An epidemiologic systems analysis of diarrhea in children in Pakistan is presented. Application of additive Bayesian network modeling to 2005-2006 data from the Pakistan Social and Living Standards ...Measurement Survey reveals the complexity of child diarrhea as a disease system. The key distinction between standard analytical approaches, such as multivariable regression, and Bayesian network analyses is that the latter attempt to not only identify statistically associated variables but also, additionally and empirically, separate these into those directly and indirectly dependent upon the outcome variable. Such discrimination is vastly more ambitious but has the potential to reveal far more about key features of complex disease systems. Additive Bayesian network analyses across 41 variables from the Pakistan Social and Living Standards Measurement Survey identified 182 direct dependencies but with only 3 variables: 1) access to a dry pit latrine (protective; odds ratio = 0.67); 2) access to an atypical water source (protective; odds ratio = 0.49); and 3) no formal garbage collection (unprotective; odds ratio = 1.32), supported as directly dependent with the presence of diarrhea. All but 2 of the remaining variables were also, in turn, directly or indirectly dependent upon these 3 key variables. These results are contrasted with the use of a standard approach (multivariable regression).
This study examines the relationship between synovial hypoxia and cellular bioenergetics with synovial inflammation.
Primary rheumatoid arthritis synovial fibroblasts (RASF) were cultured with ...hypoxia, dimethyloxalylglycine (DMOG) or metabolic intermediates. Mitochondrial respiration, mitochondrial DNA mutations, cell invasion, cytokines, glucose and lactate were quantified using specific functional assays. RASF metabolism was assessed by the XF24-Flux Analyzer. Mitochondrial structural morphology was assessed by transmission electron microscopy (TEM). In vivo synovial tissue oxygen (tpO
mmHg) was measured in patients with inflammatory arthritis (n=42) at arthroscopy, and markers of glycolysis/oxidative phosphorylation (glyceraldehyde 3-phosphate dehydrogenase (GAPDH), PKM2, GLUT1, ATP) were quantified by immunohistology. A subgroup of patients underwent contiguous MRI and positron emission tomography (PET)/CT imaging. RASF and human dermal microvascular endothelial cells (HMVEC) migration/angiogenesis, transcriptional activation (HIF1α, pSTAT3, Notch1-IC) and cytokines were examined in the presence of glycolytic inhibitor 3-(3-Pyridinyl)-1-(4-pyridinyl)-2-propen-1-one (3PO).
DMOG significantly increased mtDNA mutations, mitochondrial membrane potential, mitochondrial mass, reactive oxygen species and glycolytic RASF activity with concomitant attenuation of mitochondrial respiration and ATP activity (all p<0.01). This was coupled with altered mitochondrial morphology. Hypoxia-induced lactate levels (p<0.01), which in turn induced basic fibroblast growth factor (bFGF) secretion and RASF invasiveness (all p<0.05). In vivo glycolytic markers were inversely associated with synovial tpO
levels <20 mm Hg, in contrast ATP was significantly reduced (all p<0.05). Decrease in GAPDH and GLUT1 was paralleled by an increase in in vivo tpO
in tumour necrosis factor alpha inhibitor (TNFi) responders. Novel PET/MRI hybrid imaging demonstrated close association between metabolic activity and inflammation. 3PO significantly inhibited RASF invasion/migration, angiogenic tube formation, secretion of proinflammatory mediators (all p<0.05), and activation of HIF1α, pSTAT3 and Notch-1IC under normoxic and hypoxic conditions.
Hypoxia alters cellular bioenergetics by inducing mitochondrial dysfunction and promoting a switch to glycolysis, supporting abnormal angiogenesis, cellular invasion and pannus formation.
