This review provides an overview of recent developments in "chemical virology." Viruses, as materials, provide unique nanoscale scaffolds that have relevance in chemical biology and nanotechnology, ...with diverse areas of applications. Some fundamental advantages of viruses, compared to synthetically programmed materials, include the highly precise spatial arrangement of their subunits into a diverse array of shapes and sizes and many available avenues for easy and reproducible modification. Here, we will first survey the broad distribution of viruses and various methods for producing virus-based nanoparticles, as well as engineering principles used to impart new functionalities. We will then examine the broad range of applications and implications of virus-based materials, focusing on the medical, biotechnology, and energy sectors. We anticipate that this field will continue to evolve and grow, with exciting new possibilities stemming from advancements in the rational design of virus-based nanomaterials.
Two Phase 3 Trials of Baricitinib for Alopecia Areata King, Brett; Ohyama, Manabu; Kwon, Ohsang ...
New England journal of medicine/The New England journal of medicine,
05/2022, Letnik:
386, Številka:
18
Journal Article
Recenzirano
Odprti dostop
Alopecia areata is an autoimmune condition characterized by rapid hair loss in the scalp, eyebrows, and eyelashes, for which treatments are limited. Baricitinib, an oral, selective, reversible ...inhibitor of Janus kinases 1 and 2, may interrupt cytokine signaling implicated in the pathogenesis of alopecia areata.
We conducted two randomized, placebo-controlled, phase 3 trials (BRAVE-AA1 and BRAVE-AA2) involving adults with severe alopecia areata with a Severity of Alopecia Tool (SALT) score of 50 or higher (range, 0 no scalp hair loss to 100 complete scalp hair loss). Patients were randomly assigned in a 3:2:2 ratio to receive once-daily baricitinib at a dose of 4 mg, baricitinib at a dose of 2 mg, or placebo. The primary outcome was a SALT score of 20 or less at week 36.
We enrolled 654 patients in the BRAVE-AA1 trial and 546 in the BRAVE-AA2 trial. The estimated percentage of patients with a SALT score of 20 or less at week 36 was 38.8% with 4-mg baricitinib, 22.8% with 2-mg baricitinib, and 6.2% with placebo in BRAVE-AA1 and 35.9%, 19.4%, and 3.3%, respectively, in BRAVE-AA2. In BRAVE-AA1, the difference between 4-mg baricitinib and placebo was 32.6 percentage points (95% confidence interval CI, 25.6 to 39.5), and the difference between 2-mg baricitinib and placebo was 16.6 percentage points (95% CI, 9.5 to 23.8) (P<0.001 for each dose vs. placebo). In BRAVE-AA2, the corresponding values were 32.6 percentage points (95% CI, 25.6 to 39.6) and 16.1 percentage points (95% CI, 9.1 to 23.2) (P<0.001 for each dose vs. placebo). Secondary outcomes for baricitinib at a dose of 4 mg but not at a dose of 2 mg generally favored baricitinib over placebo. Acne, elevated levels of creatine kinase, and increased levels of low- and high-density lipoprotein cholesterol were more common with baricitinib than with placebo.
In two phase 3 trials involving patients with severe alopecia areata, oral baricitinib was superior to placebo with respect to hair regrowth at 36 weeks. Longer trials are required to assess the efficacy and safety of baricitinib for alopecia areata. (Funded by Eli Lilly under license from Incyte; BRAVE-AA1 and BRAVE-AA2 ClinicalTrials.gov numbers, NCT03570749 and NCT03899259.).
Zika Virus Shedding in Semen of Symptomatic Infected Men Mead, Paul S; Duggal, Nisha K; Hook, Sarah A ...
New England journal of medicine/The New England journal of medicine,
04/2018, Letnik:
378, Številka:
15
Journal Article
Recenzirano
Odprti dostop
Zika virus (ZIKV) is an emerging mosquito-borne flavivirus that has been linked to adverse birth outcomes. Previous reports have shown that person-to-person transmission can occur by means of sexual ...contact.
We conducted a prospective study involving men with symptomatic ZIKV infection to determine the frequency and duration of ZIKV shedding in semen and urine and to identify risk factors for prolonged shedding in these fluids. Specimens were obtained twice per month for 6 months after illness onset and were tested by real-time reverse-transcriptase-polymerase-chain-reaction (RT-PCR) assay for ZIKV RNA and by Vero cell culture and plaque assay for infectious ZIKV.
