RelB acts as a molecular switch to drive chronic inflammation in glioblastoma multiforme (GBM).

Inflammation is a homeostatic response to tissue injury or infection, which is normally short- lived and quickly resolves to limit tissue damage. In contrast, chronic inflammation has been linked to a variety of human diseases, including cancers such as glioblastoma multiforme (GBM). GBMs are very aggressive tumors with very low patient survival rates, which have not improved in several decades. GBM tumors are characterized by necrosis and profound inflammation; with cytokines secreted by both GBM cells and the tumor microenvironment. The mechanisms by which chronic inflammation develops and persists in GBM regardless of multiple anti-inflammatory feedback loops remain elusive. This project identifies a molecular switch which promotes chronic inflammation in GBM, but not primary human astrocytes

Initial B Cell Activation Induces Metabolic Reprogramming and Mitochondrial Remodeling.

B lymphocytes provide adaptive immunity by generating antigen-specific antibodies and supporting the activation of T cells. Little is known about how global metabolism supports naive B cell activation to enable an effective immune response. By coupling RNA sequencing (RNA-seq) data with glucose isotopomer tracing, we show that stimulated B cells increase programs for oxidative phosphorylation (OXPHOS), the tricarboxylic acid (TCA) cycle, and nucleotide biosynthesis, but not glycolysis. Isotopomer tracing uncovered increases in TCA cycle intermediates with almost no contribution from glucose. Instead, glucose mainly supported the biosynthesis of ribonucleotides. Glucose restriction did not affect B cell functions, yet the inhibition of OXPHOS or glutamine restriction markedly impaired B cell growth and differentiation. Increased OXPHOS prompted studies of mitochondrial dynamics, which revealed extensive mitochondria remodeling during activation. Our results show how B cell metabolism adapts with stimulation and reveals unexpected details for carbon utilization and mitochondrial dynamics at the start of a humoral immune response

Masterov Kliuch and the Early Upper Palaeolithic of the Transbaikal, Siberia

In 1996, archaeological excavations were conducted at the Masterov Kliuch site, located east of Lake Baikal, Siberia. Three archaeological components were uncovered, all occurring in colluvial deposits. The two lower components (I and II) are Palaeolithic in age and character. Component I is an early Upper Palaeolithic industry dated to 32,500-30,000 years ago (B.P.), and is in a primary context. Component II is undated but is also assignable to the early Upper Palaeolithic based on typology, although it appears to have been redeposited. Artifact assemblages from these two components are blade-based and include retouched blades and flakes, knives, denticulates, end scrapers, gravers, and burins. Component III represents a Bronze Age occupation dated to around 2900 B.P. The Palaeolithic industries at Masterov Kliuch are technologically/typologically similar to other initial Upper Palaeolithic industries in Siberia, and appear to represent some of the easternmost manifestations of an early Upper Palaeolithic technocomplex that spanned inner Asia from Uzbekistan to the Transbaikal between about 42,000 and 30,000 B.P. Our findings have further implications for Upper Palaeolithic research in northern Asia, especially regarding site formation processes and hunter-gatherer raw material procurement. First, like Masterov Kliuch, most early Upper Palaeolithic sites across northern Asia lie in colluvial settings and may not be in pristine, primary contexts, so that interpretations of stone features such as hearths or dwellings may be suspect. Second, study of the Masterov Kliuch lithic industries indicates that huntergatherers exclusively utilized local lithic resources in the manufacture of tools, and that raw material procurement strategies were embedded within other subsistence pursuits. This pattern of local, embedded raw material procurement is seen in virtually all other early Upper Palaeolithic sites in Siberia, while "logistical," longdistance procurement strategies, characteristic of the early Upper Palaeolithic of western Eurasia, did not appear in Siberia until much later in time, after about 25,000 B.P. KEYWORDS: Siberia, early Upper Palaeolithic, geoarchaeology, lithic technology, raw material procurement

