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A cis-regulatory genetic element which targets gene expression to stem cells, termed stem cell enhancer, serves as a molecular handle for stem cell-specific genetic engineering. Here we show the generation and characterization of a tamoxifen-inducible CreER

The 4C Mortality Score (4C Score) was designed to risk stratify hospitalised patients with COVID-19. We assessed inclusion of 4C Score in COVID-19 management guidance and its documentation in patients’ case notes in January 2021 in UK hospitals. 4C Score was included within guidance by 50% of sites, though score documentation in case notes was highly variable. Higher documentation of 4C Score was associated with score integration within admissions proformas, inclusion of 4C Score variables or link to online calculator, and management decisions. Integration of 4C Score within clinical pathways may encourage more widespread use.

SummaryA cis-regulatory genetic element which targets gene expression to stem cells, termed stem cell enhancer, serves as a molecular handle for stem cell-specific genetic engineering. Here we show the generation and characterization of a tamoxifen-inducible CreERT2 transgenic (Tg) mouse employing previously identified hematopoietic stem cell (HSC) enhancer for Runx1, eR1 (+24m). Kinetic analysis of labeled cells after tamoxifen injection and transplantation assays revealed that eR1-driven CreERT2 activity marks dormant adult HSCs which slowly but steadily contribute to unperturbed hematopoiesis. Fetal and child HSCs which are uniformly or intermediately active were also efficiently targeted. Notably, a gene ablation at distinct developmental stages, enabled by this system, resulted in different phenotypes. Similarly, an oncogenic Kras induction at distinct ages caused different spectrums of malignant diseases. These results demonstrate that the eR1-CreERT2 Tg mouse serves as a powerful resource for the analyses of both normal and malignant HSCs at all developmental stages.

We perform a detailed calculation of the various contributions to the fluctuation conductivity of a granular metal close to its superconducting transition. We find three distinct regions of power law behavior in reduced temperature, $\ensuremath{\eta}=(T\ensuremath{-}{T}_{c})/{T}_{c}$, with crossovers at $\mathrm{\ensuremath{\Gamma}}/{T}_{c}$ and ${E}_{\text{Th}}/{T}_{c}$, where $\mathrm{\ensuremath{\Gamma}}$ is the electron tunneling rate, and ${E}_{\text{Th}}$ is the Thouless energy of a grain. The calculation includes both intergrain and intragrain degrees of freedom. This complete theory of the fluctuation region in granular superconductors is then compared to experimental results from boron-doped nanocrystalline diamond, using the assumption of a constant phase breaking rate ${\ensuremath{\tau}}_{\ensuremath{\phi}}^{\ensuremath{-}1}$. We find a semiquantitative agreement between the theoretical and experimental results only in the case of large phase breaking. We argue that there may be a phase breaking mechanism in granular metals worthy of further experimental and theoretical investigation.

Variation in antibiotic (ATB) use exists between neonatal intensive care units (NICUs) without demonstrated benefit to outcomes tested. Studies show that early-onset sepsis occurs in up to 2% of NICU patients, yet antibiotics (ABX) were started in over 50% of neonates admitted to our NICUs. An internal audit identified variations in prescribing practices and excessive use of ABX. As a result, we introduced ATB stewardship to our NICUs in 2015 to reduce unnecessary usage of these medications.We used standard quality improvement methodology utilizing multiple iterative plan-do-study-act cycles during a 6-year project to test various interventions aimed at using ABX wisely. Specifically, our goals were to reduce ABX on admission (AA), percent of patients who continued on ABX beyond 72 hours of life (AC), and ATB utilization rate in our 3 NICUs by 28% for each metric. Interventions implemented included the development of an ATB stewardship program consisting of a multidisciplinary team that met regularly, creation of tools and guidelines for evaluations of sepsis and ATB use, universal use of the neonatal early-onset sepsis calculator for all newborns 34 weeks and older gestational age, education regarding noninitiation of ABX for maternal indications in clinically well newborns, and discontinuation within 48 hours for asymptomatic newborns with negative blood cultures.AA, AC, and ATB utilization rate decreased by 34.1%, 45.3%, and 34.9%, respectively, in our 3 NICUs.By introducing ATB stewardship in our NICUs, we exceeded our predetermined goal of significantly reducing ATB usage.

The Wnt signaling ligand WNT5B is implicated in various developmental pathways, both in normal and pathological physiology. Most of the research on WNT5B has been associated with expression analysis and disease states, leaving the signaling pathways underexplored. Here, we review the current understandings of WNT5B's regulation of signal transduction, from receptors to downstream mediators and transcription factors. We also describe its roles in β-catenin-dependent and β-catenin-independent (Planar Cell Polarity and Wnt/Ca2+) Wnt signaling.

