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Heparan sulfate proteoglycans (HSPG) are composed of unbranched, negatively charged heparan sulfate (HS) polysaccharides attached to a variety of cell surface or extracellular matrix proteins. Widely expressed, they mediate many biological activities, including angiogenesis, blood coagulation, developmental processes, and cell homeostasis. HSPG are highly sulfated and broadly used by a range of pathogens, especially viruses, to attach to the cell surface. In this review, we summarize the current knowledge on HSPG–virus interactions and distinguish viruses with established HS binding, viruses that bind HS only after intra-host or cell culture adaptation, and finally, viruses whose dependence on HS for infection is debated. We also provide an overview of the antiviral compounds designed to interfere with HS binding. Many questions remain about the true importance of these receptors in vivo, knowledge that is critical for the design of future antiviral therapies.

Although many techniques exist for preparing microcapsules, it is still challenging to fabricate them in an efficient and scalable process without compromising functionality and encapsulation efficiency. We demonstrated a simple one-step approach that exploits a versatile host-guest system and uses microfluidic droplets to generate porous microcapsules with easily customizable functionality. The capsules comprise a polymer-gold nanoparticle composite held together by cucurbit[8]uril ternary complexes. The dynamic yet highly stable micrometer-sized structures can be loaded in one step during capsule formation and are amenable to on-demand encapsulant release.The internal chemical environment can be probed with surface enhanced Raman spectroscopy.

Detecting viruses, which have significant impact on health and the economy, is essential for controlling and combating viral infections. In recent years there has been a focus towards simpler and faster detection methods, specifically through the use of electronic-based detection at the point-of-care. Point-of-care sensors play a particularly important role in the detection of viruses. Tests can be performed in the field or in resource limited regions in a simple manner and short time frame, allowing for rapid treatment. Electronic based detection allows for speed and quantitative detection not otherwise possible at the point-of-care. Such approaches are largely based upon voltammetry, electrochemical impedance spectroscopy, field effect transistors, and similar electrical techniques. Here, we systematically review electronic and electrochemical point-of-care sensors for the detection of human viral pathogens. Using the reported limits of detection and assay times we compare approaches both by detection method and by the target analyte of interest. Compared to recent scoping and narrative reviews, this systematic review which follows established best practice for evidence synthesis adds substantial new evidence on 1) performance and 2) limitations, needed for sensor uptake in the clinical arena. 104 relevant studies were identified by conducting a search of current literature using 7 databases, only including original research articles detecting human viruses and reporting a limit of detection. Detection units were converted to nanomolars where possible in order to compare performance across devices. This approach allows us to identify field effect transistors as having the fastest median response time, and as being the most sensitive, some achieving single-molecule detection. In general, we found that antigens are the quickest targets to detect. We also observe however, that reports are highly variable in their chosen metrics of interest. We suggest that this lack of systematisation across studies may be a major bottleneck in sensor development and translation. Where appropriate, we use the findings of the systematic review to give recommendations for best reporting practice.

Viral infections kill millions yearly. Available antiviral drugs are virus-specific and active against a limited panel of human pathogens. There are broad-spectrum substances that prevent the first step of virus-cell interaction by mimicking heparan sulfate proteoglycans (HSPG), the highly conserved target of viral attachment ligands (VALs). The reversible binding mechanism prevents their use as a drug, because, upon dilution, the inhibition is lost. Known VALs are made of closely packed repeating units, but the aforementioned substances are able to bind only a few of them. We designed antiviral nanoparticles with long and flexible linkers mimicking HSPG, allowing for effective viral association with a binding that we simulate to be strong and multivalent to the VAL repeating units, generating forces (∼190 pN) that eventually lead to irreversible viral deformation. Virucidal assays, electron microscopy images, and molecular dynamics simulations support the proposed mechanism. These particles show no cytotoxicity, and in vitro nanomolar irreversible activity against herpes simplex virus (HSV), human papilloma virus, respiratory syncytial virus (RSV), dengue and lenti virus. They are active ex vivo in human cervicovaginal histocultures infected by HSV-2 and in vivo in mice infected with RSV.

