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Despite reports of striking outcomes, immunotherapy efficacy in melanoma is limited to subsets of patients 1, 2. Combining immunotherapies with other modalities has yielded limited improvements but also adverse events requiring cessation of treatment 1. In addition to ineffective patient stratification, efficacy can be impaired by paucity of tumor-infiltrating lymphocytes (TILs). Thus, effective strategies to safely increase TILs are urgently needed to improve immunotherapies 3. Here, we report that dietary administration of the sugar L-fucose triggers CD4+T cell-mediated increases in TILs, anti-tumor immunity, and enhanced immune checkpoint blockade responses. This is induced by the fucosylation and cell surface enrichment of the MHC-II protein HLA-DRB1 in melanoma. Single-cell immunofluorescent staining analysis of patient melanoma specimens demonstrates that fucosylation and fucosylated HLA-DRB1 is associated with intratumoral T cell abundance and anti-PD1 responder status. Our findings demonstrate that fucosylation is a key mediator of anti-tumor immunity, via regulation of melanoma cell surface HLA-DRB1 and induction of anti-tumor immunity, suggesting use of melanoma fucosylation as a novel strategy to stratify patients for immunotherapies. Importantly, our study suggests that L-fucose represents a powerful, non-toxic agent for safely increasing anti-tumor immunity and immunotherapy efficacy in melanoma.

ICB therapy has transformed cancer treatment; durable responses in difficult-to-treat cancers have been observed. Despite this most patients (pts) don’t respond to ICB (primary resistance), and many pts who initially respond eventually relapse (acquired resistance). Primary resistance is associated with tumor cell extrinsic factors, e.g., the immunosuppressive nature of the tumor microenvironment (TME), while acquired resistance is associated with tumor intrinsic factors, e.g., downregulation of MHC1, preventing T cell recognition. Treatments to overcome ICB resistance are necessary. WU-NK-101 is a PBMC-derived, cytokine-reprogrammed, expanded, and cryopreserved off-the-shelf memory NK cell product. WU-NK-101 cells capture the memory-like NK cell biology of cytokine-induced memory-like (CIML) NK cells, exhibiting enhanced cytotoxicity, metabolic fitness/flexibility, and resistance to TME immunosuppression (Muth et al. EHA 2022; Rutella et al. ESMO 2022). Bone marrow biopsies, collected from R/R AML pts who received CIML-NK cells (NCT01898793), were interrogated using immune gene expression (GE) profiling and spatially resolved proteomics (IO360® panel, n = 740 genes, and GeoMx® DSP; NanoString Technologies). Higher T-cell infiltration was noted post CIML-NK. CIBERSORT deconvoluted GE data inferred higher abundance of macrophages, γδT cells and activated dendritic cells on day 28 post-treatment. GE signatures showed downregulation of NFIL3 and FAM30A (log2 fold-change Citation Format: Tom A. Leedom, Barbara Muz, Jaykumar Vadakekolathu, John J. Muth, Xiao-Hua Li, Gregory Watson, Kristaan Magee, Ryan P. Sullivan, Melissa Berrien-Elliott, Todd Fenigher, Sergio Rutella, Matthew L. Cooper, Ayman Kabakibi, Jan K. Davidson-Moncada. xWU-NK-101 as salvage therapy post immune checkpoint blockade (ICB) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6418.

Innovative financing models are emerging globally to advance nature-based solutions (NBS) that can cost-effectively enhance infrastructure performance, meet Sustainable Development Goals, and mitigate the negative impacts of climate change. Despite the potential for NBS to generate attractive returns and provide significant cost-savings, these financing models remain underutilized. Consequently, NBS are not achieving their full potential and a tranche of pent up green capital is sidelined. This report highlights five proven NBS financing strategies that leverage private finance: green bonds, blended market-rate and concessional loans, land-based financing strategies, insurance policies, and endowments. This report also outlines current barriers to the successful scaling of these financing strategies in Latin America and the Caribbean and identifies the approaches and enabling conditions needed to overcome them.

