Title: At-Home Drug Errors Common for Kids With Cancer, Research Shows
Category: Health News
Created: 5/3/2013 10:35:00 AM
Last Editorial Review: 5/3/2013 12:00:00 AM

Title: Pediatricians Should Plan for Anthrax Attack, U.S. Experts Say
Category: Health News
Created: 4/28/2014 9:35:00 AM
Last Editorial Review: 4/28/2014 12:00:00 AM

Title: Statin Users Eating More Bad Food Than a Decade Ago, Study Shows
Category: Health News
Created: 4/25/2014 12:35:00 PM
Last Editorial Review: 4/28/2014 12:00:00 AM

Title: Japan Quake Shows How Stress Alters the Brain
Category: Health News
Created: 4/29/2014 12:35:00 PM
Last Editorial Review: 4/30/2014 12:00:00 AM

Title: Doctors Say Head Lice Should Not Bar Kids From School
Category: Health News
Created: 4/27/2015 12:00:00 AM
Last Editorial Review: 4/27/2015 12:00:00 AM

Title: Drugs Show Promise for Some Advanced Lung Cancers
Category: Health News
Created: 4/29/2015 12:00:00 AM
Last Editorial Review: 4/30/2015 12:00:00 AM

Title: Businesses Should Be Mindful of Zika Danger to Workers, CDC Says
Category: Health News
Created: 4/22/2016 12:00:00 AM
Last Editorial Review: 4/25/2016 12:00:00 AM

Title: FDA Proposes Ban on 'Shock' Device Used to Curb Self-Harm
Category: Health News
Created: 4/22/2016 12:00:00 AM
Last Editorial Review: 4/25/2016 12:00:00 AM

Title: With Flu Shot, Timing May Be Everything
Category: Health News
Created: 4/26/2016 12:00:00 AM
Last Editorial Review: 4/26/2016 12:00:00 AM

Title: Antibody Shot Protects Monkeys From HIV-Like Infection
Category: Health News
Created: 4/27/2016 12:00:00 AM
Last Editorial Review: 4/28/2016 12:00:00 AM

Title: U.S. Moves to Avert Shortage of Yellow Fever Vaccine
Category: Health News
Created: 4/28/2017 12:00:00 AM
Last Editorial Review: 5/1/2017 12:00:00 AM

Title: California Handgun Sales Spiked After 2 Mass Shootings
Category: Health News
Created: 5/1/2017 12:00:00 AM
Last Editorial Review: 5/2/2017 12:00:00 AM

Title: Depression's Gender Gap Shows Up in Pre-Teen Years
Category: Health News
Created: 5/2/2017 12:00:00 AM
Last Editorial Review: 5/3/2017 12:00:00 AM

Title: Reasons Why Parents Should Be Wary of '13 Reasons Why'
Category: Health News
Created: 5/4/2017 12:00:00 AM
Last Editorial Review: 5/4/2017 12:00:00 AM

Title: Arthritis Drug Shows Promise for Ulcerative Colitis
Category: Health News
Created: 5/3/2017 12:00:00 AM
Last Editorial Review: 5/4/2017 12:00:00 AM

Title: The Other Opioid Crisis: Shortages at U.S. Hospitals
Category: Health News
Created: 5/2/2018 12:00:00 AM
Last Editorial Review: 5/2/2018 12:00:00 AM

Title: Why You Should Unwind After a Tough Day at Work
Category: Health News
Created: 5/1/2018 12:00:00 AM
Last Editorial Review: 5/2/2018 12:00:00 AM

Title: Many Women With Heart Disease Falling Short on Exercise
Category: Health News
Created: 4/26/2019 12:00:00 AM
Last Editorial Review: 4/29/2019 12:00:00 AM

Title: Newer Diabetes Drug Shows Promise in Kids, Teens
Category: Health News
Created: 4/30/2019 12:00:00 AM
Last Editorial Review: 4/30/2019 12:00:00 AM

Title: Could You Be Short on Vitamin B12?
Category: Health News
Created: 5/2/2019 12:00:00 AM
Last Editorial Review: 5/2/2019 12:00:00 AM

