High-fat, low-carbohydrate diets, known as ketogenic diets, have been used as a non-pharmacological treatment for refractory epilepsy. A key mechanism of this treatment is thought to be the ...generation of ketones, which provide brain cells (neurons and astrocytes) with an energy source that is more efficient than glucose, resulting in beneficial downstream metabolic changes, such as increasing adenosine levels, which might have effects on seizure control. However, some studies have challenged the central role of ketones because medium-chain fatty acids, which are part of a commonly used variation of the diet (the medium-chain triglyceride ketogenic diet), have been shown to directly inhibit AMPA receptors (glutamate receptors), and to change cell energetics through mitochondrial biogenesis. Through these mechanisms, medium-chain fatty acids rather than ketones are likely to block seizure onset and raise seizure threshold. The mechanisms underlying the ketogenic diet might also have roles in other disorders, such as preventing neurodegeneration in Alzheimer's disease, the proliferation and spread of cancer, and insulin resistance in type 2 diabetes. Analysing medium-chain fatty acids in future ketogenic diet studies will provide further insights into their importance in modified forms of the diet. Moreover, the results of these studies could facilitate the development of new pharmacological and dietary therapies for epilepsy and other disorders.
Safety surveillance of vaccines against COVID-19 is critical to ensure safety, maintain trust, and inform policy.
To monitor 23 serious outcomes weekly, using comprehensive health records on a ...diverse population.
This study represents an interim analysis of safety surveillance data from Vaccine Safety Datalink. The 10 162 227 vaccine-eligible members of 8 participating US health plans were monitored with administrative data updated weekly and supplemented with medical record review for selected outcomes from December 14, 2020, through June 26, 2021.
Receipt of BNT162b2 (Pfizer-BioNTech) or mRNA-1273 (Moderna) COVID-19 vaccination, with a risk interval of 21 days for individuals after vaccine dose 1 or 2 compared with an interval of 22 to 42 days for similar individuals after vaccine dose 1 or 2.
Incidence of serious outcomes, including acute myocardial infarction, Bell palsy, cerebral venous sinus thrombosis, Guillain-Barré syndrome, myocarditis/pericarditis, pulmonary embolism, stroke, and thrombosis with thrombocytopenia syndrome. Incidence of events that occurred among vaccine recipients 1 to 21 days after either dose 1 or 2 of a messenger RNA (mRNA) vaccine was compared with that of vaccinated concurrent comparators who, on the same calendar day, had received their most recent dose 22 to 42 days earlier. Rate ratios (RRs) were estimated by Poisson regression, adjusted for age, sex, race and ethnicity, health plan, and calendar day. For a signal, a 1-sided P < .0048 was required to keep type I error below .05 during 2 years of weekly analyses. For 4 additional outcomes, including anaphylaxis, only descriptive analyses were conducted.
A total of 11 845 128 doses of mRNA vaccines (57% BNT162b2; 6 175 813 first doses and 5 669 315 second doses) were administered to 6.2 million individuals (mean age, 49 years; 54% female individuals). The incidence of events per 1 000 000 person-years during the risk vs comparison intervals for ischemic stroke was 1612 vs 1781 (RR, 0.97; 95% CI, 0.87-1.08); for appendicitis, 1179 vs 1345 (RR, 0.82; 95% CI, 0.73-0.93); and for acute myocardial infarction, 935 vs 1030 (RR, 1.02; 95% CI, 0.89-1.18). No vaccine-outcome association met the prespecified requirement for a signal. Incidence of confirmed anaphylaxis was 4.8 (95% CI, 3.2-6.9) per million doses of BNT162b2 and 5.1 (95% CI, 3.3-7.6) per million doses of mRNA-1273.
In interim analyses of surveillance of mRNA COVID-19 vaccines, incidence of selected serious outcomes was not significantly higher 1 to 21 days postvaccination compared with 22 to 42 days postvaccination. While CIs were wide for many outcomes, surveillance is ongoing.
