Increased computing power and greater access to online data have led to rapid growth in the use of computer-aided text analysis (CATA) and machine learning methods. Using “big data”, researchers have ...not only advanced new streams of research, but also new research methodologies. Noting this trend and simultaneously recognizing the value of traditional research methods, we lay out a methodology that bridges the gap between old and new approaches to operationalize old constructs in new ways. With a combination of web scraping, CATA, and supervised machine learning, using labeled ground truth data (i.e., data with known inputs and outputs), we train a model to predict CIP (Charismatic-Ideological-Pragmatic) leadership styles from running text. To illustrate this method, we apply the model to classify U.S. state governors’ COVID-19 press briefings according to their CIP leadership style. In addition, we demonstrate content and convergent validity of the method.
DNA mismatch repair deficiency drives microsatellite instability (MSI). Cells with MSI accumulate numerous frameshift mutations. Frameshift mutations affecting cancer-related genes may promote ...tumorigenesis and, therefore, are shared among independently arising MSI tumors. Consequently, such recurrent frameshift mutations can give rise to shared immunogenic frameshift peptides (FSPs) that represent ideal candidates for a vaccine against MSI cancer. Pathogenic germline variants of mismatch repair genes cause Lynch syndrome (LS), a hereditary cancer syndrome affecting approximately 20–25 million individuals worldwide. Individuals with LS are at high risk of developing MSI cancer. Previously, we demonstrated safety and immunogenicity of an FSP-based vaccine in a phase I/IIa clinical trial in patients with a history of MSI colorectal cancer. However, the cancer-preventive effect of FSP vaccination in the scenario of LS has not yet been demonstrated.
A genome-wide database of 488,235 mouse coding mononucleotide repeats was established, from which a set of candidates was selected based on repeat length, gene expression, and mutation frequency. In silico prediction, in vivo immunogenicity testing, and epitope mapping was used to identify candidates for FSP vaccination.
We identified 4 shared FSP neoantigens (Nacad FSP-1, Maz FSP-1, Senp6 FSP-1, Xirp1 FSP-1) that induced CD4/CD8 T cell responses in naïve C57BL/6 mice. Using VCMsh2 mice, which have a conditional knockout of Msh2 in the intestinal tract and develop intestinal cancer, we showed vaccination with a combination of only 4 FSPs significantly increased FSP-specific adaptive immunity, reduced intestinal tumor burden, and prolonged overall survival. Combination of FSP vaccination with daily naproxen treatment potentiated immune response, delayed tumor growth, and prolonged survival even more effectively than FSP vaccination alone.
Our preclinical findings support a clinical strategy of recurrent FSP neoantigen vaccination for LS cancer immunoprevention.
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Vaccination of Lynch syndrome mice with shared immunogenic frameshift peptide neoantigens derived from recurrent frameshift mutations reduced intestinal tumor formation and prolonged survival, even more efficiently upon parallel nonsteroidal anti-inflammatory drug treatment.
Adjuvant properties of bacterial cell wall components like MPLA (monophosphoryl lipid A) are well described and have gained FDA approval for use in vaccines such as Cervarix. MPLA is the product of ...chemically modified lipooligosaccharide (LOS), altered to diminish toxic proinflammatory effects while retaining adequate immunogenicity. Despite the virtually unlimited number of potential sources among bacterial strains, the number of useable compounds within this promising class of adjuvants are few. We have developed bacterial enzymatic combinatorial chemistry (BECC) as a method to generate rationally designed, functionally diverse lipid A. BECC removes endogenous or introduces exogenous lipid A-modifying enzymes to bacteria, effectively reprogramming the lipid A biosynthetic pathway. In this study, BECC is applied within an avirulent strain of
to develop structurally distinct LOS molecules that elicit differential Toll-like receptor 4 (TLR4) activation. Using reporter cell lines that measure NF-κB activation, BECC-derived molecules were screened for the ability to induce a lower proinflammatory response than
LOS. Their structures exhibit varied, dose-dependent, TLR4-driven NF-κB activation with both human and mouse TLR4 complexes. Additional cytokine secretion screening identified molecules that induce levels of tumor necrosis factor alpha (TNF-α) and interleukin-8 (IL-8) comparable to the levels induced by phosphorylated hexa-acyl disaccharide (PHAD). The lead candidates demonstrated potent immunostimulation in mouse splenocytes, human primary blood mononuclear cells (PBMCs), and human monocyte-derived dendritic cells (DCs). This newly described system allows directed programming of lipid A synthesis and has the potential to generate a diverse array of TLR4 agonist candidates.
