Antibodies play major roles in immunity to malaria; however, a limited understanding of mechanisms mediating protection is a major barrier to vaccine development. We have demonstrated that acquired ...human anti-malarial antibodies promote complement deposition on the merozoite to mediate inhibition of erythrocyte invasion through C1q fixation and activation of the classical complement pathway. Antibody-mediated complement-dependent (Ab-C′) inhibition was the predominant invasion-inhibitory activity of human antibodies; most antibodies were non-inhibitory without complement. Inhibitory activity was mediated predominately via C1q fixation, and merozoite surface proteins 1 and 2 were identified as major targets. Complement fixation by antibodies was very strongly associated with protection from both clinical malaria and high-density parasitemia in a prospective longitudinal study of children. Ab-C′ inhibitory activity could be induced by human immunization with a candidate merozoite surface-protein vaccine. Our findings demonstrate that human anti-malarial antibodies have evolved to function by fixing complement for potent invasion-inhibitory activity and protective immunity.
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•Antibodies function with complement to inhibit P. falciparum replication•Antibodies fix C1q to block invasion and lyse merozoites•Complement-fixing antibodies are strongly associated with immunity in children•Antibody-complement inhibition can be induced by human vaccination
Antibodies are important in immunity to malaria, but their protective function has been unclear. Boyle and colleagues report that acquired and vaccine-induced human antibodies recruit complement to block infection of erythrocytes and blood-stage replication of Plasmodium falciparum.
After many decades of vaccination, measles epidemiology varies greatly between and within countries. National immunization programs are therefore encouraged to conduct regular situation analyses and ...to leverage models to adapt interventions to local needs. Here, we review applications of models to develop locally tailored interventions to support control and elimination efforts. In general, statistical and semi-mechanistic transmission models can be used to synthesize information from vaccination coverage, measles incidence, demographic, and/or serological data, offering a means to estimate the spatial and age-specific distribution of measles susceptibility. These estimates complete the picture provided by vaccination coverage alone, by accounting for natural immunity. Dynamic transmission models can then be used to evaluate the relative impact of candidate interventions for measles control and elimination and the expected future epidemiology. In most countries, models predict substantial numbers of susceptible individuals outside the age range of routine vaccination, which affects outbreak risk and necessitates additional intervention to achieve elimination. More effective use of models to inform both vaccination program planning and evaluation requires the development of training to enhance broader understanding of models and where feasible, building capacity for modelling in-country, pipelines for rapid evaluation of model predictions using surveillance data, and clear protocols for incorporating model results into decision-making.
We report four previously undescribed families with germline BRCA1‐associated protein‐1 gene (BAP1) mutations and expand the clinical phenotype of this tumor syndrome. The tumor spectrum in these ...families is predominantly uveal malignant melanoma (UMM), cutaneous malignant melanoma (CMM) and mesothelioma, as previously reported for germline BAP1 mutations. However, mutation carriers from three new families, and one previously reported family, developed basal cell carcinoma (BCC), thus suggesting inclusion of BCC in the phenotypic spectrum of the BAP1 tumor syndrome. This notion is supported by the finding of loss of BAP1 protein expression by immunochemistry in two BCCs from individuals with germline BAP1 mutations and no loss of BAP1 staining in 53 of sporadic BCCs consistent with somatic mutations and loss of heterozygosity of the gene in the BCCs occurring in mutation carriers. Lastly, we identify the first reported recurrent mutation in BAP1 (p.R60X), which occurred in three families from two different continents. In two of the families, the mutation was inherited from a common founder but it arose independently in the third family.
Developmental programming, which proposes that “insults” or “stressors” during intrauterine or postnatal development can have not only immediate but also long-term consequences for healthy and ...productivity, has emerged as a major biological principle, and based on studies in many animal species also seems to be a universal phenomenon. In eutherians, the placenta appears to be programmed during its development, which has consequences for fetal growth and development throughout pregnancy, and likewise has long-term consequences for postnatal development, leading to programming of organ function of the offspring even into adulthood. This review summarizes our current understanding of the placenta’s role in developmental programming, the mechanisms involved, and the challenges remaining.
All transiting planet observations are at risk of contamination from nearby, unresolved stars. Blends dilute the transit signal, causing the planet to appear smaller than it really is, or producing a ...false positive detection when the target star is blended with an eclipsing binary. High spatial resolution adaptive optics images are an effective way of resolving most blends. Here we present visual companions and detection limits for 12 Kepler planet candidate host stars, of which 4 have companions within 4". One system (KOI 1537) consists of two similar-magnitude stars separated by 0".1, while KOI 174 has a companion at 0".5. In addition, observations were made of 15 transiting planets that were previously discovered by other surveys. The only companion found within 1" of a known planet is the previously identified companion to WASP-2b. An additional four systems have companions between 1" and 4": HAT-P-30b (3".7, Delta Ks = 2.9), HAT-P-32b (2".9, Delta Ks = 3.4), TrES-1b (2".3, Delta K s = 7.7), and WASP-P-33b (1".9, Delta Ks = 5.5), some of which have not been reported previously. Depending on the spatial resolution of the transit photometry for these systems, these companion stars may require a reassessment of the planetary parameters derived from transit light curves. For all systems observed, we report the limiting magnitudes beyond which additional fainter objects located 0".1-4" from the target may still exist.
