It is widely appreciated that effective human vaccines directed against viral pathogens elicit neutralizing antibodies (NAbs). The passive transfer of anti-HIV-1 NAbs conferring sterilizing immunity ...to macaques has been used to determine the plasma neutralization titers, which must be present at the time of exposure, to prevent acquisition of SIV/HIV chimeric virus (SHIV) infections. We administered five recently isolated potent and broadly acting anti-HIV neutralizing monoclonal antibodies (mAbs) to rhesus macaques and challenged them intrarectally 24 h later with either of two different R5-tropic SHIVs. By combining the results obtained from 60 challenged animals, we determined that the protective neutralization titer in plasma preventing virus infection in 50% of the exposed monkeys was relatively modest (∼1:100) and potentially achievable by vaccination.
Peracetic acid (PAA) is a promising alternative to chlorine for disinfection; however, bacterial regrowth after PAA disinfection is poorly understood. This study compared the regrowth of bacteria ...(Gram-negative Pseudomonas aeruginosa PAO1 and Gram-positive Bacillus sp.) after disinfection with PAA or free chlorine. In the absence of organic matter, PAA and free chlorine prevented the regrowth of planktonic cells of P. aeruginosa PAO1 at C·t (= disinfectant concentration × contact time) doses of (28.5 ± 9.8) mg PAA·min·L−1 and (22.5 ± 10.6) mg Cl2·min·L−1, respectively, suggesting that they had comparable efficiencies in preventing the regrowth of planktonic bacteria. For comparison, the minimum C·t doses of PAA and free chlorine to prevent the regrowth of P. aeruginosa PAO1 biofilm cells in the absence of organic matter were (14,000 ± 1,732) mg PAA·min·L−1 and (6,500 ± 2,291) mg Cl2·min·L−1, respectively. PAA was less effective than free chlorine in killing bacteria within biofilms in the absence of organic matter most likely because PAA reacts with biofilm matrix constituents slower than free chlorine. In the presence of organic matter, although the bactericidal efficiencies of both disinfectants significantly decreased, PAA was less affected due to its slower reaction with organic matter and/or slower self-decomposition. For instance, in a dilute Lysogeny broth-Miller, the minimum concentrations of PAA and free chlorine to prevent the regrowth of planktonic P. aeruginosa PAO1 were 20 mg PAA·L−1 and 300 mg Cl2·L−1, respectively. While both disinfectants are strong oxidants disrupting cell membrane, environmental scanning electron microscopy (ESEM) revealed that PAA made holes in the center of the cells, whereas free chlorine desiccated the cells. Overall, this study shows that PAA is a powerful disinfectant to prevent bacterial regrowth even in the presence of organic matter.
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•PAA and chlorine effectively killed planktonic cells in the absence of organic matter (OM).•PAA was less effective than chlorine in preventing cell regrowth after biofilm treatment in the absence of OM.•PAA was more effective than chlorine in preventing cell regrowth in the presence of OM.•PAA disinfection was less affected by OM compared with chlorination.•PAA caused holes to form in the center of cells, whereas chlorine desiccated the bacteria.
Mild traumatic brain injuries (mTBI) constitute a significant health concern with clinical symptoms ranging from headaches to cognitive deficits. Despite the myriad of symptoms commonly reported ...following this injury, there is still a lack of knowledge on the various pathophysiological changes that occur. Preclinical studies are at the forefront of discovery delineating the changes that occur within this heterogeneous injury, with the emergence of translational models such as closed-head impact models allowing for further exploration of this injury mechanism. In the current study, male rats were subjected to a closed-head controlled cortical impact (cCCI), producing a concussion (mTBI). The pathological effects of this injury were then evaluated using immunoflourescence seven days following. The results exhibited a unique glial-specific inflammatory response, with both the ipsilateral and contralateral sides of the cortex and hippocampus showing pathological changes following impact. Overall these findings are consistent with glial changes reported following concussions and may contribute to subsequent symptoms.
