level of NUF2 protein in OC in vitro. Meanwhile, we utilized the Tumor Immune Estimation Resource to analyze the correlation between the NDC80 complex and immunocyte infiltration. Results: The NDC80 complex expression level was prominently higher in OC tissues than in non-OC ovarian tissues and correlated with advanced histologic grade characteristics. Gene expression profiling interactive analysis and the Kaplan-Meier survival curve uncovered a close relationship between high expression of the NDC80 complex and poor overall survival in OC patients. The univariate Cox regression hazard model produced age, pathologic stage, tumor status, primary therapy outcome, SPC24 expression level, and Karnofsky performance score as prognostic factors for OC patients. NDC80 complex expression levels were highly associated with immune cell infiltration, showing NK CD56 bright cells and NK cells with a negative correlation and T helper 2 cells with a positive correlation (P<0.05). Conclusion: These findings provide evidence that an increased expression level of the NDC80 complex is closely associated with the progression of OC and could also serve as a novel target of immunotherapy in OC.

NDC1 promotes hepatocellular carcinoma tumorigenesis by targeting BCAP31 to activate PI3K/AKT signaling.

Hepatocellular carcinoma (HCC) is among the world's worst malignancies. Nuclear division cycle 1 (NDC1) is an essential membrane-integral nucleoporin, found in this study to be significantly increased in primary HCC. A multivariate analysis revealed that higher NDC1 expression was linked to worse outcome in HCC patients. Mouse xenograft tumors overexpressing NDC1 grew rapidly, and HCC cells overexpressing NDC1 showed enhanced proliferation, invasion, and migration in vitro. In contrast, knocking down NDC1 had the opposite effects in vitro. Furthermore, co-immunoprecipitation and liquid chromatograph mass spectrometer analyses revealed that NDC1 activated PI3K/AKT signaling by interacting with BCAP31. In summary, NDC1 and BCAP31 cooperate to promote the PI3K/AKT pathway, which is essential for HCC carcinogenesis. This suggests that NDC1 is predictive of prognosis in HCC.

KNL1 and NDC80 represent new universal markers for the detection of functional centromeres in plants.

Centromere is the chromosomal site of kinetochore assembly and microtubule attachment for chromosome segregation. Given its importance, markers that allow specific labeling of centromeric chromatin throughout the cell cycle and across all chromosome types are sought for facilitating various centromere studies. Antibodies against the N-terminal region of CENH3 are commonly used for this purpose, since CENH3 is the near-universal marker of functional centromeres. However, because the N-terminal region of CENH3 is highly variable among plant species, antibodies directed against this region usually function only in a small group of closely related species. As a more versatile alternative, we present here antibodies targeted to the conserved domains of two outer kinetochore proteins, KNL1 and NDC80. Sequence comparison of these domains across more than 350 plant species revealed a high degree of conservation, particularly within a six amino acid motif, FFGPVS in KNL1, suggesting that both antibodies would function in a wide range of plant species. This assumption was confirmed by immunolabeling experiments in angiosperm (monocot and dicot) and gymnosperm species, including those with mono-, holo-, and meta-polycentric chromosomes. In addition to centromere labeling on condensed chromosomes during cell division, both antibodies detected the corresponding regions in the interphase nuclei of most species tested. These results demonstrated that KNL1 and NDC80 are better suited for immunolabeling centromeres than CENH3, because antibodies against these proteins offer incomparably greater versatility across different plant species which is particularly convenient for studying the organization and function of the centromere in non-model species.

Greenhouse gas mitigation scenarios in the solid waste sector for compliance with the Brazilian NDC: Case study of the Recife metropolitan area, Brazil.

The Intergovernmental Panel on Climate Change (IPCC) indicates that the waste sector is a potential emitter of methane gas (CH4), which has a greenhouse effect up to 28 times greater than that of carbon dioxide (CO2). The management of municipal solid waste (MSW) generates greenhouse gases (GHG) directly through emissions from the process itself as well as indirectly through transportation and energy consumption. The objective of this study was to evaluate the GHG emissions contributed by the waste sector in the Recife metropolitan region (RMR) and to define mitigation scenarios to comply with the Brazilian Nationally Determined Contribution (NDC), a result of the Paris Agreement. To achieve this, an exploratory study was carried out, including a literature review, collection of data, estimation of emissions using the IPCC model (2006), and comparison between the values assumed by the country in 2015 and those estimated in the adopted mitigation scenarios. The RMR is composed of 15 municipalities, has an area of 3,216,262 km2 and a population of 4,054,866 inhabitants (2018), generating approximality 1.4 million t-year of MSW. It was estimated that, in the period from 2006 to 2018, 25.4 million tCO2e were emitted. The comparative analysis between the absolute values defined in the Brazilian NDC and the results from the mitigation scenarios showed that approximately 36 million tCO2e could be avoided through the disposal of MSW in the RMR, equivalent to a 52% reduction in emissions estimated for 2030, a percentage greater than the 47% reduction assumed in the Paris Agreement.