BackgroundYAC128 transgenic mice carry human HTT with an expanded CAG repeat. This model is particularly useful for evaluating therapies targeting the human HTT gene and/or protein.AimsTo better understand the molecular phenotype of YAC128 mice at the RNA and protein level.MethodsA QuantiGene assay was designed to gain insights into incomplete splicing in the context of human HTT, and to evaluate the lowering efficiency of therapeutic compounds. RNAscope was implemented to visualize HTT transcripts and immunohistochemistry to characterise HTT aggregation spatiotemporally. HTRF measured the levels of the total HTT protein and the pathogenic exon 1 HTT. Mouse embryonic fibroblasts (MEFs) from YAC128 mice were used for screening agents targeting human HTT transcript.ResultsMicroscopic analysis revealed that the full-length HTT mRNA (FL-HTT) was retained in RNA nuclear clusters together with the incompletely spliced HTT1a transcript. These clusters were not observed in zQ175 HD mouse model where, instead, FL-Htt and Htt1a mRNAs were detected as mostly cytoplasmic molecules. Immunohistochemistry showed a progressive appearance of aggregated HTT in nuclei in the cortex, striatum, hippocampus and cerebellum. HTRF indicated that the level of exon 1 HTT was highest in the cerebellum. Soluble mutant exon 1 HTT decreased with age, with concomitant increase in aggregated HTT. In YAC128 MEFs, HTT1a was detected and ASOs targeting HTT were efficient in lowering HTT levels in this model system.ConclusionsHuman HTTundergoes incomplete splicing in brains of YAC128 mice. The RNA clusters detected may have direct therapeutic implications, with pathogenic or protective consequences

Viruses are microscopic pathogens capable of causing disease and are responsible for a range of human mortality and morbidity worldwide. They can be rendered harmless or destroyed with a range of antiviral chemical compounds. Cucurbit[n]urils (CB[n]s) are a macrocycle chemical compound existing as a range of homologues; due to their structure they can bind to biological materials, acting as supramolecular host to guests, such as amino acids. Due to the increasing need for a non-toxic antiviral compound, we investigated whether cucurbit[n]urils could act in an antiviral manner. We have found that certain cucurbit[n]uril homologues do indeed have an antiviral effect against a range of viruses, including RSV and SARS-CoV-2. In particular, we demonstrate that CB[7] is the active homologue of CB[n] mixtures, having an antiviral effect against enveloped and non-enveloped species. High levels of efficacy were observed with five-minute contact times across different viruses. We also demonstrate that CB[7] acts with an extracellular virucidal mode of action via host-guest supramolecular interactions between viral surface proteins and the CB[n] cavity, rather than via cell internalisation or a virustatic mechanism. This finding demonstrates that CB[7] acts as a supramolecular virucidal antiviral (a mechanism distinct from other current extracellular antivirals) demonstrating the potential of supramolecular interactions for future antiviral disinfectants. Competing Interest Statement AH, BC, and RC are or were employees of Aqdot Ltd. All other authors (LMJ, ES, LB, MG and STJ) declare no competing financial interests.

Polyglutamine (polyQ) tract expansion leads to proteotoxic misfolding and drives a family of nine diseases. We study spinal and bulbar muscular atrophy (SBMA), a progressive degenerative disorder of the neuromuscular system caused by the polyQ androgen receptor (AR). Using a knock-in mouse model of SBMA, AR113Q mice, we show that E3 ubiquitin ligases which are a hallmark of the canonical muscle atrophy machinery are not induced in AR113Q muscle. Similarly, we find no evidence to suggest dysfunction of signaling pathways that trigger muscle hypertrophy or impairment of the muscle stem cell niche. Instead, we find that skeletal muscle atrophy is characterized by diminished function of the transcriptional regulator Myocyte Enhancer Factor 2 (MEF2), a regulator of myofiber homeostasis. Decreased expression of MEF2 target genes is age- and glutamine tract length-dependent, occurs due to polyQ AR proteotoxicity, and is associated with sequestration of MEF2 into intranuclear inclusions in muscle. Skeletal muscle from R6/2 mice, a model of Huntington disease which develops progressive atrophy, also sequesters MEF2 into inclusions and displays age-dependent loss of MEF2 target genes. Similarly, SBMA patient muscle shows loss of MEF2 target gene expression, and restoring MEF2 activity in AR113Q muscle rescues fiber size and MEF2-regulated gene expression. This work establishes MEF2 impairment as a novel mechanism of skeletal muscle atrophy downstream of toxic polyglutamine proteins and as a therapeutic target for muscle atrophy in these disorders.