A total of 1327 semen samples from 184 men and 1038 urine samples from 183 men were obtained 14 to 304 days after illness onset. ZIKV RNA was detected in the urine of 7 men (4%) and in the semen of 60 (33%), including in semen samples from 22 of 36 men (61%) who were tested within 30 days after illness onset. ZIKV RNA shedding in semen decreased substantially during the 3 months after illness onset but continued for 281 days in 1 man (1%). Factors that were independently associated with prolonged RNA shedding included older age, less frequent ejaculation, and the presence of certain symptoms at the time of initial illness. Infectious ZIKV was isolated from 3 of 78 semen samples with detectable ZIKV RNA, all obtained within 30 days after illness onset and all with at least 7.0 log
ZIKV RNA copies per milliliter of semen.
ZIKV RNA was commonly present in the semen of men with symptomatic ZIKV infection and persisted in some men for more than 6 months. In contrast, shedding of infectious ZIKV appeared to be much less common and was limited to the first few weeks after illness onset. (Funded by the Centers for Disease Control and Prevention.).
Abstract
Acute exposure to high-dose gamma radiation due to radiological disasters or cancer radiotherapy can result in radiation-induced lung injury (RILI), characterized by acute pneumonitis and ...subsequent lung fibrosis. A microfluidic organ-on-a-chip lined by human lung alveolar epithelium interfaced with pulmonary endothelium (Lung Alveolus Chip) is used to model acute RILI in vitro. Both lung epithelium and endothelium exhibit DNA damage, cellular hypertrophy, upregulation of inflammatory cytokines, and loss of barrier function within 6 h of radiation exposure, although greater damage is observed in the endothelium. The radiation dose sensitivity observed on-chip is more like the human lung than animal preclinical models. The Alveolus Chip is also used to evaluate the potential ability of two drugs - lovastatin and prednisolone - to suppress the effects of acute RILI. These data demonstrate that the Lung Alveolus Chip provides a human relevant alternative for studying the molecular basis of acute RILI and may be useful for evaluation of new radiation countermeasure therapeutics.
Nociceptive pain is a hallmark of many chronic inflammatory conditions including inflammatory bowel diseases (IBDs); however, whether pain-sensing neurons influence intestinal inflammation remains ...poorly defined. Employing chemogenetic silencing, adenoviral-mediated colon-specific silencing, and pharmacological ablation of TRPV1+ nociceptors, we observed more severe inflammation and defective tissue-protective reparative processes in a murine model of intestinal damage and inflammation. Disrupted nociception led to significant alterations in the intestinal microbiota and a transmissible dysbiosis, while mono-colonization of germ-free mice with Gram+Clostridium spp. promoted intestinal tissue protection through a nociceptor-dependent pathway. Mechanistically, disruption of nociception resulted in decreased levels of substance P, and therapeutic delivery of substance P promoted tissue-protective effects exerted by TRPV1+ nociceptors in a microbiota-dependent manner. Finally, dysregulated nociceptor gene expression was observed in intestinal biopsies from IBD patients. Collectively, these findings indicate an evolutionarily conserved functional link between nociception, the intestinal microbiota, and the restoration of intestinal homeostasis.
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•TRPV1+ nociceptors are protective in a murine model of intestinal inflammation•Ablation of TRPV1+ nociceptors leads to a transmissible microbial dysbiosis•Clostridium spp. colonization drives nociceptor-mediated tissue protection in mice•TRPV1+ nociceptor-derived substance P promotes intestinal tissue protection
Gut-innervating TRPV1+ nociceptors influence the composition of the intestinal microbiota to limit inflammation and promote intestinal tissue protection.
Dietary fibres can exert beneficial anti-inflammatory effects through microbially fermented short-chain fatty acid metabolites 1,2 , although the immunoregulatory roles of most fibre diets and their ...microbiota-derived metabolites remain poorly defined. Here, using microbial sequencing and untargeted metabolomics, we show that a diet of inulin fibre alters the composition of the mouse microbiota and the levels of microbiota-derived metabolites, notably bile acids. This metabolomic shift is associated with type 2 inflammation in the intestine and lungs, characterized by IL-33 production, activation of group 2 innate lymphoid cells and eosinophilia. Delivery of cholic acid mimics inulin-induced type 2 inflammation, whereas deletion of the bile acid receptor farnesoid X receptor diminishes the effects of inulin. The effects of inulin are microbiota dependent and were reproduced in mice colonized with human-derived microbiota. Furthermore, genetic deletion of a bile-acid-metabolizing enzyme in one bacterial species abolishes the ability of inulin to trigger type 2 inflammation. Finally, we demonstrate that inulin enhances allergen- and helminth-induced type 2 inflammation. Taken together, these data reveal that dietary inulin fibre triggers microbiota-derived cholic acid and type 2 inflammation at barrier surfaces with implications for understanding the pathophysiology of allergic inflammation, tissue protection and host defence.
