Marine and terrestrial influences on ice nucleating particles during continuous springtime measurements in an Arctic oilfield location

Aerosols that serve as ice nucleating particles (INPs) have the potential to modulate cloud microphysical properties and can therefore impact cloud radiative forcing (CRF) and precipitation formation processes. In remote regions such as the Arctic, aerosol–cloud interactions are severely understudied yet may have significant implications for the surface energy budget and its impact on sea ice and snow surfaces. Further, uncertainties in model representations of heterogeneous ice nucleation are a significant hindrance to simulating Arctic mixed-phase cloud processes. We present results from a campaign called INPOP (Ice Nucleating Particles at Oliktok Point), which took place at a US Department of Energy Atmospheric Radiation Measurement (DOE ARM) facility in the northern Alaskan Arctic. Three time- and size-resolved aerosol impactors were deployed from 1 March to 31 May 2017 for offline ice nucleation and chemical analyses and were co-located with routine measurements of aerosol number and size. The largest particles (i.e., ≥ 3 µm or “coarse mode”) were the most efficient INPs by inducing freezing at the warmest temperatures. During periods with snow- and ice-covered surfaces, coarse mode INP concentrations were very low (maximum of 6 × 10−4 L−1 at −15 ∘C), but higher concentrations of warm-temperature INPs were observed during late May (maximum of 2 × 10−2 L−1 at −15 ∘C). These higher concentrations were attributed to air masses originating from over open Arctic Ocean water and tundra surfaces. To our knowledge, these results represent the first INP characterization measurements in an Arctic oilfield location and demonstrate strong influences from mineral and marine sources despite the relatively high springtime pollution levels. Ultimately, these results can be used to evaluate the anthropogenic and natural influences on aerosol composition and Arctic cloud properties

Mechanistic insight into the pathology of polyalanine expansion disorders revealed by a mouse model for x linked hypopituitarism

Extent: 9 p.Polyalanine expansions in transcription factors have been associated with eight distinct congenital human diseases. It is thought that in each case the polyalanine expansion causes misfolding of the protein that abrogates protein function. Misfolded proteins form aggregates when expressed in vitro; however, it is less clear whether aggregation is of relevance to these diseases in vivo. To investigate this issue, we used targeted mutagenesis of embryonic stem (ES) cells to generate mice with a polyalanine expansion mutation in Sox3 (Sox3-26ala) that is associated with X-linked Hypopituitarism (XH) in humans. By investigating both ES cells and chimeric mice, we show that endogenous polyalanine expanded SOX3 does not form protein aggregates in vivo but rather is present at dramatically reduced levels within the nucleus of mutant cells. Importantly, the residual mutant protein of chimeric embryos is able to rescue a block in gastrulation but is not sufficient for normal development of the hypothalamus, a region that is functionally compromised in Sox3 null embryos and individuals with XH. Together, these data provide the first definitive example of a disease-relevant PA mutant protein that is both nuclear and functional, thereby manifesting as a partial loss-of-function allele.James Hughes Sandra Piltz, Nicholas Rogers, Dale McAninch, Lynn Rowley and Paul Thoma

Clinical features of spinal and bulbar muscular atrophy

Spinal and bulbar muscular atrophy is an X-linked motor neuron disease caused by a CAG repeat expansion in the androgen receptor gene. To characterize the natural history and define outcome measures for clinical trials, we assessed the clinical history, laboratory findings and muscle strength and function in 57 patients with genetically confirmed disease. We also administered self-assessment questionnaires for activities of daily living, quality of life and erectile function. We found an average delay of over 5 years from onset of weakness to diagnosis. Muscle strength and function correlated directly with serum testosterone levels and inversely with CAG repeat length, age and duration of weakness. Motor unit number estimation was decreased by about half compared to healthy controls. Sensory nerve action potentials were reduced in nearly all subjects. Quantitative muscle assessment and timed 2 min walk may be useful as meaningful indicators of disease status. The direct correlation of testosterone levels with muscle strength indicates that androgens may have a positive effect on muscle function in spinal and bulbar muscular atrophy patients, in addition to the toxic effects described in animal models

Variations in the G6PC2/ABCB11 genomic region are associated with fasting glucose levels

Identifying the genetic variants that regulate fasting glucose concentrations may further our understanding of the pathogenesis of diabetes. We therefore investigated the association of fasting glucose levels with SNPs in 2 genome-wide scans including a total of 5,088 nondiabetic individuals from Finland and Sardinia. We found a significant association between the SNP rs563694 and fasting glucose concentrations (P = 3.5 × 10–7). This association was further investigated in an additional 18,436 nondiabetic individuals of mixed European descent from 7 different studies. The combined P value for association in these follow-up samples was 6.9 × 10–26, and combining results from all studies resulted in an overall P value for association of 6.4 × 10–33. Across these studies, fasting glucose concentrations increased 0.01–0.16 mM with each copy of the major allele, accounting for approximately 1% of the total variation in fasting glucose. The rs563694 SNP is located between the genes glucose-6-phosphatase catalytic subunit 2 (G6PC2) and ATP-binding cassette, subfamily B (MDR/TAP), member 11 (ABCB11). Our results in combination with data reported in the literature suggest that G6PC2, a glucose-6-phosphatase almost exclusively expressed in pancreatic islet cells, may underlie variation in fasting glucose, though it is possible that ABCB11, which is expressed primarily in liver, may also contribute to such variation