Governments across Latin America and the Caribbean (LAC) face challenges in extending and maintaining infrastructure to serve their populations, especially as climate change and ecosystem degradation endanger communities and infrastructure assets across the region. To help address these challenges, the Inter-American Development Bank (IDB) aims to increase its support of Nature-based Solutions (NBS) in accordance with the banks 2020 Environmental and Social Sustainability Mainstreaming Action Plan. This Issue Brief serves two main functions. First, it describes IDB's growing focus on NBS and provides a tour of IDBs main offerings regarding NBS project support and investment. Second, it serves as a baseline of IDBs activities related to NBS from which the bank and partners can build upon moving forward. Going forward, IDB will ramp up support for clients to incorporate NBS considerations and opportunity analysis in country agreements and throughout all stages of project preparation, from investment identification to execution.

Nature-based solutions (NBS) can contribute to equitable and sustainable development across Latin America and the Caribbean and represent an important investment opportunity for national and subnational governments, infrastructure service providers, development banks, and corporations. Examining the status of NBS efforts and results within the region can shed light on what is required to drive more investment towards NBS projects. To chart a pathway forward, this brief provides a regional review of NBS projects, their status, and implications for investment. These NBS projects aim to address a variety of objectives, including securing water supply, improving water quality, reducing landslide risk, and helping to manage urban flooding, river flooding, or coastal flooding and erosion. The projects utilize a broad range of types of NBS, from forest management to coral reef restoration. This brief outlines the difficulties to scaling NBS adoption in the region and identifies strategies to address the challenges moving forward.

Global environmental change is one of the most pressing issues facing future generations. Equipping schoolchildren with a clear understanding of physical geography is therefore a key educational priority. Effectively engaging schoolchildren with complex scientific ideas can be challenging, but with the appropriate tools, scientists can play a valuable role in developing meaningful science communication experiences. Climate Explorers addressed these issues by forging a collaboration between physical geography and social science academics, and 320 UK school students and their teachers in seven primary (elementary) schools. Using insights from co-production techniques and storytelling, the project aimed to 1) produce new open access, online climate science education resources, and 2) test co-production and storytelling approaches to physical geography science engagement. Our findings demonstrated that school children responded especially well to working with ‘real life’ scientists, where meaningful and memorable educational interactions were forged through the use of narratives, personal experiences and tailored language. Here we summarise our approach, and provide templates that can be readily applied by scientists working across the physical geography spectrum anywhere in the world. The flexibility of the templates means that they can be adapted and developed for a range of formats, from small-scale community workshops to national-scale educational initiatives, for delivery both in-person or online. We hope that our approach will provide a springboard to transform and enhance physical geography science communication more broadly.

The Latin American and Caribbean (LAC) region enjoys an exuberant natural wealth; with 16 percent of the planets land, the region is home to 40 percent of the worlds biological diversity. This report investigates and provides a good overview of the regions efforts to mainstream natural capital and biodiversity concerns into public policy. It also provides a series of policy tools and instruments:payments for ecosystems services, innovation in managing protected areas, conservation trust funds, nature-based solutions for infrastructure, small-scale sustainable fisheries management, natural capital and ecosystem accounting, and ecosystem-based adaptation in agriculture. Two key lessons emerge from this report. First, mainstreaming natural capital and biodiversity considerations into day-to-day activities inevitably requires the involvement of multiple stakeholders (from communities to private firms) that should become central players in constructing and governing LACs natural wealth. Still, all the tools described in this report share a common feature: strong endorsement and support from government institutions, well beyond environmental authorities. Second, the lessons derived from policy tools with a longer history are evidence of the constant political, financial, and technical challenges faced by these policies for long-term sustainability. Although some of the policy tools described in this report have a long history, none of them can take their survival for granted. Solving the financial and technical challenges is typically the only functioning strategy to deal with political issues. The report suggests a series of key enabling conditions that facilitate mainstreaming natural capital and biodiversity considerations into public policy.