Pan-cancer analysis and experimental validation identify ndc1 as a potential immunological, prognostic and therapeutic biomarker in pancreatic cancer.

NDC1 is a transmembrane nucleoporin that participates in cell mitosis. In the field of oncology, NDC1 has shown its potential as a prognostic marker for multiple tumors. However, pan-cancer analysis of NDC1 to fully explore its role in tumors has not been performed and little is reported on its role in pancreatic cancers. In the present study, a pan-cancer analysis of NDC1 was performed using a bioinformatic approach. Survival analysis was performed by univariate Cox regression analysis and Kaplan-Meier survival analysis. Subsequently, the relationship between NDC1 and immune cell infiltration, TMB/MSI and drug sensitivity was analyzed. Moreover, the mechanism of NDC1 in pancreatic cancer were further analyzed by GSEA, GSVA. Finally, we conducted in vitro experiments including MTT, scratch, EdU, and apoptosis assays to explore the function of NDC1 in pancreatic cancer cells. High expression of NDC1 was demonstrated in 28 cancer types. Univariate Cox regression analysis revealed that NDC1 expression was closely associated with the survival outcome of 15 cancer types, and further Kaplan-Meier survival analysis showed negative associations with the progression-free survival in 14 cancers. In addition, a significant association between the NDC1 expression and immune cell infiltration in tumor microenvironment, immune-related genes, common tumor-regulatory and drug sensitivity was observed. Furthermore, NDC1 is abnormally expressed in pancreatic cancer, and is closely related to the prognosis of pancreatic cancer patients and chemosensitivity. The study reveals that NDC1 could be used as a potential immunological, prognostic and therapeutic target for pancreatic cancer.

Catalysing the monitoring and evaluation of Nationally Determined Contributions through North-South cooperation.

The recent 6th Assessment Report by Intergovernmental Panel on Climate Change has been damning to the world. An overwhelming amount of evidence that Nationally Determined Contributions (NDCs) can contribute to stabilising or reversing the course of impacts of climate change is now common. Given the likely update of NDC measures compounded by their complexities and limited resources, it is imperative to adopt effective Monitoring & Evaluation (M&E) systems to ensure that NDCs achieve their planned objectives. Effective roll-out and M&E of NDCs require full participation from all actors in various countries. However, despite existing evidence that shows the developing countries are the most affected by climate change, the role of their researchers in climate change research is not known. Therefore, the need to investigate the global North-South disparities and develop an agenda for future research about NDCs is imperative. To address this gap, a systematic review was undertaken using appropriate terms in Web of Science, Dimensions and ScienceDirect to identify relevant literature. The analysis of the identified literature led to two main findings. Firstly, most studies about NDCs are conducted by global North research institutes and researchers with very little involvement of those from the global South. Secondly, there is a global paucity of research about M&E of NDCs measures. As a major recommendation, while countries should equitably contribute to rolling out NDC projects, research should play a key role and should be inclusive as possible representing voices from the global North and South.

Stable kinetochore-microtubule attachment requires loop-dependent Ndc80-Ndc80 binding.

During cell division, kinetochores link chromosomes to spindle microtubules. The Ndc80 complex, a crucial microtubule binder, populates each kinetochore with dozens of copies. Whether adjacent Ndc80 complexes cooperate to promote microtubule binding remains unclear. Here we demonstrate that the Ndc80 loop, a short sequence that interrupts the Ndc80 coiled-coil at a conserved position, folds into a more rigid structure than previously assumed and promotes direct interactions between full-length Ndc80 complexes on microtubules. Mutations in the loop impair these Ndc80-Ndc80 interactions, prevent the formation of force-resistant kinetochore-microtubule attachments, and cause cells to arrest in mitosis for hours. This arrest is not due to an inability to recruit the kinetochore-microtubule stabilizing SKA complex and cannot be overridden by mutations in the Ndc80 tail that strengthen microtubule attachment. Thus, loop-mediated organization of adjacent Ndc80 complexes is crucial for stable end-on kinetochore-microtubule attachment and spindle assembly checkpoint satisfaction.