Efforts to assess risks to the financial system associated with climate change are growing. These commonly combine the use of integrated assessment models to obtain possible changes in global mean temperature (GMT) and then use coupled climate models to map those changes onto finer spatial scales to estimate changes in other variables. Other methods use data mined from ‘ensembles of opportunity’ such as the Coupled Model Intercomparison Project (CMIP). Several challenges with current approaches have been identified. Here, we focus on demonstrating the issues inherent in applying global ‘top-down’ climate scenarios to explore financial risks at geographical scales of relevance to financial institutions (e.g. city-scale). We use data mined from the CMIP to determine the degree to which estimates of GMT can be used to estimate changes in the annual extremes of temperature and rainfall, two compound events (heatwaves and drought, and extreme rain and strong winds), and whether the emission scenario provides insights into the change in the 20, 50 and 100 year return values for temperature and rainfall. We show that GMT provides little insight on how acute risks likely material to the financial sector (‘material extremes’) will change at a city-scale. We conclude that ‘top-down’ approaches are likely to be flawed when applied at a granular scale, and that there are risks in employing the approaches used by, for example, the Network of Central Banks and Supervisors for Greening the Financial System. Most fundamental, uncertainty associated with projections of future climate extremes must be propagated through to estimating risk. We strongly encourage a review of existing top-down approaches before they develop into de facto standards and note that existing approaches that use a ‘bottom-up’ strategy (e.g. catastrophe modelling and storylines) are more likely to enable a robust assessment of material risk.

The Large Area Telescope (LAT), the primary instrument for the Fermi Gamma-ray Space Telescope (Fermi) mission, is an imaging, wide field-of-view, high-energy gamma-ray telescope, covering the energy range from 30 MeV to more than 300 GeV. We describe the performance of the instrument at the 10-year milestone. LAT performance remains well within the specifications defined during the planning phase, validating the design choices and supporting the compelling case to extend the duration of the Fermi mission. The details provided here will be useful when designing the next generation of high-energy gamma-ray observatories., 60 pages, 28 figures. Published in ApJS

Hydrophobic latent C-terminal thioesters were converted into thioesters, and were also coupled with cysteine in one-pot reactions, using conditions generally compatible with hydrophobic materials. The reaction conditions (ethanethiol and triethylamine in a mixture of DMF and THF) are compatible with acid-labile protecting groups (Boc/t-Bu) that are standard in Fmoc peptide synthesis.

WNT5B, a member of the WNT family of proteins that is closely related to WNT5A, is required for cell migration, cell proliferation, or cell differentiation in many cell types. WNT5B signals through the non-canonical β-catenin-independent signaling pathway and often functions as an antagonist of canonical WNT signaling. Although WNT5B has a high amino acid identity with WNT5A and is often assumed to have similar activities, WNT5B often exhibits unique expression patterns and functions. Here, we describe the distinct effects and mechanisms of WNT5B on development, bone, adipose tissue, cardiac tissue, the nervous system, the mammary gland, the lung and hematopoietic cells, compared to WNT5A. We also highlight aberrances in non-canonical WNT5B signaling contributing to diseases such as osteoarthritis, osteoporosis, obesity, type 2 diabetes mellitus, neuropathology, and chronic diseases associated with aging, as well as various cancers.

The Probe Of Extreme Multi-Messenger Astrophysics (POEMMA) is designed to accurately observe ultra-high-energy cosmic rays (UHECRs) and cosmic neutrinos from space with sensitivity over the full celestial sky. POEMMA will observe the extensive air showers (EASs) from UHECRs and UHE neutrinos above 20 EeV via air fluorescence. Additionally, POEMMA will observe the Cherenkov signal from upward-moving EASs induced by Earth-interacting tau neutrinos above 20 PeV. The POEMMA spacecraft are designed to quickly re-orientate to follow up transient neutrino sources and obtain unparalleled neutrino flux sensitivity. Developed as a NASA Astrophysics Probe-class mission, POEMMA consists of two identical satellites flying in loose formation in 525 km altitude orbits. Each POEMMA instrument incorporates a wide field-of-view (45$^\circ$) Schmidt telescope with over 6 m$^2$ of collecting area. The hybrid focal surface of each telescope includes a fast (1~$\mu$s) near-ultraviolet camera for EAS fluorescence observations and an ultrafast (10~ns) optical camera for Cherenkov EAS observations. In a 5-year mission, POEMMA will provide measurements that open new multi-messenger windows onto the most energetic events in the universe, enabling the study of new astrophysics and particle physics at these otherwise inaccessible energies., Comment: 66 pages, 53 figures; JCAP accepted version