Ammonia (NH3) is a promising energy resource owing to its high hydrogen density. However, its widespread application is restricted by the lack of efficient and corrosion-resistant storage materials. ...Here, we report high NH3 adsorption in a series of robust metal–organic framework (MOF) materials, MFM-300(M) (M = Fe, V, Cr, In). MFM-300(M) (M = Fe, VIII, Cr) show fully reversible capacity for >20 cycles, reaching capacities of 16.1, 15.6, and 14.0 mmol g–1, respectively, at 273 K and 1 bar. Under the same conditions, MFM-300(VIV) exhibits the highest uptake among this series of MOFs of 17.3 mmol g–1. In situ neutron powder diffraction, single-crystal X-ray diffraction, and electron paramagnetic resonance spectroscopy confirm that the redox-active V center enables host–guest charge transfer, with VIV being reduced to VIII and NH3 being oxidized to hydrazine (N2H4). A combination of in situ inelastic neutron scattering and DFT modeling has revealed the binding dynamics of adsorbed NH3 within these MOFs to afford a comprehensive insight into the application of MOF materials to the adsorption and conversion of NH3.
Photosynthetic CO
fixation in plants is limited by the inefficiency of the CO
-assimilating enzyme Rubisco. In most eukaryotic algae, Rubisco aggregates within a microcompartment known as the ...pyrenoid, in association with a CO
-concentrating mechanism that improves photosynthetic operating efficiency under conditions of low inorganic carbon. Recent work has shown that the pyrenoid matrix is a phase-separated, liquid-like condensate. In the alga Chlamydomonas reinhardtii, condensation is mediated by two components: Rubisco and the linker protein EPYC1 (Essential Pyrenoid Component 1). Here, we show that expression of mature EPYC1 and a plant-algal hybrid Rubisco leads to spontaneous condensation of Rubisco into a single phase-separated compartment in Arabidopsis chloroplasts, with liquid-like properties similar to a pyrenoid matrix. This work represents a significant initial step towards enhancing photosynthesis in higher plants by introducing an algal CO
-concentrating mechanism, which is predicted to significantly increase the efficiency of photosynthetic CO
uptake.
Cyanobacteria are key organisms in the global ecosystem, useful models for studying metabolic and physiological processes conserved in photosynthetic organisms, and potential renewable platforms for ...production of chemicals. Characterizing cyanobacterial metabolism and physiology is key to understanding their role in the environment and unlocking their potential for biotechnology applications. Many aspects of cyanobacterial biology differ from heterotrophic bacteria. For example, most cyanobacteria incorporate a series of internal thylakoid membranes where both oxygenic photosynthesis and respiration occur, while CO2 fixation takes place in specialized compartments termed carboxysomes. In this review, we provide a comprehensive summary of our knowledge on cyanobacterial physiology and the pathways in Synechocystis sp. PCC 6803 (Synechocystis) involved in biosynthesis of sugar-based metabolites, amino acids, nucleotides, lipids, cofactors, vitamins, isoprenoids, pigments and cell wall components, in addition to the proteins involved in metabolite transport. While some pathways are conserved between model cyanobacteria, such as Synechocystis, and model heterotrophic bacteria like Escherichia coli, many enzymes and/or pathways involved in the biosynthesis of key metabolites in cyanobacteria have not been completely characterized. These include pathways required for biosynthesis of chorismate and membrane lipids, nucleotides, several amino acids, vitamins and cofactors, and isoprenoids such as plastoquinone, carotenoids, and tocopherols. Moreover, our understanding of photorespiration, lipopolysaccharide assembly and transport, and degradation of lipids, sucrose, most vitamins and amino acids, and haem, is incomplete. We discuss tools that may aid our understanding of cyanobacterial metabolism, notably CyanoSource, a barcoded library of targeted Synechocystis mutants, which will significantly accelerate characterization of individual proteins.
Two-dimensional (2D) materials provide a unique platform for spintronics and valleytronics due to the ability to combine vastly different functionalities into one vertically stacked heterostructure, ...where the strengths of each of the constituent materials can compensate for the weaknesses of the others. Graphene has been demonstrated to be an exceptional material for spin transport at room temperature; however, it lacks a coupling of the spin and optical degrees of freedom. In contrast, spin/valley polarization can be efficiently generated in monolayer transition metal dichalcogenides (TMD) such as MoS2 via absorption of circularly polarized photons, but lateral spin or valley transport has not been realized at room temperature. In this Letter, we fabricate monolayer MoS2/few-layer graphene hybrid spin valves and demonstrate, for the first time, the opto-valleytronic spin injection across a TMD/graphene interface. We observe that the magnitude and direction of spin polarization is controlled by both helicity and photon energy. In addition, Hanle spin precession measurements confirm optical spin injection, spin transport, and electrical detection up to room temperature. Finally, analysis by a one-dimensional drift-diffusion model quantifies the optically injected spin current and the spin transport parameters. Our results demonstrate a 2D spintronic/valleytronic system that achieves optical spin injection and lateral spin transport at room temperature in a single device, which paves the way for multifunctional 2D spintronic devices for memory and logic applications.