3D rhombohedral microcrystals metal-organic frameworks for electrochemical and fluorescence sensing of tetracycline.

Zirconium-based metal-organic frameworks (MOF) exhibiting 3D rhombohedral microcrystals were synthesized by the solvothermal method. The structure, morphology, composition, and optical properties of the synthesized MOF were carried out using different spectroscopic, microscopic, and diffraction techniques. Synthesized MOF was rhombohedral in shape and the cage structure of these crystalline molecules was the active binding site of the analyte, tetracycline (TET). The electronic property and size of the cages are chosen such that a specific interaction with TET was observed. Sensing of the analyte was demonstrated by both the electrochemical and fluorescent techniques. The MOF had significant luminescent properties and exhibited excellent electro-catalytic activity due to embedded zirconium metal ions. An electrochemical and fluorescence sensor was fabricated towards TET where TET binds via hydrogen bond to MOF, and causes fluorescence quenching due to the transfer of electrons. Both approaches exhibited high selectivity and good stability in the presence of interfering molecules such as antibiotics, biomolecules, and ions; and showed excellent reliability in tap water and wastewater sample analysis.

Coordination between the Ndc80 complex and dynein is essential for microtubule plus-end capture by kinetochores during early mitosis.

Mitotic kinetochores are initially captured by dynamic microtubules via a "search-and-capture" mechanism. The microtubule motor, dynein, is critical for kinetochore capture as it has been shown to transport microtubule-attached chromosomes toward the spindle pole during prometaphase. The microtubule-binding nuclear division cycle 80 (Ndc80) complex that is recruited to kinetochores in prophase is known to play a central role in forming kinetochore-microtubule (kMT) attachments in metaphase. It is not yet clear, however, how Ndc80 contributes to initial kMT capture during prometaphase. Here, by combining CRISPR/Cas9-mediated knockout and RNAi technology with assays specific to study kMT capture, we show that mitotic cells lacking Ndc80 exhibit substantial defects in this function during prometaphase. Rescue experiments show that Ndc80 mutants deficient in microtubule-binding are unable to execute proper kMT capture. While cells inhibited of dynein alone are predominantly able to make initial kMT attachments, cells co-depleted of Ndc80 and dynein show severe defects in kMT capture. Further, we use an in vitro total internal reflection fluorescence microscopy assay to reconstitute microtubule capture events, which suggest that Ndc80 and dynein coordinate with each other for microtubule plus-end capture and that the phosphorylation status of Ndc80 is critical for productive kMT capture. A novel interaction between Ndc80 and dynein that we identify in prometaphase extracts might be critical for efficient plus-end capture. Thus, our studies, for the first time, identify a distinct event in the formation of initial kMT attachments, which is directly mediated by Ndc80 and in coordination with dynein is required for efficient kMT capture and chromosome alignment.

Characterisation of the trans-membrane nucleoporins GP210 and NDC1 in Arabidopsis thaliana.

The nuclear pore is structurally conserved across eukaryotes as are many of the pore's constituent proteins. The transmembrane nuclear pore proteins GP210 and NDC1 span the nuclear envelope holding the nuclear pore in place. Orthologues of GP210 and NDC1 in Arabidopsis were investigated through characterisation of T-DNA insertional mutants. While the T-DNA insert into GP210 reduced expression of the gene, the insert in the NDC1 gene resulted in increased expression in both the ndc1 mutant as well as the ndc1/gp210 double mutant. The ndc1 and gp210 individual mutants showed little phenotypic difference from wild-type plants, but the ndc1/gp210 mutant showed a range of phenotypic effects. As with many plant nuclear pore protein mutants, these effects included non-nuclear phenotypes such as reduced pollen viability, reduced growth and glabrous leaves in mature plants. Importantly, however, ndc1/gp210 exhibited nuclear-specific effects including modifications to nuclear shape in different cell types. We also observed functional changes to nuclear transport in ndc1/gp210 plants, with low levels of cytoplasmic fluorescence observed in cells expressing nuclear-targeted GFP. The lack of phenotypes in individual insertional lines, and the relatively mild phenotype suggests that additional transmembrane nucleoporins, such as the recently-discovered CPR5, likely compensate for their loss.