Background Disturbed sleep is associated with cognitive decline in neurodegenerative diseases such as Alzheimer's disease (AD) and frontotemporal dementia (FTD). The progressive sequence of how ...neurodegeneration affects aspects of sleep architecture in conjunction with behavioural changes is not well understood. Methods We investigated changes in sleep architecture, spectral power and circadian rhythmicity in the tet-off rTg4510 mouse overexpressing human P301L tau within the same subjects over time. Doxycycline-induced transgene-suppressed rTg4510 mice, tTa carriers and wild-type mice were used as comparators. Spectral power and sleep stages were measured from within the home cage environment using EEG electrodes. In addition, locomotor activity and performance during a T-maze task were measured. Results Spectral power in the delta and theta bands showed a time-dependent decrease in rTg4510 mice compared to all other groups. After the initial changes in spectral power, wake during the dark period increased whereas NREM and number of REM sleep bouts decreased in rTg4510 compared to wild-type mice. Home cage locomotor activity in the dark phase significantly increased in rTg4510 compared to wild-type mice by 40 weeks of age. Peak-to-peak circadian rhythm amplitude and performance in the T-maze was impaired throughout the experiment independent of time. At 46 weeks, rTG4510 mice had significant degeneration in the hippocampus and cortex whereas doxycycline-treated rTG4510 mice were protected. Pathology significantly correlated with sleep and EEG outcomes, in addition to locomotor and cognitive measures. Conclusions We show that reduced EEG spectral power precedes reductions in sleep and home cage locomotor activity in a mouse model of tauopathy. The data shows increasing mutant tau changes sleep architecture, EEG properties, behaviour and cognition, which suggest tau-related effects on sleep architecture in patients with neurodegenerative diseases. Keywords: Alzheimer's disease, Frontotemporal dementia, Behaviour, Sleep, Spectral power, Cognition, Neurodegeneration, Pathology, Tau, rTg4510
We search Dark Energy Survey (DES) Year 3 imaging for galaxy-galaxy strong gravitational lenses using convolutional neural networks, extending previous work with new training sets and covering a ...wider range of redshifts and colors. We train two neural networks using images of simulated lenses, then use them to score postage-stamp images of 7.9 million sources from DES chosen to have plausible lens colors based on simulations. We examine 1175 of the highest-scored candidates and identify 152 probable or definite lenses. Examining an additional 20,000 images with lower scores, we identify a further 247 probable or definite candidates. After including 86 candidates discovered in earlier searches using neural networks and 26 candidates discovered through visual inspection of blue-near-red objects in the DES catalog, we present a catalog of 511 lens candidates.
Histone methyl transferase EZH2 (Enhancer of Zeste Homolog 2) is generally associated with H3K27 methylation and gene silencing, as a member of the polycomb repressor 2 (PRC2) complex. ...Immunoprecipitation and mass spectrometry of the EZH2-protein interactome in estrogen receptor positive, breast cancer-derived MCF7 cells revealed EZH2 interactions with subunits of chromatin remodeler SWI/SNF complex and TRIM28, which formed a complex with EZH2 distinct from PRC2. Unexpectedly, transcriptome profiling showed that EZH2 primarily activates, rather than represses, transcription in MCF7 cells and with TRIM28 co-regulates a set of genes associated with stem cell maintenance and poor survival of breast cancer patients. TRIM28 depletion repressed EZH2 recruitment to chromatin and expression of this gene set, in parallel with decreased CD44
/CD24
mammosphere formation. Mammosphere formation, inhibited by EZH2 depletion, was rescued by ectopic expression of EZH2 but not by TRIM28 expression or by EZH2 mutated at the region (pre-SET domain) of TRIM28 interaction. These results support PRC2-independent functions of EZH2 and TRIM28 in activation of gene expression that promotes mammary stem cell enrichment and maintenance.
Remote sensing observations and climate models indicate that the Greenland Ice Sheet (GrIS) has been losing mass since the late 1990s, mostly due to enhanced surface melting from rising summer ...temperatures. However, in situ observational records of GrIS melt rates over recent decades are rare. Here we develop a record of frozen meltwater in the west GrIS percolation zone preserved in seven firn cores. Quantifying ice layer distribution as a melt feature percentage (MFP), we find significant increases in MFP in the southernmost five cores over the past 50 years to unprecedented modern levels (since 1550 CE). Annual to decadal changes in summer temperatures and MFP are closely tied to changes in Greenland summer blocking activity and North Atlantic sea surface temperatures since 1870. However, summer warming of ~1.2°C since 1870–1900, in addition to warming attributable to recent sea surface temperature and blocking variability, is a critical driver of high modern MFP levels.
Plain Language Summary
Computer models and satellites show that the amount of snow melting each summer on Greenland has increased since the 1990s, but it is difficult to confirm this directly on the ice sheet. When surface snow melts, the water spreads into deeper layers of snow and refreezes as an ice layer. As fresh snow buries each summer's ice layers, the history of snowmelt is preserved in the ice sheet. We describe seven ice cores collected from western Greenland that contain the history of ice layers back to 1966. We find more ice layers, caused by more summer melting, since the 1990s. By comparing our ice cores to a longer ice core from the same area, we show that today's melt rates are the highest in this region since at least 1550 CE. Year‐to‐year changes in the amount of melting are mostly caused by changes in the number of summer high‐pressure systems and fluctuating ocean temperatures near Greenland. Although both of these processes have contributed to recent high melt rates, Greenland is 1.2°C warmer today than during similar conditions in the 1890s. This “extra” warming is most likely caused by human greenhouse gas emissions, leading to the unusual melt rates of recent years.
Key Points
Ice cores from the West Greenland percolation zone confirm a significant increase in surface melt rates since the early 1990s
Modern melt rates in West Greenland are unmatched in a composite ice core melt record back to 1550 CE
Greenland blocking, regional sea surface temperatures, and a long‐term summer warming trend are required to explain modern melt rates
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