After decades of research, our understanding of when and why individuals infected with
develop clinical malaria is still limited. Correlates of immune protection are often sought through prospective ...cohort studies, where measured host factors are correlated against the incidence of clinical disease over a set period of time. However, robustly inferring individual-level protection from these population-level findings has proved difficult due to small effect sizes and high levels of variance underlying such data. In order to better understand the nature of these inter-individual variations, we analysed the long-term malaria epidemiology of children ≤12 years old growing up under seasonal exposure to the parasite in the sub-location of Junju, Kenya. Despite the cohort's limited geographic expanse (ca. 3km x 10km), our data reveal a high degree of spatial and temporal variability in malaria prevalence and incidence rates, causing individuals to experience varying levels of exposure to the parasite at different times during their life. Analysing individual-level infection histories further reveal an unexpectedly high variability in the rate at which children experience clinical malaria episodes. Besides exposure to the parasite, measured as disease prevalence in the surrounding area, we find that the birth time of year has an independent effect on the individual's risk of experiencing a clinical episode. Furthermore, our analyses reveal that those children with a history of an above average number of episodes are more likely to experience further episodes during the upcoming transmission season. These findings are indicative of phenotypic differences in the rates by which children acquire clinical protection to malaria and offer important insights into the natural variability underlying malaria epidemiology.
Succinate dehydrogenase inhibitors (SDHIs) are fungicides used in control of numerous fungal plant pathogens, including of Erysiphe necator, the causal agent of grapevine powdery mildew (GPM). Here, ...the sdhb, sdhc, and sdhd genes of E. necator were screened for mutations that may associate with SDHI resistance. GPM samples were collected from 2017 to 2020 from the U.S. states of California, Oregon, Washington and Michigan, and the Canadian province of British Columbia. Forty-five polymorphisms were identified in the three sdh genes, 17 of which caused missense mutations. Of these, the SDHC-p.I244V substitution was shown in this study to reduce sensitivity of E. necator to boscalid and fluopyram, whereas the SDHC-p.G25R substitution did not affect SDHI sensitivity. Of the other 15 missense mutations, the SDHC-p.H242R substitution was shown in previous studies to reduce sensitivity of E. necator towards boscalid, whereas the equivalents of the SDHB-p.H242L, SDHC-p.A83V, and SDHD-p.I71F substitutions were shown to reduce sensitivity to SDHIs in other fungi. Generally, only a single amino acid substitution was present in the SDHB, SDHC, or SDHD subunit of E. necator isolates but missense mutations putatively associated with SDHI resistance were widely distributed in the sampled areas and increased in frequency over time. Finally, isolates that had decreased sensitivity to boscalid or fluopyram were identified but with no or only the SDHC-p.G25R amino acid substitution present in SDHB, SDHC, and SDHD subunits. This suggests that target-site mutations is likely not the only mechanism conferring resistance to SDHIs in E. necator.
Footrot is a polymicrobial infectious disease in sheep causing severe lameness, leading to one of the industry's largest welfare problems. The complex etiology of footrot makes
or
investigations ...difficult. Computational methods offer a solution to understanding the bacteria involved and how they may interact with the host, ultimately providing a way to identify targets for future hypothesis-driven investigative work. Here, we present the first combined global analysis of bacterial community transcripts together with the host immune response in healthy and diseased ovine feet during a natural polymicrobial infection state using metatranscriptomics. The intratissue and surface bacterial populations and the most abundant bacterial transcriptomes were analyzed, demonstrating that footrot-affected skin has reduced diversity and increased abundances of not only the causative bacterium Dichelobacter nodosus but also other species such as Mycoplasma fermentans and Porphyromonas asaccharolytica. Host transcriptomics reveals the suppression of biological processes related to skin barrier function, vascular functions, and immunosurveillance in unhealthy interdigital skin, supported by histological findings that type I collagen (associated with scar tissue formation) is significantly increased in footrot-affected interdigital skin compared to outwardly healthy skin. Finally, we provide some interesting indications of host and pathogen interactions associated with virulence genes and the host spliceosome, which could lead to the identification of future therapeutic targets.
Three groups of five rumen and duodenum cannulated fauna-free sheep were used in a 28d experiment. One group remained fauna-free, whereas the second (EN) and third (PP) groups, respectively, were ...inoculated intraruminally with the protozoan species Entodinium caudatum and Polyplastron multivesiculatum. Rumen fluid, duodenal digesta and faecal samples were collected during the last 12d. The flow of digesta to the duodenum was determined using Yb and Co as dual-phase markers. 15Nitrogen and phosphatidylcholine were used as markers to calculate the duodenal flow of bacterial and protozoal N, respectively. Results showed an increase (P<0·1) in the rumen concentration of NH3-N and total volatile fatty acids, and a decrease (P<0·05) in the duodenal flow of non-NH3-N and bacterial N in sheep with EN and PP monofaunas, compared with fauna-free sheep. There were no differences (P>0·05) in these variables between the two monofauna groups. Protozoal N accounted for 8% of the duodenal non-NH3-N flow in the EN-monofaunated sheep, whereas no such flow was detected in the PP-monofaunated sheep. Apparent rumen digestibility of organic matter, neutral detergent fibre and acid detergent fibre were similar (P>0·05) in the monofaunated groups of sheep, but rumen acid detergent fibre digestibility was higher (P<0·05) in the monofaunated than in the fauna-free groups. Experimental results suggested that, unlike EN, the PP monofauna might not contribute to the duodenal flow of microbial protein, whereas both monofaunas showed a virtually equal degree of predation on rumen bacteria.
