Correlating Infall with Deuterium Fractionation in Dense Cores

We present a survey of HCO+ (3-2) observations pointed towards dense cores with previous measurements of N(N2D+)/N(N2H+). Of the 26 cores in this survey, five show the spectroscopic signature of outward motion, nine exhibit neither inward nor outward motion, eleven appear to be infalling, and one is not detected. We compare the degree of deuterium fractionation with infall velocities calculated from the HCO+ spectra and find that those cores with [D]/[H] > 0.1 are more likely to have the signature of inward motions than cores with smaller [D]/[H] ratios. Infall motions are also much more common in cores with masses exceeding their thermal Jeans masses. The fastest infall velocity measured belongs to one of the two protostellar cores in our survey, L1521F, and the observed motions are typically on the order of the sound speed.Comment: Accepted to Ap

Gamma-ray production from resonant betatron oscillations of accelerated electrons in a plasma wake

The laser-plasma wakefield accelerator is a novel ultra-compact particle accelerator. A very intense laser pulse focused onto plasma can excites plasma density waves. Electrons surfing these waves can be accelerated to very high energies with unprecedented accelerating gradients in excess of 1 GV/cm. While accelerating, electrons undergo transverse betatron oscillations and emit synchrotron-like x-ray radiation into a narrow on-axis cone, which is enhanced when electrons interact with the electromagnetic field of the laser. In this case, the laser can resonantly drive the electron motion, lading to direct laser acceleration. This occurs when the betatron frequency matches the Doppler down-shifted frequency of the laser. As a consequence, the number of photons emitted is strongly enhanced and the critical photon energy is increases to 100’s of ke

Power Factor Enhancement in Solution‐Processed Organic n‐Type Thermoelectrics Through Molecular Design

A new class of high‐performance n‐type organic thermoelectric materials, self‐doping perylene diimide derivatives with modified side chains, is reported. These materials achieve the highest n‐type thermoelectric performance of solution‐processed organic materials reported to date, with power factors as high as 1.4 μW/mK^2. These results demonstrate that molecular design is a promising strategy for enhancing organic thermoelectric performance

The Long-Baseline Neutrino Experiment: Exploring Fundamental Symmetries of the Universe

The preponderance of matter over antimatter in the early Universe, the dynamics of the supernova bursts that produced the heavy elements necessary for life and whether protons eventually decay --- these mysteries at the forefront of particle physics and astrophysics are key to understanding the early evolution of our Universe, its current state and its eventual fate. The Long-Baseline Neutrino Experiment (LBNE) represents an extensively developed plan for a world-class experiment dedicated to addressing these questions. LBNE is conceived around three central components: (1) a new, high-intensity neutrino source generated from a megawatt-class proton accelerator at Fermi National Accelerator Laboratory, (2) a near neutrino detector just downstream of the source, and (3) a massive liquid argon time-projection chamber deployed as a far detector deep underground at the Sanford Underground Research Facility. This facility, located at the site of the former Homestake Mine in Lead, South Dakota, is approximately 1,300 km from the neutrino source at Fermilab -- a distance (baseline) that delivers optimal sensitivity to neutrino charge-parity symmetry violation and mass ordering effects. This ambitious yet cost-effective design incorporates scalability and flexibility and can accommodate a variety of upgrades and contributions. With its exceptional combination of experimental configuration, technical capabilities, and potential for transformative discoveries, LBNE promises to be a vital facility for the field of particle physics worldwide, providing physicists from around the globe with opportunities to collaborate in a twenty to thirty year program of exciting science. In this document we provide a comprehensive overview of LBNE's scientific objectives, its place in the landscape of neutrino physics worldwide, the technologies it will incorporate and the capabilities it will possess.Comment: Major update of previous version. This is the reference document for LBNE science program and current status. Chapters 1, 3, and 9 provide a comprehensive overview of LBNE's scientific objectives, its place in the landscape of neutrino physics worldwide, the technologies it will incorporate and the capabilities it will possess. 288 pages, 116 figure

Association of Variants in the SPTLC1 Gene With Juvenile Amyotrophic Lateral Sclerosis