Neglected diseases caused by arenaviruses such as Lassa virus (LASV) and filoviruses like Ebola virus (EBOV) primarily afflict resource-limited countries, where antiviral drug development is often ...minimal. Previous studies have shown that many approved drugs developed for other clinical indications inhibit EBOV and LASV and that combinations of these drugs provide synergistic suppression of EBOV, often by blocking discrete steps in virus entry. We hypothesize that repurposing of combinations of orally administered approved drugs provides effective suppression of arenaviruses. In this report, we demonstrate that arbidol, an approved influenza antiviral previously shown to inhibit EBOV, LASV, and many other viruses, inhibits murine leukemia virus (MLV) reporter viruses pseudotyped with the fusion glycoproteins (GPs) of other arenaviruses (Junin virus JUNV, lymphocytic choriomeningitis virus LCMV, and Pichinde virus PICV). Arbidol and other approved drugs, including aripiprazole, amodiaquine, sertraline, and niclosamide, also inhibit infection of cells by infectious PICV, and arbidol, sertraline, and niclosamide inhibit infectious LASV. Combining arbidol with aripiprazole or sertraline results in the synergistic suppression of LASV and JUNV GP-bearing pseudoviruses. This proof-of-concept study shows that arenavirus infection
can be synergistically inhibited by combinations of approved drugs. This approach may lead to a proactive strategy with which to prepare for and control known and new arenavirus outbreaks.
The impacts of the molecular weight (MW), viscosity, and solubility of β-glucan on the rate of in vitro starch digestion and estimated glycemic index (GI) were evaluated. Extracted oat starch and ...β-glucan suspensions with high, medium, and low MW were heated to gelatinize the starch. The viscosity increased and the solubility decreased with an increase in the MW of β-glucan. The in vitro starch hydrolysis of the mixtures and a control, white bread, increased as the digestion time increased. As the MW of β-glucan increased, the starch hydrolysis decreased during in vitro digestion. The in vitro estimated GI of the mixture without β-glucan, determined from the starch hydrolysis rate, was 88.3 for Jim and 80.0 for N979, which decreased to 68.4 and 66.8, respectively, with the inclusion of high-MW β-glucan. The estimated GI values were negatively correlated with the β-glucan peak and final viscosities (r = −0.81 and −0.82). These results illustrated the importance of viscosity attributed to the β-glucan MW on starch hydrolysis during in vitro digestion. These findings will help to develop new food products with a low GI by using oat β-glucan.
There are no FDA licensed vaccines or therapeutics for Venezuelan equine encephalitis virus (VEEV) which causes a debilitating acute febrile illness in humans that can progress to encephalitis. ...Previous studies demonstrated that murine and macaque monoclonal antibodies (mAbs) provide prophylactic and therapeutic efficacy against VEEV peripheral and aerosol challenge in mice. Additionally, humanized versions of two neutralizing mAbs specific for the E2 glycoprotein, 1A3B-7 and 1A4A-1, administered singly protected mice against aerosolized VEEV. However, no studies have demonstrated protection in nonhuman primate (NHP) models of VEEV infection. Here, we evaluated a chimeric antibody 1A3B-7 (c1A3B-7) containing mouse variable regions on a human IgG framework and a humanized antibody 1A4A-1 containing a serum half-life extension modification (Hu-1A4A-1-YTE) for their post-exposure efficacy in NHPs exposed to aerosolized VEEV. Approximately 24 hours after exposure, NHPs were administered a single bolus intravenous mAb. Control NHPs had typical biomarkers of VEEV infection including measurable viremia, fever, and lymphopenia. In contrast, c1A3B-7 treated NHPs had significant reductions in viremia and lymphopenia and on average approximately 50% reduction in fever. Although not statistically significant, Hu-1A4A-1-YTE administration did result in reductions in viremia and fever duration. Delay of treatment with c1A3B-7 to 48 hours post-exposure still provided NHPs protection from severe VEE disease through reductions in viremia and fever. These results demonstrate that post-exposure administration of c1A3B-7 protected macaques from development of severe VEE disease even when administered 48 hours following aerosol exposure and describe the first evaluations of VEEV-specific mAbs for post-exposure prophylactic use in NHPs. Viral mutations were identified in one NHP after c1A3B-7 treatment administered 24 hrs after virus exposure. This suggests that a cocktail-based therapy, or an alternative mAb against an epitope that cannot mutate without resulting in loss of viral fitness may be necessary for a highly effective therapeutic.