Osteosarcoma is a rare but deadly pediatric bone cancer. As it stands, there is no targeted therapy available for osteosarcoma. Therefore, patients are left with chemotherapy and surgical resection as their only treatment options. Further, osteosarcoma frequently metastasizes to the lungs and patients with metastatic disease have a dismal overall survival rate of 20% due to the lack of targeted therapy. Therefore, the goal of this study is to understand the role of the WNT5B signaling pathway in osteosarcoma, as it could be a potential therapeutic target. Using RNA sequencing from publicly available data sets and immunohistochemistry on tumor microarrays, we show that WNT5B is overexpressed in a subset of osteosarcoma patients. In these high expressing patients, WNT5B’s overexpression correlates to metastasis and worse overall survival. Due to the significant increase in WNT5B expression between primary tumors and metastasis, we began looking at the stem cell population of osteosarcoma cells. By selecting for the osteosarcoma stem cells using spheroid assays, we show that both protein and mRNA levels of WNT5B are enhanced in the stem cell population compared to the standard adherent cell population. Then, we looked at stemness markers and we show that WNT5B regulates the stemness gene SOX2. We then performed limiting dilution sphere assays to assess the role of WNT5B in sphere forming. We reveal that WNT5B is directly responsible for the sphere forming efficiency, as evidenced by a 50% reduction in spheres formed between 143B control and 143B WNT5B knockdown cells. Additionally, WNT5B drives proliferation and migration of osteosarcoma cancer stem cells as there is significantly decreased sphere size and migratory distance in WNT5B knockdown cells compared to control cells, and there is significantly increased sphere size and migration with the addition of recombinant WNT5B. Through revealing a novel role for WNT5B in osteosarcoma cancer stem cells, we present the WNT5B pathway as a candidate for therapeutically targeting the clinical implications of cancer stem cells, that is, the development of chemoresistance, metastasis and relapse. Citation Format: Rachel S. Perkins, Sarocha Suthon, Gustavo A. Miranda-Carboni, Susan A. Krum. WNT5B in osteosarcoma stem cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3894.

This paper details preliminary photon measurements with the monolithic silicon detector ATLASPix, a pixel detector built and optimized for the CERN experiment ATLAS. The goal of this paper is to determine the promise of pixelated silicon in future space-based gamma-ray experiments. With this goal in mind, radioactive photon sources were used to determine the energy resolution and detector response of ATLASPix; these are novel measurements for ATLASPix, a detector built for a ground-based particle accelerator. As part of this project a new iteration of monolithic Si pixels, named AstroPix, have been created based on ATLASPix, and the eventual goal is to further optimize AstroPix for gamma-ray detection by constructing a prototype Compton telescope. The energy resolution of both the digital and analog output of ATLASPix is the focus of this paper, as it is a critical metric for Compton telescopes. It was found that with the analog output of the detector, the energy resolution of a single pixel was 7.69 ± 0.13% at 5.89 keV and 7.27 ± 1.18% at 30.1 keV, which exceeds the conservative baseline requirements of 10% resolution at 60 keV and is an encouraging start to an optimistic goal of

AMEGO is a combined Compton and pair-production telescope designed to survey the sky from ∼ 200 keV to > 10 GeV. The prototype, known as ComPair, will undergo beam tests in 2021 and a short-duration balloon flight the following year. The ComPair tracker is based on ten layers of 10 cm × 10 cm double-sided silicon detectors read out with a custom front-end based on the IDEAS VATA460 ASIC and a Zynq SoC ARM+FPGA running petalinux. In this contribution, we will discuss detector and ASIC characterization, calibration systems, and the overall design of the ComPair silicon tracker.

BurstCube aims to expand sky coverage in order to detect, localize, and rapidly disseminate information about gamma-ray bursts (GRBs). BurstCube is a ’6U’ CubeSat with an instrument comprised of 4 Cesium Iodide (CsI) scintillators coupled to arrays of Silicon photo-multipliers (SiPMs) and will be sensitive to gamma-rays between 50 keV and 1 MeV. BurstCube will assist current observatories, such as Swift and Fermi, in the detection of GRBs as well as provide astronomical context to gravitational wave (GW) events detected by LIGO, Virgo, and KAGRA. BurstCube is currently in its development phase with a launch readiness date in early 2022.

