Currently there are no approved vaccines or specific therapies to prevent or treat Zika virus (ZIKV) infection. We interrogated a library of FDA-approved drugs for their ability to block infection of ...human HuH-7 cells by a newly isolated ZIKV strain (ZIKV MEX_I_7). More than 20 out of 774 tested compounds decreased ZIKV infection in our in vitro screening assay. Selected compounds were further validated for inhibition of ZIKV infection in human cervical, placental, and neural stem cell lines, as well as primary human amnion cells. Established anti-flaviviral drugs (e.g., bortezomib and mycophenolic acid) and others that had no previously known antiviral activity (e.g., daptomycin) were identified as inhibitors of ZIKV infection. Several drugs reduced ZIKV infection across multiple cell types. This study identifies drugs that could be tested in clinical studies of ZIKV infection and provides a resource of small molecules to study ZIKV pathogenesis.
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•774 FDA-approved drugs screened for anti-Zika virus activity in a human hepatoma cell line•Over 20 compounds showed anti-Zika virus activity•Selected compounds validated in human neural stem cells and primary amnion cells
Currently there is no approved therapy to treat Zika virus (ZIKV) infection. Barrows et al. present a screen of FDA-approved drugs for anti-ZIKV activity in a hepatoma cell line. Selected compounds from the more than 20 identified candidates were validated in human neural stem cells and primary amnion cells.
We determined the association between urine pH and blood acid-base indicators and assessed a urine pH cut-off value to predict severe metabolic acidosis under field conditions in cows fed acidogenic ...diets. Eighty-six cows were sampled for urine and blood. Urine pH was evaluated immediately after collection, and blood acid-base status was evaluated within 2 hours of collection using a portable blood analyzer. Twenty-five cows were classified as having severe metabolic acidosis (blood pH ≤ 7.4; bicarbonate < 24 mmol/L, base excess ≤ −0.5; PCO2 low to normal concentrations and urine pH between 4.88 and 5.71. There was a positive linear association between urine pH and blood pH (r = 0.46), and between urine pH and base excess (r = 0.74). The area under the ROC curve was 0.91 (CI 95 %= 0.84–0.96; good-excellent test). The optimal cut-off value for urine pH to categorize a cow with severe metabolic acidosis was 5.5 (94 % specificity and 72 % sensitivity). For each 0.1 unit of decrease in urine pH below 5.5, cows were 1.6 times (95 % CI= 1.3–2.1) more likely to exhibit a severe metabolic acidosis. We conclude that a urine pH of 5.5 or less is indicative of more life-threatening metabolic acidosis in dairy cows.
•Urine pH ≤ 5.5 is related to severe metabolic acidosis.•A cut-off value of urine pH 5.5 to predict a cow with severe metabolic acidosis has a 94 % of sensitivity and 72 % of specificity.•The area under the ROC curve was 0.9085 ± 0.0308.•For each 0.1 unit of urine pH below 5.5, cows are 1.55 times more likely to have a severe metabolic acidosis.
•Pea protein forms coacervates with pectin at specific mixing ratios and pHs.•Coacervation is highly dependent on the physicochemical properties of pectin.•Higher degrees of esterification and ...blockiness of pectin increase complex formation.•Pectin can improve the solubility of pea protein at pH 4.5.
The complex coacervation of pea protein isolate (PPI) with commercial pectic polysaccharides high methoxy citrus pectin (P90, 90 representing DE), apple pectin (P78) sugar beet pectin (P62), low methoxy citrus pectin (P29) of different degrees of esterification (DE) and galacturonic acid content (GalA) and blockiness (DB), was investigated. The maximum amount of coacervates formed at a biopolymer weight mixing ratio of 4:1 for all PPI-pectin mixtures, with the exception of PPI-P29 where maximum coacervation occurred at the 10:1 mixing ratio. The pH at which maximum interactions occurred was pH 3.4–3.5 (PPI: P90/P78) and 3.7–3.8 (PPI: P62/P29). PPI complexed with pectins with high levels of DE (low levels of GalA) and DB displayed greater interactions at optimal mixing conditions compared to pectin having lower levels of esterification and blockiness. The addition of P78 to PPI greatly increased protein solubility at pH 4.5.
Flaviviruses, such as dengue, Japanese encephalitis, tick-borne encephalitis, West Nile, yellow fever, and Zika viruses, are critically important human pathogens that sicken a staggeringly high ...number of humans every year. Most of these pathogens are transmitted by mosquitos, and not surprisingly, as the earth warms and human populations grow and move, their geographic reach is increasing. Flaviviruses are simple RNA–protein machines that carry out protein synthesis, genome replication, and virion packaging in close association with cellular lipid membranes. In this review, we examine the molecular biology of flaviviruses touching on the structure and function of viral components and how these interact with host factors. The latter are functionally divided into pro-viral and antiviral factors, both of which, not surprisingly, include many RNA binding proteins. In the interface between the virus and the hosts we highlight the role of a noncoding RNA produced by flaviviruses to impair antiviral host immune responses. Throughout the review, we highlight areas of intense investigation, or a need for it, and potential targets and tools to consider in the important battle against pathogenic flaviviruses.