There is an urgent need to develop effective vaccines against infectious diseases that continue to be major causes of morbidity and mortality worldwide. Making effective vaccines requires selecting an adjuvant to strengthen an appropriate and protective immune response. This work describes a practical method, bacterial enzymatic combinatorial chemistry (BECC), for generating functionally diverse molecules for adjuvant use. These molecules were analyzed in cell culture for their ability to initiate immune stimulatory activity. Several of the assays described herein show promising
cytokine production and costimulatory molecule expression results, suggesting that the BECC molecules may be useful in future vaccine preparations.
AbstractQuantifying the effect of reduced gravity on the behavior of granular matter is essential to understanding the evolution of planetary morphology and will likely affect the design of future ...extraterrestrial habitats. Yet despite recent research, the effect of reduced gravity/confining pressure on strength remains undetermined, with scarce results ranging from no effect to opposing trends. In this study, we employ high-fidelity discrete element simulations (DEM) of passive failure experiments to measure the influence of gravity on the peak and steady-state friction angle, and the angle of repose of sand. The results are compared against recently reported physical experiments, lending the latter support based on micromechanical information, that is unattainable experimentally. We find that the friction angles experience a small increase with decreasing gravity, while the angle of repose remains almost constant.
The best-characterized Toll-like receptor 4 (TLR4) ligands are lipopolysaccharide (LPS) and its chemically modified and detoxified variant, monophosphoryl lipid A (MPL). Although both molecules are ...active for human TLR4, they demonstrate a potency preference for mouse TLR4 based on data from transfected cell lines and primary cells of both species. After a high throughput screening process of small molecule libraries, we have discovered a new class of TLR4 agonist with a species preference profile differing from MPL. Products of the 4-component Ugi synthesis reaction were demonstrated to potently trigger human TLR4-transfected HEK cells but not mouse TLR4, although inclusion of the human MD2 with mTLR4 was able to partially recover activity. Co-expression of CD14 was not required for optimal activity of Ugi compounds on transfected cells, as it is for LPS. The species preference profile for the panel of Ugi compounds was found to be strongly active for human and cynomolgus monkey primary cells, with reduced but still substantial activity for most Ugi compounds on guinea pig cells. Mouse, rat, rabbit, ferret, and cotton rat cells displayed little or no activity when exposed to Ugi compounds. However, engineering the human versions of TLR4 and MD2 to be expressed in mTLR4/MD2 deficient mice allowed for robust activity by Ugi compounds both in vitro and in vivo. These findings extend the range of compounds available for development as agonists of TLR4 and identify novel molecules which reverse the TLR4 triggering preference of MPL for mouse TLR4 over human TLR4. Such compounds may be amenable to formulation as more potent human-specific TLR4L-based adjuvants than typical MPL-based adjuvants.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract
We present James Webb Space Telescope (JWST) Mid-Infrared Instrument (MIRI) integral-field spectroscopy of the nearby merging, luminous infrared galaxy, NGC 7469. This galaxy hosts a Seyfert ...type-1.5 nucleus, a highly ionized outflow, and a bright, circumnuclear star-forming ring, making it an ideal target to study active galactic nucleus (AGN) feedback in the local universe. We take advantage of the high spatial/spectral resolution of JWST/MIRI to isolate the star-forming regions surrounding the central active nucleus and study the properties of the dust and warm molecular gas on ∼100 pc scales. The starburst ring exhibits prominent polycyclic aromatic hydrocarbon (PAH) emission, with grain sizes and ionization states varying by only ∼30%, and a total star formation rate of 10–30
M
⊙
yr
−1
derived from fine structure and recombination emission lines. Using pure rotational lines of H
2
we detect 1.2 × 10
7
M
⊙
of warm molecular gas at a temperature higher than 200 K in the ring. All PAH bands get significantly weaker toward the central source, where larger and possibly more ionized grains dominate the emission, likely the result of the ionizing radiation and/or the fast wind emerging from the AGN. The small grains and warm molecular gas in the bright regions of the ring however display properties consistent with normal star-forming regions. These observations highlight the power of JWST to probe the inner regions of dusty, rapidly evolving galaxies for signatures of feedback and inform models that seek to explain the coevolution of supermassive black holes and their hosts.
Failures in sand in reduced gravity environments Marshall, Jason P.; Hurley, Ryan C.; Arthur, Dan ...
Journal of the mechanics and physics of solids,
April 2018, 2018-04-00, 20180401, Letnik:
113
Journal Article
Recenzirano
The strength of granular materials, specifically sand is important for understanding physical phenomena on other celestial bodies. However, relatively few experiments have been conducted to determine ...the dependence of strength properties on gravity. In this work, we experimentally investigated relative values of strength (the peak friction angle, the residual friction angle, the angle of repose, and the peak dilatancy angle) in Earth, Martian, Lunar, and near-zero gravity. The various angles were captured in a classical passive Earth pressure experiment conducted on board a reduced gravity flight and analyzed using digital image correlation. The data showed essentially no dependence of the peak friction angle on gravity, a decrease in the residual friction angle between Martian and Lunar gravity, no dependence of the angle of repose on gravity, and an increase in the dilation angle between Martian and Lunar gravity. Additionally, multiple flow surfaces were seen in near-zero gravity. These results highlight the importance of understanding strength and deformation mechanisms of granular materials at different levels of gravity.