Lichens contribute significantly to the biodiversity and functioning of many ecosystems. Although lichens are useful air pollution bioindicators and may respond in significant ways to global change, they are studied infrequently under field conditions in chamberless exposure systems. We surveyed corticolous lichens on paper birch (Betula papyrifera) and trembling aspen (Populus tremuloides) after 10 years exposure (1998-2007) to elevated CO

Despite ongoing controversy, several strategic frameworks for defining chemicals of concern (e.g., persistent, bioaccumulative, toxic [PBT]; persistent, mobile, toxic [PMT]; persistent organic pollutant [POP]) share persistence as a key criterion. Persistence should be considered over the entire chemical life cycle from production to disposal, including hazardous waste management. As a case study, we evaluate persistence criteria in hazardous waste regulations in Washington state, USA, illustrate impacts on reported waste, and propose refinements in these criteria. Although Washington state defines persistence based on half-life (>1 y) and specific chemical groups that exceed summed concentration thresholds in waste (i.e., >0.01% halogenated organic compounds [HOCs] and >1.0% polycyclic aromatic hydrocarbons [PAHs]), persistence is typically addressed with HOC and PAH evaluation but seldom with half-life estimation. Notably, persistence is considered (with no specific criteria) in corresponding federal regulations in the United States (Resource Conservation and Recovery Act). Consequently, businesses in Washington state report annual amounts of state hazardous waste (including persistent waste) separately from federal hazardous waste. Total state-only waste, and total state and federal waste combined, nearly doubled (by weight) from 2008 to 2018. For the period 2016 to 2018, persistence criteria captured 17% of state-only waste and 2% of total state and federal waste combined. Two recommendations are proposed to improve persistence criteria in hazardous waste regulations. First, Washington state should consider aligning its half-life criterion with federal and European Union PBT definitions (e.g., 60-120 d) for consistency and provide specific methods for half-life estimation. Second, the state should consider expanding its list of persistent chemical groups (e.g., siloxanes, organometallics) with protective concentration thresholds. Ultimately, to the extent possible, Washington state should strive toward harmonizing persistence in hazardous waste regulations with corresponding criteria in global PBT, PMT, and POP frameworks. Integr Environ Assess Manag 2021;17:455-464. © 2020 SETAC.

Background Hospital professionals must attend to patients’ satisfaction with care. Along with technical quality of care, patients’ personal characteristics may affect that satisfaction, but standard demographics research often overlooks cultural links. Methods We, therefore, asked 58 San Antonio, Texas, inpatients their satisfaction with care and examined responses for attitudes related to ethnic—Mexican-American (MA), Euro-American (EA), or African-American (AA)—and gender cultures. Results Many attitudes occurred widely. Most respondents expected doctors to attend them faithfully, inform them honestly, and pursue their needs and wishes singularly. Most also trusted doctors, and expressed satisfaction with doctors’ generally exemplary character and service ethic. But most respondents also feared hospital treatments, and some expressed dissatisfaction that doctors had inadequately informed them or ignored their wishes. Only rare attitudes distinguished particular ethnic-gender groups. Unlike other groups few EA or AA men expressed dissatisfactions. But some MA and EA women said hospitals use too many caregivers or coordinate care poorly. Furthermore, most AA women expressed no explicit trust in doctors, and most EA women expressed actual distrust of doctors, often doubting their technical competence or altruism. Conclusions These findings suggest a novel perspective: a unique inpatient culture, largely unaffected by ethnic group or gender. Patients interpret their hospital experience through that culture. Hospital professionals might respond with both universal measures (addressing patients’ fears, dissatisfactions, and distrust) and targeted ones (explicitly asking EA and AA men about dissatisfactions, and AA and EA women about distrust). Such culturally grounded measures may help maintain or increase inpatients’ satisfaction.

Hematopoietic ontogeny consists of two broad programs: an initial hematopoietic stem cell (HSC)-independent program arising from the yolk sac followed by HSC-dependent hematopoiesis arising from intra-embryonic arteries. While HSC-independent erythro-myeloid (EMP) progenitors and rare lymphoid progenitors, as well as HSCs, sequentially seed the fetal liver and generate blood cells, the transition from HSC-independent to HSC-derived hematopoiesis remains poorly characterized. To help resolve this question, we developed Mds1CreER mice, which inducibly express Cre-recombinase specifically in HSCs. Our lineage tracing studies indicate that HSC-derived progeny significantly expand in the liver between E14.5-E16.5. Additionally, we find that HSCs contribute the majority of F4/80+ macrophages in adult spleen and marrow, in contrast to their limited contribution to macrophage populations in brain, liver and lungs. The Mds1CreER mouse model will be useful to deconvolute the complexity of hematopoiesis as it unfolds in the embryo and functions postnatally.