Situating Ecology as a Big-Data Science FARLEY, SCOTT S.; DAWSON, ANDRIA; GORING, SIMON J. ...
BioScience/Bioscience,
08/2018, Letnik:
68, Številka:
8
Journal Article
Recenzirano
Odprti dostop
Ecology has joined a world of big data. Two complementary frameworks define big data: data that exceed the analytical capacities of individuals or disciplines or the “Four Vs” axes of volume, ...variety, veracity, and velocity. Variety predominates in ecoinformatics and limits the scalability of ecological science. Volume varies widely. Ecological velocity is low but growing as data throughput and societal needs increase. Ecological big-data systems include in situ and remote sensors, community data resources, biodiversity databases, citizen science, and permanent stations. Technological solutions include the development of open code- and data-sharing platforms, flexible statistical models that can handle heterogeneous data and sources of uncertainty, and cloud-computing delivery of high-velocity computing to large-volume analytics. Cultural solutions include training targeted to early and current scientific workforce and strengthening collaborations among ecologists and data scientists. The broader goal is to maximize the power, scalability, and timeliness of ecological insights and forecasting.
The members of the pathogenesis-related protein 1 (PR-1) family are among the most abundantly produced proteins in plants on pathogen attack, and PR-1 gene expression has long been used as a marker ...for salicylic acid-mediated disease resistance. However, despite considerable interest over several decades, their requirement and role in plant defence remains poorly understood. Recent reports have emerged demonstrating that PR-1 proteins possess sterol-binding activity, harbour an embedded defence signalling peptide, and are targeted by plant pathogens during host infection. These studies have re-energised the field and provided long-awaited insights into a possible PR-1 function. Here we review the current status of PR-1 proteins and discuss how these recent advances shed light on putative roles for these enigmatic proteins.
Recent studies have shown that plant pathogenesis-related protein 1 (PR-1) family members bind sterols. This function is responsible for antimicrobial activity towards sterol auxotrophs such as Phytophthora species. However, the link between sterol binding and the proposed broader antimicrobial function of PR-1 remains unclear.
PR-1 proteins harbour an embedded C-terminal peptide (CAPE) involved in plant immune signalling. Evidence suggests that CAPE has a signalling role that facilitates defence responses against microbial pathogens and also herbivores. The CAPE response is independent of other defence signalling pathways such as those elicited by recognised pathogen-associated molecular patterns.
The significance of PR-1 proteins during plant–microbe interactions is now realised, with a growing list of identified pathogen effector proteins that directly interact with PR-1 during infection.
Upon recognition of pathogen virulence effectors, plant nucleotide-binding leucine-rich repeat (NLR) proteins induce defense responses including localized host cell death. In an effort to understand ...the molecular mechanisms leading to this response, we examined the Arabidopsis thaliana NLR protein RECOGNITION OF PERONOSPORA PARASITICA1 (RPP1), which recognizes the Hyaloperonospora arabidopsidis effector ARABIDOPSIS THALIANA RECOGNIZED1 (ATR1). Expression of the N-terminus of RPP1, including the Toll/interleukin-1 receptor (TIR) domain ("N-TIR"), elicited an effector-independent cell death response, and we used allelic variation in TIR domain sequences to define the key residues that contribute to this phenotype. Further biochemical characterization indicated that cell death induction was correlated with N-TIR domain self-association. In addition, we demonstrated that the nucleotide-binding (NB)-ARC1 region of RPP1 self-associates and plays a critical role in cell death activation, likely by facilitating TIR:TIR interactions. Structural homology modeling of the NB subdomain allowed us to identify a putative oligomerization interface that was shown to influence NB-ARC1 self-association. Significantly, full-length RPP1 exhibited effector-dependent oligomerization and, although mutations at the NB-ARC1 oligomerization interface eliminated cell death induction, RPP1 self-association was unaffected, suggesting that additional regions contribute to oligomerization. Indeed, the leucine-rich repeat domain of RPP1 also self-associates, indicating that multiple interaction interfaces exist within activated RPP1 oligomers. Finally, we observed numerous intramolecular interactions that likely function to negatively regulate RPP1, and present a model describing the transition to an active NLR protein.
