The pursuit of future energy systems that can meet electricity demands while supporting the attainment of societal environment goals, including mitigating climate change and reducing pollution in the ...air, has led to questions regarding the viability of continued use of natural gas. Natural gas use, particularly for electricity generation, has increased in recent years due to enhanced resource availability from non-traditional reserves and pressure to reduce greenhouse gasses (GHG) from higher-emitting sources, including coal generation. While lower than coal emissions, current natural gas power generation strategies primarily utilize combustion with higher emissions of GHG and criteria pollutants than other low-carbon generation options, including renewable resources. Furthermore, emissions from life cycle stages of natural gas production and distribution can have additional detrimental GHG and air quality (AQ) impacts. On the other hand, natural gas power generation can play an important role in supporting renewable resource integration by (1) providing essential load balancing services, and (2) supporting the use of gaseous renewable fuels through the existing infrastructure of the natural gas system. Additionally, advanced technologies and strategies including fuel cells and combined cooling heating and power (CCHP) systems can facilitate natural gas generation with low emissions and high efficiencies. Thus, the role of natural gas generation in the context of GHG mitigation and AQ improvement is complex and multi-faceted, requiring consideration of more than simple quantification of total or net emissions. If appropriately constructed and managed, natural gas generation could support and advance sustainable and renewable energy. In this paper, a review of the literature regarding emissions from natural gas with a focus on power generation is conducted and discussed in the context of GHG and AQ impacts. In addition, a pathway forward is proposed for natural gas generation and infrastructure to maximize environmental benefits and support renewable resources in the attainment of emission reductions.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
In structure-based virtual screening, compound ranking through a consensus of scores from a variety of docking programs or scoring functions, rather than ranking by scores from a single program, ...provides better predictive performance and reduces target performance variability. Here we compare traditional consensus scoring methods with a novel, unsupervised gradient boosting approach. We also observed increased score variation among active ligands and developed a statistical mixture model consensus score based on combining score means and variances. To evaluate performance, we used the common performance metrics ROCAUC and EF1 on 21 benchmark targets from DUD-E. Traditional consensus methods, such as taking the mean of quantile normalized docking scores, outperformed individual docking methods and are more robust to target variation. The mixture model and gradient boosting provided further improvements over the traditional consensus methods. These methods are readily applicable to new targets in academic research and overcome the potentially poor performance of using a single docking method on a new target.
Full text
Available for:
IJS, KILJ, NUK, PNG, UL, UM
Combination anti-cytotoxic T lymphocyte antigen 4 (CTLA-4) and anti-programmed cell death protein 1 (PD-1) therapy promotes antitumor immunity and provides superior benefit to patients with ...advanced-stage melanoma compared with either therapy alone. T cell immunity requires recognition of antigens in the context of major histocompatibility complex (MHC) class I and class II proteins by CD8
and CD4
T cells, respectively. We examined MHC class I and class II protein expression on tumor cells from previously untreated melanoma patients and correlated the results with transcriptional and genomic analyses and with clinical response to anti-CTLA-4, anti-PD-1, or combination therapy. Most (>50% of cells) or complete loss of melanoma MHC class I membrane expression was observed in 78 of 181 cases (43%), was associated with transcriptional repression of
,
,
, and
, and predicted primary resistance to anti-CTLA-4, but not anti-PD-1, therapy. Melanoma MHC class II membrane expression on >1% cells was observed in 55 of 181 cases (30%), was associated with interferon-γ (IFN-γ) and IFN-γ-mediated gene signatures, and predicted response to anti-PD-1, but not anti-CTLA-4, therapy. We conclude that primary response to anti-CTLA-4 requires robust melanoma MHC class I expression. In contrast, primary response to anti-PD-1 is associated with preexisting IFN-γ-mediated immune activation that includes tumor-specific MHC class II expression and components of innate immunity when MHC class I is compromised. The benefits of combined checkpoint blockade may be attributable, in part, to distinct requirements for melanoma-specific antigen presentation to initiate antitumor immunity.
NG2-expressing glia (NG2 glia) are a uniformly distributed and mitotically active pool of cells in the central nervous system (CNS). In addition to serving as progenitors of myelinating ...oligodendrocytes, NG2 glia might also fulfill physiological roles in CNS homeostasis, although the mechanistic nature of such roles remains unclear. Here, we report that ablation of NG2 glia in the prefrontal cortex (PFC) of the adult brain causes deficits in excitatory glutamatergic neurotransmission and astrocytic extracellular glutamate uptake and induces depressive-like behaviors in mice. We show in parallel that chronic social stress causes NG2 glia density to decrease in areas critical to Major Depressive Disorder (MDD) pathophysiology at the time of symptom emergence in stress-susceptible mice. Finally, we demonstrate that loss of NG2 glial secretion of fibroblast growth factor 2 (FGF2) suffices to induce the same behavioral deficits. Our findings outline a pathway and role for NG2 glia in CNS homeostasis and mood disorders.