This chapter looks at the impact artificial water provision has had upon the sustainable management of both livestock and wildlife populations in the semi-arid savannahs of Botswana. It takes a holistic cross sectoral view as to the role boreholes have historically played in livestock and wildlife management and how their use needs to be adapted to effectively address climate change. As such it frames the UN’s Sustainable Development Goal (SDG) 15 ‘Life on Land’ fully within SDG 13 ‘Climate Action’ so as to ensure sustainable natural resource management. With Southern Africa savannahs, and those in Botswana in particular, becoming drier and hotter and more prone to droughts and wildfire, particular emphasis is placed upon the need to increase the mobility of both domestic and wild ungulates in order to compensate for the increased spatial and temporal variability in available forage. The chapter emphasises how ‘shared’ landscapes in which rural populations benefit from both domestic stock and wildlife populations are likely to be increasingly important in combatting climate change and reducing human wildlife conflict. The importance of traditional modes of livestock keeping and the wealth of indigenous traditional knowledge (ITK) that exists in rural communities are also emphasised. Case studies are drawn from the Kalahari, Makgadikgadi and Northern ecosystems, to illustrate how sustainable development can be achieved if existing management tools, such as artificial water points (AWPs,) are applied strategically at the appropriate spatial and temporal scale. Reference to the past reveals the importance of a ‘drought corridor’ that enabled mammals and other wildlife to adapt to past episodes of climate change in Africa, which in a modern day context would link the KALAhari to the RIft VAlley (KALARIVA) via a Trans Frontier Conservation Landscape (TFCL). AWPs are regarded as a key management measure that should be used this Century to facilitate the necessary range shifts of key ungulate species along the drought corridor, and also ensure their seasonal and drought related movements are optimised to utilise available forage and minimise die-offs. As such the opportunities presented by a deteriorating climate are emphasised together with Botswana’s potential to lead the way in Southern Africa through implementation of its existing Policies and its leading role in the conservation of free ranging ungulates.

Background Hemophagocytic lymphohistiocytosis (HLH) is a rare and life-threatening disease. It is characterized by impaired natural killer cell and cytotoxic lymphocyte function leading to dysregulated macrophage phagocytosis of erythrocytes, leukocytes and platelets. Coupled with a massive release of cytokines this rapidly leads to multi-organ failure and mortality if not treated promptly. Case presentation We report a case of pregnancy-associated, treatment-resistant HLH with no identified risk factors. Conclusion It is likely that HLH is an unrecognized cause of intractable fever and disseminated intravascular coagulation (DIC) in young pregnant women and it should be included in the differential diagnosis when patients do not respond to typical therapies. High serum ferritin should further prompt consideration of this diagnosis. This rare disease is often not thought of and many gynecologist obstetricians have never heard of it, making this case report of essential importance to reignite the interest in HLH, particularly when it occurs during pregnancy.

A molecular-level mechanism of alkali induced konjac glucomannan (KGM) hydrogel gelation processing is considered with the application of nuclear magnetic resonance (NMR) spectroscopy and atomic force microscopy (AFM) as complementary methods to diffusive wave spectroscopy (DWS) microrheology and thermoanalysis. It is shown that deacetylation of KGM chains occurs immediately upon mixing with Na2CO3, inducing self-packaging. Partial unfolding of the packed loose structure of dehydrated KGM is observed upon heating. The configuration transition from random coils to self-assembling filament networks takes place before KGM aggregating to form large irreversible bundles with a lower degree of cross-linking. The gelation is not fulfilled until the temperature is increased to above 70 °C when the significant agglomeration is initiated among transitional fibrils to form junction zones essentially composed of acetyl-free portions. This suggests the intermolecular aggregation of KGM chains not simply regarding to hydrogen bonds, but essentially relating to hydrophobic interactions.

Inv(3q26) and t(3:3)(q21;q26) are specific to poor-prognosis myeloid malignancies, and result in marked overexpression of EVI1, a zinc-finger transcription factor and myeloid-specific oncoprotein. Despite extensive study, the mechanism by which EVI1 contributes to myeloid malignancy remains unclear. Here we describe a new mouse model that mimics the transcriptional effects of 3q26 rearrangement. We show that EVI1 overexpression causes global distortion of hematopoiesis, with suppression of erythropoiesis and lymphopoiesis, and marked premalignant expansion of myelopoiesis that eventually results in leukemic transformation. We show that myeloid skewing is dependent on DNA binding by EVI1, which upregulates Spi1, encoding master myeloid regulator PU.1. We show that EVI1 binds to the −14 kb upstream regulatory element (−14kbURE) at Spi1; knockdown of Spi1 dampens the myeloid skewing. Furthermore, deletion of the −14kbURE at Spi1 abrogates the effects of EVI1 on hematopoietic stem cells. These findings support a novel mechanism of leukemogenesis through EVI1 overexpression., Chr3q26 rearrangements cause overexpression of EVI1 and associate with myeloid neoplasms, but the mechanism behind this association is unclear. Here, using a novel mouse model they show that EVI1 causes premalignant myeloid expansion with suppression of other lineages through upregulation of Spi1/PU.1.