Background: High-risk human papillomavirus (HPV) types play a major role in the development of cervical cancer in vivo and can induce immortalization of primary human keratinocytes in vitro. ...Activation of the telomere-lengthening enzyme telomerase constitutes a key event in both processes. Because losses of alleles from chromosome 6 and increased telomerase activity have been observed in high-grade premalignant cervical lesions, we analyzed whether human chromosome 6 harbors a putative telomerase repressor locus that may be involved in HPV-mediated immortalization. Methods: Microcell-mediated chromosome transfer was used to introduce chromosomes 6 and 11 to the in vitro generated HPV type 16 (HPV16)-immortalized keratinocyte cell line FK16A and to the in vivo derived HPV16-containing cervical cancer cell line SiHa. Hybrid clones were analyzed for growth characteristics, telomerase activity, human telomerase reverse transcriptase (hTERT) and HPV16 E6 expression, and telomere length. FK16A hybrid clones were also transduced with an hTERT-containing retrovirus to examine the effect of ectopic hTERT expression on growth. Statistical tests were two-sided. Results: Introduction of human chromosome 6 but not of chromosome 11 to both cell lines yielded hybrid cells that demonstrated crisis-like features (i.e., enlarged and flattened morphology, vacuolation, and multinucleation) and underwent growth arrest after a marked lag period. In the chromosome 6 hybrid clones analyzed, telomerase activity and hTERT messenger RNA (mRNA) expression were statistically significantly reduced compared with those in the chromosome 11 hybrid clones (for telomerase activity, P = .004 for the FK16A hybrids and P = .039 for the SiHa hybrids; for hTERT mRNA expression, P = .003 for the FK16A hybrids). The observed growth arrest was associated with telomeric shortening. Ectopic expression of hTERT in FK16A cells could prevent the telomeric shortening-based growth arrest induced by chromosome 6. Conclusions: Chromosome 6 may harbor a repressor of hTERT transcription, the loss of which may be involved in HPV-mediated immortalization.
While short sleep could promote neurodegeneration, long sleep may be a marker of ongoing neurodegeneration, potentially as a result of neuroinflammation. The objective was to evaluate sleep patterns ...with age of expected Alzheimer's disease (AD) onset and neuroinflammation.
We tested 203 dementia-free participants (68.5±5.4y/o, 78M). The PREVENT-AD cohort includes older persons with a parental history of AD whose age was nearing their expected AD onset. We estimated expected years to AD onset by subtracting the participant's age from their parent's at AD dementia onset. We extracted actigraphy sleep variables of interest (times of sleep onset and morning awakening, time in bed, sleep efficiency, sleep duration) and general profiles (sleep fragmentation, phase delay, hypersomnia). CSF inflammatory biomarkers were assessed with OLINK multiplex technology.
Proximity to, or exceeding, expected age of onset was associated with a sleep profile suggestive of hypersomnia (longer sleep, later morning awakening time). This hypersomnia sleep profile was associated with higher CSF neuroinflammatory biomarkers (IL-6, MCP-1, global score). Interactions analyses revealed that some of these sleep-neuroinflammation associations were present mostly in those closer/exceeding the age of expected AD onset, APOE4 carriers, and those with better memory performance.
Proximity to, or exceeding, parental AD dementia onset was associated with a longer sleep pattern, which was related to elevated proinflammatory CSF biomarkers. We speculate that longer sleep may serve a compensatory purpose potentially triggered by neuroinflammation as individuals are approaching AD onset. Further studies should investigate whether neuroinflammatory-triggered long sleep duration could mitigate cognitive deficits.
Increasing adoption of nanotechnologies in personal care products is outpacing comprehensive evaluation of consumer safety risks involving exposure to nano-additives. This review examines the ...prevalence of personal care products containing nanomaterials, the means by which humans are exposed to nanomaterials during use of these products, and our current understanding of the corresponding health effects in humans after exposure. Efforts to minimize negative impacts through sustainability practices and regulation are also discussed. Upon evaluating three online databases of nano-enabled consumer products, we focused our review on personal care products containing silver (Ag), titanium dioxide (TiO2), and zinc oxide (ZnO) nanoparticles as these were found to be the most prevalent in personal care products. Up to 90% of all nano-enabled personal care products involve intentional or unintentional dermal exposure. Nanomaterial release from personal care products, and subsequent toxicity to consumers, are highly dependent on nanoparticle shapes, sizes, and association chemistries with other personal care product ingredients. In turn, these characteristics are dependent on chemical manufacturing routes. Upon reviewing the literature on life-cycle analysis of manufacturing processes, we found that the most rigorous analyses available employ multi-criteria decision tools. The conflicting perspectives of manufacturers and consumer advocacy groups on how to regulate nano-enabled personal care products illustrate the need for more experimental data.
•Toxicity data must tie nanomaterial/formula interactions to human bio-response.•Quantifying nanoparticle synthesis sustainability helps predict consumer exposures.•FDA currently defers safety decisions to industry, not consumer stakeholders.
The malaria parasite Plasmodium falciparum has evolved to prolong its duration of infection by antigenic variation of a major immune target on the surface of the infected red blood cell. This immune ...evasion strategy depends on the sequential, rather than simultaneous, appearance of immunologically distinct variants. Although the molecular mechanisms by which a single organism switches between variants are known in part, it remains unclear how an entire population of parasites within the host can synchronize expression to avoid rapidly exhausting the variant repertoire. Here we show that short-lived, partially cross-reactive immune responses to parasite-infected erythrocyte surface antigens can produce a cascade of sequentially dominant antigenic variants, each of which is the most immunologically distinct from its preceding types. This model reconciles several previously unexplained and apparently conflicting epidemiological observations by demonstrating that individuals with stronger cross-reactive immune responses can, paradoxically, be more likely to sustain chronic infections. Antigenic variation has always been seen as an adaptation of the parasite to evade host defence: we show that the coordination necessary for the success of this strategy might be provided by the host.
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