Pain places a devastating burden on patients and society and current pain therapeutics exhibit limitations in efficacy, unwanted side effects and the potential for drug abuse and diversion. Although ...genetic evidence has clearly demonstrated that the voltage-gated sodium channel, Nav1.7, is critical to pain sensation in mammals, pharmacological inhibitors of Nav1.7 have not yet fully recapitulated the dramatic analgesia observed in Nav1.7-null subjects. Using the tarantula venom-peptide ProTX-II as a scaffold, we engineered a library of over 1500 venom-derived peptides and identified JNJ63955918 as a potent, highly selective, closed-state Nav1.7 blocking peptide. Here we show that JNJ63955918 induces a pharmacological insensitivity to pain that closely recapitulates key features of the Nav1.7-null phenotype seen in mice and humans. Our findings demonstrate that a high degree of selectivity, coupled with a closed-state dependent mechanism of action is required for strong efficacy and indicate that peptides such as JNJ63955918 and other suitably optimized Nav1.7 inhibitors may represent viable non-opioid alternatives for the pharmacological treatment of severe pain.
Modulation of the acetylation state of histones plays a pivotal role in the regulation of gene expression. Histone deacetylases (HDACs) catalyze the removal of acetyl groups from lysines near the N ...termini of histones. This reaction promotes the condensation of chromatin, leading to repression of transcription. HDAC deregulation has been linked to several types of cancer, suggesting a potential use for HDAC inhibitors in oncology. Here we describe the first crystal structures of a human HDAC: the structures of human HDAC8 complexed with four structurally diverse hydroxamate inhibitors. This work sheds light on the catalytic mechanism of the HDACs, and on differences in substrate specificity across the HDAC family. The structure also suggests how phosphorylation of Ser39 affects HDAC8 activity.
Aquifex aeolicus was one of the earliest diverging, and is one of the most thermophilic, bacteria known. It can grow on hydrogen, oxygen, carbon dioxide, and mineral salts. The complex metabolic ...machinery needed for A. aeolicus to function as a chemolithoautotroph (an organism which uses an inorganic carbon source for biosynthesis and an inorganic chemical energy source) is encoded within a genome that is only one-third the size of the E. coli genome. Metabolic flexibility seems to be reduced as a result of the limited genome size. The use of oxygen (albeit at very low concentrations) as an electron acceptor is allowed by the presence of a complex respiratory apparatus. Although this organism grows at 95 degrees C, the extreme thermal limit of the Bacteria, only a few specific indications of thermophily are apparent from the genome. Here we describe the complete genome sequence of 1,551,335 base pairs of this evolutionarily and physiologically interesting organism.
A novel gel formulation was selected for intravaginal delivery of the GnRH agonist (triptorelin) for synchronizing ovulation in pigs. Studies with gilt models were used to assess LH response ...profiles. The lowest dose of triptorelin that induced the most gilts to show an LH surge was 100 μg in 1.2% methylcellulose gel. This formulation had a similar effect in weaned sows while also advancing ovulation. The timing of administration was evaluated in sows after weaning. Administration at 96 h induced more sows to ovulate (58%) by 48 h compared to treatment at estrus (45%) or for controls (34%), but the desired level of ovulation synchrony was not achieved. As a result, greater doses of triptorelin were tested and 200 μg given at 96 h after weaning, induced 81% of sows to ovulate within 48 h after treatment. The best synchrony of ovulation occurred when given at 96 h after weaning compared to earlier or later intervals. The optimum time to give a single fixed time AI (SFT-AI) after administration of 200 μg of triptorelin in 1.2% gel (OvuGel®) at 96 h after weaning was tested. A SFT-AI at 22 ± 2 h after OvuGel achieved the highest fertility and was practical for staff during the normal work day. In field trials, a SFT-AI 22 ± 2 h after all weaned sows were treated with OvuGel improved (P = 0.04) farrowing rate to 82.5% compared to control sows weaned (80.1%), with no effect on numbers of pigs born alive (12.1). Research continues for identifying the advantages for use of OvuGel in different production systems, and potential application for use in gilts.
•OvuGel® was developed to deliver the GnRH agonist triptorelin as an intravaginal gel.•OvuGel use in weaned sows, has been effective for synchronizing ovulation.•OvuGel use with a single fixed time AI results in similar fertility to control sows mated multiple times based on estrus.