Clear air turbulence forecasting has historically been a challenge. In recent years, many tools have been developed that have provided a measure of success. These tools can always be improved. This study focuses on one of these tools, Gary Ellrod’s Turbulence Index (Ellrod Index), and attempts to determine if the index could be improved by the addition of other turbulence factors. The study began with the most recent version of the Ellrod Index and examined it in conjunction with Richardson Number, horizontal shear, stability gradient, and temperature gradient. The indices were then verified against 16 pilot reports of turbulence over the north Pacific. None of the examined variables added significantly to the Ellrod Index, which performed at 75% accuracy. Four case studies were examined in additional detail to attempt to identify other potential turbulence drivers. It was ultimately determined that the Ellrod Index performs as well as can be determined by this study, the additional factors did not improve performance.

Autochthonous transmission of arboviruses poses significant threats to global health and economies. Yet, no effective antivirals exist. Building on our previous antiviral star-polymer, we designed zwitterionic star-polymers for efficacy in high protein environments. A polymer with 12% positively charged monomer (Zwitterionic Polymer-ZP12) exhibited broad-spectrum, biocompatible antiviral activity against Alphaviridae, Flaviviridae, Herpesviridae, and Picornaviridae. Using murine models for Chikungunya virus (CHIKV) infection, ZP12 treatment (10 mg/kg every 24 hours for 7 days) reduced tissue viral load by 90% 3 days post-infection and significantly alleviated CHIKV-induced joint swelling. Mechanistically, ZP12 downregulated CHIKV-driven immunopathogenesis by reducing viral load and dampening CD4+ T cell and macrophage activation in virus-infected joints. With no current antiviral interventions for these arboviruses, ZP12 represents a promising intervention for combating future pandemics.

Converting biomass to useful products through synthesis gas (syngas) fermentation has the potential to replace petroleum based products with biobased ones; however, these process are limited in their application. One of the most significant limiting steps in syngas fermentations is the gas-liquid mass transfer in the bioreactor due to the low solubilities of the major syngas components, CO and H2. Hence, to explore possible solutions for over coming the gas-liquid mass transfer barrier, a non-traditional external airlift loop reactor is considered. This study evaluates the hydrodynamics and gas-liquid mass transfer rates in an external airlift loop reactor with an area ratio of 1:16 operating under different conditions. Two downcomer configurations are investigated consisting of the downcomer vent open or closed to the atmosphere. Experiments for these two configurations are carried out over a range of superficial gas velocities (UG) from UG = 0.5 to 20 cm/s using three aeration plates with open area ratios of 0.66, 0.99 and 2.22%. These results are compared to a bubble column operating under similar conditions. Water quality variations are also investigated over the same range of UG with the downcomer open to the atmosphere. Experimental results show that the gas holdup in the riser does not vary significantly with a change in the downcomer configuration or bubble column operation, while a considerable variation is observed in the downcomer gas holdup. Gas holdup in both the riser and downcomer are found to increase with increasing superficial gas velocity. Test results also show that the maximum gas holdup for the three aeration plates is similar, but that the gas holdup trends are different. The superficial liquid velocity is found to vary considerably for the two downcomer configurations. However, for both cases, the superficial liquid velocity is a function of the superficial gas velocity and/or the flow condition in the downcomer. These observed variations are independent of the aerator plate open area ratio. Gas-liquid mass transfer results indicate that mass transfer rates do vary for oxygen and carbon monoxide gas species. Gas-liquid mass transfer rates are observed to increase linearly with UG in the presence of a surfactant and to increase similarly to riser gas holdup with UG for deionized water and ionic solutions. The gas-liquid mass transfer rates are relatively unaffected by the reactor configuration. The results also show that the addition of a surfactant or ionic compounds has a significant effect on mass transfer, where the surfactant restricts gas-liquid mass transfer and the ionic compounds enhance gas-liquid mass transfer.