Interactions between microplastic (MP) and fine-grained suspended sediment in natural waters are important for the environmental fate of plastic particles. Estuaries are transitional areas between ...freshwater and open marine systems and are recognized as important accumulation zones for MPs. However, there is a knowledge gap on the processes driving the sedimentation of MPs in estuaries, especially with regard to positively buoyant MPs. Here we show from settling tube experiments that positively buoyant and non-spherical MP HDPE particles in different size-fractions (63–500 μm) and concentrations (1 and 5 mg l−1) rapidly flocculate and settle with natural fine-grained sediment in natural seawater. Our results demonstrate that flocculation is a key process for the vertical transport of MP in estuaries. The implication is that land-based sources of positively buoyant HDPE MP transported by rivers will likely settle and accumulate in estuarine environments and thereby increase the concentration of MP in the benthic zone.
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•Flocculation with fine-grained sediments enables the settling of positively buoyant HDPE microplastic.•Even large HDPE microplastic (300–500 μm) rapidly flocculated and settled with fine-grained sediments.•Flocculation is an important mechanism for the vertical transport of positively buoyant microplastic in estuarine settings.
•Broadly neutralizing antibodies against influenza virus hemagglutinin are described.•Different antibodies employ different strategies to inhibit or neutralize influenza virus.•The design of ...influenza inhibitors, treatment and vaccines are discussed.
Despite available antivirals and vaccines, influenza continues to be a major cause of mortality worldwide. Vaccination generally induces an effective, but strain-specific antibody response. As the virus continually evolves, new vaccines have to be administered almost annually when a novel strain becomes dominant. Furthermore, the sporadic emerging resistance to neuraminidase inhibitors among circulating strains suggests an urgent need for new therapeutic agents. Recently, several cross-reactive antibodies have been described, which neutralize an unprecedented spectrum of influenza viruses. These broadly neutralizing antibodies generally target conserved functional regions on the major influenza surface glycoprotein hemagglutinin (HA). The characterization of their neutralization breadth and epitopes on HA could stimulate the development of new antibody-based antivirals and broader influenza vaccines. This article forms part of a symposium in Antiviral Research on “Treatment of influenza: targeting the virus or the host.”
The identification of human broadly neutralizing antibodies (bnAbs) targeting the hemagglutinin (HA) stem revitalized hopes of developing a universal influenza vaccine. Using a rational design and ...library approach, we engineered stable HA stem antigens ("mini-HAs") based on an H1 subtype sequence. Our most advanced candidate exhibits structural and bnAb binding properties comparable to those of full-length HA, completely protects mice in lethal heterologous and heterosubtypic challenge models, and reduces fever after sublethal challenge in cynomolgus monkeys. Antibodies elicited by this mini-HA in mice and nonhuman primates bound a wide range of HAs, competed with human bnAbs for HA stem binding, neutralized H5N1 viruses, and mediated antibody-dependent effector activity. These results represent a proof of concept for the design of HA stem mimics that elicit bnAbs against influenza A group 1 viruses.
Broadly neutralizing antibodies against highly variable pathogens have stimulated the design of vaccines and therapeutics. We report the use of diverse camelid single-domain antibodies to influenza ...virus hemagglutinin to generate multidomain antibodies with impressive breadth and potency. Multidomain antibody MD3606 protects mice against influenza A and B infection when administered intravenously or expressed locally from a recombinant adeno-associated virus vector. Crystal and single-particle electron microscopy structures of these antibodies with hemagglutinins from influenza A and B viruses reveal binding to highly conserved epitopes. Collectively, our findings demonstrate that multidomain antibodies targeting multiple epitopes exhibit enhanced virus cross-reactivity and potency. In combination with adeno-associated virus-mediated gene delivery, they may provide an effective strategy to prevent infection with influenza virus and other highly variable pathogens.
Diet is increasingly recognized as an important determinant of human fertility, with most research focused on specific nutrients or food groups. However, there has been limited assessment of the ...effect of dietary patterns on fertility.
We evaluated the association between 4 dietary patterns the alternative Mediterranean Diet (aMed), the Healthy Eating Index-2010 (HEI-2010), the Danish Dietary Guidelines (DDGI), and the Dietary Inflammatory Index (DII) and fecundability in 2 preconception cohorts of couples trying to conceive: SF (SnartForaeldre.dk) in Denmark and PRESTO (Pregnancy Study Online) in North America.