Elevated NDC1 expression predicts poor prognosis and correlates with immunity in hepatocellular carcinoma.

Background: NDC1 was identified to be a tumor-promoting factor in non-small cell lung cancer and cervical cancer. However, no report had clarified the relationship between NDC1 and hepatocellular carcinoma (HCC). In this paper, we explored the expression and potential functions of NDC1 in HCC for the first time through the rational application of bioinformatics and relevant basic experiments. Methods: NDC1-related expression profiles and clinical data of HCC patients were collected from The Cancer Genome Atlas (TCGA) database, which were verified via quantitative real-time polymerase chain reaction (qRT-PCR), immunohistochemistry and the Clinical Proteomic Tumor Analysis Consortium (CPTAC) database. Univariate and multivariate Cox regression analyses were used to identify NDC1 as an independent factor for HCC prognosis, and NDC1-related signaling pathways were determined by gene set enrichment analysis (GSEA). Furthermore, we deeply probed the potential links of NDC1 to immunity and immune response. Finally, the bioeffects and underlying mechanisms of ectopic NDC1 overexpression and depletion were determined in HepG2 cells by immunoblotting, flow cytometry, Cell-Counting-Kit-8 (CCK-8), and EDU (5-Ethynyl-2'-deoxyuridine). Results: Up-regulated expression of NDC1 was detected by means of the TCGA database, which was consistent with the results obtained from further qRT-PCR, immunohistochemistry and the CPTAC database. Kaplan-Meier (K-M) survival analysis revealed a worse prognosis in HCC patients with high NDC1 expression. Besides, NDC1 was certified to be closely linked to tumor histologic grade, clinical stage and T stage. Moreover, univariate and multivariate Cox regression analyses defined NDC1 as an independent element for HCC prognosis. NDC1-related signaling pathways, utilizing GSEA analysis, were subsequently found out. What's more, NDC1 expression was detected to be enormously associated with microsatellite instability (MSI), immune cell infiltration, immune checkpoint molecules and immune cell pathways. As for immunotherapy, we discovered that different risk groups tended to have different immune checkpoint inhibitor responses, which indicated crucial implication value of NDC1 for HCC immunotherapy. More interestingly, we observed that the overexpression of NDC1 could promote the migration and invasion of HCC cells. Conclusions: Our article demonstrated that NDC1 might serve as a valuable predictor in the prognosis and immunotherapy of HCC. NDC1 played an oncogenic role in HCC.

Ir Nanoparticles Anchored on Metal-Organic Frameworks for Efficient Overall Water Splitting under pH-Universal Conditions.

The construction of high-activity and low-cost electrocatalysts is critical for efficient hydrogen production by water electrolysis. Herein, we developed an advanced electrocatalyst by anchoring well-dispersed Ir nanoparticles on nickel metal-organic framework (MOF) Ni-NDC (NDC: 2,6-naphthalenedicarboxylic) nanosheets. Benefiting from the strong synergy between Ir and MOF through interfacial Ni-O-Ir bonds, the synthesized Ir@Ni-NDC showed exceptional electrocatalytic performance for hydrogen evolution reaction (HER), oxygen evolution reaction (OER) and overall water splitting in a wide pH range, superior to commercial benchmarks and most reported electrocatalysts. Theoretical calculations revealed that the charge redistribution of Ni-O-Ir bridge induced the optimization of H2 O, OH* and H* adsorption, thus leading to the accelerated electrochemical kinetics for HER and OER. This work provides a new clue to exploit bifunctional electrocatalysts for pH-universal overall water splitting.

Structure of the Ndc80 complex and its interactions at the yeast kinetochore-microtubule interface.

The conserved Ndc80 kinetochore complex, Ndc80c, is the principal link between mitotic spindle microtubules and centromere-associated proteins. We used AlphaFold 2 (AF2) to obtain predictions of the Ndc80 'loop' structure and of the Ndc80 : Nuf2 globular head domains that interact with the Dam1 subunit of the heterodecameric DASH/Dam1 complex (Dam1c). The predictions guided design of crystallizable constructs, with structures close to the predicted ones. The Ndc80 'loop' is a stiff, α-helical 'switchback' structure; AF2 predictions and positions of preferential cleavage sites indicate that flexibility within the long Ndc80c rod occurs instead at a hinge closer to the globular head. Conserved stretches of the Dam1 C terminus bind Ndc80c such that phosphorylation of Dam1 serine residues 257, 265 and 292 by the mitotic kinase Ipl1/Aurora B can release this contact during error correction of mis-attached kinetochores. We integrate the structural results presented here into our current molecular model of the kinetochore-microtubule interface. The model illustrates how multiple interactions between Ndc80c, DASH/Dam1c and the microtubule lattice stabilize kinetochore attachments.