Title: An Expert's Guide to Healthier Grocery Shopping
Category: Health News
Created: 5/2/2019 12:00:00 AM
Last Editorial Review: 5/2/2019 12:00:00 AM

Title: Treatments Targeting Social Behavior Hormone Show Promise With Autism
Category: Health News
Created: 5/1/2019 12:00:00 AM
Last Editorial Review: 5/2/2019 12:00:00 AM

Title: After Trump Hypes Use of a Lupus Med Against COVID-19, Lupus Patients Face Shortages
Category: Health News
Created: 4/25/2020 12:00:00 AM
Last Editorial Review: 4/27/2020 12:00:00 AM

Title: Coronavirus Antibody Tests Show Inaccuracies, as Some States Prepare to Reopen
Category: Health News
Created: 4/25/2020 12:00:00 AM
Last Editorial Review: 4/27/2020 12:00:00 AM

Title: What Is a Pulse Oximeter, and Should You Get One to Warn of COVID-19?
Category: Health News
Created: 4/28/2020 12:00:00 AM
Last Editorial Review: 4/29/2020 12:00:00 AM

Title: Coronavirus Vaccine Shows Promise
Category: Health News
Created: 4/29/2020 12:00:00 AM
Last Editorial Review: 4/29/2020 12:00:00 AM

Title: Health Tip: Should I Get a Cholesterol Test?
Category: Health News
Created: 12/10/2019 12:00:00 AM
Last Editorial Review: 12/10/2019 12:00:00 AM

Title: Marijuana Withdrawal Is Real, Study Shows
Category: Health News
Created: 4/10/2020 12:00:00 AM
Last Editorial Review: 4/13/2020 12:00:00 AM

Title: Experimental Drug Shows Promise for Schizophrenia
Category: Health News
Created: 4/16/2020 12:00:00 AM
Last Editorial Review: 4/17/2020 12:00:00 AM

Title: Birth Control Pill vs. Shot (Depo-Provera): Similarities and Differences
Category: Diseases and Conditions
Created: 6/15/2017 12:00:00 AM
Last Editorial Review: 4/13/2020 12:00:00 AM

Title: Flu Vaccine Making a Strong Showing This Season
Category: Health News
Created: 2/20/2020 12:00:00 AM
Last Editorial Review: 2/21/2020 12:00:00 AM

Title: Magnetic Brain 'Zap' Shows Promise Against Severe Depression
Category: Health News
Created: 4/7/2020 12:00:00 AM
Last Editorial Review: 4/8/2020 12:00:00 AM

Title: Traveling Abroad? Make Sure Your Measles Shot Is Up to Date
Category: Health News
Created: 7/24/2019 12:00:00 AM
Last Editorial Review: 7/24/2019 12:00:00 AM

Extreme elongation distinguishes about one-fourth of cotton (Gossypium sp.) seed epidermal cells as "lint" fibers, useful for the textile industry, from "fuzz" fibers (<5 mm). Ligon lintless-2 (Li₂), a dominant mutation that results in no lint fiber but normal fuzz fiber, offers insight into pathways and mechanisms that differentiate spinnable cotton from its progenitors. A genetic map developed using 1,545 F2 plants showed that marker CISP15 was 0.4 cM from Li₂, and "dominant" simple sequence repeat (SSR) markers (i.e. with null alleles in the Li₂ genotype) SSR7 and SSR18 showed complete linkage with Li₂. Nonrandom distribution of markers with null alleles suggests that the Li₂ phenotype results from a 176- to 221-kb deletion of the terminal region of chromosome 18 that may have been masked in prior pooled-sample mapping strategies. The deletion includes 10 genes with putative roles in fiber development. Two Glycosyltransferase Family 1 genes showed striking expression differences during elongation of wild-type versus Li₂ fiber, and virus-induced silencing of these genes in the wild type induced Li₂-like phenotypes. Further, at least 7 of the 10 putative fiber development genes in the deletion region showed higher expression in the wild type than in Li₂ mutants during fiber development stages, suggesting coordinated regulation of processes in cell wall development and cell elongation, consistent with the hypothesis that some fiber-related quantitative trait loci comprise closely spaced groups of functionally diverse but coordinately regulated genes.