Despite considerable efforts at developing therapeutic vaccines for cancer, clinical translation of preclinical successes has been challenging, largely due to the difficulty of inducing strong and ...sustained cytotoxic T lymphocyte (CTL) responses in patients. Several peptide-based cancer vaccines have failed to show sustainable tumor regression in the clinic, possibly because of a lack of optimization of both the adjuvant and antigen components of the preparations. Here, we aimed to develop and optimize a vaccine format utilizing a synthetic long peptide (SLP) containing the human papilloma virus 16 (HPV16) E7 antigen, with a centrally located defined MHC class I epitope, and evaluate its immunogenicity and efficacy in combination with various adjuvant formulations.
E7
SLP was tested alone or in combination with toll-like receptor (TLR)3, TLR4, TLR7/8 and TLR9 agonists and formulated in oil-in-water (o/w) or water-in-oil (w/o) emulsions to determine a vaccine format inducing a robust CD8 T cell response in murine models. Once a lead vaccine format was determined, we examined its ability to inhibit tumor growth in the murine TC-1 model that expresses HPV16 E7 antigen.
We identified the TLR9 agonist CpG formulated in a squalene-based o/w emulsion as the most potent adjuvant, inducing the expansion of multifunctional antigen specific CD8 T cells with cytolytic potential. We also demonstrated that SLP E7
+ CpG + o/w emulsion vaccine can provide prophylactic and more importantly, therapeutic benefit in the TC-1 murine tumor model.
Our results demonstrate that the novel vaccine format E7 SLP + CpG delivered in an o/w emulsion holds potential for the promotion of strong CTL responses and tumor eradication and encourages further development of peptide/adjuvant vaccines in cancer immunotherapy strategies.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
In an era of rapid advances in artificial intelligence, the deployment of robots in organizations is accelerating. Further, robotic capabilities are expanding to serve a broader range of leadership ...behaviors related to task accomplishment and relationship support. Despite the increasing use of robots in various roles across different industries, research on human-robot collaboration in the workplace is lagging behind. As such, the current research aims to provide a state-of-the-science review and directions for future work in this underdeveloped area. Drawing on current leadership paradigms, we review human-robot collaboration studies from four academic disciplines with a history of publishing such work (i.e., management, economics, psychology, engineering) and propose that the research trajectory of human-robot collaboration parallels the evolution of leadership research paradigms (i.e., leader centric, relational view, and follower centric). Given that leadership is an inherently multilevel phenomenon, we apply a levels-of-analysis framework to integrate and synthesize human-robot collaboration studies from cross-disciplinary research areas. Based on our findings, we offer suggestions for future research in terms of conceptualization, theory building and testing, practical implications, and ethical considerations.
Abstract
James Webb Space Telescope (JWST) Mid-Infrared Instrument (MIRI) images of the luminous infrared (IR) galaxy VV 114 are presented. This redshift ∼0.020 merger has a western component (VV ...114W) rich in optical star clusters and an eastern component (VV 114E) hosting a luminous mid-IR nucleus hidden at UV and optical wavelengths by dust lanes. With MIRI, the VV 114E nucleus resolves primarily into bright NE and SW cores separated by 630 pc. This nucleus comprises 45% of the 15
μ
m light of VV 114, with the NE and SW cores having IR luminosities,
L
IR
(8 − 1000
μ
m) ∼ 8 ± 0.8 × 10
10
L
⊙
and ∼ 5 ± 0.5 × 10
10
L
⊙
, respectively, and IR densities, Σ
IR
≳ 2 ± 0.2 × 10
13
L
⊙
kpc
−2
and ≳ 7 ± 0.7 × 10
12
L
⊙
kpc
−2
, respectively—in the range of Σ
IR
for the Orion star-forming core and the nuclei of Arp 220. The NE core, previously speculated to have an active galactic nucleus (AGN), has starburst-like mid-IR colors. In contrast, the VV 114E SW core has AGN-like colors. Approximately 40 star-forming knots with
L
IR
∼ 0.02–5 × 10
10
L
⊙
are identified, 28% of which have no optical counterpart. Finally, diffuse emission accounts for 40%–60% of the mid-IR emission. Mostly notably, filamentary polycyclic aromatic hydrocarbon (PAH) emission stochastically excited by UV and optical photons accounts for half of the 7.7
μ
m light of VV 114. This study illustrates the ability of JWST to detect obscured compact activity and distributed PAH emission in the most extreme starburst galaxies in the local universe.
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