Angiotensin-converting enzyme 2 (ACE2) is the main entry point in airway epithelial cells for SARS-CoV-2. ACE2 binding to the SARS-CoV-2 protein spike triggers viral fusion with the cell plasma ...membrane, resulting in viral RNA genome delivery into the host. Despite ACE2's critical role in SARS-CoV-2 infection, full understanding of ACE2 expression, including in response to viral infection, remains unclear. ACE2 was thought to encode five transcripts and one protein of 805 amino acids. In the present study, we identify a novel short isoform of ACE2 expressed in the airway epithelium, the main site of SARS-CoV-2 infection. Short ACE2 is substantially upregulated in response to interferon stimulation and rhinovirus infection, but not SARS-CoV-2 infection. This short isoform lacks SARS-CoV-2 spike high-affinity binding sites and, altogether, our data are consistent with a model where short ACE2 is unlikely to directly contribute to host susceptibility to SARS-CoV-2 infection.
We present a new four‐parameter model of the D‐region (60–90 km) ionospheric electron density, useful in very low frequency (VLF, 3–30 kHz) remote sensing. VLF waves have a long history of use to ...indirectly infer D‐region conditions, as they reflect efficiently and thus are sensitive to small changes in the electron density. Most historical efforts use VLF observations along with a forward model of the D‐region and VLF propagation. The ionospheric assumptions in the forward model are altered until the output matches the observation. The most common D‐region model, known as the Wait‐Spies ionosphere, takes the electron density as exponentially increasing with altitude and specifies a height and steepness. This model was designed to capture the VLF propagation variations evident at a single frequency. The real D‐region is likely more complex. The limited number of D‐region rocket passes that have previously been compiled tend to show the existence of a “ledge” somewhere between 70 and 90 km. Broadband VLF signals emitted from lightning allows a more sophisticated parametrization. Using carefully averaged amplitudes and phases of VLF sferics, we formulate a more general four‐parameter D‐region model that includes a ledge discontinuity. Using lightning‐emitted VLF observations along with a theoretical model, we find that this model better describes the ionosphere during the daytime. During the ambient nighttime and during a solar flare the two‐parameter ionosphere may be sufficient, at least for the purposes of calculating broadband VLF propagation, since the ledge either weakens or moves outside the altitude range of VLF sensitivity.
Plain Language Summary
The Earth's ionosphere can be thought of as the border zone between Earth's atmosphere and space environment, between 60 and 1,000 km altitude. In this region, the thinning air is electrically charged by radiation from the sun, among other things, creating many free electrons. The ionosphere is important because, for example, it impacts several important forms of communication, both ground‐to‐ground and satellite‐to‐ground. The lowest part of the ionosphere is called the D‐region 60–90 km, and it is particularly tough to measure. For decades, researchers have fit a line to describe the number of electrons in the D‐region as a function of altitude. Fitting a line is not so good but it is often the best we can do since we have so little information. It is probably not very close to reality. By using untapped information contained in the radio emissions from lightning, which propagate in the VLF band (3–30 kHz) many thousands of kilomerter, we are able to describe the D‐region conditions with a more complicated shape that is closer to the physical reality.
Key Points
A new four‐parameter model of D‐region ionospheric electron density is introduced to better capture the D‐region ledge
With this model, VLF remote sensing with broadband lightning sferics detect the depth and location of the ledge during the daytime
During a solar flares and at nighttime, the ledge either dissipates or falls outside the altitude range of VLF sensitivity
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