Importance: Juvenile amyotrophic lateral sclerosis (ALS) is a rare form of ALS characterized by age of symptom onset less than 25 years and a variable presentation.Objective: To identify the genetic variants associated with juvenile ALS.Design, Setting, and Participants: In this multicenter family-based genetic study, trio whole-exome sequencing was performed to identify the disease-associated gene in a case series of unrelated patients diagnosed with juvenile ALS and severe growth retardation. The patients and their family members were enrolled at academic hospitals and a government research facility between March 1, 2016, and March 13, 2020, and were observed until October 1, 2020. Whole-exome sequencing was also performed in a series of patients with juvenile ALS. A total of 66 patients with juvenile ALS and 6258 adult patients with ALS participated in the study. Patients were selected for the study based on their diagnosis, and all eligible participants were enrolled in the study. None of the participants had a family history of neurological disorders, suggesting de novo variants as the underlying genetic mechanism.Main Outcomes and Measures: De novo variants present only in the index case and not in unaffected family members.Results: Trio whole-exome sequencing was performed in 3 patients diagnosed with juvenile ALS and their parents. An additional 63 patients with juvenile ALS and 6258 adult patients with ALS were subsequently screened for variants in the SPTLC1 gene. De novo variants in SPTLC1 (p.Ala20Ser in 2 patients and p.Ser331Tyr in 1 patient) were identified in 3 unrelated patients diagnosed with juvenile ALS and failure to thrive. A fourth variant (p.Leu39del) was identified in a patient with juvenile ALS where parental DNA was unavailable. Variants in this gene have been previously shown to be associated with autosomal-dominant hereditary sensory autonomic neuropathy, type 1A, by disrupting an essential enzyme complex in the sphingolipid synthesis pathway.Conclusions and Relevance: These data broaden the phenotype associated with SPTLC1 and suggest that patients presenting with juvenile ALS should be screened for variants in this gene.</p

Sex difference and intra-operative tidal volume: Insights from the LAS VEGAS study

BACKGROUND: One key element of lung-protective ventilation is the use of a low tidal volume (VT). A sex difference in use of low tidal volume ventilation (LTVV) has been described in critically ill ICU patients.OBJECTIVES: The aim of this study was to determine whether a sex difference in use of LTVV also exists in operating room patients, and if present what factors drive this difference.DESIGN, PATIENTS AND SETTING: This is a posthoc analysis of LAS VEGAS, a 1-week worldwide observational study in adults requiring intra-operative ventilation during general anaesthesia for surgery in 146 hospitals in 29 countries.MAIN OUTCOME MEASURES: Women and men were compared with respect to use of LTVV, defined as VT of 8 ml kg-1 or less predicted bodyweight (PBW). A VT was deemed 'default' if the set VT was a round number. A mediation analysis assessed which factors may explain the sex difference in use of LTVV during intra-operative ventilation.RESULTS: This analysis includes 9864 patients, of whom 5425 (55%) were women. A default VT was often set, both in women and men; mode VT was 500 ml. Median [IQR] VT was higher in women than in men (8.6 [7.7 to 9.6] vs. 7.6 [6.8 to 8.4] ml kg-1 PBW, P &lt; 0.001). Compared with men, women were twice as likely not to receive LTVV [68.8 vs. 36.0%; relative risk ratio 2.1 (95% CI 1.9 to 2.1), P &lt; 0.001]. In the mediation analysis, patients' height and actual body weight (ABW) explained 81 and 18% of the sex difference in use of LTVV, respectively; it was not explained by the use of a default VT.CONCLUSION: In this worldwide cohort of patients receiving intra-operative ventilation during general anaesthesia for surgery, women received a higher VT than men during intra-operative ventilation. The risk for a female not to receive LTVV during surgery was double that of males. Height and ABW were the two mediators of the sex difference in use of LTVV.TRIAL REGISTRATION: The study was registered at Clinicaltrials.gov, NCT01601223