Achieving net-zero emissions targets: An analysis of long-term scenarios using an integrated assessment model.

More than 100 countries have communicated or adopted new Nationally Determined Contributions (NDCs) and net-zero target pledges. We investigate the impact on global, national, sectoral, and individual greenhouse gas emissions projections under different scenarios based on the announced NDCs and net-zero pledges using the IMAGE integrated assessment model. Our results show that while the net-zero pledges, if implemented, could be an important step forward, they are still not enough to achieve the Paris Agreement goals of well below 2°C and preferably 1.5°C by the end of the century. Still, our net-zero scenarios project significant all-sector decarbonization, in particular, electricity; however, certain sectors like industry and transport prove hard to completely abate.

Methylation of CENP-A/Cse4 on arginine 143 and lysine 131 regulates kinetochore stability in yeast.

Post-translational modifications on histones are well known to regulate chromatin structure and function, but much less information is available on modifications of the centromeric histone H3 variant and their effect at the kinetochore. Here, we report two modifications on the centromeric histone H3 variant CENP-A/Cse4 in the yeast Saccharomyces cerevisiae, methylation at arginine 143 (R143me) and lysine 131 (K131me), that affect centromere stability and kinetochore function. Both R143me and K131me lie in the core region of the centromeric nucleosome, near the entry/exit sites of the DNA from the nucleosome. Unexpectedly, mutation of Cse4-R143 (cse4-R143A) exacerbated the kinetochore defect of mutations in components of the NDC80 complex of the outer kinetochore (spc25-1) and the MIND complex (dsn1-7). The analysis of suppressor mutations of the spc25-1 cse4-R143A growth defect highlighted residues in Spc24, Ndc80, and Spc25 that localize to the tetramerization domain of the NDC80 complex and the Spc24-Spc25 stalk, suggesting that the mutations enhance interactions among NDC80 complex components and thus stabilize the complex. Furthermore, the Set2 histone methyltransferase inhibited kinetochore function in spc25-1 cse4-R143A cells, possibly by methylating Cse4-K131. Taken together, our data suggest that Cse4-R143 methylation and Cse4-K131 methylation affect the stability of the centromeric nucleosome, which is detrimental in the context of defective NDC80 tetramerization and can be compensated for by strengthening interactions among NDC80 complex components.

Belize Blue Carbon: Establishing a national carbon stock estimate for mangrove ecosystems.

Mangrove ecosystems are among the most economically and ecologically valuable marine environments in the world. Mangroves are effective at long-term carbon storage within their sediments and are estimated to hold 12 billion metric tons of carbon worldwide. These ecosystems are therefore vitally important for carbon sequestration and, by extension, climate change mitigation. As part of the Paris Agreement, participating countries agree to provide plans to reduce their carbon emissions, or nationally determined contributions (NDCs). However, despite mangroves being recognized as important nature-based solutions, many countries still lack national data on carbon stocks and must use global or regional averages, which may not be sufficiently accurate. Here, we present the national carbon stock estimate of mangrove ecosystems for the NDC of Belize, acquired through a collaborative approach involving government agencies and NGOs. We conducted a comprehensive sampling of mangroves across the country, including a range of mangrove ecotypes. The mean total ecosystem carbon stock (TECS) for the nation was 444.1 ± 21.0 Mg C ha-1, with 74.4 ± 6.2 Mg C ha-1 in biomass stocks, and 369.7 ± 17.7 Mg C ha-1 in sediment stocks. Combining these data with a recent mapping effort, we provide the first national comprehensive mangrove carbon stock estimate of 25.7 Tg C. The national mean from this study varies from previous global analyses, which can under- or overestimate TECS by as much as 0.6 Tg C and 16.5 Tg C, respectively, depending on the study. These data supported the NDC update of Belize, and can be used to inform the country's mangrove protection and restoration commitments. The collaborative approach of this work should serve as a blueprint for other countries seeking to conserve natural blue carbon sinks as a strategy to achieve their climate targets.