Previous studies have shown that triptorelin gel (TG) given intravaginally in gel form is effective for advancing the time of ovulation in weaned sows. Three experiments were performed to determine ...the effects of altering the dose and timing of administration of intravaginal TG for advancing and synchronizing ovulation in weaned sows. In all experiments, estrus was detected twice or three times daily and ultrasound was performed to determine ovulation at 8-hour intervals. In experiment 1, sows (n = 131) received intravaginal gel containing 0 (Placebo), 25, 100, or 200 μg of TG at 96 hours after weaning and sows were inseminated on each day of standing estrus. Wean-to-estrus interval and duration of estrus were correlated (P < 0.0001) with estrus duration longer in TG (P < 0.05) compared with Placebo. More sows ovulated (P < 0.001) by 48 hours after treatment with 200 (81%), 100 (64%), and 25 μg (63%) of TG compared with Placebo (42%). The farrowing rate and total pigs born did not differ (P > 0.10). In experiment 2, sows (n = 126) received 200 μg of TG at 72, 84, or 96 hours after weaning or were untreated (Control-96). Sows receiving TG were inseminated once 24 to 28 hours after treatment. Control-96 sows were inseminated on each day of standing estrus. Wean-to-estrus interval was not affected by treatment, but wean-to-ovulation interval was reduced (P < 0.05) by TG-72 and TG-84 compared with TG-96 and Control-96. More sows ovulated 40 hours after treatment (P < 0.001) with TG-72 (56.5%) and TG-84 (32.2%) compared with TG-96 and Control-96 (13%) and for all TG treatments 48 hours after treatment (64%) compared with Control-96 (34%, P < 0.05). The farrowing rate was lower (P < 0.05) for sows assigned to TG-72 and TG-84 compared with TG-96 and Control-96, whereas the number of liveborn pigs did not differ (P > 0.10). In experiment 3, sows (n = 113) were assigned to receive no treatment (Control), intravaginal gel alone (Placebo), or 200 μg of TG given intravaginally (OvuGel) at 96 hours after weaning. Wean-to-estrus interval did not differ, but the duration of estrus tended (P < 0.10) to be reduced with OvuGel compared with the other treatments. More sows ovulated (P < 0.001) by 48 hours after OvuGel treatment (79.1%) compared with Control (46.4%) and Placebo (37.9%) and by 56 hours (P < 0.05). The farrowing rate and the number of liveborn pigs did not differ among treatments. The results of these studies indicate that 200 μg of TG given intravaginally at 96 hours after weaning (OvuGel) synchronizes ovulation and results in fertility similar to Controls.
•Interval from last feeding of progestogen to estrus in mature gilts is related to time of ovulation.•Treatment of progestogen synchronized gilts with triptorelin at 120h after last feeding of ...Matrix, increased synchrony of ovulation.•Treatment of progestagen synchronized gilts with 100 to 400mg of triptorelin improved the proportion of gilts ovulating within a 24h period.
Estrus and ovulation responses in Matrix-treated gilts may affect ovulation synchrony in response to triptorelin. In experiment 1, estrus and ovulation measures at 12h intervals after last Matrix feeding (LMF) were analyzed. For the 398 gilts that displayed estrus, 87.4% were detected on Days 6–8 after LMF. Duration of estrus was 24–60h for 85.6% of gilts and negatively correlated with interval from LMF to estrus (r=−0.53, P<0.0001). The estrus to ovulation interval was positively correlated with duration of estrus (r=0.61, P<0.0001). In experiment 2, gilts (n=96) received intravaginal treatment with 2mL of gel containing placebo (Control) at 96h, 200μg of triptorelin at 96h (TRP96), 120h (TRP120) or 144h (TRP144) after LMF. Estrus measures did not differ (P>0.10) among treatments. The proportion of gilts ovulating 32–56h after treatment was greater for TRP120 and TRP144 (P<0.01) compared to other treatments. The treatment to ovulation intervals for all triptorelin treatments were shorter (P<0.001) than Control. In experiment 3, gilts (n=86) received placebo (Control), 100μg (TRP100), 200μg (TRP200), or 400μg (TRP400) of triptorelin at 120h after LMF. There was no effect of treatment (P>0.10) on estrus or on interval from LMF to estrus. The proportion of gilts ovulating by 40, 48 and 56h after treatment increased (P<0.05) with triptorelin compared to Control. Our results indicate that gilts receiving 100–400μg of triptorelin at 120h after LMF had the greatest ovulation synchrony 24–48h following treatment. These studies provide important information for developing a procedure for a single insemination in synchronized gilts.