Plants require a high concentration of ascorbate as a redox buffer for survival under stress conditions, such as high light. Dehydroascorbate reductases (DHARs) are enzymes that catalyze the reduction of DHA to ascorbate using reduced glutathione (GSH) as an electron donor, allowing rapid ascorbate recycling. However, a recent study using an Arabidopsis (Arabidopsis thaliana) triple mutant lacking all three DHAR genes (herein called dhar) did not find evidence for their role in ascorbate recycling under oxidative stress. To further study the function of DHARs, we generated dhar Arabidopsis plants as well as a quadruple mutant line combining dhar with an additional vtc2 mutation that causes ascorbate deficiency. Measurements of ascorbate in these mutants under low- or high-light conditions indicated that DHARs have a nonnegligible impact on full ascorbate accumulation under high light, but that they are dispensable when ascorbate concentrations are low to moderate. Because GSH itself can reduce DHA nonenzymatically, we used the pad2 mutant that contains ~30% of the wild-type GSH level. The pad2 mutant accumulated ascorbate at a wild-type level under high light; however, when the pad2 mutation was combined with dhar, there was near-complete inhibition of high-light–dependent ascorbate accumulation. The lack of ascorbate accumulation was consistent with a marked increase in the ascorbate degradation product threonate. These findings indicate that ascorbate recycling capacity is limited in dhar pad2 plants, and that both DHAR activity and GSH content set a threshold for high-light–induced ascorbate accumulation.

We thank F. Guezguez and H. Ben Saad for raising important questions on recommendations for assessing a bronchodilator response (BDR) in children. The authors summarise how recommended outcome measures and cut-offs for BDR in children vary between guidelines, and raise questions about our study [1].

Members of the flavivirus genus share a high level of sequence similarity and often circulate in the same geographical regions. However, whether T cells induced by one viral species cross-react with other related flaviviruses has not been globally addressed. In this study, we tested pools of epitopes derived from dengue (DENV), Zika (ZIKV), Japanese encephalitis (JEV), West Nile (WNV), and yellow fever (YFV) viruses by intracellular cytokine staining (ICS) using peripheral blood mononuclear cells (PBMCs) of individuals naturally exposed to DENV or immunized with DENV (TV005) or YF17D vaccine. CD8 T cell responses recognized epitopes from multiple flaviviruses; however, the magnitude of cross-reactive responses was consistently severalfold lower than those to the autologous epitope pools and was associated with lower expression of activation markers such as CD40L, CD69, and CD137. Next, we characterized the antigen sensitivity of short-term T cell lines (TCL) representing 29 different individual epitope/donor combinations. TCL derived from DENV monovalent vaccinees induced CD8 and CD4 T cells that cross-reacted within the DENV serocomplex but were consistently associated with >100-fold-lower antigen sensitivity for most other flaviviruses, with no cross-recognition of YFV-derived peptides. CD8 and CD4 TCL from YF17D vaccinees were associated with very limited cross-reactivity with any other flaviviruses and in five out of eight cases >1,000-fold-lower antigen sensitivity. Overall, our data suggest limited cross-reactivity for both CD4 and CD8 T cell responses between flaviviruses and have implications for understanding immunity elicited by natural infection and strategies to develop live attenuated vaccines against flaviviral species.

IMPORTANCE The envelope (E) protein is the dominant target of neutralizing antibodies for dengue virus (DENV) and yellow fever virus (YFV). Accordingly, several DENV vaccine constructs use the E protein in a live attenuated vaccine format, utilizing a backbone derived from a heterologous flavivirus (such as YF) as a delivery vector. This backbone comprises the nonstructural (NS) and capsid (C) antigens, which are dominant targets of T cell responses. Here, we demonstrate that cross-reactivity at the level of T cell responses among different flaviviruses is very limited, despite high levels of sequence homology. Thus, the use of heterologous flavivirus species as a live attenuated vaccine vector is not likely to generate optimal T cell responses and might thus impair vaccine performance.