Following an extensive contact tracing exercise at a school in a London borough with one of highest tuberculosis (TB) rates in England, we estimated the background prevalence of latent TB infection to be significantly less than the widely accepted 10%. We screened 271 pupils aged 14–15 years in two groups: 96 pupils in group 1 had significant exposure (>8 h/week in the same room) to a case of infectious TB and 175 in group 2 who had minimal exposure. In group 1, 26% were diagnosed with latent or active TB, compared to 6.3% in group 2. Risk factors for TB infection (e.g. previous exposure or link to high-prevalence communities) were analysed using a cohort study design. In the univariable analysis only being in contact group 1 was statistically significantly associated with being a case (OR 5.25, 95%,P< 0.001). In the multivariable model contact group 1 remained significantly associated with being a case (adjusted OR 4.40,P= 0.001). We concluded that the 6.3% yield of TB infection in contact group 2 is either similar to or higher than the background prevalence rate of latent TB infection (LTBI) in this high TB prevalence London borough. Other parts of England with lower TB prevalence are likely to have even lower LTBI rates.

In the adult mammalian forebrain, oligodendrocyte precursor cells (OPCs), also known as NG2 glia are distributed ubiquitously throughout the gray and white matter. They remain proliferative and continuously generate myelinating oligodendrocytes throughout life. In response to a demyelinating insult, OPCs proliferate rapidly and differentiate into oligodendrocytes which contribute to myelin repair. In addition to OPCs, neural stem cells (NSCs) in the subventricular zone (SVZ) also contribute to remyelinating oligodendrocytes, particularly in demyelinated lesions in the vicinity of the SVZ, such as the corpus callosum. To determine the relative contribution of local OPCs and NSC-derived cells toward myelin repair, we performed genetic fate mapping of OPCs and NSCs and compared their ability to generate oligodendrocytes after acute demyelination in the corpus callosum created by local injection of &alpha, lysophosphatidylcholine (LPC). We have found that local OPCs responded rapidly to acute demyelination, expanded in the lesion within seven days, and produced oligodendrocytes by two weeks after lesioning. By contrast, NSC-derived NG2 cells did not significantly increase in the lesion until four weeks after demyelination and generated fewer oligodendrocytes than parenchymal OPCs. These observations suggest that local OPCs could function as the primary responders to repair acutely demyelinated lesion, and that NSCs in the SVZ contribute to repopulating OPCs following their depletion due to oligodendrocyte differentiation.

Vegetation data collected around 8 piospheres in the southern Kalahari of Botswana show livestock impacts on vegetation cover and composition to be of limited spatial extent around the watering point. Dune crests can become active up to a distance of 1.2 km from the borehole with the latter sitting within an area of bare ground and a spectacular cauldron of active dunes some 50–200 m out. Data from an abandoned borehole show that the bare ground zone or “sacrifice zone” does recover, albeit with forbs and annuals, which serve to stabilise the formerly active dunes. Greater concern over the impact of piospheres lies beyond the sacrifice zone to the effects livestock keeping has had upon the resilience of the Kalahari ecosystem and the creation of large tracts of “empty Savannah”. Livestock expansion has acted to block migratory corridors that link the protected areas and in turn trigger largely reactive wildlife management measures. These include fencing and Artificial Waterpoint Provision in an attempt to redress spiralling human wildlife conflict and the isolation of wild ungulates from historical sources of surface water, particularly in a drought. Successive aerial surveys of Kalahari ungulates show the failure of migratory ungulates such as blue wildebeest and red hartebeest to recover from the drastic die‐offs that occurred in the 1980s drought. The need to manage the Kalahari ecosystem as a whole to ensure coexistence between domestic and wild ungulate populations and a greater diversity of livelihood opportunities to the benefit of impoverished rural communities is emphasised.

Summary Background Rheumatic heart disease (RHD) is a major public health problem in low– and middle–income countries (LMICs), with a paucity of high–quality trial data to improve patient outcomes. Investigators felt that involvement in a recent large, observational RHD study impacted positively on their practice, but this was poorly defined. Aim The purpose of this study was to document the experience of investigators and research team members from LMICs who participated in a prospective, multi–centre study, the global Rheumatic Heart Disease Registry (REMEDY), conducted in 25 centres in 14 countries from 2010 to 2012. Methods We conducted an online survey of site personnel to identify and quantify their experiences. Telephone interviews were conducted with a subset of respondents to gather additional qualitative data. We asked about their experiences, positive and negative, and about any changes in RHD management practices resulting from their participation in REMEDY as a registry site. Results The majority of respondents in both the survey and telephone interviews indicated that participation as a registry site improved their management of RHD patients. Administrative changes included increased attention to follow–up appointments and details in patient records. Clinical changes included increased use of penicillin prophylaxis, and more frequent INR monitoring and contraceptive counselling. Conclusions Our study demonstrates that participation in clinical research on RHD can have a positive impact on patient management. Furthermore, REMEDY has led to increased patient awareness and improved healthcare workers’ knowledge and efficiency in caring for RHD patients.

