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Stemming biodiversity loss requires greater investment in conservation and more efficient use of available resources. Prioritizing conservation actions that yield the most biodiversity benefit for the least cost can help maximize return on investment. Actions that have co‐benefits for other objectives, such as climate change mitigation, can also help mobilize additional funds for conservation. We used Priority Threat Management to identify actions to secure the greatest number of species groups of conservation concern for the least cost in the Lake Simcoe‐Rideau ecoregion, Ontario—one of Canada's biodiversity crisis ecoregions. We also estimated the carbon sequestration benefits of actions related to land protection and restoration. We found that without additional investment in conservation, 13 of 16 species groups were expected to have <50% probability of persistence in this ecoregion by 2050. Implementing all proposed strategies would yield the greatest biodiversity benefits and secure 12 of the 16 species groups with ≥60% probability of persistence, at a cost of CA $113 million per year over 27 years. In comparison, investing CA$ 97 million per year in landowner stewardship, habitat protection and restoration and regeneration strategies could secure 10 species groups and improve the probability of persistence of one additional group from 39% to 55%. The habitat protection and restoration strategies also deliver direct carbon benefits of around 11.2 Mt in total avoided CO2 emissions and 137.6 Mt CO2 in total potential sequestration, respectively, over the long‐term, thus supporting alignment with climate change mitigation targets and delivering co‐benefits that may further justify investment. Practical implication. By estimating the costs and demonstrating the expected benefits and potential carbon co‐benefits of conservation actions, Priority Threat Management can help maximize return on investment and identify actions that address multiple environmental crises. We worked with a diverse group of local experts to identify cost‐effective and complementary management strategies that could help secure the persistence of species of conservation concern for the least cost in the Lake Simcoe‐Rideau ecoregion of Southern Ontario. We found that without additional investment in conservation, 130 out of 133 species of conservation concern in the region could be lost by 2050. Investing up to $113 million more per year on strategies informed by local experts can help reverse this outcome, securing up to 100 species while also delivering significant co‐benefits for climate change mitigation objectives.

I am a 63-year-old, widowed since 1972. I was once married (white man, because of that I am not allowed to live on the reserve). I don't remember ever getting so-called freebies. I have been wearing glasses since I was 40 years old and in all that time I never got free frames. A mere $0 is paid by Indian Affairs.

Metabolic dysfunction-associated steatotic liver disease (MASLD, formerly known as non-alcoholic fatty liver disease) is a leading cause of chronic liver disease worldwide. MASLD can progress to metabolic dysfunction-associated steatohepatitis (MASH, formerly known as non-alcoholic steatohepatitis) with subsequent liver cirrhosis and hepatocellular carcinoma formation. The advent of current technologies such as single-cell and single-nuclei RNA sequencing have transformed our understanding of the liver in homeostasis and disease. The next frontier is contextualizing this single-cell information in its native spatial orientation. This understanding will markedly accelerate discovery science in hepatology, resulting in a further step-change in our knowledge of liver biology and pathobiology. In this Review, we discuss up-to-date knowledge of MASLD development and progression and how the burgeoning field of spatial genomics is driving exciting new developments in our understanding of human liver disease pathogenesis and therapeutic target identification. This Perspective discusses single-cell and single-nuclei RNA sequencing in metabolic dysfunction-associated steatotic liver disease and explains how our understanding of the pathology of the disease will accelerate following the advances in spatial transcriptomics.

Background In the last decade, the importance of DNA methylation in the functioning of the central nervous system has been highlighted through associations between methylation changes and differential expression of key genes involved in aging and neurodegenerative diseases. In frontotemporal lobar degeneration (FTLD), aberrant methylation has been reported in causal disease genes including GRN and C9orf72 ; however, the genome-wide contribution of epigenetic changes to the development of FTLD remains largely unexplored. Methods We performed reduced representation bisulfite sequencing of matched pairs of post-mortem tissue from frontal cortex (FCX) and cerebellum (CER) from pathologically confirmed FTLD patients with TDP-43 pathology (FTLD-TDP) further divided into five subtypes and including both sporadic and genetic forms ( N  = 25 pairs per group), and neuropathologically normal controls ( N  = 42 pairs). Case-control differential methylation analyses were performed, both at the individual CpG level, and in regions of grouped CpGs (differentially methylated regions; DMRs), either including all genomic locations or only gene promoters. Gene Ontology (GO) analyses were then performed using all differentially methylated genes in each group of sporadic patients. Finally, additional datasets were queried to prioritize candidate genes for follow-up. Results Using the largest FTLD-TDP DNA methylation dataset generated to date, we identified thousands of differentially methylated CpGs (FCX = 6,520; CER = 7,134) and several hundred DMRs in FTLD-TDP brains (FCX = 134; CER = 219). Of these, less than 10% are shared between pathological subgroups. Combining additional datasets, we identified, validated and replicated hypomethylation of CAMTA1 in TDP-A potentially also impacting additional genes in the locus. GO analysis further implicated DNA methylation in myelination and developmental processes, as well as important disease-relevant mechanisms with subtype specificity such as protein phosphorylation and DNA damage repair in TDP-A, cholesterol biosynthesis in TDP-B, and protein localization in TDP-C. Conclusions We identify methylation changes in all FTLD-TDP patient groups and show that most changes are unique to a specific pathological FTLD-TDP subtype, suggesting that these subtypes not only have distinct transcriptomic and genetic signatures, but are also epigenetically distinct. Our study constitutes an invaluable resource to the community and highlights the need for further studies to profile additional epigenetic layers within each FTLD-TDP pathological subtype.