Disorders of oxygen transport are commonly attributed to inadequate carrying capacity (anemia) but may also relate to inefficient gas exchange by red blood cells (RBCs), a process that is poorly characterized yet assumed to be rapid. Without direct measurements of gas exchange at the single-cell level, the barriers to O2...

Zhi-Jun Zhao, Davina Derous, Abby Gerrard, Jing Wen, Xue Liu, Song Tan, Catherine Hambly, and John R. Speakman

Lactating mice increase food intake 4- to 5-fold, reaching an asymptote in late lactation. A key question is whether this asymptote reflects a physiological constraint, or a maternal investment strategy (a ‘restraint’). We exposed lactating mice to periods of food restriction, hypothesizing that if the limit reflected restraint, they would compensate by breaching the asymptote when refeeding. In contrast, if it was a constraint, they would by definition be unable to increase their intake on refeeding days. Using isotope methods, we found that during food restriction, the females shut down milk production, impacting offspring growth. During refeeding, food intake and milk production rose again, but not significantly above unrestricted controls. These data provide strong evidence that asymptotic intake in lactation reflects a physiological/physical constraint, rather than restraint. Because hypothalamic neuropeptide Y (Npy) was upregulated under both states of restriction, this suggests the constraint is not imposed by limits in the capacity to upregulate hunger signalling (the saturated neural capacity hypothesis). Understanding the genetic basis of the constraint will be a key future goal and will provide us additional information on the nature of the constraining factors on reproductive output, and their potential links to life history strategies.

Samantha M. Logan, Kama E. Szereszewski, Nigel C. Bennett, Daniel W. Hart, Barry van Jaarsveld, Matthew E. Pamenter, and Kenneth B. Storey

Mole-rats are champions of self-preservation, with increased longevity compared to other rodents their size, strong antioxidant capabilities, and specialized defenses against endogenous oxidative stress. However, how the brains of these subterranean mammals handle acute in vivo hypoxia is poorly understood. This study is the first to examine the molecular response to low oxygen in six different species of hypoxia-tolerant mole-rats from sub-Saharan Africa. Protein carbonylation, a known marker of DNA damage (hydroxy-2’-deoxyguanosine), and antioxidant capacity did not change following hypoxia but HIF-1 protein levels increased significantly in the brains of two species. Nearly 30 miRNAs known to play roles in hypoxia-tolerance were differentially regulated in a species-specific manner. The miRNAs exhibiting the strongest response to low oxygen stress inhibit apoptosis and regulate neuroinflammation, likely providing neuroprotection. A principal component analysis using a subset of the molecular targets assessed herein revealed differences between control and hypoxic groups for two solitary species (Georychus capensis and Bathyergus suillus), which are ecologically adapted to a normoxic environment, suggesting a heightened sensitivity to hypoxia relative to species that may experience hypoxia more regularly in nature. By contrast, all molecular data were included in the PCA to detect a difference between control and hypoxic populations of eusocial Heterocephalus glaber, indicating they may require many lower-fold changes in signaling pathways to adapt to low oxygen settings. Finally, none of the Cryptomys hottentotus subspecies showed a statistical difference between control and hypoxic groups, presumably due to hypoxia-tolerance derived from environmental pressures associated with a subterranean and social lifestyle.

Jonathan M. Whittamore

Oxalate is a common constituent of kidney stones but the mechanism of its transport across epithelia are not well understood. With prior research on the role of the intestine focused on mammals this study considered oxalate handling by teleost fish. Given the osmotic challenge of seawater (SW), teleosts have limited scope for urinary oxalate excretion relative to freshwater (FW). The marine teleost intestine was hypothesized as the principal route for oxalate elimination thus demanding epithelial secretion. To test this, intestinal ¹⁴C-oxalate flux was compared between FW- and SW-acclimated sailfin molly (Poecilia latipinna). In SW, oxalate was secreted at remarkable rates (367.90±22.95 pmol cm^–2 h^–1) which were similar following FW transfer (387.59±27.82 pmol cm^–2 h^–1), implying no regulation by salinity. Nevertheless, this ability to secrete oxalate 15-19 times higher than mammalian small intestine supports this proposal of the teleost gut as a previously unrecognized excretory pathway.

