The high mannose patch (HMP) of the HIV envelope protein (Env) is the structure most frequently targeted by broadly neutralizing antibodies; therefore, many researchers have attempted to use mimics ...of this region as a vaccine immunogen. In our previous efforts, vaccinating rabbits with evolved HMP mimic glycopeptides containing Man9 resulted in an overall antibody response targeting the glycan core and linker rather than the full glycan or Manα1→2Man tips of Man9 glycans. A possible reason could be processing of our immunogen by host serum mannosidases. We sought to test whether more prolonged dosing could increase the antibody response to intact glycans, possibly by increasing the availability of intact Man9 to germinal centers. Here, we describe a study investigating the impact of immunization regimen on antibody response by testing immunogen delivery through bolus, an exponential series of mini doses, or a continuously infusing mini-osmotic pump. Our results indicate that, with our glycopeptide immunogens, standard bolus immunization elicited the strongest HIV Env-binding antibody response, even though higher overall titers to the glycopeptide were elicited by the exponential and pump regimens. Antibody selectivity for intact glycan was, if anything, slightly better in the bolus-immunized animals.
Unhealthy diets, the rise of non-communicable diseases, and the declining health of the planet are highly intertwined, where food production and consumption are major drivers of increases in ...greenhouse gas emissions, substantial land use, and adverse health such as cancer and mortality. To assess the potential co-benefits from shifting to more sustainable diets, we aimed to investigate the associations of dietary greenhouse gas emissions and land use with all-cause and cause-specific mortality and cancer incidence rates.
Using data from 443 991 participants in the European Prospective Investigation into Cancer and Nutrition (EPIC) study, a multicentre prospective cohort, we estimated associations between dietary contributions to greenhouse gas emissions and land use and all-cause and cause-specific mortality and incident cancers using Cox proportional hazards regression models. The main exposures were modelled as quartiles. Co-benefits, encompassing the potential effects of alternative diets on all-cause mortality and cancer and potential reductions in greenhouse gas emissions and land use, were estimated with counterfactual attributable fraction intervention models, simulating potential effects of dietary shifts based on the EAT–Lancet reference diet.
In the pooled analysis, there was an association between levels of dietary greenhouse gas emissions and all-cause mortality (adjusted hazard ratio HR 1·13 95% CI 1·10–1·16) and between land use and all-cause mortality (1·18 1·15–1·21) when comparing the fourth quartile to the first quartile. Similar associations were observed for cause-specific mortality. Associations were also observed between all-cause cancer incidence rates and greenhouse gas emissions, when comparing the fourth quartile to the first quartile (adjusted HR 1·11 95% CI 1·09–1·14) and between all-cause cancer incidence rates and land use (1·13 1·10–1·15); however, estimates differed by cancer type. Through counterfactual attributable fraction modelling of shifts in levels of adherence to the EAT–Lancet diet, we estimated that up to 19–63% of deaths and up to 10–39% of cancers could be prevented, in a 20-year risk period, by different levels of adherence to the EAT–Lancet reference diet. Additionally, switching from lower adherence to the EAT–Lancet reference diet to higher adherence could potentially reduce food-associated greenhouse gas emissions up to 50% and land use up to 62%.
Our results indicate that shifts towards universally sustainable diets could lead to co-benefits, such as minimising diet-related greenhouse gas emissions and land use, reducing the environmental footprint, aiding in climate change mitigation, and improving population health.
European Commission (DG-SANCO), the International Agency for Research on Cancer (IARC), MRC Early Career Fellowship (MR/M501669/1).
Glutamate is the major excitatory neurotransmitter in the mammalian central nervous system (CNS). Experimental evidence indicates that glutamate receptor antagonists may limit tumor growth. This ...study explores expression of glutamate receptor subunits in pediatric CNS tumors. Samples from 8 ependymomas, 4 glioblastomas, 6 medulloblastomas and 8 low grade astrocytomas were analysed. RNA was used for semiquantitative and quantitative RT-PCR. We examined expression of NMDA receptor subunits NR1-NR3B, AMPA receptor subunits GluR1-GluR4, kainate receptor subunits GluR5-GluR7, KA1, KA2 and metabotropic receptor subunits mGluR1-8. Paraffin embedded samples were immunohistochemically stained for selected subunits.All glutamate receptor subunits were differentially expressed in the tumors examined. Expression of NR2D, NR3A, KA1, GluR4, mGluR1, mGluR4, mGluR5 and mGluR6 was higher in the high grade tumors compared to human brain (HB). In low grade astrocytomas expression of glutamate receptor subunits was comparable or lower than in HB. Immunohistochemistry revealed expression of several glutamate receptor subunit proteins in tumor specimen. This study demonstrates expression of glutamate receptor subunits in pediatric CNS tumors. Together with experimental evidence indicating that interference with glutamate signalling may suppress tumor growth, our findings suggest that adjunctive treatment with glutamate receptor modulators may be a feasible therapeutic option for pediatric patients with CNS tumors.