Biomolecules in bodily fluids such as plasma can adsorb to the surface of nanoparticles and influence their biological properties. This phenomenon, known as the protein corona, is well established in ...the field of synthetic nanotechnology but has not been described in the context of plant virus nanoparticles (VNPs). The interaction between VNPs derived from Tobacco mosaic virus (TMV) and plasma proteins is investigated, and it is found that the VNP protein corona is significantly less abundant compared to the corona of synthetic particles. The formed corona is dominated by complement proteins and immunoglobulins, the binding of which can be reduced by PEGylating the VNP surface. The impact of the VNP protein corona on molecular recognition and cell targeting in the context of cancer and thrombosis is investigated. A library of functionalized TMV rods with polyethylene glycol (PEG) and peptide ligands targeting integrins or fibrin(ogen) show different dispersion properties, cellular interactions, and in vivo fates depending on the properties of the protein corona, influencing target specificity, and non‐specific scavenging by macrophages. Our results provide insight into the in vivo properties of VNPs and suggest that the protein corona effect should be considered during the development of efficacious, targeted VNP formulations.
The interactions between targeted plant virus‐based nanoparticles (VNPs) and blood plasma proteins and their consequences are investigated. The number of proteins associated with VNPs in situ is lower than for synthetic nanoparticles; complement proteins and immunoglobulins dominate. The consequences of protein adsorption for molecular targeting and in vivo biodistribution are demonstrated.
Nanomaterials with elongated architectures have been shown to possess differential tumor homing properties compared to their spherical counterparts. Here, we investigate whether this phenomenon is ...mirrored by plant viral nanoparticles that are filamentous (Potato virus X) or spherical (Cowpea mosaic virus). Our studies demonstrate that Potato virus X (PVX) and Cowpea mosaic virus (CPMV) show distinct biodistribution profiles and differ in their tumor homing and penetration efficiency. Analogous to what is seen with inorganic nanomaterials, PVX shows enhanced tumor homing and tissue penetration. Human tumor xenografts exhibit higher uptake of PEGylated filamentous PVX compared to CPMV, particularly in the core of the tumor. This is supported by immunohistochemical analysis of the tumor sections, which indicates greater penetration and accumulation of PVX within the tumor tissues. The enhanced tumor homing and retention properties of PVX along with its higher payload carrying capacity make it a potentially superior platform for applications in cancer drug delivery and imaging applications.
The size and shape of nanocarriers can affect their fate in vivo, but little is known about the effect of nanocarrier aspect ratio on biodistribution in the setting of cancer imaging and drug ...delivery. The production of nanoscale anisotropic materials is a technical challenge. A unique biotemplating approach based on of rod-shaped nucleoprotein nanoparticles with predetermined aspect ratios (AR 3.5, 7, and 16.5) is used. These rigid, soft-matter nanoassemblies are derived from tobacco mosaic virus (TMV) components. The role of nanoparticle aspect ratio is investigated, while keeping the surface chemistries constant, using either PEGylated stealth nanoparticles or receptor-targeted RGD-displaying formulations. Aspect ratio has a profound impact on the behavior of the nanoparticles in vivo and in vitro. PEGylated nanorods with the lowest aspect ratio (AR 3.5) achieve the most efficient passive tumor-homing behavior because they can diffuse most easily, whereas RGD-labeled particles with a medium aspect ratio (AR 7) are more efficient at tumor targeting because this requires a balance between infusibility and ligand-receptor interactions. The in vivo behavior of nanoparticles can therefore be tailored to control biodistribution, longevity, and tumor penetration by modulating a single parameter: the aspect ratio of the nanocarrier.
Mineral adsorption-induced molecular fractionation of dissolved organic matter (DOM) affects the composition of both DOM and OM adsorbed and thus stabilized by minerals. However, it remains unclear ...what mineral properties control the magnitude of DOM fractionation. Using a combined technique approach that leverages the molecular composition identified by ultrahigh resolution 21 T Fourier transform ion cyclotron resonance mass spectrometry and adsorption isotherms, we catalogue the compositional differences that occur at the molecular level that results in fractionation due to adsorption of Suwannee River fulvic acid on aluminum (Al) and iron (Fe) oxides and a phyllosilicate (allophane) species of contrasting properties. The minerals of high solubility (i.e., amorphous Al oxide, boehmite, and allophane) exhibited much stronger DOM fractionation capabilities than the minerals of low solubility (i.e., gibbsite and Fe oxides). Specifically, the former released Al3+ to solution (0.05–0.35 mM) that formed complexes with OM and likely reduced the surface hydrophobicity of the mineral-OM assemblage, thus increasing the preference for adsorbing polar DOM molecules. The impacts of mineral solubility are exacerbated by the fact that interactions with DOM also enhance metal release from minerals. For sparsely soluble minerals, the mineral surface hydrophobicity, instead of solubility, appeared to be the primary control of their DOM fractionation power. Other chemical properties seemed less directly relevant than surface hydrophobicity and solubility in fractionating DOM.
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