Jorge de Costa, Gustavo Barja, and Pedro F. Almaida-Pagan

Lipid composition of cell membranes is linked to metabolic rate and lifespan in mammals and birds but very little information is available for fishes. In this study, three fish species of the short-lived annual genus Nothobranchius with different maximum lifespan potentials (MLSP) and the longer-lived outgroup species Aphyosemion australe were studied to test whether they conform to the predictions of the longevity-homeoviscous adaptation (LHA) theory of aging. Lipid analyses were performed in whole fish samples and peroxidation indexes (PIn) for every PL class and for the whole membrane, were calculated. Total PL content was significantly lower in A. australe and N. korthausae, the two species with the highest MLSP, and a negative correlation between membrane total PIn and fish MLSP was found, this meaning that the longer-lived fish species have more saturated membranes and therefore, a lower susceptibility to oxidative damage, as the LHA theory posits.

Scarlet J. Park and William W. Ja

Factors that mediate ethanol preference in Drosophila melanogaster are not well understood. A major confound has been the use of diverse methods to estimate ethanol consumption. We measured fly consumptive ethanol preference on base diets varying in nutrients, taste, and ethanol concentration. Both sexes showed ethanol preference that was abolished on high nutrient concentration diets. Additionally, manipulating total food intake without altering the nutritive value of the base diet or the ethanol concentration was sufficient to evoke or eliminate ethanol preference. Absolute ethanol intake and food volume consumed were stronger predictors of ethanol preference than caloric intake or the dietary caloric content. Our findings suggest that the effect of the base diet on ethanol preference is largely mediated by total consumption associated with the delivery medium, which ultimately determines the level of ethanol intake. We speculate that a physiologically relevant threshold for ethanol intake is essential for preferential ethanol consumption.

Shih-Jung Hsu and Bo Cheng

In the presence of wind or background image motion, flies are able to maintain a constant retinal slip velocity via regulating flight speed to the extent permitted by their locomotor capacity. Here we investigated the retinal slip compensation of tethered blue-bottle flies (Calliphora vomitoria) flying semi-freely along an annular corridor in a magnetically levitated flight mill enclosed by two motorized cylindrical walls. We perturbed the flies’ retinal slip via spinning the cylindrical walls, generating bilaterally averaged retinal slip perturbations from -0.3 to 0.3 m·s^–1 (or -116.4 to 116.4 deg.·s^–1) When the perturbation was less than ~0.1 m·s^–1 (38.4 deg.·s^–1), the flies successfully compensated the perturbations and maintained a retinal slip velocity by adjusting their airspeed up to 20%. However, with greater retinal slip perturbation, the flies’ compensation became saturated, as the flies’ airspeed plateaued, indicating that they were unable to further maintain a constant retinal slip velocity. The compensation gain, i.e., the ratio of airspeed compensation and retinal slip perturbation, depended on the spatial frequency of the grating patterns, being the largest at 12 m^–1 (0.04 deg.^–1).

