Snake River Sockeye Salmon Habitat and Limnological Research: 2005 Annual Report.

In March 1990, the Shoshone-Bannock Tribes petitioned the National Marine Fisheries Service (NMFS) to list Snake River sockeye salmon (Oncorhynchus nerka) as endangered. Snake River sockeye salmon were officially listed as endangered in November 1991 under the Endangered Species Act (56 FR 58619). In 1991, the Snake River Sockeye Salmon Habitat and Limnological Research Project was implemented. This project is part of an interagency effort to prevent the extinction of the Redfish Lake stock of Snake River sockeye salmon. The Shoshone-Bannock Tribal goal for this project is two tiered: The immediate goal is to increase the population of Snake River sockeye salmon while preserving the unique genetic characteristics of the Evolutionarily Significant Unit (ESU). The Tribes long term goal is to maintain a viable population that warrants delisting and provides Tribal harvest opportunities. The Bonneville Power Administration (BPA) provides funding for this interagency recovery. Collaborators in the recovery effort include the National Oceanic and Atmospheric Administration (NOAA), the Idaho Department of Fish and Game (IDFG), the University of Idaho (UI), and the Shoshone-Bannock Tribes (SBT). This report summarizes activities conducted by Shoshone-Bannock Tribal Fisheries Department personnel during the 2005 calendar year. Project tasks include: (1) monitor limnological parameters of the Sawtooth Valley lakes to assess lake productivity; (2) conduct lake fertilization in Pettit and Alturas lakes; (3) reduce the number of mature kokanee spawning in Fishhook and Alturas Lake creeks; (4) monitor and enumerate sockeye salmon smolt migration from Pettit and Alturas lakes; (5) monitor spawning kokanee escapement and estimate fry recruitment in Fishhook, Alturas Lake, and Stanley Lake creeks; (6) conduct sockeye and kokanee salmon population surveys; (7) evaluate potential competition and predation between stocked juvenile sockeye salmon and a variety of fish species in Redfish, Pettit, and Alturas lakes; and (8) assist IDFG with captive broodstock production activities

RTOG 0518: Randomized Phase III Trial to Evaluate Zoledronic Acid for Prevention of Osteoporosis and Associated Fractures in Prostate Cancer Patients

Background: RTOG 0518 evaluated the potential benefit of zoledronic acid therapy in preventing bone fractures for patients with high grade and/or locally advanced, non-metastatic prostate adenocarcinoma receiving luteinizing hormone-releasing hormone (LHRH) agonist and radiotherapy (RT). Methods: Eligible patients with T-scores of the hip ( −2.5 vs. > −1.0) and negative bone scans were prospectively randomized to either zoledronic acid, 4 mg, concurrently with the start of RT and then every six months for a total of 6 infusions (Arm 1) or observation (Arm 2). Vitamin D and calcium supplements were given to all patients. Secondary objectives included quality of life (QOL) and bone mineral density (BMD) changes over a period of three years. Results: Of 109 patients accrued before early closure, 96 were eligible. Median follow-up was 36.3 months for Arm I and 34.8 months for Arm 2. Only two patients experienced a bone fracture (1 in each arm) resulting in no difference in freedom from any bone fracture (p=0.95), nor in QOL. BMD percent changes from baseline to 36 months were statistically improved with the use of zoledronic acid compared to observation for the lumbar spine (6% vs. −5%, p<0.0001), left total hip (1% vs. −8%, p=0.0002), and left femoral neck (3% vs. −8%, p=0.0007). Conclusions: For patients with advanced, non-metastatic prostate cancer receiving LHRH agonist and RT, the use of zoledronic acid was associated with statistically improved BMD percent changes. The small number of accrued patients resulted in decreased statistical power to detect any differences in the incidence of bone fractures or QOL

Identification of pre-leukaemic haematopoietic stem cells in acute leukaemia.

In acute myeloid leukaemia (AML), the cell of origin, nature and biological consequences of initiating lesions, and order of subsequent mutations remain poorly understood, as AML is typically diagnosed without observation of a pre-leukaemic phase. Here, highly purified haematopoietic stem cells (HSCs), progenitor and mature cell fractions from the blood of AML patients were found to contain recurrent DNMT3A mutations (DNMT3A(mut)) at high allele frequency, but without coincident NPM1 mutations (NPM1c) present in AML blasts. DNMT3A(mut)-bearing HSCs showed a multilineage repopulation advantage over non-mutated HSCs in xenografts, establishing their identity as pre-leukaemic HSCs. Pre-leukaemic HSCs were found in remission samples, indicating that they survive chemotherapy. Therefore DNMT3A(mut) arises early in AML evolution, probably in HSCs, leading to a clonally expanded pool of pre-leukaemic HSCs from which AML evolves. Our findings provide a paradigm for the detection and treatment of pre-leukaemic clones before the acquisition of additional genetic lesions engenders greater therapeutic resistance

