Mass bleaching associated with unusually high sea temperatures represents one of the greatest threats to corals and coral reef ecosystems. Deeper reef areas are hypothesized as potential refugia, but ...the susceptibility of Scleractinian species over depth has not been quantified. During the most severe bleaching event on record, we found up to 83% of coral cover severely affected on Maldivian reefs at a depth of 3–5 m, but significantly reduced effects at 24–30 m. Analysis of 153 species' responses showed depth, shading and species identity had strong, significant effects on susceptibility. Overall, 73.3% of the shallow-reef assemblage had individuals at a depth of 24–30 m with reduced effects, potentially mitigating local extinction and providing a source of recruits for population recovery. Although susceptibility was phylogenetically constrained, species-level effects caused most lineages to contain some partially resistant species. Many genera showed wide variation between species, including Acropora, previously considered highly susceptible. Extinction risk estimates showed species and lineages of concern and those likely to dominate following repeated events. Our results show that deeper reef areas provide refuge for a large proportion of Scleractinian species during severe bleaching events and that the deepest occurring individuals of each population have the greatest potential to survive and drive reef recovery.
Critical knowledge gaps regarding infection with Mycobacterium ulcerans, the cause of Buruli ulcer (BU), have impeded development of new therapeutic approaches and vaccines for prevention of this ...neglected tropical disease. Here, we review the current understanding of host-pathogen interactions and correlates of immune protection to explore the case for establishing a controlled human infection model of M. ulcerans infection. We also summarise the overarching safety considerations and present a rationale for selecting a suitable challenge strain.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
DNA modification is known to regulate experience-dependent gene expression. However, beyond cytosine methylation and its oxidated derivatives, very little is known about the functional importance of ...chemical modifications on other nucleobases in the brain. Here we report that in adult mice trained in fear extinction, the DNA modification N6-methyl-2'-deoxyadenosine (m6dA) accumulates along promoters and coding sequences in activated prefrontal cortical neurons. The deposition of m6dA is associated with increased genome-wide occupancy of the mammalian m6dA methyltransferase, N6amt1, and this correlates with extinction-induced gene expression. The accumulation of m6dA is associated with transcriptional activation at the brain-derived neurotrophic factor (Bdnf) P4 promoter, which is required for Bdnf exon IV messenger RNA expression and for the extinction of conditioned fear. These results expand the scope of DNA modifications in the adult brain and highlight changes in m6dA as an epigenetic mechanism associated with activity-induced gene expression and the formation of fear extinction memory.
In this Perspective, we expand the notion of temporal regulation of RNA in the brain and propose that the qualitative nature of RNA and its metabolism, together with RNA abundance, are essential for ...the molecular mechanisms underlying experience-dependent plasticity. We discuss emerging concepts in the newly burgeoning field of epitranscriptomics, which are predicted to be heavily involved in cognitive function. These include activity-induced RNA modifications, RNA editing, dynamic changes in the secondary structure of RNA, and RNA localization. Each is described with an emphasis on its role in regulating the function of both protein-coding genes, as well as various noncoding regulatory RNAs, and how each might influence learning and memory.