Plus-stranded RNA viruses have limited coding capacity and have to co-opt numerous pro-viral host factors to support their replication. Many of the co-opted host factors support the biogenesis of the ...viral replication compartments and the formation of viral replicase complexes on subverted subcellular membrane surfaces. Tomato bushy stunt virus (TBSV) exploits peroxisomal membranes, whereas the closely-related carnation Italian ringspot virus (CIRV) hijacks the outer membranes of mitochondria. How these organellar membranes can be recruited into pro-viral roles is not completely understood. Here, we show that the highly conserved Fis1 mitochondrial fission protein is co-opted by both TBSV and CIRV via direct interactions with the p33/p36 replication proteins. Deletion of FIS1 in yeast or knockdown of the homologous Fis1 in plants inhibits tombusvirus replication. Instead of the canonical function in mitochondrial fission and peroxisome division, the tethering function of Fis1 is exploited by tombusviruses to facilitate the subversion of membrane contact site (MCS) proteins and peroxisomal/mitochondrial membranes for the biogenesis of the replication compartment. We propose that the dynamic interactions of Fis1 with MCS proteins, such as the ER resident VAP tethering proteins, Sac1 PI4P phosphatase and the cytosolic OSBP-like oxysterol-binding proteins, promote the formation and facilitate the stabilization of virus-induced vMCSs, which enrich sterols within the replication compartment. We show that this novel function of Fis1 is exploited by tombusviruses to build nuclease-insensitive viral replication compartment.
The intricate interactions between viruses and hosts include exploitation of host cells for viral replication by using many cellular resources, metabolites and energy. Tomato bushy stunt virus ...(TBSV), similar to other (+)RNA viruses, induces major changes in infected cells that lead to the formation of large replication compartments consisting of aggregated peroxisomal and ER membranes. Yet, it is not known how TBSV obtains the energy to fuel these energy-consuming processes. In the current work, the authors discovered that TBSV co-opts the glycolytic ATP-generating Pgk1 phosphoglycerate kinase to facilitate the assembly of new viral replicase complexes. The recruitment of Pgk1 into the viral replication compartment is through direct interaction with the viral replication proteins. Altogether, we provide evidence that the ATP generated locally within the replication compartment by the co-opted Pgk1 is used to fuel the ATP-requirement of the co-opted heat shock protein 70 (Hsp70) chaperone, which is essential for the assembly of new viral replicase complexes and the activation of functional viral RNA-dependent RNA polymerase. The advantage of direct recruitment of Pgk1 into the virus replication compartment could be that the virus replicase assembly does not need to intensively compete with cellular processes for access to ATP. In addition, local production of ATP within the replication compartment could greatly facilitate the efficiency of Hsp70-driven replicase assembly by providing high ATP concentration within the replication compartment.
Dietary whey and casein proteins decrease food intake and body weight and improve glycemic control; however, little is known about the underlying mechanisms.
We determined the effects of dietary ...whey, casein, and a combination of the 2 on energy balance, hormones, glucose metabolism, and taste preference in rats.
In Expt. 1, Obesity Prone CD (OP-CD) rats were fed a high-fat control diet (33% fat energy) for 8 wk, and then randomly assigned to 4 isocaloric dietary treatments (n = 12/group): the control treatment (CO; 14% protein energy from egg white), the whey treatment (WH; 26% whey + 14% egg white), the casein treatment (CA; 26% casein + 14% egg white), or the whey plus casein treatment (WHCA; 13% whey + 13% casein + 14% egg white) for 28 d. Measurements included food intake, energy expenditure, body composition, metabolic hormones, glucose tolerance and key tissue markers of glucose and energy metabolism. In Expt. 2, naïve OP-CD rats were randomly assigned to 3 groups (n = 8/group). During an 8 d conditioning period, each group received on alternate days either the CO or WH, CO or CA, or CO or WHCA. Subsequently, preferences for the test diets were assessed on 2 consecutive days with food intake measurements at regular intervals.