Minimal information for studies of extracellular vesicles (MISEV2023): From basic to advanced approaches

Extracellular vesicles (EVs), through their complex cargo, can reflect the state of their cell of origin and change the functions and phenotypes of other cells. These features indicate strong biomarker and therapeutic potential and have generated broad interest, as evidenced by the steady year-on-year increase in the numbers of scientific publications about EVs. Important advances have been made in EV metrology and in understanding and applying EV biology. However, hurdles remain to realising the potential of EVs in domains ranging from basic biology to clinical applications due to challenges in EV nomenclature, separation from non-vesicular extracellular particles, characterisation and functional studies. To address the challenges and opportunities in this rapidly evolving field, the International Society for Extracellular Vesicles (ISEV) updates its 'Minimal Information for Studies of Extracellular Vesicles', which was first published in 2014 and then in 2018 as MISEV2014 and MISEV2018, respectively. The goal of the current document, MISEV2023, is to provide researchers with an updated snapshot of available approaches and their advantages and limitations for production, separation and characterisation of EVs from multiple sources, including cell culture, body fluids and solid tissues. In addition to presenting the latest state of the art in basic principles of EV research, this document also covers advanced techniques and approaches that are currently expanding the boundaries of the field. MISEV2023 also includes new sections on EV release and uptake and a brief discussion of in vivo approaches to study EVs. Compiling feedback from ISEV expert task forces and more than 1000 researchers, this document conveys the current state of EV research to facilitate robust scientific discoveries and move the field forward even more rapidly

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Old Babylonian contracts in the Michael C. Carlos Museum Emory University

This article is the primary publication of ten Old Babylonian contracts housed at the Michael C. Carlos Museum, Emory University. Topics include loans, a tenancy agreement, adoption, and harrowing

From Oslo to Atlanta: an Old Babylonian prism collecting model contracts

This paper is the edition of an Old Babylonian prism collecting twenty-nine model contracts. It has been reconstructed by putting together fragments that are currently housed in Europe (Schøyen Collection, Oslo) and the USA (Emory University, Altanta)

Elemental Characterization of PM_2.5 and PM₁₀ Emitted from Light Duty Vehicles in the Washburn Tunnel of Houston, Texas: Release of Rhodium, Palladium, And Platinum

We report the elemental composition, including Rh, Pd, and Pt, of total (i.e., tailpipe and nontailpipe) PM_2.5 and PM₁₀ emissions from predominantly gasoline-driven light-duty vehicles (LDVs) traversing the Washburn Tunnel in Houston, Texas during November and December, 2012. Using a novel sample preparation and dynamic reaction cell-quadrupole-inductively coupled plasma-mass spectrometry technique, we quantify the emission of numerous representative, transition, and lanthanoid elements. Two sets of time integrated PM samples were collected over 3–4week duration both inside the tunnel as well as from the tunnel ventilation air supply to derive accurate LDV source profiles incorporating three platinum group elements (PGEs) for the first time. Average Rh, Pd, and Pt concentrations from the tunnel ventilation air supply were 1.5, 11.1, and 4.5pgm^–3 in PM_2.5 and 3.8, 23.1, and 15.1pgm^–3 in PM₁₀, respectively. Rh, Pd, and Pt levels were elevated inside the Washburn Tunnel reaching 12.5, 91.1, and 30.1pgm^–3 in PM_2.5 and 36.3, 214, and 61.1pgm^–3 in PM₁₀, respectively. Significantly higher enrichment factors of Cu, Zr, Rh, Pd, Sb, and Pt (referenced to Ti in the upper continental crust) inside the tunnel compared with the ventilation air supply suggested that they are unique elemental tracers of PM derived from gasoline-driven LDVs. This highlights the importance of advancing methods to quantify the trace level PGE emissions as a technique to more accurately estimate LDVs’ contributions to airborne PM. Using the emission profile based on PGEs and ambient quantification, mass balancing revealed that approximately half the fine PM mass in the tunnel could be attributed to tailpipe emissions, approximately one-quarter to road dust, with smaller contributions from brake (7%) and tire (3%) wear. On the other hand, PM₁₀ mostly originated from resuspended road dust (∼50%), with progressively lower contributions from tailpipe emissions (14%), brake wear (9%), and tire wear (2%)