Optic atrophy 1 (OPA1) is a dynamin protein that mediates mitochondrial fusion at the inner membrane. OPA1 is also necessary for maintaining the cristae and thus essential for supporting cellular energetics. OPA1 exists as membrane-anchored long form (L-OPA1) and short form (S-OPA1) that lacks the transmembrane region and is generated by cleavage of L-OPA1. Mitochondrial dysfunction and cellular stresses activate the inner membrane–associated zinc metallopeptidase OMA1 that cleaves L-OPA1, causing S-OPA1 accumulation. The prevailing notion has been that L-OPA1 is the functional form, whereas S-OPA1 is an inactive cleavage product in mammals, and that stress-induced OPA1 cleavage causes mitochondrial fragmentation and sensitizes cells to death. However, S-OPA1 contains all functional domains of dynamin proteins, suggesting that it has a physiological role. Indeed, we recently demonstrated that S-OPA1 can maintain cristae and energetics through its GTPase activity, despite lacking fusion activity. Here, applying oxidant insult that induces OPA1 cleavage, we show that cells unable to generate S-OPA1 are more sensitive to this stress under obligatory respiratory conditions, leading to necrotic death. These findings indicate that L-OPA1 and S-OPA1 differ in maintaining mitochondrial function. Mechanistically, we found that cells that exclusively express L-OPA1 generate more superoxide and are more sensitive to Ca2+-induced mitochondrial permeability transition, suggesting that S-OPA1, and not L-OPA1, protects against cellular stress. Importantly, silencing of OMA1 expression increased oxidant-induced cell death, indicating that stress-induced OPA1 cleavage supports cell survival. Our findings suggest that S-OPA1 generation by OPA1 cleavage is a survival mechanism in stressed cells.

The Larne and Portpatrick basins, located in the North Channel between SW Scotland and Northern Ireland, have been the target of a small programme of petroleum exploration activities since 1971. A total of five hydrocarbon exploration wells have been drilled within the two basins, although as of yet no commercial discoveries have been made. The presence of hydrocarbon shows alongside the discovery of two good-quality reservoir–seal couplets within Triassic and underlying Permian strata has encouraged exploration within the region. The focus of this study is to evaluate the geology and hydrocarbon prospectivity of the Portpatrick Basin and the offshore section of the Larne Basin. This is achieved through the use of seismic reflection data, and gravity and aeromagnetic data, alongside sedimentological, petrophysical and additional available datasets from both onshore and offshore wells, boreholes and previously published studies. The primary reservoir interval, the Lower–Middle Triassic Sherwood Sandstone Group (c. 600–900 m gross thickness), is distributed across both basins and shows good to excellent porosity (10–25%) and permeability (10–1000 mD) within the Larne Basin. The Middle–Late Triassic Mercia Mudstone Group should provide an excellent top seal where present due to the presence of thick regionally extensive halite deposits, although differential erosion has removed this seal from the margins of the Larne and Portpatrick basins. The Carboniferous, which has been postulated to contain organic-rich source-rock horizons, as inferred from their presence in adjacent basins, has not yet been penetrated within the depocentre of either basin. There is, therefore, some degree of uncertainty regarding the quality and distribution of a potential source rock. The interpretation of seismic reflection profiles presented here, alongside the occurrence of hydrocarbon shows, indicates the presence of organic-rich pre-Permian sedimentary rocks within both basins. 1D petroleum system modelling of the Larne-2 borehole shows that the timing of hydrocarbon generation and migration within the basins is a significant risk, with many traps post-dating the primary hydrocarbon charge. Well-failure analysis has revealed that trap breach associated with kilometre-scale uplift events, and the drilling of wells off-structure due to a lack of good-quality subsurface data, have contributed to the lack of discoveries. While the Larne and Portpatrick basins have many elements required for a working petroleum system, along with supporting hydrocarbon shows, the high risks coupled with the small scale of potential discoveries makes the Portpatrick Basin and offshore section of the Larne Basin poorly prospective for oil and gas discovery.

Thematic collection: This article is part of the Under-explored plays and frontier basins of the UK continental shelf collection available at: http://www.lyellcollection.org/cc/under-explored-plays-and-frontier-basins-of-the-uk-continental-shelf