In Expt. 1, food intake was decreased by 17-37% for the first 14 d in the WH and CA rats, and by 18-34% only for the first 4 d in the WHCA compared with the CO rats. Fat mass decreased by 21-28% for the WH rats and 17-33% for the CA rats from day 14 onward, but by 30% only on day 28 in WHCA rats, relative to CO rats. Thus, food intake, body weight, and fat mass decreased more rapidly in WH and CA rats than in WHCA rats. Energy expenditure in WH rats decreased for the first 4 d compared with CA and WHCA rats, and for the first 7 d compared with the CO rats. Circulating leptin, glucose-dependent insulinotropic polypeptide, interleukin 6, and glucose concentrations were lower in WH, CA, and WHCA rats than in CO rats. Plasma glucagon-like peptide 1 concentrations were greater in WH than in CA or WHCA rats. The improvements in glucose tolerance were greater in WH than in WHCA rats. The plasma membrane glucose transporter 4 (GLUT4)-to-total GLUT4 ratio in skeletal muscle was greater in CA and WHCA rats than in CO rats; other markers of glucose and energy metabolism in the adipose and cardiac tissues did not differ. In Expt. 2, during 4 conditioning trials, daily food intake was decreased in WH, CA, and WHCA rats by 26-37%, 30-43%, and 23-33%, respectively, compared with CO rats. Preferences for WH and CA rats were 45% and 31% lower, respectively, than those for CO rats, but that for WHCA rats did not differ.
Together, these data demonstrate that in obese rats, whey, casein, and their combination improve energy balance through differential effects on food intake, taste preference, energy expenditure, glucose tolerance, and gut hormone secretion.
The performance of solar photovoltaic (SPV) power plants is adversely affected by soiling losses caused by natural dust deposition on the module surface. The size and density of dust particles vary ...depending on the location. Thus, it is essential to investigate the impact of dust collection on SPV module performance. This work investigates the effect of dust build-up on the low-iron glass surface and the performance of SPV modules. To analyze the characteristics of these dust particles, low-iron glass samples have been chosen, which resemble a front glass surface of the SPV module. To study the holistic pattern of the natural dust accumulation of a particular area, low-iron glass samples have been placed with three different positions like vertical, horizontal, and local tilt angle for Building Integrated Photovoltaic Systems (BIPV) and rooftop PV power plant applications. The mineralogical study of dust particles provides insight in determining the transmittance loss from the glass surface of solar PV modules due to the local soiling loss. Furthermore, the electrical power output of the SPV modules has been monitored at various levels of dust accumulation. Moreover, these findings indicate that natural dust deposition at selected site locations significantly reduces energy generation from PV modules.
•The effect of natural dust on solar PV module glass surfaces has been investigated.•Optical studies are done to determine dust particle size and distribution.•The mineralogy of dust particles has been studied to determine local soiling loss.•Studies on the effect of soiling loss on solar PV power output have been presented.
•Anionic diets prevent clinical hypocalcemia by inducing a metabolic acidosis.•Overdosing anionic salts may induce a more severe metabolic acidosis.•A severe metabolic acidosis has proved not to be ...advantageous to dairy cows.•Metabolic acidosis can be monitored through the evaluation of urine pH.•A urine pH of 6.0–6.8 has been sufficient to prevent milk fever in dairy cows.
Hypocalcemia remains a common metabolic disorder of dairy cattle; therefore, an efficient prevention is still challenging. Among the various prevention strategies for hypocalcemia is the use of anionic compounds to induce a mild metabolic acidosis during the prepartum period. Acid-base status can be readily assessed through urine pH. Accordingly, a target urine pH during the prepartum period between 6.0 and 6.8 has been recommended for Holstein cows; however, in several countries, including the US, certain nutritional strategies are still focused on benchmarking the urine pH to below 6.0. Unfortunately, over-acidification can have no advantages and/or detrimental effects on both the dam and her offspring. In this review, updated information regarding the use of anionic diets on prepartum dairy cows and the potential negative impact of such diets on both cow and calf performance are discussed. There is an urgent need for studies that will elucidate the pathophysiological mechanisms by which very acidotic diets may impact the well-being and productive efficiency of dairy cows, and the transgenerational effects of such diets on offspring performance and survival.
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•Metathesized palm (PMTAG) oil polyol is used to prepare PU foams.•Both the rigid and the flexible foams displayed high thermal stability.•Strength of PMTAG rigid foams (2.6MPa) ...higher than that of palm and soybean oils.•PMTAG flexible foams displayed recovery in thickness higher than 90%.
Polyols derived from 1-butene cross metathesized palm oil (PMTAG polyol) were used to prepare improved rigid and flexible foams. The chemical structure, thermal degradation, thermal transition behavior and compressive strength of the foams were determined using FTIR (Fourier Transform Infrared Spectroscopy), TGA (Thermogravimetric analysis), DSC (Differential Scanning Calorimetry) and texture analyzer, respectively. Their cellular structure was investigated by SEM (Scanning Electron Microscopy). Both the rigid and the flexible foams from the metathesized palm oil polyol displayed high thermal stability (Ton of degradation of ∼253°C) comparable to commercial and other vegetable oil polyol foams. The rigid foams from the polyol of PMTAG presented compressive strengths as high as 2.6MPa, a value higher than similar foams prepared from palm oil polyol or highly unsaturated vegetable oils such soybean and canola oil based polyols. The flexible foams from the metathesized palm oil polyol displayed excellent flexibility with more than 90% recovery in thickness after compression.
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