Introduction The majority of publications regarding breast cancer GEPTs rarely supply detailed breast tumor histopathology in their outcome studies. As a result, the cost effective role of clinical risk assessment with histopathology of breast carcinomas tends to be minimized. The aims of this study are to characterize the details of breast tumor histopathology of patients with Oncotype Dx Recurrence Scores (RS) of 10 or less, and determine if Oncotype Dx offers value and clinical utility for patients with these low grade tumors Methods A total of 459 patients (18%) with Oncotype Dx RS of 10 or less were retrieved from a registry of 2558 patients with Oncotype Dx results. Patients had five years of follow-up with tumor registry and were treated with endocrine therapy alone. Tissue slides were available to review on 441/459 patients. Recorded details included (1) histopathologic type of carcinoma (2) mitotic score (MS), tubule formation, nuclear pleomorphism and Notttingham histologc (NG) grade. (3) Estrogen (ER) and progesterone (PgR) semiquantitated by Allred Score and Histologic Score (H Score: strong 200-300, moderate 100-199, weak Results Patient ages were 33-92, with mean/median age of 60, and all had endocrine therapy alone. 148 of 441(34%) patients had carcinomas of “special types”, notable for low grade/good prognosis including tubular 22(15%), cribriform 15 (10.1%), papillary 17 (11.5%), and mucinous 28 (21%), along with 63 (42.5%) low grade classic lobular carcinomas and 3 (2%) low grade mixed ductal and lobular carcinomas. All 148 tumors had a MS of 1, were NG1 and had high ER HScores (280 median/263 mean) (Allred Scores 7-8) and high PR HScores (210 median/201 mean) (Allred Scores 6-8). The remaining 293 tumors were ductal carcinomas of no special type (NST), and 261/293 (89%) of these had a MS of 1/NG2. Of the remaining cases, 10 (3%) had a MS of 2/NG2, 18 (6%) had MS of 2/NG3 and four (1%) were MS3/NG3. Estrogen receptor H Score/Allred Score was strong (Allred Score 7-8) in 395/441 (89.6%), moderate in 45 (10.2%) and weak in 1 patient (0.2%). Progesterone HScores were strong in (Allred Score 6-8) 269/441 (76%) and moderate in the remainder. Strong and moderate ER comprised 99.8% of tumors. Thus, tumors with MS1, and NG1, all with ER HScore >200 (Allred Score of 7-8) were enriched in the RS At 5 years, 433 patients (98%) were alive, 8 were dead, 1 from breast cancer due to distant recurrence. The 5-year breast cancer specific survival for this group was 99.7%. [95%CI 98.5-99.9.] 87 cases were accrued in the ongoing prospective study to date. There were 15/87 (17%) cases, 95% of which were correctly identified by pathologists as having an RS 22. Conclusions Pathologists can identify these low risk tumors with high accuracy. Oncotype Dx lacks clinical value and utility in this setting. Citation Format: Dabbs DJ, Serdy K, Onisko A, Clark BZ, Bhargava R, Smalley S, Perkins S, Brufsky AM. The clinical utility of oncotype Dx for patients with recurrence scores of 10 or less: A value based pathology study of tumor histopathology and outcomes analysis in an integrated delivery and finance health system [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P4-08-04.

The reaction of mer-[RuCl3(S-TMSO)2(O-TMSO)] (TMSO = tetramethylene sulfoxide) with azoles (pyrazole = pzH and 3,5-dimethylpyrazole = dmpzH) in dichloromethane produced the complexes mer-[RuCl3(S-TMSO)(pzH)2] 1, mer-[RuCl3(S-TMSO)(O-TMSO)(pzH)] 2, mer-[RuCl3(S-TMSO)(dmpzH)2] 3, and mer-[RuCl3(S-TMSO)(O-TMSO)(dmpzH)] 4. These complexes were characterized using analytical, spectroscopic, and electrochemical techniques, as well as single-crystal X-ray diffraction analysis. Cytotoxicity assays on NB-Nu-39, a human neuroblastoma cell line, revealed that compounds 3 and 4, bearing methyl groups at the 3- and 5-positions of the pyrazole ring, exhibited significant cytotoxic activity towards neuroblastoma cells with IC50 values of 14.5 μM and 12.9 μM, respectively. The IC50 value of NAMI-A was 12.4 μM, which is very close to that of 4. In contrast, compounds 1 and 2 exhibited no appreciable cytotoxic activity towards neuroblastoma cells (IC50 ≫ 100 μM). The lipophilicity of complexes 1–4 was measured by the shake-flask method to obtain the partition coefficient. These studies reveal that lipophilicity may be a determining factor in the anticancer activity and pharmacological behavior of these Ru(III) complexes.