•NG2 glia loss affects the glutaminergic systems in the PFC•NG2 glia loss in the PFC induces behavioral deficits via loss of secreted FGF2•NG2 glia density is reduced in subjects with MDD and in susceptible mice after SDSP•Restoration of NG2 glia density rescues cellular and behavioral aberrations
Functional contribution of glia to the pathophysiology of mental disorders is poorly understood. Birey and colleagues describe a role for NG2 glial cell in mediating CNS homeostasis, the loss of which leads to the emergence of depressive-like behaviors in mice.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Movement is fundamental to human and animal life, emerging through interaction of complex neural, muscular, and skeletal systems. Study of movement draws from and contributes to diverse fields, ...including biology, neuroscience, mechanics, and robotics. OpenSim unites methods from these fields to create fast and accurate simulations of movement, enabling two fundamental tasks. First, the software can calculate variables that are difficult to measure experimentally, such as the forces generated by muscles and the stretch and recoil of tendons during movement. Second, OpenSim can predict novel movements from models of motor control, such as kinematic adaptations of human gait during loaded or inclined walking. Changes in musculoskeletal dynamics following surgery or due to human-device interaction can also be simulated; these simulations have played a vital role in several applications, including the design of implantable mechanical devices to improve human grasping in individuals with paralysis. OpenSim is an extensible and user-friendly software package built on decades of knowledge about computational modeling and simulation of biomechanical systems. OpenSim's design enables computational scientists to create new state-of-the-art software tools and empowers others to use these tools in research and clinical applications. OpenSim supports a large and growing community of biomechanics and rehabilitation researchers, facilitating exchange of models and simulations for reproducing and extending discoveries. Examples, tutorials, documentation, and an active user forum support this community. The OpenSim software is covered by the Apache License 2.0, which permits its use for any purpose including both nonprofit and commercial applications. The source code is freely and anonymously accessible on GitHub, where the community is welcomed to make contributions. Platform-specific installers of OpenSim include a GUI and are available on simtk.org.
Full text
Available for:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Cultivated strawberry emerged from the hybridization of two wild octoploid species, both descendants from the merger of four diploid progenitor species into a single nucleus more than 1 million years ...ago. Here we report a near-complete chromosome-scale assembly for cultivated octoploid strawberry (Fragaria × ananassa) and uncovered the origin and evolutionary processes that shaped this complex allopolyploid. We identified the extant relatives of each diploid progenitor species and provide support for the North American origin of octoploid strawberry. We examined the dynamics among the four subgenomes in octoploid strawberry and uncovered the presence of a single dominant subgenome with significantly greater gene content, gene expression abundance, and biased exchanges between homoeologous chromosomes, as compared with the other subgenomes. Pathway analysis showed that certain metabolomic and disease-resistance traits are largely controlled by the dominant subgenome. These findings and the reference genome should serve as a powerful platform for future evolutionary studies and enable molecular breeding in strawberry.
Full text
Available for:
EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Ferroptosis is a form of cell death that results from the catastrophic accumulation of lipid reactive oxygen species (ROS). Oncogenic signaling elevates lipid ROS production in many tumor types and ...is counteracted by metabolites that are derived from the amino acid cysteine. In this work, we show that the import of oxidized cysteine (cystine) via system x
is a critical dependency of pancreatic ductal adenocarcinoma (PDAC), which is a leading cause of cancer mortality. PDAC cells used cysteine to synthesize glutathione and coenzyme A, which, together, down-regulated ferroptosis. Studying genetically engineered mice, we found that the deletion of a system x
subunit,
, induced tumor-selective ferroptosis and inhibited PDAC growth. This was replicated through the administration of cyst(e)inase, a drug that depletes cysteine and cystine, demonstrating a translatable means to induce ferroptosis in PDAC.
Clonal hemopoiesis driven by leukemia-associated gene mutations can occur without evidence of a blood disorder. To investigate this phenomenon, we interrogated 15 mutation hot spots in blood DNA from ...4,219 individuals using ultra-deep sequencing. Using only the hot spots studied, we identified clonal hemopoiesis in 0.8% of individuals under 60, rising to 19.5% of those ≥90 years, thus predicting that clonal hemopoiesis is much more prevalent than previously realized. DNMT3A-R882 mutations were most common and, although their prevalence increased with age, were found in individuals as young as 25 years. By contrast, mutations affecting spliceosome genes SF3B1 and SRSF2, closely associated with the myelodysplastic syndromes, were identified only in those aged >70 years, with several individuals harboring more than one such mutation. This indicates that spliceosome gene mutations drive clonal expansion under selection pressures particular to the aging hemopoietic system and explains the high incidence of clonal disorders associated with these mutations in advanced old age.
Display omitted
•Clonal hemopoiesis is an almost inevitable consequence of aging in humans•Spliceosome gene mutations drove clonal hemopoiesis only in persons aged ≥70 years•NPM1 mutations behave as gatekeepers for leukemogenesis
McKerrell et al. employ ultra-deep sequencing to show that age-related clonal hemopoiesis is much more common than previously realized. They find that clonal hemopoiesis, driven by mutations in spliceosome genes SF3B1 and SRSF2, was noted exclusively in individuals aged 70 years or older and that NPM1 mutations are not seen in association with this phenomenon, endorsing their close association with leukemogenesis.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Over the past few decades, groundwater wells installed in rural areas throughout the major river basins draining the Himalayas have become the main source of drinking water for tens of millions of ...people. Groundwater in this region is much less likely to contain microbial pathogens than surface water but often contains hazardous amounts of arsenic--a known carcinogen. Arsenic enters groundwater naturally from rocks and sediment by coupled biogeochemical and hydrologic processes, some of which are presently affected by human activity. Mitigation of the resulting health crisis in South and Southeast Asia requires an understanding of the transport of arsenic and key reactants such as organic carbon that could trigger release in zones with presently low groundwater arsenic levels.
Highlights • We surveyed the literature for clinical applications of wearable systems. • Wearable sensing can identify movement disorders and assess surgical outcomes. • Wearable feedback can improve ...walking stability and reduce joint loading. • Future work should implement in natural environments such as home or work.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
PDF
