55 research outputs found
Railroads in Tuolumne County, California : their role and importance to specific industries and their impact on county economic development, 1897-1917
During most of the nineteenth century and the early years of the twentieth numerous railroads were built throughout America. Some. grew into gigantic systems with names we recognize today; Southern Pacific, Atchison, Topeka & Santa Fe, Chesapeake & Ohio. Others faded into oblivion. But all, successful or not, were built to fill transportation needs.
In Tuolumne County, California, located along the Mother. Lode and stretching into the high Sierra Nevada, the first railroad reached the county in 1897. By World War I a number of rail lines had been built. Several, having served their purpose, had already been removed by that time. They played varying roles in the different industries of the county; mining and minerals, lumber, hydroelectric power and agriculture, as well as passenger service.
After the war many things changed. Automobiles and trucks successfully competed for some traffic. Mining suffered as labor costs increased while gold held at a price fixed by the government. Dams built by public agencies dwarfed the earlier projects of private industry. And, outside capitalists acquired control of companies that had formerly been locally owned and managed. The transportation picture changed dramatically from what: it had been before the war.
The purpose of this paper is to study those early years of the twentieth century in Tuolumne County. What were the needs for railroads in different: industries and enterprises in the county between 1897 and 1917; and what was their importance to those industries? And finally what was the impact of railroads on the economic development of Tuolumne County as a whole?
By focusing on an area with a relatively self-contained railroad network it is hoped that influences in the economy will be more apparent. Trends identified here should find application in other areas. It is also hoped that topics for future research will be suggested and that methods and resources for that research will be suggested
Lysyl-tRNA synthetase as a drug target in malaria and cryptosporidiosis
Malaria and cryptosporidiosis, caused by apicomplexan parasites, remain major drivers of global child mortality. New drugs for the treatment of malaria and cryptosporidiosis, in particular, are of high priority; however, there are few chemically validated targets. The natural product cladosporin is active against blood- and liver-stage; Plasmodium falciparum; and; Cryptosporidium parvum; in cell-culture studies. Target deconvolution in; P. falciparum; has shown that cladosporin inhibits lysyl-tRNA synthetase (; Pf; KRS1). Here, we report the identification of a series of selective inhibitors of apicomplexan KRSs. Following a biochemical screen, a small-molecule hit was identified and then optimized by using a structure-based approach, supported by structures of both; Pf; KRS1 and; C. parvum; KRS (; Cp; KRS). In vivo proof of concept was established in an SCID mouse model of malaria, after oral administration (ED; 90; = 1.5 mg/kg, once a day for 4 d). Furthermore, we successfully identified an opportunity for pathogen hopping based on the structural homology between; Pf; KRS1 and; Cp; KRS. This series of compounds inhibit; Cp; KRS and; C. parvum; and; Cryptosporidium hominis; in culture, and our lead compound shows oral efficacy in two cryptosporidiosis mouse models. X-ray crystallography and molecular dynamics simulations have provided a model to rationalize the selectivity of our compounds for; Pf; KRS1 and; Cp; KRS vs. (human); Hs; KRS. Our work validates apicomplexan KRSs as promising targets for the development of drugs for malaria and cryptosporidiosis
The JWST Early Release Science Program for Direct Observations of Exoplanetary Systems IV: NIRISS Aperture Masking Interferometry Performance and Lessons Learned
We present a performance analysis for the aperture masking interferometry
(AMI) mode on board the James Webb Space Telescope Near Infrared Imager and
Slitless Spectrograph (JWST/NIRISS). Thanks to self-calibrating observables,
AMI accesses inner working angles down to and even within the classical
diffraction limit. The scientific potential of this mode has recently been
demonstrated by the Early Release Science (ERS) 1386 program with a deep search
for close-in companions in the HIP 65426 exoplanetary system. As part of ERS