The Annual Economic Survey of Federal Gulf Shrimp Permit Holders: Report on the Design, Implementation, and Descriptive Results for 2006

This technical memorandum documents the design, implementation, data preparation, and descriptive results for the 2006 Annual Economic Survey of Federal Gulf Shrimp Permit Holders. The data collection was designed by the NOAA Fisheries Southeast Fisheries Science Center Social Science Research Group to track the financial and economic status and performance by vessels holding a federal moratorium permit for harvesting shrimp in the Gulf of Mexico. A two page, self-administered mail survey collected total annual costs broken out into seven categories and auxiliary economic data. In May 2007, 580 vessels were randomly selected, stratified by state, from a preliminary population of 1,709 vessels with federal permits to shrimp in offshore waters of the Gulf of Mexico. The survey was implemented during the rest of 2007. After many reminder and verification phone calls, 509 surveys were deemed complete, for an ineligibility-adjusted response rate of 90.7%. The linking of each individual vessel’s cost data to its revenue data from a different data collection was imperfect, and hence the final number of observations used in the analyses is 484. Based on various measures and tests of validity throughout the technical memorandum, the quality of the data is high. The results are presented in a standardized table format, linking vessel characteristics and operations to simple balance sheet, cash flow, and income statements. In the text, results are discussed for the total fleet, the Gulf shrimp fleet, the active Gulf shrimp fleet, and the inactive Gulf shrimp fleet. Additional results for shrimp vessels grouped by state, by vessel characteristics, by landings volume, and by ownership structure are available in the appendices. The general conclusion of this report is that the financial and economic situation is bleak for the average vessels in most of the categories that were evaluated. With few exceptions, cash flow for the average vessel is positive while the net revenue from operations and the “profit” are negative. With negative net revenue from operations, the economic return for average shrimp vessels is less than zero. Only with the help of government payments does the average owner just about break even. In the short-term, this will discourage any new investments in the industry. The financial situation in 2006, especially if it endures over multiple years, also is economically unsustainable for the average established business. Vessels in the active and inactive Gulf shrimp fleet are, on average, 69 feet long, weigh 105 gross tons, are powered by 505 hp motor(s), and are 23 years old. Three-quarters of the vessels have steel hulls and 59% use a freezer for refrigeration. The average market value of these vessels was $175,149 in 2006, about a hundred-thousand dollars less than the average original purchase price. The outstanding loans averaged$91,955, leading to an average owner equity of $83,194. Based on the sample, 85 owner-operated. On average, these vessels burned 52,931 gallons of fuel, landed 101,268 pounds of shrimp, and received$2.47 per pound of shrimp. Non-shrimp landings added less than 1% to cash flow, indicating that the federal Gulf shrimp fishery is very specialized. The average total cash outflow was $243,415 of which$108,775 was due to fuel expenses alone. The expenses for hired crew and captains were on average $54,866 which indicates the importance of the industry as a source of wage income. The resulting average net cash flow is$16,225 but has a large standard deviation. For the population of active Gulf shrimp vessels we can state with 95% certainty that the average net cash flow was between $9,500 and$23,000 in 2006. The median net cash flow was $11,843. Based on the income statement for active Gulf shrimp vessels, the average fixed costs accounted for just under a quarter of operating expenses (23.1 The average labor contribution (as captain) of an owner-operator is estimated at about$19,800. The average net revenue from operations is negative $7,429, and is statistically different and less than zero in spite of a large standard deviation. The economic return to Gulf shrimping is negative 4$13,662, leads to an average loss before taxes of $907 for the vessel owners. The confidence interval of this value straddles zero, so we cannot reject, with 95 The average inactive Gulf shrimp vessel is generally of a smaller scale than the average active vessel. Inactive vessels are physically smaller, are valued much lower, and are less dependent on loans. Fixed costs account for nearly three quarters of the total operating expenses of$11,926, and only 6% of these vessels have hull insurance. With an average net cash flow of negative $7,537, the inactive Gulf shrimp fleet has a major liquidity problem. On average, net revenue from operations is negative$11,396, which amounts to a negative 15% economic return, and owners lose $9,381 on their vessels before taxes. To sustain such losses and especially to survive the negative cash flow, many of the owners must be subsidizing their shrimp vessels with the help of other income or wealth sources or are drawing down their equity. Active Gulf shrimp vessels in all states but Texas exhibited negative returns. The Alabama and Mississippi fleets have the highest assets (vessel values), on average, yet they generate zero cash flow and negative$32,224 net revenue from operations. Due to their high (loan) leverage ratio the negative 11% economic return is amplified into a negative 21% return on equity. In contrast, for Texas vessels, which actually have the highest leverage ratio among the states, a 1% economic return is amplified into a 13% return on equity. From a financial perspective, the average Florida and Louisiana vessels conform roughly to the overall average of the active Gulf shrimp fleet. It should be noted that these results are averages and hence hide the variation that clearly exists within all fleets and all categories. Although the financial situation for the average vessel is bleak, some vessels are profitable. (PDF contains 101 pages