Probing the diabetes and colorectal cancer relationship using gene – environment interaction analyses

BackgroundDiabetes is an established risk factor for colorectal cancer. However, the mechanisms underlying this relationship still require investigation and it is not known if the association is modified by genetic variants. To address these questions, we undertook a genome-wide gene-environment interaction analysis.MethodsWe used data from 3 genetic consortia (CCFR, CORECT, GECCO; 31,318 colorectal cancer cases/41,499 controls) and undertook genome-wide gene-environment interaction analyses with colorectal cancer risk, including interaction tests of genetics(G)xdiabetes (1-degree of freedom; d.f.) and joint testing of Gxdiabetes, G-colorectal cancer association (2-d.f. joint test) and G-diabetes correlation (3-d.f. joint test).ResultsBased on the joint tests, we found that the association of diabetes with colorectal cancer risk is modified by loci on chromosomes 8q24.11 (rs3802177, SLC30A8 - ORAA: 1.62, 95% CI: 1.34-1.96; ORAG: 1.41, 95% CI: 1.30-1.54; ORGG: 1.22, 95% CI: 1.13-1.31; p-value(3-d.f.): 5.46 x 10(-11)) and 13q14.13 (rs9526201, LRCH1 - ORGG: 2.11, 95% CI: 1.56-2.83; ORGA: 1.52, 95% CI: 1.38-1.68; ORAA: 1.13, 95% CI: 1.06-1.21; p-value(2-d.f.): 7.84 x 10(-09)).DiscussionThese results suggest that variation in genes related to insulin signaling (SLC30A8) and immune function (LRCH1) may modify the association of diabetes with colorectal cancer risk and provide novel insights into the biology underlying the diabetes and colorectal cancer relationship

Magnetic fields during the early stages of massive star formation - I. Accretion and disk evolution

We present simulations of collapsing 100 M_\sun mass cores in the context of massive star formation. The effect of variable initial rotational and magnetic energies on the formation of massive stars is studied in detail. We focus on accretion rates and on the question under which conditions massive Keplerian disks can form in the very early evolutionary stage of massive protostars. For this purpose, we perform 12 simulations with different initial conditions extending over a wide range in parameter space. The equations of magnetohydrodynamics (MHD) are solved under the assumption of ideal MHD. We find that the formation of Keplerian disks in the very early stages is suppressed for a mass-to-flux ratio normalised to the critical value \mu below 10, in agreement with a series of low-mass star formation simulations. This is caused by very efficient magnetic braking resulting in a nearly instantaneous removal of angular momentum from the disk. For weak magnetic fields, corresponding to \mu > 10, large-scale, centrifugally supported disks build up with radii exceeding 100 AU. A stability analysis reveals that the disks are supported against gravitationally induced perturbations by the magnetic field and tend to form single stars rather than multiple objects. We find protostellar accretion rates of the order of a few 10^-4 M_\sun yr^-1 which, considering the large range covered by the initial conditions, vary only by a factor of ~ 3 between the different simulations. We attribute this fact to two competing effects of magnetic fields. On the one hand, magnetic braking enhances accretion by removing angular momentum from the disk thus lowering the centrifugal support against gravity. On the other hand, the combined effect of magnetic pressure and magnetic tension counteracts gravity by exerting an outward directed force on the gas in the disk thus reducing the accretion onto the protostars.Comment: 22 pages, 17 figures, accepted for publication in MNRAS, updated to final versio

Diversity of respiratory parameters and metabolic adaptation to low oxygen tension in mesenchymal stromal cells

Objective Cell metabolism has been shown to play an active role in regulation of stemness and fate decision. In order to identify favorable culture conditions for mesenchymal stromal cells (MSCs) prior to transplantation, this study aimed to characterize the metabolic function of MSCs from different developmental stages in response to different oxygen tension during expansion. Materials and methods We cultured human fetal cardiac MSCs and human adult bone-marrow MSCs for a week under hypoxia (3% O2) and normoxia (20% O2). We performed mitochondrial characterization and assessed oxygen consumption- and extracellular acidification-rates (OCR and ECAR) in addition to oxygen-sensitive respiration and mitochondrial complex activities, using both the Seahorse and Oroboros systems. Results Adult and fetal MSCs displayed similar basal respiration and mitochondrial amount, however fetal MSCs had lower spare respiratory capacity and apparent coupling efficiency. Fetal MSCs expanded in either hypoxia or normoxia demonstrated similar acidification rates, while adult MSCs downregulated their aerobic glycolysis in normoxia. Acute decrease in oxygen tension caused a higher respiratory inhibition in adult compared to fetal MSCs. In both sources of MSCs, minor changes in complex activities in normoxic and hypoxic cultures were found. Conclusions In contrast to adult MSCs, fetal MSCs displayed similar respiration and aerobic glycolysis at different O2 culture concentrations during expansion. Adult MSCs adjusted their respiration to glycolytic activities, depending on the culture conditions thus displaying a more mature metabolic function. These findings are relevant for establishing optimal in vitro culturing conditions, with the aim to maximize engraftment and therapeutic outcome.CC BY-NC-ND 4.0Corresponding author: Department of Surgical Sciences, Uppsala University, 751 85, Uppsala, Sweden. E-mail address: [email protected] (K.-H. Grinnemo).Available online 3 February 2022, Version of Record 5 February 2022The project was funded by Karolinska Institute-Mayo Clinic Collaborative Grant 2013; The Swedish Research Council young investigator: 2013–3590; Stockholm county; The Swedish Research Council; The Family Erling-Persson Foundation; ERC-2018-AdG (834860 EYELETS); Uppsala county; Uppsala County Association against Heart and Lung Diseases; and Higher Education of the Russian Federation (agreement no. 075-15-2020-899).</p

