Intra- and interspecies interactions between prion proteins and effects of mutations and polymorphisms

Recently, crystallization of the prion protein in a dimeric form was reported. Here we show that native soluble homogenous FLAG-tagged prion proteins from hamster, man and cattle expressed in the baculovirus system are predominantly dimeric. The PrP/PrP interaction was confirmed in Semliki Forest virus-RNA transfected BHK cells co-expressing FLAG- and oligohistidine-tagged human PrP. The yeast two-hybrid system identified the octarepeat region and the C-terminal structured domain (aa90-aa230) of PrP as PrP/PrP interaction domains. Additional octarepeats identified in patients suffering from fCJD reduced (wtPrP versus PrP+90R) and completely abolished (PrP+90R versus PrP+90R) the PrP/PrP interaction in the yeast two-hybrid system. In contrast, the Met/Val polymorphism (aa129), the GSS mutation Pro102Leu and the FFI mutation Asp178Asn did not affect PrP/PrP interactions. Proof of interactions between human or sheep and bovine PrP, and sheep and human PrP, as well as lack of interactions between human or bovine PrP and hamster PrP suggest that interspecies PrP interaction studies in the yeast two-hybrid system may serve as a rapid pre-assay to investigate species barriers in prion diseases

Differential expression of the nuclear-encoded mitochondrial transcriptome in pediatric septic shock.

INTRODUCTION: Increasing evidence supports a role for mitochondrial dysfunction in organ injury and immune dysregulation in sepsis. Although differential expression of mitochondrial genes in blood cells has been reported for several diseases in which bioenergetic failure is a postulated mechanism, there are no data about the blood cell mitochondrial transcriptome in pediatric sepsis. METHODS: We conducted a focused analysis using a multicenter genome-wide expression database of 180 children ≤ 10 years of age with septic shock and 53 healthy controls. Using total RNA isolated from whole blood within 24 hours of PICU admission for septic shock, we evaluated 296 nuclear-encoded mitochondrial genes using a false discovery rate of 1%. A series of bioinformatic approaches were applied to compare differentially expressed genes across previously validated gene expression-based subclasses (groups A, B, and C) of pediatric septic shock. RESULTS: In total, 118 genes were differentially regulated in subjects with septic shock compared to healthy controls, including 48 genes that were upregulated and 70 that were downregulated. The top scoring canonical pathway was oxidative phosphorylation, with general downregulation of the 51 genes corresponding to the electron transport system (ETS). The top two gene networks were composed primarily of mitochondrial ribosomal proteins highly connected to ETS complex I, and genes encoding for ETS complexes I, II, and IV that were highly connected to the peroxisome proliferator activated receptor (PPAR) family. There were 162 mitochondrial genes differentially regulated between groups A, B, and C. Group A, which had the highest maximum number of organ failures and mortality, exhibited a greater downregulation of mitochondrial genes compared to groups B and C. CONCLUSIONS: Based on a focused analysis of a pediatric septic shock transcriptomic database, nuclear-encoded mitochondrial genes were differentially regulated early in pediatric septic shock compared to healthy controls, as well as across genotypic and phenotypic distinct pediatric septic shock subclasses. The nuclear genome may be an important mechanism contributing to alterations in mitochondrial bioenergetic function and outcomes in pediatric sepsis

Refining the Pediatric Multiple Organ Dysfunction Syndrome

Since its introduction into the medical literature in the 1970s, the term multiple organ dysfunction syndrome (or some variant) has been applied broadly to any patient with >1 concurrent organ dysfunction. However, the epidemiology, mechanisms, time course, and outcomes among children with multiple organ dysfunction vary substantially. We posit that the term pediatric multiple organ dysfunction syndrome (or MODS) should be reserved for patients with a systemic pathologic state resulting from a common mechanism (or mechanisms) that affects numerous organ systems simultaneously. In contrast, children in whom organ injuries are attributable to distinct mechanisms should be considered to have additive organ system dysfunctions but not the syndrome of MODS. Although such differentiation may not always be possible with current scientific knowledge, we make the case for how attempts to differentiate multiple organ dysfunction from other states of additive organ dysfunctions can help to evolve clinical and research priorities in diagnosis, monitoring, and therapy from largely organ-specific to more holistic strategies

An extreme proto-cluster of luminous dusty starbursts in the early Universe

We report the identification of an extreme proto-cluster of galaxies in the early Universe whose core (nicknamed Distant Red Core, DRC) is formed by at least ten dusty star-forming galaxies (DSFGs), confirmed to lie at $z_{\rm spec} = 4.002$ via detection of [CI](1-0), $^{12}$CO(6-5), $^{12}$CO(4-3), $^{12}$CO(2-1) and ${\rm H_2O} (2_{11} - 2_{02})$ emission lines, detected using ALMA and ATCA. The spectroscopically-confirmed components of the proto-cluster are distributed over a ${\rm 260\, kpc \times 310\, kpc}$ region and have a collective obscured star-formation rate (SFR) of $\sim 6500 \, M_\odot \, {\rm yr}^{-1}$, considerably higher than has been seen before in any proto-cluster of galaxies or over-densities of DSFGs at $z \gtrsim 4$. Most of the star formation is taking place in luminous DSFGs since no Ly$\alpha$ emitters are detected in the proto-cluster core, apart from a Ly$\alpha$ blob located next to one of the DRC dusty components and extending over $60\,{\rm kpc}$. The total obscured SFR of the proto-cluster could rise to ${\rm SFR} \sim 14,400 \, M_\odot \, {\rm yr}^{-1}$ if all the members of an over-density of bright DSFGs discovered around DRC in a wide-field LABOCA 870-$\mu$m image are part of the same structure. The total halo mass of DRC could be as high as $\sim 4.4 \times 10^{13}\,M_\odot$ and could be the progenitor of a Coma-like cluster at $z = 0$. The relatively short gas-depletion times of the DRC components suggest either the presence of a mechanism able to trigger extreme star formation simultaneously in galaxies spread over a few hundred kpc or the presence of gas flows from the cosmic web able to sustain star formation over several hundred million years.Comment: Submitted to ApJ. Minor updates added, including a change of the source name. Comments welcom