Clostridioides difficile infection (CDI) is one of the most common health care-associated infections that can cause significant morbidity and mortality. CDI diagnosis involves laboratory testing in conjunction with clinical assessment. The objective of this study was to assess the performance of various C. difficile tests and to compare clinical characteristics, Xpert C. difficile/Epi (PCR) cycle threshold (C_T), and Singulex Clarity C. diff toxins A/B (Clarity) concentrations between groups with discordant test results. Unformed stool specimens from 200 hospitalized adults (100 PCR positive and 100 negative) were tested by cell cytotoxicity neutralization assay (CCNA), C. diff Quik Chek Complete (Quik Chek), Premier Toxins A and B, and Clarity. Clinical data, including CDI severity and CDI risk factors, were compared between discordant test results. Compared to CCNA, PCR had the highest sensitivity at 100% and Quik Chek had the highest specificity at 100%. Among clinical and laboratory data studied, prevalences of leukocytosis, prior antibiotic use, and hospitalizations were consistently higher across all subgroups in comparisons of toxin-positive to toxin-negative patients. Among PCR-positive samples, the median C_T was lower in toxin-positive samples than in toxin-negative samples; however, C_T ranges overlapped. Among Clarity-positive samples, the quantitative toxin concentration was significantly higher in toxin-positive samples than in toxin-negative samples as determined by CCNA and Quik Chek Toxin A and B. Laboratory tests for CDI vary in sensitivity and specificity. The quantitative toxin concentration may offer value in guiding CDI diagnosis and treatment. The presence of leukocytosis, prior antibiotic use, and previous hospitalizations may assist with CDI diagnosis, while other clinical parameters may not be consistently reliable.

Glucagon-like peptide-2 (GLP-2) agonists have therapeutic potential in clinical indications in which the integrity or absorptive function of the intestinal mucosa is compromised, such as in short bowel syndrome (SBS). Native hGLP-2, a 33–amino acid peptide secreted from the small intestine, contributes to nutritional absorption but has a very short half-life because of enzymatic cleavage and renal clearance and thus is of limited therapeutic value. The GLP-2 analog teduglutide (Revestive/Gattex; Shire Inc.) has been approved for use in SBS since 2012 but has a once-daily injection regimen. Pharmacokinetic (PK) and pharmacodynamic studies confirm that apraglutide, a novel GLP-2 analog, has very low clearance, long elimination half-life, and high plasma protein binding compared with GLP-2 analogs teduglutide and glepaglutide. Apraglutide and teduglutide retain potency and selectivity at the GLP-2 receptor comparable to native hGLP-2, whereas glepaglutide was less potent and less selective. In rat intravenous PK studies, hGLP-2, teduglutide, glepaglutide, and apraglutide had clearances of 25, 9.9, 2.8, and 0.27 ml/kg per minute, respectively, and elimination half-lives of 6.4, 19, 16, and 159 minutes, respectively. The unique PK profile of apraglutide administered via intravenous and subcutaneous routes was confirmed in monkey and minipig and translated into significantly greater in vivo pharmacodynamic activity, measured as small intestinal growth in rats. Apraglutide showed greater intestinotrophic activity than the other peptides when administered at less-frequent dosing intervals because of its prolonged half-life. We postulate that apraglutide offers several advantages over existing GLP-2 analogs and is an excellent candidate for the treatment of gastrointestinal diseases, such as SBS.

Yen-Ling Lian, Kuan-Wei Chen, Yu-Ting Chou, Ting-Ling Ke, Bi-Chang Chen, Yu-Chun Lin, and Linyi Chen

Myoblast fusion is required for myotube formation during myogenesis, and defects in myoblast differentiation and fusion have been implicated in a number of diseases, including human rhabdomyosarcoma. Although transcriptional regulation of the myogenic program has been studied extensively, the mechanisms controlling myoblast fusion remain largely unknown. This study identified and characterized the dynamics of a distinct class of blebs, termed bubbling blebs, which are smaller than those that participate in migration. The formation of these bubbling blebs occurred during differentiation and decreased alongside a decline in phosphatidylinositol-(3,4,5)-trisphosphate (PIP3) at the plasma membrane before myoblast fusion. In a human rhabdomyosarcoma-derived (RD) cell line that exhibits strong blebbing dynamics and myoblast fusion defects, PIP3 was constitutively abundant on the membrane during myogenesis. Targeting phosphatase and tensin homolog (PTEN) to the plasma membrane reduced PIP3 levels, inhibited bubbling blebs and rescued myoblast fusion defects in RD cells. These findings highlight the differential distribution and crucial role of PIP3 during myoblast fusion and reveal a novel mechanism underlying myogenesis defects in human rhabdomyosarcoma.