Long-term neuropsychiatric impairments have become a growing concern following blast-related traumatic brain injury (bTBI) in active military personnel and Veterans. Neuropsychiatric impairments such ...as anxiety and depression are common comorbidities that Veterans report months, even years following injury. To understand these chronic behavioral outcomes following blast injury, there is a need to study the link between anxiety, depression, and neuropathology. The hippocampus and motor cortex (MC) have been regions of interest when studying cognitive deficits following blast exposure, but clinical studies of mood disorders such as major depressive disorder (MDD) report that these two regions also play a role in the manifestation of anxiety and depression. With anxiety and depression being common long-term outcomes following bTBI, it is imperative to study how chronic pathological changes within the hippocampus and/or MC due to blast contribute to the development of these psychiatric impairments. In this study, we exposed male rats to a repeated blast overpressure (~17 psi) and evaluated the chronic behavioral and pathological effects on the hippocampus and MC. Results demonstrated that the repeated blast exposure led to depression-like behaviors 36 weeks following injury, and anxiety-like behaviors 2-, and 52-weeks following injury. These behaviors were also correlated with astrocyte pathology (glial-fibrillary acid protein, GFAP) and dendritic alterations (Microtubule-Associated Proteins, MAP2) within the hippocampus and MC regions at 52 weeks. Overall, these findings support the premise that chronic glial pathological changes within the brain contribute to neuropsychiatric impairments following blast exposure.
Currently, no approved therapeutics exist to treat or prevent infections induced by Ebola viruses, and recent events have demonstrated an urgent need for rapid discovery of new treatments. ...Repurposing approved drugs for emerging infections remains a critical resource for potential antiviral therapies. We tested ~2600 approved drugs and molecular probes in an in vitro infection assay using the type species, Zaire ebolavirus. Selective antiviral activity was found for 80 U.S. Food and Drug Administration-approved drugs spanning multiple mechanistic classes, including selective estrogen receptor modulators, antihistamines, calcium channel blockers, and antidepressants. Results using an in vivo murine Ebola virus infection model confirmed the protective ability of several drugs, such as bepridil and sertraline. Viral entry assays indicated that most of these antiviral drugs block a late stage of viral entry. By nature of their approved status, these drugs have the potential to be rapidly advanced to clinical settings and used as therapeutic countermeasures for Ebola virus infections.
The in vitro starch digestion rate and estimated glycemic index (GI) of oat flours and oat starches from typical and high β-glucan oat lines were evaluated along with the impact of heating on starch ...digestion. Flour from oat lines ('Jim', 'Paul', IA95, and N979 containing 4.0, 5.3, 7.4, and 7.7% β-glucan, respectively) was digested by pepsin and porcine pancreatin. To determine the impact of heating on starch digestion, oat slurries were prepared by mixing oat flour and water (1:8 ratio) and heating for 10 min prior to digestion. Viscosity, as measured on a Rapid Visco Analyzer, increased with increases in concentration and molecular weight of β-glucan. The in vitro starch digestion of oat flours and a control, white bread made from wheat flour, increased as the digestion time increased. Starch digestion of oat flour was slower than that of the control (p < 0.05). Heat treatment of oat-flour slurries increased the starch digestion from a range of 31–39% to a range of 52–64% measured after 180 min of in vitro digestion. There were no differences in starch digestibility among oat starches extracted from the different oat lines. The GI, estimated by starch hydrolysis of oat flours, ranged from 61 to 67, which increased to a range of 77–86 after heating. Oat-flour slurries prepared from IA95 and N979 lines with high β-glucan concentrations had lower GI values than did slurries made from Jim and Paul lines. Starch digestion was negatively correlated with β-glucan concentrations in heated oat-flour slurries (R 2 = 0.92). These results illustrate that the oat soluble fiber, β-glucan, slowed the rate of starch digestion. This finding will help to develop new food products with low GI by using oat β-glucan.
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