Participants completed a baseline questionnaire on sociodemographic, anthropometric, and lifestyle factors and, 10 d later, a validated cohort-specific FFQ. We used data from these respective FFQs to calculate adherence to each dietary pattern. Participants completed bimonthly follow-up questionnaires for ≤12 mo or until pregnancy, whichever came first. We restricted analyses to 3429 SF and 5803 PRESTO participants attempting pregnancy for ≤6 cycles at enrollment. We used proportional probabilities regression models to estimate fecundability ratios (FRs) and 95% CIs, adjusting for potential confounders.
Greater DII, indicative of a less anti-inflammatory diet (i.e., poorer diet quality), was associated with reduced fecundability in both SF and PRESTO (DII ≥ -1.5 compared with < -3.3: FR: 0.83; 95% CI: 0.71, 0.97 and FR: 0.82; 95% CI: 0.73, 0.93, respectively). In PRESTO, greater adherence to the aMed or to the HEI-2010 was associated with greater fecundability. In SF, there was no appreciable association between the aMed and fecundability, whereas greater adherence to the DDGI was associated with greater fecundability.
In prospective preconception cohort studies from Denmark and North America, higher-quality diets, including diets lower in inflammatory effects, were associated with greater fecundability.
Summary
Background
The carbohydrate alpha‐gal epitope is present in many animal proteins, including those of red meat and animal immunoglobulins, such as cat IgA. Systemic anaphylaxis to the ...alpha‐gal epitope has recently been described.
Objective
To investigate and compare the prevalence of alpha‐gal‐specific (s)IgE and its associated factors in the general adult population from two separated (Northern and Southern) European regions (Denmark and Spain, respectively).
Methods
Cross‐sectional study of 2297 and 444 randomly selected adults from 11 municipalities in Denmark and one in Spain. Alpha‐gal sIgE was assessed by ImmunoCAP to bovine thyroglobulin. Additional assessments included a panel of skin prick test (SPT) to common aeroallergens and epidemiological factors, including the history of tick bites in the Danish series.
Results
The prevalence of positive (≥ 0.1 kUA/L) sIgE to alpha‐gal was 5.5% and 8.1% in the Danish and Spanish series, respectively. The prevalence of sIgE ≥ 0.35 kUA/L was 1.8% and 2.2% in Denmark and Spain, respectively. Alpha‐gal sIgE positivity was associated with pet ownership in both series and, particularly, cat ownership (data available in the Danish series). Alpha‐gal sIgE positivity was associated with atopy (SPT positivity) in both series, although it was not associated with SPT positivity to cat or dog dander. Alpha‐gal sIgE positivity was strongly associated with a history of tick bites.
Conclusions and Clinical Relevance
The prevalence of alpha‐gal sIgE antibodies in these general adult European populations is similarly low. The presence of alpha‐gal sIgE antibodies is associated with a history of tick bites, atopy, and cat ownership.
During development of the central nervous system not all axons are myelinated, and axons may have distinct myelination patterns. Furthermore, the number of myelin sheaths formed by each ...oligodendrocyte is highly variable. However, our current knowledge about the axo‐glia communication that regulates the formation of myelin sheaths spatially and temporally is limited. By using axon‐mimicking microfibers and a zebrafish model system, we show that axonal ephrin‐A1 inhibits myelination. Ephrin‐A1 interacts with EphA4 to activate the ephexin1‐RhoA‐Rock‐myosin 2 signaling cascade and causes inhibition of oligodendrocyte process extension. Both in myelinating co‐cultures and in zebrafish larvae, activation of EphA4 decreases myelination, whereas myelination is increased by inhibition of EphA4 signaling at different levels of the pathway, or by receptor knockdown. Mechanistically, the enhanced myelination is a result of a higher number of myelin sheaths formed by each oligodendrocyte, not an increased number of mature cells. Thus, we have identified EphA4 and ephrin‐A1 as novel negative regulators of myelination. Our data suggest that activation of an EphA4‐RhoA pathway in oligodendrocytes by axonal ephrin‐A1 inhibits stable axo‐glia interaction required for generating a myelin sheath.
Main Points
Axonal Ephrin‐A1 inhibits myelination EphA4 activation inhibits myelination.
Inhibition of signaling through EphA4, RhoA or Rock enhances myelination by increasing the number of myelin sheaths generated per cell.