Effect of histology on stereotactic body radiotherapy for non-small cell lung cancer oligometastatic pulmonary lesions

BACKGROUND: Stereotactic body radiotherapy (SBRT) is commonly used to provide targeted treatment to metastatic lung disease. Investigation is needed to understand the influence of histology on treatment outcomes. We report how tumor histology affects local control (LC) in a cohort of patients with non-small cell lung cancer (NSCLC) receiving SBRT for oligometastatic and recurrent pulmonary lesions. METHODS: Patients who received SBRT to recurrent or oligometastatic NSCLC pulmonary lesions from 2015-2019 at our institution were included in this retrospective cohort study. Minimum follow-up was 2 months. Kaplan-Meier (KM) analysis was performed to assess local progression-free survival (LPFS). Local failure cumulative incidence curves using death as a competing risk factor were also generated. RESULTS: A total of 147 treated lesions from 83 patients were included: 95 lesions from 51 patients with lung adenocarcinoma and 52 lesions from 32 patients with lung squamous cell carcinoma (SqCC). Median follow-up was 23 [interquartile range (IQR): 9.5-44.5] months for adenocarcinoma, and 11.5 (6-32.25) months for SqCC. Two-year LC was 89% for adenocarcinoma and 77% for SqCC (P=0.04). Median overall survival (OS) was 24.5 (10-46.25) months for adenocarcinoma and 14.5 (7.75-23.25) months for SqCC. Adenocarcinoma had improved LPFS over SqCC (P=0.014). SqCC was associated with increased local failure risk that approached statistical significance (P=0.061) with death as a competing risk. Overall toxicity incidence was 8.2% with no G3+ toxicities. CONCLUSIONS: For SBRT-treated oligometastatic or recurrent NSCLC pulmonary lesions, adenocarcinoma histology is associated with improved 2-year LC and LPFS compared to SqCC and reduced incidence of local recurrence (LR) with death as a competing risk

Experimentally engineered mutations in a ubiquitin hydrolase, UBP-1, modulate in vivo susceptibility to artemisinin and chloroquine in Plasmodium berghei

As resistance to artemisinins (current frontline drugs in malaria treatment) emerges in south East Asia, there is an urgent need to identify the genetic determinants and understand the molecular mechanisms underpinning such resistance. Such insights could lead to prospective interventions to contain resistance and prevent the eventual spread to other malaria endemic regions. Artemisinin reduced susceptibility in South East Asia (SEA) has been primarily linked to mutations in P. falciparum Kelch-13, which is currently widely recognised as a molecular marker of artemisinin resistance. However, 2 mutations in a ubiquitin hydrolase, UBP-1, have been previously associated with artemisinin reduced susceptibility in a rodent model of malaria and some cases of UBP-1 mutation variants associating with artemisinin treatment failure have been reported in Africa and SEA. In this study, we have employed CRISPR-Cas9 genome editing and pre-emptive drug pressures to test these artemisinin susceptibility associated mutations in UBP-1 in P. berghei sensitive lines in vivo. Using these approaches, we have shown that the V2721F UBP-1 mutation results in reduced artemisinin susceptibility, while the V2752F mutation results in resistance to chloroquine and moderately impacts tolerance to artemisinins. Genetic reversal of the V2752F mutation restored chloroquine sensitivity in these mutant lines while simultaneous introduction of both mutations could not be achieved and appears to be lethal. Interestingly, these mutations carry a detrimental growth defect, which would possibly explain their lack of expansion in natural infection settings. Our work has provided independent experimental evidence on the role of UBP-1 in modulating parasite responses to artemisinin and chloroquine under in vivo conditions