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

Integration of biochemical and physical signals during directed cell migration

Neutrophils are professional migrators within our body, moving from the bloodstream through dense forests of extracellular matrix to reach sites of infection and initiate an immune response. While we have long appreciated the role of biochemical signals in neutrophil recruitment, increasing attention is being given to the role of physical signals during this process. For example, membrane tension and membrane shape changes arise as neutrophils navigate complex 3D environments in vivo, which can impact the path cells take through tissue. However, how this information is relayed back to the cytoskeleton has remained largely unexplored. In this thesis we probe the link between biochemical and physical inputs to better understand how neutrophils integrate environmental signals to ensure robust directed migration.In Chapter 2 we establish how intrinsic protein self-organization and external membrane curvature work together to pattern the actin nucleation promoting factor WAVE. Using super-resolution microscopy, we find that WAVE forms rings at the saddle-shaped necks of membrane invaginations in the absence of actin polymer. Dual inputs from WAVE’s propensity to oligomerize and curvature sensitivity explain this enrichment pattern and inform our understanding of WAVE propagation in the presence of actin. Specifically, we find that WAVE localizes to the saddle-shaped lagging regions of the leading edge to support a uniformly advancing cell front. Elucidation of the mechanisms underpinning WAVE organization has provided initial insights into the integration of internal biochemical signals with external cell shape in organizing the actin cytoskeleton.In Chapter 3 we continue on this theme and highlight how WASP, another actin nucleation promoting factor, uses a modification of these behaviors to link cell shape and cell polarity during neutrophil migration. Unlike WAVE, WASP persistently enriches to substrate-induced invaginations in the presence of actin. Additionally, WASP assembles into focal structures rather than linear structures. We find that these properties allow WASP to link sites of local membrane deformation to the cytoskeleton by promoting actin polymerization and aligned migration in textured environments. Strikingly, this property requires concomitant inputs from cell shape and cell polarity. WASP only engages with curved membranes at the cell front, which supports forward advance. We show that WASP is essential for integration of substrate features with directed migration, which could have implications for migration through collagen meshworks in vivo. Finally, Chapter 4 presents unpublished work exploring the molecular mechanisms of cell polarity through GTPase regulation by Rho GEFs and GAPs using HEK293T cells as a model system. Using CRISPR we endogenously label highly expressed GEFs and GAPs. We describe a system for polarizing HEK293T cells and report candidate GEFs and GAPs that enrich to induced cell protrusions. Finally, we supply a protocol for phenotyping the migration of HEK293T GEF or GAP knockout cell lines and provide a positive control in the form of Rac1 knockout. Ultimately, GEFs and GAPs exhibiting loss of function phenotypes would be followed up in the consitituively polarized, highly motile neutrophil cell line HL-60

Integration of biochemical and physical signals during directed cell migration

Neutrophils are professional migrators within our body, moving from the bloodstream through dense forests of extracellular matrix to reach sites of infection and initiate an immune response. While we have long appreciated the role of biochemical signals in neutrophil recruitment, increasing attention is being given to the role of physical signals during this process. For example, membrane tension and membrane shape changes arise as neutrophils navigate complex 3D environments in vivo, which can impact the path cells take through tissue. However, how this information is relayed back to the cytoskeleton has remained largely unexplored. In this thesis we probe the link between biochemical and physical inputs to better understand how neutrophils integrate environmental signals to ensure robust directed migration.In Chapter 2 we establish how intrinsic protein self-organization and external membrane curvature work together to pattern the actin nucleation promoting factor WAVE. Using super-resolution microscopy, we find that WAVE forms rings at the saddle-shaped necks of membrane invaginations in the absence of actin polymer. Dual inputs from WAVE’s propensity to oligomerize and curvature sensitivity explain this enrichment pattern and inform our understanding of WAVE propagation in the presence of actin. Specifically, we find that WAVE localizes to the saddle-shaped lagging regions of the leading edge to support a uniformly advancing cell front. Elucidation of the mechanisms underpinning WAVE organization has provided initial insights into the integration of internal biochemical signals with external cell shape in organizing the actin cytoskeleton.In Chapter 3 we continue on this theme and highlight how WASP, another actin nucleation promoting factor, uses a modification of these behaviors to link cell shape and cell polarity during neutrophil migration. Unlike WAVE, WASP persistently enriches to substrate-induced invaginations in the presence of actin. Additionally, WASP assembles into focal structures rather than linear structures. We find that these properties allow WASP to link sites of local membrane deformation to the cytoskeleton by promoting actin polymerization and aligned migration in textured environments. Strikingly, this property requires concomitant inputs from cell shape and cell polarity. WASP only engages with curved membranes at the cell front, which supports forward advance. We show that WASP is essential for integration of substrate features with directed migration, which could have implications for migration through collagen meshworks in vivo. Finally, Chapter 4 presents unpublished work exploring the molecular mechanisms of cell polarity through GTPase regulation by Rho GEFs and GAPs using HEK293T cells as a model system. Using CRISPR we endogenously label highly expressed GEFs and GAPs. We describe a system for polarizing HEK293T cells and report candidate GEFs and GAPs that enrich to induced cell protrusions. Finally, we supply a protocol for phenotyping the migration of HEK293T GEF or GAP knockout cell lines and provide a positive control in the form of Rac1 knockout. Ultimately, GEFs and GAPs exhibiting loss of function phenotypes would be followed up in the consitituively polarized, highly motile neutrophil cell line HL-60