Molecular markers are fast, efficient and reliable in detecting distinct differences between genotypes at DNA level. In particular, polymerase chain reaction (PCR)-based markers are widely preferred for genotype characterization in diverse crop species, including maize. It is impossible, however, to obtain the entire information required in plant breeding and conservation programmes solely from a single marker system without integration with other technique(s). The current study was, therefore, initiated to compare results from random amplified polymorphic DNA (RAPD) and simple sequence repeats (SSR) markers in combination with high resolution melt analysis for effectiveness in detecting genetic variability or similarity among selected QPM inbred lines. Eight fresh leaf samples (two per line) were collected from each line for DNA extraction. The genomic DNA extracts were subjected to polymerase chain reaction (PCR) and high resolution melt analyses which involved three RAPD primers and three SSR primer pairs using a Real-Time PCR System. The curves of the HRM analysis showed fairly similar melt patterns among the lines for both types of marker systems. Results obtained from the gel-electrophoresis and genetic distance measures for RAPD markers were also in agreement with the HRM analysis. In general, both marker systems in combination with HRM analyses were able to detect genetic variations within and between the inbred lines, thus justifying the potential use of HRM analysis and indicating the possibility of excluding the use of gel-electrophoresis at the early stage of screening of large number of samples of newly developed inbred lines in order to save time and resources. Key words: Genetic variability, polymerase chain reaction, quality protein maize, random amplified polymorphic DNA, simple sequence repeats.

In multisensor target tracking systems measurements from different sensors on the same target exhibit, typically, biases. These biases can be accounted for as fixed random variables by the Schmidt-Kalman filter. Furthermore, measurements from the same target can arrive out of sequence. This “out-of-sequence” measurement (OOSM) problem was recently solved and a procedure for updating the state with a multistep-lag measurement using the simpler “1-step-lag” algorithm was developed for the situation without measurement biases. The present work presents the solution to the combined problem of handling biases from multiple sensors when their measurements arrive out of sequence.

We present our experience with the design and teaching of a graduate-level networking hardware course in which students design and build an Internet router. Each team of two students (one proficient in hardware and one proficient in software) design and develop a fully functional router that routes live Internet traffic and inter-operates with other students' routers via a simple routing protocol. Hardware is designed in Verilog using an industry-standard design flow on a specially designed platform, called NetFPGA. Software is written in user-space using a high-level language. Software and hardware are combined and tested using real network traffic over arbitrary private topologies using a custom tool, called VNS. Our approach is distinguished in that both hardware and software can be designed, tested and deployed remotely over the Internet. Our goal is to give students experience in the design of complex networking systems. In our initial course offering in Spring 2004, all teams successfully implemented fully functional routers in less than ten weeks. We will pilot courses outside of Stanford using the remote teaching infrastructure presented in this paper.

Pyruvate formate-lyase (PFL) catalyses the non-oxidative dissimilation of pyruvate to formate and acetyl-CoA using a radical-chemical mechanism. The enzyme is enzymically interconverted between inactive and active forms, the active form contains an organic free radical located on a glycyl residue in the C-terminal portion of the polypeptide chain. Introduction of the radical into PFL only occurs anaerobically, and the activating enzyme responsible is an iron-sulphur protein that uses S-adenosyl methionine as cofactor and reduced flavodoxin as reductant. As the radical form of PFL is inactivated by molecular oxygen it is safeguarded during the transition to aerobiosis by conversion back to the radical-free, oxygen-stable form. This reaction is catalysed by the anaerobically induced multimeric enzyme alcohol dehydrogenase. The genes encoding PFL and its activating enzyme are adjacent on the chromosome but form discrete transcriptional units. This genetic organization is highly conserved in many, but not all, organisms that have PFL. Recent studies have shown that proteins exhibiting significant similarity to PFL and its activating enzyme are relatively widespread in facultative and obligate anaerobic eubacteria, as well as archaea. The physiological function of many of these PFL-like enzymes remains to be established. It is becoming increasingly apparent that glycyl radical enzymes are more prevalent than previously surmised. They represent a class of enzymes with unusual biochemistry and probably predate the appearance of molecular oxygen.