Genes in the postgenomic era

We outline three very different concepts of the gene - 'instrumental', 'nominal', and 'postgenomic'. The instrumental gene has a critical role in the construction and interpretation of experiments in which the relationship between genotype and phenotype is explored via hybridization between organisms or directly between nucleic acid molecules. It also plays an important theoretical role in the foundations of disciplines such as quantitative genetics and population genetics. The nominal gene is a critical practical tool, allowing stable communication between bioscientists in a wide range of fields grounded in well-defined sequences of nucleotides, but this concept does not embody major theoretical insights into genome structure or function. The post-genomic gene embodies the continuing project of understanding how genome structure supports genome function, but with a deflationary picture of the gene as a structural unit. This final concept of the gene poses a significant challenge to conventional assumptions about the relationship between genome structure and function, and between genotype and phenotype

Ampk regulates IgD expression but not energy stress with B cell activation.

Ampk is an energy gatekeeper that responds to decreases in ATP by inhibiting energy-consuming anabolic processes and promoting energy-generating catabolic processes. Recently, we showed that Lkb1, an understudied kinase in B lymphocytes and a major upstream kinase for Ampk, had critical and unexpected roles in activating naïve B cells and in germinal center formation. Therefore, we examined whether Lkb1 activities during B cell activation depend on Ampk and report surprising Ampk activation with in vitro B cell stimulation in the absence of energy stress, coupled to rapid biomass accumulation. Despite Ampk activation and a controlling role for Lkb1 in B cell activation, Ampk knockout did not significantly affect B cell activation, differentiation, nutrient dynamics, gene expression, or humoral immune responses. Instead, Ampk loss specifically repressed the transcriptional expression of IgD and its regulator, Zfp318. Results also reveal that early activation of Ampk by phenformin treatment impairs germinal center formation but does not significantly alter antibody responses. Combined, the data show an unexpectedly specific role for Ampk in the regulation of IgD expression during B cell activation

Four new T dwarfs identified in PanSTARRS 1 commissioning data

A complete well-defined sample of ultracool dwarfs is one of the key science programs of the Pan-STARRS 1 optical survey telescope (PS1). Here we combine PS1 commissioning data with 2MASS to conduct a proper motion search (0.1--2.0\arcsec/yr) for nearby T dwarfs, using optical+near-IR colors to select objects for spectroscopic followup. The addition of sensitive far-red optical imaging from PS1 enables discovery of nearby ultracool dwarfs that cannot be identified from 2MASS data alone. We have searched 3700 sq. deg. of PS1 y-band (0.95--1.03 um) data to y$\approx$19.5 mag (AB) and J$\approx$16.5 mag (Vega) and discovered four previously unknown bright T dwarfs. Three of the objects (with spectral types T1.5, T2 and T3.5) have photometric distances within 25 pc and were missed by previous 2MASS searches due to more restrictive color selection criteria. The fourth object (spectral type T4.5) is more distant than 25 pc and is only a single-band detection in 2MASS. We also examine the potential for completing the census of nearby ultracool objects with the PS1 3$\pi$ survey.Comment: 25 pages, 8 figures, 5 table, AJ accepted, updated to comply with Pan-STARRS1 naming conventio