The objective of this study was to determine the effects of supplementing glycerol and soybean oil in drinking water on feed and water intake, calculated energy balance, and production performance of ...periparturient dairy cows. Ninety multiparous Holstein dairy cows were randomly assigned to 1 of 3 treatments: 1) no nutrients supplemented in the drinking water (control); 2) 20g/L of glycerin supplemented in the drinking water (glycerol); and 3) 10g/L of soybean oil supplemented in the drinking water (SBO). The trial lasted from 7 d prepartum to 7 d postpartum. Cows were offered a close-up and milking cow TMR for ad libitum intake, pre- and postpartum, respectively. The dry matter intake of cows supplemented with glycerol and SBO was lower than for the control cows throughout the experimental period but not different from each other. Water intake for the control cows was greater than the average for the glycerol and SBO cows prepartum, and greater than for SBO cows but similar to that of glycerol cows postpartum. Glycerol cows consumed more water than SBO cows. There were no differences in energy intake and energy balance of the cows pre- and postpartum. Serum triacylglycerol concentration for glycerol cows was lower than for the control and SBO cows prepartum and was lower than for the SBO cows postpartum. There were no differences in the serum nonesterified fatty acids and glucose concentrations throughout the experiment. There were no differences in the serum β-hydroxybutyrate (BHBA) concentrations at parturition, but serum BHBA concentration of the glycerol cows was greater than for control and SBO cows during the prepartum period. However, during the postpartum period, serum BHBA concentrations of the control cows were greater than for glycerol and SBO cows. There were no differences in calf birth weights or milk yield and composition. Although the glucogenic property of glycerol supplemented in the drinking water at 20g/L may not have been sufficient to elicit a milk yield response, it did reduce the concentration of BHBA postpartum.
Summary
Background
The detection of melanoma poses a substantial challenge, particularly for primary care providers (PCPs) who may have limited training in discriminating between suspicious and ...benign melanocytic lesions. The noninvasive optical transfer diagnosis (OTD) method was designed to be used by PCPs in their decision‐making process.
Objectives
To assess the potential of the OTD method by developing, training and validating an OTD indication algorithm for automated discrimination between benign melanocytic lesions and malignant lesions, based on a set of 712 lesions.
Methods
The authors performed in vivoOTD capture and subsequent analysis of 712 pigmented lesions. Of the lesions, 415 were clinically and dermoscopically benign and 297 were dermoscopically suspicious or equivocal. After image capture, all suspicious or equivocal lesions were biopsied and examined histopathologically.
Results
Of the 297 suspicious or equivocal lesions, histopathological findings revealed 80 to be malignant (64 melanomas, 13 basal cell carcinomas and 3 squamous cell carcinomas). OTD misdiagnosed one of the 80 malignant lesions as benign (sensitivity, 99%). OTD specificity was 93% for the dermoscopically benign lesions, 73% for all lesions included in the study and 36% for the clinically suspicious but histopathologically benign lesions.
Conclusions
High sensitivity and specificity, as provided by OTD in this preliminary study, would help PCPs reduce the number of referrals for dermatology consultation, excision or biopsy. Further studies are planned for screening patients in a primary care setting, with comparisons of OTD results with biopsy or dermoscopy results.
What's already known about this topic?
There is a recognized need for automated methods to screen for malignant melanoma.
A number of technologies have been developed in an attempt to address that need. One of these is optical transfer diagnosis (OTD), a methodology that uses a novel image capture and algorithmic image‐analysis system.
Prior pilot studies have shown OTD to be a promising technology for screening of melanocytic lesions.
What does this study add?
In this study of 712 benign and malignant pigmented lesions, OTD demonstrated 99% sensitivity for malignant lesions and 73% specificity for benign lesions, which compares favourably with bedside examination by dermatology specialists and with other automated technologies, and OTD had a 10‐s turnaround time.
OTD is a promising technology for future screening of melanocytic lesions.
Linked Comment: Raphael and Soyer. Br J Dermatol 2018; 178:331–333.
Plain language summary available online
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A 100 μg dose of triptorelin was tested for synchronizing ovulation in sows. In Experiment 1, conducted in April through June, sows (n = 125) were assigned to Control (untreated), TG-96 (Triptorelin ...Gel (TG) given intravaginally at 96 h post-weaning), or TG-E (given intravaginally at estrus). To optimize AI timing, sows were inseminated at 2 and 26 h after estrus for Control and TG-E and at 8 and 32 h following TG-96. Ovulation by 48 h post-treatment tended to be affected by treatment (P = 0.08) and more (P < 0.05) TG-96 sows ovulated (57.9%) compared to Controls (34.2%), but TG-E (45.1%) did not differ (P > 0.10). Duration of estrus was reduced (P < 0.005) in TG-96 (51 h) and TG-E (58 h) compared to Controls (65 h). There was no treatment effect on farrowing rate (71%) or total born (10.4). Average follicle size <6.5 mm at 96 h after weaning was associated with reduced (P < 0.01) estrus, ovulation and farrowing rate. Experiment 2 was conducted in August through September using 503 weaned sows. The TG-96 treatment reduced duration of estrus (P = 0.03), but treatment did not affect estrus expression, farrowing rate or total pigs born. In conclusion, use of a 100 μg dose of triptorelin intravaginally at 96 h or at estrus advanced ovulation and when used with timed insemination, resulted in similar farrowing rates and litter sizes comparable to sows mated based on estrus. However, ovulation induction and timed AI success may benefit from an approach that ensures sows have adequate follicle development at time of treatment.
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