A randomised study of rituximab and belimumab sequential therapy in PR3 ANCA-associated vasculitis (COMBIVAS): design of the study protocol

Background: Sequential B cell-targeted immunotherapy with BAFF antagonism (belimumab) and B cell depletion (rituximab) may enhance B cell targeting in ANCA-associated vasculitis (AAV) through several mechanisms. Methods: Study design: COMBIVAS is a randomised, double-blind, placebo-controlled trial designed to assess the mechanistic effects of sequential therapy of belimumab and rituximab in patients with active PR3 AAV. The recruitment target is 30 patients who meet the criteria for inclusion in the per-protocol analysis. Thirty-six participants have been randomised to one of the two treatment groups in a 1:1 ratio: either rituximab plus belimumab or rituximab plus placebo (both groups with the same tapering corticosteroid regimen), and recruitment is now closed (final patient enrolled April 2021). For each patient, the trial will last for 2 years comprising a 12-month treatment period followed by a 12-month follow-up period. Participants: Participants have been recruited from five of seven UK trial sites. Eligibility criteria were age ≥ 18 years and a diagnosis of AAV with active disease (newly diagnosed or relapsing disease), along with a concurrent positive test for PR3 ANCA by ELISA. Interventions: Rituximab 1000 mg was administered by intravenous infusions on day 8 and day 22. Weekly subcutaneous injections of 200 mg belimumab or placebo were initiated a week before rituximab on day 1 and then weekly through to week 51. All participants received a relatively low prednisolone (20 mg/day) starting dose from day 1 followed by a protocol-specified corticosteroid taper aiming for complete cessation by 3 months. Outcomes: The primary endpoint of this study is time to PR3 ANCA negativity. Key secondary outcomes include change from baseline in naïve, transitional, memory, plasmablast B cell subsets (by flow cytometry) in the blood at months 3, 12, 18 and 24; time to clinical remission; time to relapse; and incidence of serious adverse events. Exploratory biomarker assessments include assessment of B cell receptor clonality, B cell and T cell functional assays, whole blood transcriptomic analysis and urinary lymphocyte and proteomic analysis. Inguinal lymph node and nasal mucosal biopsies have been performed on a subgroup of patients at baseline and month 3. Discussion: This experimental medicine study provides a unique opportunity to gain detailed insights into the immunological mechanisms of belimumab-rituximab sequential therapy across multiple body compartments in the setting of AAV. Trial registration: ClinicalTrials.gov NCT03967925. Registered on May 30, 2019

Law and Neuroscience: Recommendations Submitted to the President\u27s Bioethics Commission

President Obama charged the Presidential Commission for the Study of Bioethical Issues to identify a set of core ethical standards in the neuroscience domain, including the appropriate use of neuroscience in the criminal-justice system. The Commission, in turn, called for comments and recommendations. The MacArthur Foundation Research Network on Law and Neuroscience submitted a consensus statement, published here, containing 16 specific recommendations. These are organized within three main themes: 1) what steps should be taken to enhance the capacity of the criminal justice system to make sound decisions regarding the admissibility and weight of neuroscientific evidence?; 2) to what extent can the capacity of neurotechnologies to aid in the administration of criminal justice be enhanced through research?; and 3) in what additional ways might important ethical issues at the intersection of neuroscience and criminal justice be addressed

Law and Neuroscience: Recommendations Submitted to the President\u27s Bioethics Commission

President Obama charged the Presidential Commission for the Study of Bioethical Issues to identify a set of core ethical standards in the neuroscience domain, including the appropriate use of neuroscience in the criminal-justice system. The Commission, in turn, called for comments and recommendations. The MacArthur Foundation Research Network on Law and Neuroscience submitted a consensus statement, published here, containing 16 specific recommendations. These are organized within three main themes: 1) what steps should be taken to enhance the capacity of the criminal justice system to make sound decisions regarding the admissibility and weight of neuroscientific evidence?; 2) to what extent can the capacity of neurotechnologies to aid in the administration of criminal justice be enhanced through research?; and 3) in what additional ways might important ethical issues at the intersection of neuroscience and criminal justice be addressed