Emplacement of highways and railroads has altered natural hydrologic systems by influencing surface-water flow paths and biotic communities in Mojave National Preserve. Infiltration experiments were conducted along active and abandoned channels to evaluate changes in hydrology and related effects on plant water availability and use. Simulated rainfall infiltration experiments with vegetation monitoring were conducted along an active channel upslope and a comparable abandoned channel downslope of the transportation corridor. We also conducted 90 single-ring, ponded infiltration experiments in adjacent channels to evaluate field-saturated hydraulic conductivity and particle size distributions. The abandoned channels are still morphologically evident but are disconnected from runoff sources at higher elevations. Infiltration test results show that water infiltrates twice as fast in the active channels. Excavation showed weak soil development with fewer plant roots beneath the abandoned channel. Scanning electron microscopy of surface samples showed the presence of cyanobacteria only in abandoned channels. Plants up to 3 m away from both channels showed physiological responses to channel water applied in a simulated pulse of rain. The response was short lived and less pronounced for plants adjacent to the abandoned channel, whereas those adjacent to the active channel showed responses up to 2 mo after the pulse. These responses may explain observed lower plant densities and fewer deep-rooted species along abandoned channels compared with active channels. We infer that the deeper rooting plants are more abundant where they are able to take advantage of the increased soil-water storage resulting from greater infiltration and flow frequency in active stream channels.

The ontogeny of the hematopoietic system consists of two broad programs. The first, an HSC-independent program, consists of overlapping waves of primitive, erythro-myeloid (EMP), and some lymphoid progenitors. HSC-independent hematopoiesis is required for normal fetal development, and provides self-renewing tissue-resident macrophage populations that persist in the adult. This is followed by the emergence of an HSC-dependent program that arises from arterial vessels within the body of the embryo. The overlapping emergence and lineage output of HSC-independent and HSC-derived hematopoiesis raises important questions regarding the identity and potential functional differences of their mature progeny. However, the transition from HSC-independent to HSC-derived hematopoiesis in the murine fetus remains incompletely characterized, particularly since the maturing erythroid, megakaryocytic and myeloid progeny of EMP and HSCs are currently not easily distinguishable. Additionally, lineage-tracing approaches have been challenging because they have relied largely on the temporal induction of promoters that are expressed both in HSC-independent progenitors and in HSCs, which have significant temporal overlap in their developmental emergence and result in incomplete or in mixed labeling. To help resolve this question, we have developed Mds1 CreERT2 mice, utilizing the first transcription start site of MECOM gene, which is expressed in HSC and emerging HSC (Yuasa et al., 2005 EMBO; Hou et al. 2020 Cell Research; Zhu et al. 2020, Blood). When mated with Rosa-YFP reporter mice and induced at E9.5 with tamoxifen, this construct lineage-traces pre-HSCs present in the E11.5 AGM region, as well as HSCs in the fetal liver and adult marrow. Importantly, no labeling of primitive erythroid cells, primitive macrophage-derived microglia, EMP, or EMP-derived cells in the E11.5 or E12.5 fetal liver was detected with tamoxifen induction at either E9.5 or E8.5. Analysis of E9.5 tamoxifen-treated Mds1 CreERT2Rosa26 LSL-YFP embryos indicates that HSCs have begun to generate small numbers of differentiating erythroid, myeloid and lymphoid progeny in the liver between E12.5 and E14.5. By E16.5, a significant proportion of differentiating erythroid, myeloid and B-cell lineage cells in the liver are HSC-derived, and HSCs have now begun to contribute erythroid and myeloid cells to the rapidly expanding pool of circulating blood cells. In the adult, we found increasing contributions of HSCs to macrophages in liver, lung and kidney. Interestingly, the majority of F4/80+ cells in the adult bone marrow and spleen were also lineage-traced in these mice. Thus, HSCs ultimately provide the majority of adult marrow macrophages that go on to self-maintain in the adult marrow (Hashimoto et al., 2013, Immunity). The Mds1 CreERT2 mouse model will serve as a useful to deconvolute the complexity of hematopoiesis as it unfolds in the embryo and functions postnatally. Disclosures Palis: Rubius Therapeutics: Consultancy.