Scoring Systems for Organ Dysfunction and Multiple Organ Dysfunction: The PODIUM Consensus Conference

CONTEXT Multiple scores exist to characterize organ dysfunction in children. OBJECTIVE To review the literature on multiple organ dysfunction (MOD) scoring systems to estimate severity of illness and to characterize the performance characteristics of currently used scoring tools and clinical assessments for organ dysfunction in critically ill children. DATA SOURCES Electronic searches of PubMed and Embase were conducted from January 1992 to January 2020. STUDY SELECTION Studies were included if they evaluated critically ill children with MOD, evaluated the performance characteristics of scoring tools for MOD, and assessed outcomes related to mortality, functional status, organ-specific outcomes, or other patient-centered outcomes. DATA EXTRACTION Data were abstracted into a standard data extraction form by a task force member. RESULTS Of 1152 unique abstracts screened, 156 full text studies were assessed including a total of 54 eligible studies. The most commonly reported scores were the Pediatric Logistic Organ Dysfunction Score (PELOD), pediatric Sequential Organ Failure Assessment score (pSOFA), Pediatric Index of Mortality (PIM), PRISM, and counts of organ dysfunction using the International Pediatric Sepsis Definition Consensus Conference. Cut-offs for specific organ dysfunction criteria, diagnostic elements included, and use of counts versus weighting varied substantially. LIMITATIONS While scores demonstrated an increase in mortality associated with the severity and number of organ dysfunctions, the performance ranged widely. CONCLUSIONS The multitude of scores on organ dysfunction to assess severity of illness indicates a need for unified and data-driven organ dysfunction criteria, derived and validated in large, heterogenous international databases of critically ill children

Operando measurement of lattice strain in internal combustion engine components by neutron diffraction

Engineering neutron diffraction can nondestructively and noninvasively probe stress, strain, temperature, and phase evolutions deep within bulk materials. In this work, we demonstrate operando lattice strain measurement of internal combustion engine components by neutron diffraction. A modified commercial generator engine was mounted in the VULCAN diffractometer at the Spallation Neutron Source, and the lattice strains in both the cylinder block and head were measured under static nonfiring conditions as well as steady state and cyclic transient operation. The dynamic temporal response of the lattice strain change during transient operation was resolved in two locations by asynchronous stroboscopic neutron diffraction. We demonstrated that operando neutron measurements can allow for understanding of how materials behave throughout operational engineering devices. This study opens a pathway for the industrial and academic communities to better understand the complexities of material behavior during the operation of internal combustion engines and other real-scale devices and systems and to leverage techniques developed here for future investigations of numerous new platforms and alloys

Prediction of the in situ coronal mass ejection rate for solar cycle 25: Implications for Parker Solar Probe in situ observations

The Parker Solar Probe (PSP) and Solar Orbiter missions are designed to make groundbreaking observations of the Sun and interplanetary space within this decade. We show that a particularly interesting in situ observation of an interplanetary coronal mass ejection (ICME) by PSP may arise during close solar flybys ($< 0.1$~AU). During these times, the same magnetic flux rope inside an ICME could be observed in situ by PSP twice, by impacting its frontal part as well as its leg. Investigating the odds of this situation, we forecast the ICME rate in solar cycle 25 based on 2 models for the sunspot number (SSN): (1) the forecast of an expert panel in 2019 (maximum SSN = 115), and (2) a prediction by McIntosh et al. (2020, maximum SSN = 232). We link the SSN to the observed ICME rates in solar cycles 23 and 24 with the Richardson and Cane list and our own ICME catalog, and calculate that between 1 and 7 ICMEs will be observed by PSP at heliocentric distances $< 0.1$ AU until 2025, including 1$\sigma$ uncertainties. We then model the potential flux rope signatures of such a double-crossing event with the semi-empirical 3DCORE flux rope model, showing a telltale elevation of the radial magnetic field component $B_R$, and a sign reversal in the component $B_N$ normal to the solar equator compared to field rotation in the first encounter. This holds considerable promise to determine the structure of CMEs close to their origin in the solar corona.Comment: 11 pages, 6 figures, accepted for publication in the Astrophysical Journal on 2020 September 1

The WRF Lightning Forecast Algorithm: Sensitivities to Microphysics and Other Physics Schemes in the Weather Research and Forecasting Model

No abstract availabl