 Laboratory turnaround times (TAT) influence length of stay for emergency department (ED) patients. We studied biochemistry TATs around the implementation of a plasma separating tube (PST) that omitted a 20-minute clotting step in processing when compared to the standard serum separating tubes (SST).  We compared laboratory TATs using PST vs SST in a prospective before-and-after study with a washout period. TATs for creatinine, urea, electrolytes, troponin, and N-terminal pro b-type natriuretic peptide (NT-proBNP), as well as hemolysis rates, were collected for all ED patients. Results were excluded if the TAT was four minutes or less (data entry error). We recorded the 90 percentile response times (TAT90; the time for 90% of the tests to be completed). Statistical analysis used survival analyses, Mann-Whitney U tests, and Chi-square tests of independence.  SST and PST groups were matched for days of the week, critical values, or hemolysis. There was a statistically significant reduction in median TAT and proportion completed by 60 minutes. However, the effect size was only two to four minutes in the In-Lab-TAT90 with the PST tubes for all tests, except B-type natriuretic peptide (BNP).  Reducing the machine processing time for stat blood work with PST tubes did not produce a clinically meaningful reduction of TAT. Clinically important improvement for Lab TAT requires process analysis and intervention that is inclusive of the entire system. Fractile response times at a 90 percentile for TAT within 60 minutes may be an accurate benchmark for analysis.

The liver has a unique ability to regenerate however in the setting of acute liver failure (ALF) this regenerative capacity is often overwhelmed and emergency liver transplantation is the only curative option. To advance our understanding of human liver regeneration and to inform design of pro-regenerative therapies, we use paired single-nuclei RNA sequencing (snRNAseq)combined with spatial profiling of healthy and ALF explant human livers to generate the first single-cell, pan-lineage atlas of human liver regeneration. We uncover a novel ANXA2+ migratory hepatocyte subpopulation which emerges during human liver regeneration, and a corollary migratory hepatocyte subpopulation in a mouse model of acetaminophen (APAP)-induced liver regeneration. Importantly, interrogation of necrotic wound closure and hepatocyte proliferation across multiple timepoints following APAP-induced liver injury in mice demonstrates that wound closure precedes hepatocyte proliferation. 4-D intravital imaging of APAP-induced mouse liver injury identifies motile hepatocytes at the edge of the necrotic area, enabling collective migration of the hepatocyte sheet to effect wound closure. Depletion of hepatocyte ANXA2 expression reduces HGF-induced human and mouse hepatocyte migration in vitro, and abrogates necrotic wound closure following APAP-induced mouse liver injury. Taken together, our work dissects unanticipated aspects of liver regeneration, demonstrating an uncoupling of wound closure and hepatocyte proliferation and uncovering a novel migratory hepatocyte subpopulation which mediates wound closure following liver injury. Therapies designed to promote rapid reconstitution of normal hepatic microarchitecture and reparation of the gut-liver barrier may open up new areas of therapeutic discovery in regenerative medicine.Competing Interest StatementN.C.H. has received research funding from AbbVie, Pfizer, Gilead, Boehringer-Ingelheim and Galecto, and is an advisor or consultant for Astra-Zeneca, Galecto, GSK, MSD, Pliant Therapeutics, Ambys Medicines, Mediar Therapeutics and Q32 Bio.Footnotes* https://figshare.com/articles/media/Multimodal_decoding_of_human_liver_regeneration/22100333

Currently there are no effective antifibrotic therapies for liver cirrhosis, a major killer worldwide. To obtain a cellular resolution of directly-relevant pathogenesis and to inform therapeutic design, we profile the transcriptomes of over 100,000 primary human single cells, yielding molecular definitions for the major non-parenchymal cell types present in healthy and cirrhotic human liver. We uncover a novel scar-associated TREM2+CD9+ macrophage subpopulation with a fibrogenic phenotype, that has a distinct differentiation trajectory from circulating monocytes. In the endothelial compartment, we show that newly-defined ACKR1+ and PLVAP+ endothelial cells expand in cirrhosis and are topographically located in the fibrotic septae. Multi-lineage ligand-receptor modelling of specific interactions between the novel scar-associated macrophages, endothelial cells and collagen-producing myofibroblasts in the fibrotic niche, reveals intra-scar activity of several major pathways which promote hepatic fibrosis. Our work dissects unanticipated aspects of the cellular and molecular basis of human organ fibrosis at a single-cell level, and provides the conceptual framework required to discover rational therapeutic targets in liver cirrhosis.