Chk1 Haploinsufficiency Results in Anemia and Defective Erythropoiesis

Erythropoiesis is a highly regulated and well-characterized developmental process responsible for providing the oxygen transport system of the body. However, few of the mechanisms involved in this process have been elucidated. Checkpoint Kinase 1 (Chk1) is best known for its role in the cell cycle and DNA damage pathways, and it has been shown to play a part in several pathways which when disrupted can lead to anemia.Here, we show that haploinsufficiency of Chk1 results in 30% of mice developing anemia within the first year of life. The anemic Chk1+/- mice exhibit distorted spleen and bone marrow architecture, and abnormal erythroid progenitors. Furthermore, Chk1+/- erythroid progenitors exhibit an increase in spontaneous DNA damage foci and improper contractile actin ring formation resulting in aberrant enucleation during erythropoiesis. A decrease in Chk1 RNA has also been observed in patients with refractory anemia with excess blasts, further supporting a role for Chk1 in clinical anemia.Clinical trials of Chk1 inhibitors are currently underway to treat cancer, and thus it will be important to track the effects of these drugs on red blood cell development over an extended period. Our results support a role for Chk1 in maintaining the balance between erythroid progenitors and enucleated erythroid cells during differentiation. We show disruptions in Chk1 levels can lead to anemia

Evidence for Diversity in Transcriptional Profiles of Single Hematopoietic Stem Cells

Hematopoietic stem cells replenish all the cells of the blood throughout the lifetime of an animal. Although thousands of stem cells reside in the bone marrow, only a few contribute to blood production at any given time. Nothing is known about the differences between individual stem cells that dictate their particular state of activation readiness. To examine such differences between individual stem cells, we determined the global gene expression profile of 12 single stem cells using microarrays. We showed that at least half of the genetic expression variability between 12 single cells profiled was due to biological variation in 44% of the genes analyzed. We also identified specific genes with high biological variance that are candidates for influencing the state of readiness of individual hematopoietic stem cells, and confirmed the variability of a subset of these genes using single-cell real-time PCR. Because apparent variation of some genes is likely due to technical factors, we estimated the degree of biological versus technical variation for each gene using identical RNA samples containing an RNA amount equivalent to that of single cells. This enabled us to identify a large cohort of genes with low technical variability whose expression can be reliably measured on the arrays at the single-cell level. These data have established that gene expression of individual stem cells varies widely, despite extremely high phenotypic homogeneity. Some of this variation is in key regulators of stem cell activity, which could account for the differential responses of particular stem cells to exogenous stimuli. The capacity to accurately interrogate individual cells for global gene expression will facilitate a systems approach to biological processes at a single-cell level

Multiple models guide strategies for agricultural nutrient reductions

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/136504/1/fee1472_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/136504/2/fee1472-sup-0008-WebTable7.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/136504/3/fee1472-sup-0004-WebTable3.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/136504/4/fee1472.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/136504/5/fee1472-sup-0006-WebTable5.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/136504/6/fee1472-sup-0002-WebTable1.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/136504/7/fee1472-sup-0005-WebTable4.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/136504/8/fee1472-sup-0007-WebTable6.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/136504/9/fee1472-sup-0003-WebTable2.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/136504/10/fee1472-sup-0001-WebFig1.pd

Using a Multi-Institutional Ensemble of Watershed Models to Assess Agricultural Conservation Effectiveness in a Future Climate

This study investigates the combined impacts of climate change and agricultural conservation on the magnitude and uncertainty of nutrient loadings in the Maumee River Watershed, the second-largest watershed of the Laurentian Great Lakes. Two scenarios — baseline agricultural management and increased agricultural conservation — were assessed using an ensemble of five Soil and Water Assessment Tools driven by six climate models. The increased conservation scenario included raising conservation adoption rates from a baseline of existing conservation practices to feasible rates in the near future based on farmer surveys. This increased adoption of winter cover crops on 6%–10% to 60% of cultivated cropland; subsurface placement of phosphorus fertilizers on 35%–60% to 68% of cultivated cropland; and buffer strips intercepting runoff from 29%–34% to 50% of cultivated cropland. Increased conservation resulted in statistically significant (p ≤ 0.05) reductions in annual loads of total phosphorus (41%), dissolved reactive phosphorus (18%), and total nitrogen (14%) under the highest emission climate scenario (RCP 8.5). While nutrient loads decreased with increased conservation relative to baseline management for all watershed models, different conclusions on the true effectiveness of conservation under climate change may be drawn if only one watershed model was used.publishedVersio

Hematopoietic Fingerprints: An Expression Database of Stem Cells and Their Progeny

SummaryHematopoietic stem cells (HSCs) continuously regenerate the hematologic system, yet few genes regulating this process have been defined. To identify candidate factors involved in differentiation and self-renewal, we have generated an expression database of hematopoietic stem cells and their differentiated progeny, including erythrocytes, granulocytes, monocytes, NK cells, activated and naive T cells, and B cells. Bioinformatic analysis revealed HSCs were more transcriptionally active than their progeny and shared a common activation mechanism with T cells. Each cell type also displayed unique biases in the regulation of particular genetic pathways, with Wnt signaling particularly enhanced in HSCs. We identified ∼100–400 genes uniquely expressed in each cell type, termed lineage “fingerprints.” In overexpression studies, two of these genes, Zfp105 from the NK cell lineage, and Ets2 from the monocyte lineage, were able to significantly influence differentiation toward their respective lineages, demonstrating the utility of the fingerprints for identifying genes that regulate differentiation