1386, we use the same dataset to explore the random, static, and calibration
errors of NIRISS AMI observables. We compare the observed noise properties and
achievable contrast to theoretical predictions. We explore possible sources of
calibration errors, and show that differences in charge migration between the
observations of HIP 65426 and point-spread function calibration stars can
account for the achieved contrast curves. Lastly, we use self-calibration tests
to demonstrate that with adequate calibration, NIRISS AMI can reach contrast
levels of mag. These tests lead us to observation planning
recommendations and strongly motivate future studies aimed at producing
sophisticated calibration strategies taking these systematic effects into
account. This will unlock the unprecedented capabilities of JWST/NIRISS AMI,
with sensitivity to significantly colder, lower mass exoplanets than
ground-based setups at orbital separations inaccessible to JWST coronagraphy.Comment: 20 pages, 12 figures, submitted to AAS Journal
The \textit{JWST} Early Release Science Program for Direct Observations of Exoplanetary Systems III: Aperture Masking Interferometric Observations of the star HIP\,65426 at
We present aperture masking interferometry (AMI) observations of the star HIP
65426 at as a part of the \textit{JWST} Direct Imaging Early
Release Science (ERS) program obtained using the Near Infrared Imager and
Slitless Spectrograph (NIRISS) instrument. This mode provides access to very
small inner working angles (even separations slightly below the Michelson limit
of for an interferometer), which are inaccessible with the
classical inner working angles of the \textit{JWST} coronagraphs. When combined
with \textit{JWST}'s unprecedented infrared sensitivity, this mode has the
potential to probe a new portion of parameter space across a wide array of
astronomical observations. Using this mode, we are able to achieve a contrast
of \,mag relative to the host star at a separation
of {\sim}0.07\arcsec but detect no additional companions interior to the
known companion HIP\,65426\,b. Our observations thus rule out companions more
massive than 10{-}12\,\rm{M\textsubscript{Jup}} at separations
from HIP\,65426, a region out of reach of ground or
space-based coronagraphic imaging. These observations confirm that the AMI mode
on \textit{JWST} is sensitive to planetary mass companions orbiting at the
water frost line, even for more distant stars at 100\,pc. This result
will allow the planning and successful execution of future observations to
probe the inner regions of nearby stellar systems, opening essentially
unexplored parameter space.Comment: 15 pages, 9 figures, submitted to ApJ Letter
Strong Carbon Features and a Red Early Color in the Underluminous Type Ia SN 2022xkq
We present optical, infrared, ultraviolet, and radio observations of SN
2022xkq, an underluminous fast-declining type Ia supernova (SN Ia) in NGC 1784
( Mpc), from to 180 days after explosion. The
high-cadence observations of SN 2022xkq, a photometrically transitional and
spectroscopically 91bg-like SN Ia, cover the first days and weeks following
explosion which are critical to distinguishing between explosion scenarios. The
early light curve of SN 2022xkq has a red early color and exhibits a flux
excess which is more prominent in redder bands; this is the first time such a
feature has been seen in a transitional/91bg-like SN Ia. We also present 92
optical and 19 near-infrared (NIR) spectra, beginning 0.4 days after explosion
in the optical and 2.6 days after explosion in the NIR. SN 2022xkq exhibits a
long-lived C I 1.0693 m feature which persists until 5 days post-maximum.
We also detect C II 6580 in the pre-maximum optical spectra. These
lines are evidence for unburnt carbon that is difficult to reconcile with the
double detonation of a sub-Chandrasekhar mass white dwarf. No existing
explosion model can fully explain the photometric and spectroscopic dataset of
SN 2022xkq, but the considerable breadth of the observations is ideal for
furthering our understanding of the processes which produce faint SNe Ia.Comment: 38 pages, 16 figures, accepted for publication in ApJ, the figure 15
input models and synthetic spectra are now available at
https://zenodo.org/record/837925
The JWST Early Release Science Program for Direct Observations of Exoplanetary Systems II: A 1 to 20 Micron Spectrum of the Planetary-Mass Companion VHS 1256-1257 b
We present the highest fidelity spectrum to date of a planetary-mass object.