Intellectual disability is a heterogeneous disorder with a wide phenotypic spectrum. Over 1,700 OMIM genes have been associated with this condition, many of which reside on the X-chromosome. The
...IQSEC2
gene is located on chromosome Xp11.22 and is known to play a significant role in the maintenance and homeostasis of the brain. Mutations in
IQSEC2
have been historically associated with nonsyndromic X-linked intellectual disability. Case reports of affected probands show phenotypic overlap with conditions associated with pathogenic
MECP2
,
FOXG1
,
CDKL5
, and
MEF2C
gene mutations. Affected individuals, however, have also been identified as presenting with additional clinical features including seizures, autistic-behavior, psychiatric problems, and delayed language skills. To our knowledge, only 5 deleterious mutations and 2 intragenic duplications have been previously reported in
IQSEC2
. Here we report two novel
IQSEC2
de novo truncating mutations identified through diagnostic exome sequencing in two severely affected unrelated male probands manifesting developmental delay, seizures, hypotonia, plagiocephaly, and abnormal MRI findings. Overall, diagnostic exome sequencing established a molecular diagnosis for two patients in whom traditional testing methods were uninformative while expanding on the mutational and phenotypic spectrum. In addition, our data suggests that
IQSEC2
may be more common than previously appreciated, accounting for approximately 9 % (2/22) of positive findings among patients with seizures referred for diagnostic exome sequencing. Further, these data supports recently published data suggesting that
IQSEC2
plays a more significant role in the development of X-linked intellectual disability with seizures than previously anticipated.
Abstract
Concussion biomarkers are important guides for diagnosis and return-to-duty decisions. Recent literature describes the King-Devick (KD) test as a sensitive sports-related concussion ...screener. This test involves timing an individual reading aloud 120 digits printed on three test cards. The test is commonly considered to evaluate the effects of concussion and other factors on reading-related eye movements (EMs). However, the extent to which the KD test reflects EMs remains a matter of conjecture since the test reports only reading speed and number of errors. An off-the-shelf, computerized KD with eye tracking system recently became commercially available. Two early model KD with eye tracking systems were purchased in 2015 and evaluated before deploying them for research. The evaluation consisted of two studies; one with 20 volunteers assessing the comparability of the two systems and the other with 5 volunteers to quantify the systems’ stability and repeatability over 5 successive days. The results showed that several of the systems’ reported EM response parameters lacked face validity; consequently, the systems could not be used for scientific research. This conclusion emphasizes the importance of systematic test and evaluation of new equipment before it is used for research.
Malignant glioma represents the most common primary adult brain tumor in Western industrialized countries. Despite aggressive treatment modalities, the median survival duration for patients with ...glioblastoma multiforme (GBM), the highest grade malignant glioma, has not improved significantly over past decades. One promising approach to deal with GBM is the inactivation of proteins essential for survival or progression of glioma cells by means of RNA interference (RNAi) techniques. A likely candidate for an RNAi therapy of gliomas is the inhibitor of apoptosis protein survivin. Survivin is involved in 2 main cellular processes-cell division and inhibition of apoptosis. We show here that stable RNAi of survivin induced polyploidy, apoptosis, and impaired proliferation of human U343-MG, U373-MG, H4, and U87-MG cells and of primary glioblastoma cells. Proteome profiler arrays using U373-MG cells identified a novel set of differentially expressed genes upon RNAi-mediated survivin knockdown. In particular, the death receptor TRAIL R2/DR5 was strongly upregulated in survivin-depleted glioma cells, inducing an enhanced cytotoxic response of allogeneic human NK cells. Moreover, an experimental in vivo therapy using polyethylenimine (PEI)/siRNA complexes for survivin knockdown efficiently blocked tumor growth of established subcutaneous U373-MG tumors and enhanced survival of NMRInu/nu mice orthopically transplanted with U87-MG cells. We conclude that survivin is functionally relevant in gliomas and that PEI-mediated exogenous delivery of siRNA targeting survivin is a promising strategy for glioblastoma therapy.
Plant responses to carbon (C) and water availability are strongly connected. Thus, we can learn much about the responses of modern plants to rising atmospheric carbon dioxide (CO₂) by studying their ...performance under a range of carbon and water availabilities, including very low CO₂ as in past glacial periods. We hypothesized that, especially in shallow soils, the positive effects of high CO₂ and the negative effects of low CO₂ on growth response to drought are moderated by plant size-driven feedbacks through transpiration and soil water depletion. We grew two temperate annual C₃ species, Avena sativa and Chenopodium album, in glacial (180 ppm), modern (400 ppm) and future (700 ppm) CO₂ levels and five soil water regimes in climate chambers. In both species, low CO₂ resulted in a much lower relative growth rate, biomass and total leaf area than at ambient CO₂ with higher water availability, but this difference disappeared steadily towards severe drought conditions. Elevated CO₂ increased relative growth rate, plant biomass and total leaf area of both species slightly compared with ambient CO₂. These results were especially pronounced under drought. Our results support the hypothesis that, in annuals, plant size modulates the negative drought effect at low CO₂. However, plant size-mediated effects of high CO₂ on growth response to drought were inconclusive. Further experiments should reveal the interactive effects of CO₂ and water regimes in environments closer to a field setting, both in shallow and in deep soils with unconstrained rooting, as well as in mixed communities.
Display omitted
► Natural kerolite clay: suitable adsorbent for separation in biotechnological processes. ► High selectivity: separation of phenylic alcohols and ketones in aqueous solution. ► Both a ...carbonyl group and a phenyl group are crucial for enhanced adsorption. ► Adsorbed amount of acetophenone achieves 17% (w/w).
The potential of natural clay as adsorbent for biotechnology processes was systematically investigated. Adsorption isotherms for several substrates and products of an alcohol dehydrogenase catalysed reaction were determined by static experiments. A distinct selective adsorption behaviour of natural kerolite clay was proven for aromatic ketones and alcohols in particular for acetophenone and phenylethanol. In aqueous media high adsorbed amounts (
q) were stated for those molecules to be adsorbed (adsorptive) which possess both a carbonyl and a phenyl group. This led to an adsorbed amount of 17% (w/w) for acetophenone on kerolite clay.
PDF