CD81 Is Essential for the Re-entry of Hematopoietic Stem Cells to Quiescence following Stress-Induced Proliferation Via Deactivation of the Akt Pathway

A protein that is thought to orchestrate the distribution of other signaling molecules on the cell membrane, CD81, is critical to maintaining the functional integrity of hematopoietic stem cells during their regeneration

Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised controlled, open-label, platform trial

SummaryBackground Azithromycin has been proposed as a treatment for COVID-19 on the basis of its immunomodulatoryactions. We aimed to evaluate the safety and efficacy of azithromycin in patients admitted to hospital with COVID-19.Methods In this randomised, controlled, open-label, adaptive platform trial (Randomised Evaluation of COVID-19Therapy [RECOVERY]), several possible treatments were compared with usual care in patients admitted to hospitalwith COVID-19 in the UK. The trial is underway at 176 hospitals in the UK. Eligible and consenting patients wererandomly allocated to either usual standard of care alone or usual standard of care plus azithromycin 500 mg once perday by mouth or intravenously for 10 days or until discharge (or allocation to one of the other RECOVERY treatmentgroups). Patients were assigned via web-based simple (unstratified) randomisation with allocation concealment andwere twice as likely to be randomly assigned to usual care than to any of the active treatment groups. Participants andlocal study staff were not masked to the allocated treatment, but all others involved in the trial were masked to theoutcome data during the trial. The primary outcome was 28-day all-cause mortality, assessed in the intention-to-treatpopulation. The trial is registered with ISRCTN, 50189673, and ClinicalTrials.gov, NCT04381936.Findings Between April 7 and Nov 27, 2020, of 16 442 patients enrolled in the RECOVERY trial, 9433 (57%) wereeligible and 7763 were included in the assessment of azithromycin. The mean age of these study participants was65·3 years (SD 15·7) and approximately a third were women (2944 [38%] of 7763). 2582 patients were randomlyallocated to receive azithromycin and 5181 patients were randomly allocated to usual care alone. Overall,561 (22%) patients allocated to azithromycin and 1162 (22%) patients allocated to usual care died within 28 days(rate ratio 0·97, 95% CI 0·87–1·07; p=0·50). No significant difference was seen in duration of hospital stay (median10 days [IQR 5 to >28] vs 11 days [5 to >28]) or the proportion of patients discharged from hospital alive within 28 days(rate ratio 1·04, 95% CI 0·98–1·10; p=0·19). Among those not on invasive mechanical ventilation at baseline, nosignificant difference was seen in the proportion meeting the composite endpoint of invasive mechanical ventilationor death (risk ratio 0·95, 95% CI 0·87–1·03; p=0·24).Interpretation In patients admitted to hospital with COVID-19, azithromycin did not improve survival or otherprespecified clinical outcomes. Azithromycin use in patients admitted to hospital with COVID-19 should be restrictedto patients in whom there is a clear antimicrobial indication

Imprinted genes that regulate early mammalian growth are coexpressed in somatic stem cellsImprinted genes that regulate early mammalian growth are coexpressed in somatic stem cells

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Multiple models guide strategies for agricultural nutrient reductions

For nearly twenty years in the western United States, billions of dollars have been spent to recover anadromous salmon species listed under the federal Endangered Species Act. Broad support and participation from the private and public sectors is needed to address the limiting factors to salmon viability, especially the improvement of stream and watershed health. However, in today’s fiscal and political climate it is more important than ever to demonstrate the multiple ways that conservation work benefits not just the environment but also our economy. This paper examines the employment and economic impacts of watershed restoration expenditures made in Oregon from 2001–2010, making use of multipliers developed by the University of Oregon’s Ecosystem Workforce Program. We collected data on salmon habitat restoration projects from a statewide database system, the Oregon Watershed Restoration Inventory, and grouped project activities according to the University of Oregon restoration employment and economic multiplier categories. To determine the total direct, indirect, and induced economic output and employment resulting from restoration investments, we multiplied the total project investment in each category of restoration work by the relevant multiplier. We then summed the total economic activity by project type to arrive at a total per county and the state. We found that a total of US$411.4 million was invested in 6,740 watershed restoration projects throughout the state of Oregon from 2001 to 2010, resulting in the generation of between$752.4 million and $977.5 million in economic output and 4,628 to 6,483 jobs. The jobs created by restoration activities are located mostly in rural areas, in communities hard hit by the economic downturn. Restoration activities bring a range of employment opportunities for people in construction, engineering, natural resource sciences, and other fields. The job creation potential of restoration activities compared with investments in other sectors of the economy is favorable. Restoration also stimulates demand for the products and services of local businesses such as plant nurseries, heavy equipment companies, and rock and gravel companies. Unlike in other economic sectors, restoration jobs can’t be outsourced to distant locations, so these dollars tend to stay in the local and state economy. Restoration investments also continue to accrue and pay out over time. Long-term improvements in habitat create enduring benefits, from enhanced recreational and fishing opportunities to the provision of critical ecosystem services. These findings are good news to the people of Oregon and there is tremendous opportunity to extend and replicate this work to other regions. Being able to effectively communicate the interdependencies of ecosystems and economies is critical to addressing the immense challenges of the 21st century. As long as we continue to frame trade-offs in simplistic terms like jobs versus the environment, we will be relegated to making incremental change. Whether our aim is the recovery of wild salmon in the Western United States or the abatement of greenhouse gas emissions; alternative models for economic development need to be redoubled. We have found that quantifying and presenting the economic benefits of watershed restoration reframes the conversation and opens doors to new alliances