VHS 1256 b is a 20 M widely separated (8\arcsec, a =
150 au), young, planetary-mass companion that shares photometric colors and
spectroscopic features with the directly imaged exoplanets HR 8799 c, d, and e.
As an L-to-T transition object, VHS 1256 b exists along the region of the
color-magnitude diagram where substellar atmospheres transition from cloudy to
clear. We observed VHS 1256~b with \textit{JWST}'s NIRSpec IFU and MIRI MRS
modes for coverage from 1 m to 20 m at resolutions of 1,000 -
3,700. Water, methane, carbon monoxide, carbon dioxide, sodium, and potassium
are observed in several portions of the \textit{JWST} spectrum based on
comparisons from template brown dwarf spectra, molecular opacities, and
atmospheric models. The spectral shape of VHS 1256 b is influenced by
disequilibrium chemistry and clouds. We directly detect silicate clouds, the
first such detection reported for a planetary-mass companion.Comment: Accepted ApJL Iterations of spectra reduced by the ERS team are
hosted at this link:
https://github.com/bemiles/JWST_VHS1256b_Reduction/tree/main/reduced_spectr
3 years of liraglutide versus placebo for type 2 diabetes risk reduction and weight management in individuals with prediabetes: a randomised, double-blind trial
Background:
Liraglutide 3·0 mg was shown to reduce bodyweight and improve glucose metabolism after the 56-week period of this trial, one of four trials in the SCALE programme. In the 3-year assessment of the SCALE Obesity and Prediabetes trial we aimed to evaluate the proportion of individuals with prediabetes who were diagnosed with type 2 diabetes.
Methods:
In this randomised, double-blind, placebo-controlled trial, adults with prediabetes and a body-mass index of at least 30 kg/m2, or at least 27 kg/m2 with comorbidities, were randomised 2:1, using a telephone or web-based system, to once-daily subcutaneous liraglutide 3·0 mg or matched placebo, as an adjunct to a reduced-calorie diet and increased physical activity. Time to diabetes onset by 160 weeks was the primary outcome, evaluated in all randomised treated individuals with at least one post-baseline assessment. The trial was conducted at 191 clinical research sites in 27 countries and is registered with ClinicalTrials.gov, number NCT01272219.
Findings:
The study ran between June 1, 2011, and March 2, 2015. We randomly assigned 2254 patients to receive liraglutide (n=1505) or placebo (n=749). 1128 (50%) participants completed the study up to week 160, after withdrawal of 714 (47%) participants in the liraglutide group and 412 (55%) participants in the placebo group. By week 160, 26 (2%) of 1472 individuals in the liraglutide group versus 46 (6%) of 738 in the placebo group were diagnosed with diabetes while on treatment. The mean time from randomisation to diagnosis was 99 (SD 47) weeks for the 26 individuals in the liraglutide group versus 87 (47) weeks for the 46 individuals in the placebo group. Taking the different diagnosis frequencies between the treatment groups into account, the time to onset of diabetes over 160 weeks among all randomised individuals was 2·7 times longer with liraglutide than with placebo (95% CI 1·9 to 3·9, p<0·0001), corresponding with a hazard ratio of 0·21 (95% CI 0·13–0·34). Liraglutide induced greater weight loss than placebo at week 160 (–6·1 [SD 7·3] vs −1·9% [6·3]; estimated treatment difference −4·3%, 95% CI −4·9 to −3·7, p<0·0001). Serious adverse events were reported by 227 (15%) of 1501 randomised treated individuals in the liraglutide group versus 96 (13%) of 747 individuals in the placebo group.
Interpretation:
In this trial, we provide results for 3 years of treatment, with the limitation that withdrawn individuals were not followed up after discontinuation. Liraglutide 3·0 mg might provide health benefits in terms of reduced risk of diabetes in individuals with obesity and prediabetes.