IMPORTANCE: Irreversible vision loss from primary open-angle glaucoma (POAG) can be prevented through timely diagnosis and treatment, although definitive diagnosis can be difficult in early-stage ...disease. As a consequence, large numbers of individuals with suspected glaucoma require regular monitoring, even though many of these may never develop disease and other high-risk individuals with suspected glaucoma may have delayed or inadequate treatment. POAG is one of the most heritable common diseases, and this provides an opportunity to use genetic instruments in risk-stratified screening, diagnosis, and treatment of early glaucoma. OBJECTIVE: To assess the association of glaucoma polygenic risk with glaucoma progression in early-stage disease. DESIGN, SETTING, AND PARTICIPANTS: This cohort study used clinical and genetic data obtained from a longitudinal cohort study, Progression Risk of Glaucoma: Relevant SNPs With Significant Association (PROGRESSA). Participants of European ancestry with characteristic optic nerve head changes suggestive of glaucoma were included. Data were collected between February 2012 and June 2020. Analysis took place between July 2020 and April 2022. MAIN OUTCOMES AND MEASURES: The association of a glaucoma polygenic risk score (PRS) (2673 uncorrelated variants) with rate of peripapillary retinal nerve fiber layer thinning on optical coherence tomography and progression of visual field loss on 24-2 Humphrey visual fields. RESULTS: A total of 1777 eyes from 896 individuals had sufficient data for structural progression analyses and 1563 eyes from 808 individuals for functional progression analyses. The mean (SD) age was 62.1 (9.9) years, 488 (44%) were male, and 1087 of 1103 individuals (98.5%) had European ancestry. An ancestrally matched normative population cohort (n = 17 642) was used for PRS reference. Individuals in the top 5% PRS risk group were at a higher risk of visual field progression compared with the remaining 95% after 5 years (hazard ratio, 1.5; 95% CI, 1.13-1.97; P = .005). Conversely, those in the bottom 20% PRS risk group were at a lower risk of visual field progression compared with an intermediate risk group over 3 years (hazard ratio, 0.52; 95% CI, 0.28-0.96; P = .04). CONCLUSIONS AND RELEVANCE: In this study, high polygenic risk was associated with more rapid structural and functional progression in early POAG, despite more intensive treatment. A PRS may serve as a valuable adjunct to identify individuals who stand to benefit the most from more frequent surveillance and earlier or more intensive treatment.
Glaucoma, a disease characterized by progressive optic nerve degeneration, can be prevented through timely diagnosis and treatment. We characterize optic nerve photographs of 67,040 UK Biobank ...participants and use a multitrait genetic model to identify risk loci for glaucoma. A glaucoma polygenic risk score (PRS) enables effective risk stratification in unselected glaucoma cases and modifies penetrance of the MYOC variant encoding p.Gln368Ter, the most common glaucoma-associated myocilin variant. In the unselected glaucoma population, individuals in the top PRS decile reach an absolute risk for glaucoma 10 years earlier than the bottom decile and are at 15-fold increased risk of developing advanced glaucoma (top 10% versus remaining 90%, odds ratio = 4.20). The PRS predicts glaucoma progression in prospectively monitored, early manifest glaucoma cases (P = 0.004) and surgical intervention in advanced disease (P = 3.6 × 10
). This glaucoma PRS will facilitate the development of a personalized approach for earlier treatment of high-risk individuals, with less intensive monitoring and treatment being possible for lower-risk groups.
An understanding of how memory is acquired and how it can be modified in fear-related anxiety disorders, with the enhancement of failing memories on one side and a reduction or elimination of ...traumatic memories on the other, is a key unmet challenge in the fields of neuroscience and neuropsychiatry. The latter process depends on an important form of learning called fear extinction, where a previously acquired fear-related memory is decoupled from its ability to control behaviour through repeated non-reinforced exposure to the original fear-inducing cue. Although simple in description, fear extinction relies on a complex pattern of brain region and cell-type specific processes, some of which are unique to this form of learning and, for better or worse, contribute to the inherent instability of fear extinction memory. Here, we explore an emerging layer of biology that may compliment and enrich the synapse-centric perspective of fear extinction. As opposed to the more classically defined role of protein synthesis in the formation of fear extinction memory, a neuroepigenetic view of the experience-dependent gene expression involves an appreciation of dynamic changes in the state of the entire cell: from a transient change in plasticity at the level of the synapse, to potentially more persistent long-term effects within the nucleus. A deeper understanding of neuroepigenetic mechanisms and how they influence the formation and maintenance of fear extinction memory has the potential to enable the development of more effective treatment approaches for fear-related neuropsychiatric conditions.