SARM1 (sterile alpha and TIR motif containing 1) is responsible for depletion of nicotinamide adenine dinucleotide in its oxidized form (NAD
) during Wallerian degeneration associated with ...neuropathies. Plant nucleotide-binding leucine-rich repeat (NLR) immune receptors recognize pathogen effector proteins and trigger localized cell death to restrict pathogen infection. Both processes depend on closely related Toll/interleukin-1 receptor (TIR) domains in these proteins, which, as we show, feature self-association-dependent NAD
cleavage activity associated with cell death signaling. We further show that SARM1 SAM (sterile alpha motif) domains form an octamer essential for axon degeneration that contributes to TIR domain enzymatic activity. The crystal structures of ribose and NADP
(the oxidized form of nicotinamide adenine dinucleotide phosphate) complexes of SARM1 and plant NLR RUN1 TIR domains, respectively, reveal a conserved substrate binding site. NAD
cleavage by TIR domains is therefore a conserved feature of animal and plant cell death signaling pathways.
Cytoplasmic plant immune receptors recognize specific pathogen effector proteins and initiate effector-triggered immunity. In Arabidopsis, the immune receptors RPS4 and RRS1 are both required to ...activate defense to three different pathogens. We show that RPS4 and RRS1 physically associate. Crystal structures of the N-terminal Toll–interleukin-1 receptor/resistance (TIR) domains of RPS4 and RRS1, individually and as a heterodimeric complex (respectively at 2.05, 1.75, and 2.65 angstrom resolution), reveal a conserved TIR/TIR interaction interface. We show that TIR domain heterodimerization is required to form a functional RRS1/RPS4 effector recognition complex. The RPS4 TIR domain activates effector-independent defense, which is inhibited by the RRS1 TIR domain through the heterodimerization interface. Thus, RPS4 and RRS1 function as a receptor complex in which the two components play distinct roles in recognition and signaling.
The Toll/interleukin-1 receptor/resistance protein (TIR) domain is a protein–protein interaction domain consisting of 125–200 residues, widely distributed in animals, plants and bacteria but absent ...from fungi, archea and viruses. In plants and animals, these domains are found in proteins with functions in innate immune pathways, while in bacteria, some TIR domain-containing proteins interfere with the innate immune pathways in the host. TIR domains function as protein scaffolds, mostly involving self-association and homotypic interactions with other TIR domains. In the last 15 years, the three-dimensional structures of TIR domains from several mammalian, plant and bacterial proteins have been reported. These structures, jointly with functional data including the identification of interacting proteins, have started to provide insight into the molecular basis of the assembly of animal and plant immune signaling complexes, and for host immunosuppression by bacterial pathogens. This review focuses on the current knowledge of the structures of the TIR domains and how the structure relates to function.
The generated peptides are biologically active and form tightly bound amyloid-like fibrils on the hyphal surface that repel water and facilitate the proper formation of aerial hyphae and hyphal ...attachment 2,3. Ala, alanine; Arg, arginine; Glu, glutamic acid; Ile, isoleucine; K2PP, Kex2-processed pro-domain; Leu, leucine; Lys, lysine; Pro, proline; RiPP, ribosomally synthesised and post-translationally modified peptide; Thr, threonine; Val, valine. https://doi.org/10.1371/journal.ppat.1010000.g001 The second class of cleaved fungal effectors are processed via the removal of a pro-domain from the N-terminus of the effector 7 (Fig 1A). Effectors in this class were originally identified based on the presence of a canonical Kex2 protease cleavage motif and the absence of the proceeding N-terminal region of the protein (putative pro-domain) when isolated from source 7–12. To search for putative K2PP effectors, we constrained our analysis to the first half of the effector protein sequences and searched for disorder promoting amino acids that proceeded canonical Kex2 cleavage motifs (KR, RR) or the expanded motif (LxxR) (Fig 1B) 7.
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