Stanniocalcin-1 (STC1) is a disulfide-bound homodimeric glycoprotein, first identified as a hypocalcemic hormone important for maintaining calcium homeostasis in teleost fish. STC1 was later found to ...be widely expressed in mammals, although it is not believed to function in systemic calcium regulation in these species. Several physiological functions of STC1 have been reported, although many molecular details are still lacking. We here demonstrate that STC1 is an inhibitor of the metzincin metalloproteinase, pregnancy-associated plasma protein-A (PAPP-A), which modulates insulin-like growth factor (IGF) signaling through proteolytic cleavage of IGF-binding proteins (IGFBPs). STC1 potently (Ki = 68 pm) inhibits PAPP-A cleavage of IGFBP-4, and we show in a cell-based assay that STC1 effectively antagonizes PAPP-A-mediated type 1 IGF receptor (IGF1R) phosphorylation. It has recently been found that the homologous STC2 inhibits PAPP-A proteolytic activity, and that this depends on the formation of a covalent complex between the inhibitor and the proteinase, mediated by Cys-120 of STC2. We find that STC1 is unable to bind covalently to PAPP-A, in agreement with the absence of a corresponding cysteine residue. It rather binds to PAPP-A with high affinity (KD = 75 pm). We further demonstrate that both STC1 and STC2 show inhibitory activity toward PAPP-A2, but not selected serine proteinases and metalloproteinases. We therefore conclude that the STCs are proteinase inhibitors, probably restricted in specificity to the pappalysin family of metzincin metalloproteinases. Our data are the first to identify STC1 as a proteinase inhibitor, suggesting a previously unrecognized function of STC1 in the IGF system.
Background: The molecular mechanisms behind previously reported biological effects of stanniocalcin-1 are poorly understood.
Results: Stanniocalcin-1 potently inhibits the proteolytic activity of the metzincin metalloproteinases PAPP-A and PAPP-A2, which promote insulin-like growth factor (IGF) activity in tissues.
Conclusion: Stanniocalcin-1 is a novel proteinase inhibitor.
Significance: Altered stanniocalcin-1 expression may affect IGF signaling in vivo under normal or pathological conditions.
Myelination in the central nervous system provides a unique example of how cells establish asymmetry. The myelinating cell, the oligodendrocyte, extends processes to and wraps multiple axons of ...different diameter, keeping the number of wraps proportional to the axon diameter. Local regulation of protein synthesis represents one mechanism used to control the different requirements for myelin sheath at each axo-glia interaction. Prior work has established that β1-integrins are involved in the axoglial interactions that initiate myelination. Here, we show that integrin activation regulates translation of a key sheath protein, myelin basic protein (MBP), by reversing the inhibitory effect of the mRNA 3'UTR. During oligodendrocyte differentiation and myelination α6β1-integrin interacts with hnRNP-K, an mRNA-binding protein, which binds to MBP mRNA and translocates from the nucleus to the myelin sheath. Furthermore, knockdown of hnRNP-K inhibits MBP protein synthesis during myelination. Together, these results identify a novel pathway by which axoglial adhesion molecules coordinate MBP synthesis with myelin sheath formation.
Protein lysine posttranslational modification by an increasing number of different acyl groups is becoming appreciated as a regulatory mechanism in cellular biology. Sirtuins are class III histone ...deacylases that use NAD+ as a co-substrate during amide bond hydrolysis. Several studies have described the sirtuins as sensors of the NAD+/NADH ratio, but it has not been formally tested for all the mammalian sirtuins in vitro. To address this problem, we first synthesized a wide variety of peptide-based probes, which were used to identify the range of hydrolytic activities of human sirtuins. These probes included aliphatic ϵ-N-acyllysine modifications with hydrocarbon lengths ranging from formyl (C1) to palmitoyl (C16) as well as negatively charged dicarboxyl-derived modifications. In addition to the well established activities of the sirtuins, “long chain” acyllysine modifications were also shown to be prone to hydrolytic cleavage by SIRT1–3 and SIRT6, supporting recent findings. We then tested the ability of NADH, ADP-ribose, and nicotinamide to inhibit these NAD+-dependent deacylase activities of the sirtuins. In the commonly used 7-amino-4-methylcoumarin-coupled fluorescence-based assay, the fluorophore has significant spectral overlap with NADH and therefore cannot be used to measure inhibition by NADH. Therefore, we turned to an HPLC-MS-based assay to directly monitor the conversion of acylated peptides to their deacylated forms. All tested sirtuin deacylase activities showed sensitivity to NADH in this assay. However, the inhibitory concentrations of NADH in these assays are far greater than the predicted concentrations of NADH in cells; therefore, our data indicate that NADH is unlikely to inhibit sirtuins in vivo. These data suggest a re-evaluation of the sirtuins as direct sensors of the NAD+/NADH ratio.
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