Results are presented from the multi‐institution partnership to develop a real‐time and retrospective North American Land Data Assimilation System (NLDAS). NLDAS consists of (1) four land models ...executing in parallel in uncoupled mode, (2) common hourly surface forcing, and (3) common streamflow routing: all using a 1/8° grid over the continental United States. The initiative is largely sponsored by the Global Energy and Water Cycle Experiment (GEWEX) Continental‐Scale International Project (GCIP). As the overview for nine NLDAS papers, this paper describes and evaluates the 3‐year NLDAS execution of 1 October 1996 to 30 September 1999, a period rich in observations for validation. The validation emphasizes (1) the land states, fluxes, and input forcing of four land models, (2) the application of new GCIP‐sponsored products, and (3) a multiscale approach. The validation includes (1) mesoscale observing networks of land surface forcing, fluxes, and states, (2) regional snowpack measurements, (3) daily streamflow measurements, and (4) satellite‐based retrievals of snow cover, land surface skin temperature (LST), and surface insolation. The results show substantial intermodel differences in surface evaporation and runoff (especially over nonsparse vegetation), soil moisture storage, snowpack, and LST. Owing to surprisingly large intermodel differences in aerodynamic conductance, intermodel differences in midday summer LST were unlike those expected from the intermodel differences in Bowen ratio. Last, anticipating future assimilation of LST, an NLDAS effort unique to this overview paper assesses geostationary‐satellite‐derived LST, determines the latter to be of good quality, and applies the latter to validate modeled LST.
The Plasmodium falciparum reticulocyte-binding protein homolog 5 (PfRH5) is the leading target for next-generation vaccines against the disease-causing blood-stage of malaria. However, little is ...known about how human antibodies confer functional immunity against this antigen. We isolated a panel of human monoclonal antibodies (mAbs) against PfRH5 from peripheral blood B cells from vaccinees in the first clinical trial of a PfRH5-based vaccine. We identified a subset of mAbs with neutralizing activity that bind to three distinct sites and another subset of mAbs that are non-functional, or even antagonistic to neutralizing antibodies. We also identify the epitope of a novel group of non-neutralizing antibodies that significantly reduce the speed of red blood cell invasion by the merozoite, thereby potentiating the effect of all neutralizing PfRH5 antibodies as well as synergizing with antibodies targeting other malaria invasion proteins. Our results provide a roadmap for structure-guided vaccine development to maximize antibody efficacy against blood-stage malaria.
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•Human PfRH5 vaccination induces cross-reactive neutralizing antimalarial antibodies•Neutralizing human PfRH5 antibodies bind epitopes close to the basigin binding site•Some non-neutralizing antibodies potentiate those binding several malaria proteins•Potentiating antibodies slow erythrocyte invasion by binding a new epitope on PfRH5
Analyses of human monoclonal antibodies against the Plasmodium falciparum protein PfRH5 identify a subset of non-neutralizing antibodies that synergize with a repertoire of other neutralizing antibodies by slowing the ability of malaria-causing parasites to invade red blood cells.
DNA forms conformational states beyond the right-handed double helix; however, the functional relevance of these noncanonical structures in the brain remains unknown. Here we show that, in the ...prefrontal cortex of mice, the formation of one such structure, Z-DNA, is involved in the regulation of extinction memory. Z-DNA is formed during fear learning and reduced during extinction learning, which is mediated, in part, by a direct interaction between Z-DNA and the RNA-editing enzyme Adar1. Adar1 binds to Z-DNA during fear extinction learning, which leads to a reduction in Z-DNA at sites where Adar1 is recruited. Knockdown of Adar1 leads to an inability to modify a previously acquired fear memory and blocks activity-dependent changes in DNA structure and RNA state-effects that are fully rescued by the introduction of full-length Adar1. These findings suggest a new mechanism of learning-induced gene regulation that is dependent on proteins that recognize alternate DNA structure states, which are required for memory flexibility.
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