Funding:
Novo Nordisk, Denmark
The Changing Landscape for Stroke\ua0Prevention in AF: Findings From the GLORIA-AF Registry Phase 2
Background GLORIA-AF (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation) is a prospective, global registry program describing antithrombotic treatment patterns in patients with newly diagnosed nonvalvular atrial fibrillation at risk of stroke. Phase 2 began when dabigatran, the first non\u2013vitamin K antagonist oral anticoagulant (NOAC), became available. Objectives This study sought to describe phase 2 baseline data and compare these with the pre-NOAC era collected during phase 1. Methods During phase 2, 15,641 consenting patients were enrolled (November 2011 to December 2014); 15,092 were eligible. This pre-specified cross-sectional analysis describes eligible patients\u2019 baseline characteristics. Atrial fibrillation disease characteristics, medical outcomes, and concomitant diseases and medications were collected. Data were analyzed using descriptive statistics. Results Of the total patients, 45.5% were female; median age was 71 (interquartile range: 64, 78) years. Patients were from Europe (47.1%), North America (22.5%), Asia (20.3%), Latin America (6.0%), and the Middle East/Africa (4.0%). Most had high stroke risk (CHA2DS2-VASc [Congestive heart failure, Hypertension, Age 6575 years, Diabetes mellitus, previous Stroke, Vascular disease, Age 65 to 74 years, Sex category] score 652; 86.1%); 13.9% had moderate risk (CHA2DS2-VASc = 1). Overall, 79.9% received oral anticoagulants, of whom 47.6% received NOAC and 32.3% vitamin K antagonists (VKA); 12.1% received antiplatelet agents; 7.8% received no antithrombotic treatment. For comparison, the proportion of phase 1 patients (of N = 1,063 all eligible) prescribed VKA was 32.8%, acetylsalicylic acid 41.7%, and no therapy 20.2%. In Europe in phase 2, treatment with NOAC was more common than VKA (52.3% and 37.8%, respectively); 6.0% of patients received antiplatelet treatment; and 3.8% received no antithrombotic treatment. In North America, 52.1%, 26.2%, and 14.0% of patients received NOAC, VKA, and antiplatelet drugs, respectively; 7.5% received no antithrombotic treatment. NOAC use was less common in Asia (27.7%), where 27.5% of patients received VKA, 25.0% antiplatelet drugs, and 19.8% no antithrombotic treatment. Conclusions The baseline data from GLORIA-AF phase 2 demonstrate that in newly diagnosed nonvalvular atrial fibrillation patients, NOAC have been highly adopted into practice, becoming more frequently prescribed than VKA in Europe and North America. Worldwide, however, a large proportion of patients remain undertreated, particularly in Asia and North America. (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients With Atrial Fibrillation [GLORIA-AF]; NCT01468701
Finishing the euchromatic sequence of the human genome
The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead
Weak mass loss from the Red Supergiant progenitor of the type II SN 2021yja
We present high-cadence optical, ultraviolet (UV), and near-infrared data of the nearby (D ≈ 23 Mpc) Type II supernova (SN) 2021yja. Many Type II SNe show signs of interaction with circumstellar material (CSM) during the first few days after explosion, implying that their red supergiant (RSG) progenitors experience episodic or eruptive mass loss. However, because it is difficult to discover SNe early, the diversity of CSM configurations in RSGs has not been fully mapped. SN 2021yja, first detected within ≈ 5.4 hours of explosion, shows some signatures of CSM interaction (high UV luminosity and radio and x-ray emission) but without the narrow emission lines or early light-curve peak that can accompany CSM. Here we analyze the densely sampled early light curve and spectral series of this nearby SN to infer the properties of its progenitor and CSM. We find that the most likely progenitor was an RSG with an extended envelope, encompassed by low-density CSM. We also present archival Hubble Space Telescope imaging of the host galaxy of SN 2021yja, which allows us to place a stringent upper limit of ≲ 9 M ☉ on the progenitor mass. However, this is in tension with some aspects of the SN evolution, which point to a more massive progenitor. Our analysis highlights the need to consider progenitor structure when making inferences about CSM properties, and that a comprehensive view of CSM tracers should be made to give a fuller view of the last years of RSG evolution
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