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1.
Nature ; 629(8013): 843-850, 2024 May.
Article in English | MEDLINE | ID: mdl-38658746

ABSTRACT

Angiosperms are the cornerstone of most terrestrial ecosystems and human livelihoods1,2. A robust understanding of angiosperm evolution is required to explain their rise to ecological dominance. So far, the angiosperm tree of life has been determined primarily by means of analyses of the plastid genome3,4. Many studies have drawn on this foundational work, such as classification and first insights into angiosperm diversification since their Mesozoic origins5-7. However, the limited and biased sampling of both taxa and genomes undermines confidence in the tree and its implications. Here, we build the tree of life for almost 8,000 (about 60%) angiosperm genera using a standardized set of 353 nuclear genes8. This 15-fold increase in genus-level sampling relative to comparable nuclear studies9 provides a critical test of earlier results and brings notable change to key groups, especially in rosids, while substantiating many previously predicted relationships. Scaling this tree to time using 200 fossils, we discovered that early angiosperm evolution was characterized by high gene tree conflict and explosive diversification, giving rise to more than 80% of extant angiosperm orders. Steady diversification ensued through the remaining Mesozoic Era until rates resurged in the Cenozoic Era, concurrent with decreasing global temperatures and tightly linked with gene tree conflict. Taken together, our extensive sampling combined with advanced phylogenomic methods shows the deep history and full complexity in the evolution of a megadiverse clade.


Subject(s)
Evolution, Molecular , Genes, Plant , Genomics , Magnoliopsida , Phylogeny , Fossils , Genes, Plant/genetics , Magnoliopsida/genetics , Magnoliopsida/classification , Nuclear Proteins/genetics
2.
J Exp Bot ; 75(7): 1800-1822, 2024 Mar 27.
Article in English | MEDLINE | ID: mdl-38109712

ABSTRACT

The Ranunculales are a hyperdiverse lineage in many aspects of their phenotype, including growth habit, floral and leaf morphology, reproductive mode, and specialized metabolism. Many Ranunculales species, such as opium poppy and goldenseal, have a high medicinal value. In addition, the order includes a large number of commercially important ornamental plants, such as columbines and larkspurs. The phylogenetic position of the order with respect to monocots and core eudicots and the diversity within this lineage make the Ranunculales an excellent group for studying evolutionary processes by comparative studies. Lately, the phylogeny of Ranunculales was revised, and genetic and genomic resources were developed for many species, allowing comparative analyses at the molecular scale. Here, we review the literature on the resources for genetic manipulation and genome sequencing, the recent phylogeny reconstruction of this order, and its fossil record. Further, we explain their habitat range and delve into the diversity in their floral morphology, focusing on perianth organ identity, floral symmetry, occurrences of spurs and nectaries, sexual and pollination systems, and fruit and dehiscence types. The Ranunculales order offers a wealth of opportunities for scientific exploration across various disciplines and scales, to gain novel insights into plant biology for researchers and plant enthusiasts alike.


Subject(s)
Flowers , Ranunculales , Phylogeny , Biological Evolution , Plant Leaves/genetics
3.
Med Vet Entomol ; 2024 Sep 16.
Article in English | MEDLINE | ID: mdl-39282938

ABSTRACT

Pyrethroid resistance and mechanisms for resistance for Anopheles gambiae sensus lato (s.l.) (Diptera: Culicidae) Giles, were assessed in three urban areas (vegetable farming, industrial and residential) of Abidjan. Susceptibility to pyrethroids (deltamethrin, permethrin and alphacypermethrin), with and without piperonyl butoxide (PBO) pre-exposure was evaluated. Anopheles gambiae complex members were identified using Short Interspersed Nuclear Elements PCR (SINE PCR), and resistance mechanisms (kdr-west, kdr-east and ace-1) and metabolic gene expression (CYP6P5, CYP6M2, CYP6P3, CYP6P4) were determined by real-time polymerase chain reaction (PCR). High resistance to deltamethrin, permethrin and alphacypermethrin was observed in Port-Bouet (vegetable farming) and Treichville (industrial site), whereas moderate resistance to deltamethrin and high resistance to alphacypermethrin and permethrin were found in Abobo (residential site). Pre-exposure to PBO with pyrethroid increased mortalities in all sites. In Treichville, pre-exposure to PBO restored susceptibility to deltamethrin, but not in Port-Bouet or Abobo. In Treichville, An. gambiae Giles sensu stricto (s.s.) was predominant (92.9%), whereas in Abobo and Port-Bouet, An. coluzzii Giles was predominant (73.6% and 66.4%, respectively). The highest kdr-west mutation frequency was in An. gambiae s.s. (42.8%) from Abobo, followed by An. gambiae s.s. (40%) from Port-Bouet and An. gambiae s.s. (35.6%) from Treichville. In An. coluzzii, the highest kdr-west mutation frequency was in Port-Bouet (48.2%), followed by Abobo (28.00%) and Treichville (21.4%). Mutation frequencies of kdr-east were lower in An. gambiae s.s. from Treichville (4.1%) and Port-Bouet (2.1%) and absent in An. gambiae from Abobo. In industrial and vegetable farming areas, CYP6P3 and CYP6M2 were overexpressed compared with Kisumu. The study suggests An. gambiae s.l. distribution and pyrethroid resistance are influenced by human activities. Treichville's industrial area favoured An. gambiae s.s., whereas Abobo's residential and Port-Bouet's vegetable farming areas were dominated by An. coluzzii. Resistance in Treichville and Port-Bouet was associated with kdr (west and east) genes and metabolic genes, whereas in residential areas, only kdr-west genes were observed. These data suggest that PBO + deltamethrin impregnated nets could aid malaria control, benefiting industrial areas of Côte d'Ivoire and other African cities.

4.
Int J Sports Med ; 45(6): 422-435, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38401534

ABSTRACT

Inducing a heat-acclimated phenotype via repeated heat stress improves exercise capacity and reduces athletes̓ risk of hyperthermia and heat illness. Given the increased number of international sporting events hosted in countries with warmer climates, heat acclimation strategies are increasingly popular among endurance athletes to optimize performance in hot environments. At the tissue level, completing endurance exercise under heat stress may augment endurance training adaptation, including mitochondrial and cardiovascular remodeling due to increased perturbations to cellular homeostasis as a consequence of metabolic and cardiovascular load, and this may improve endurance training adaptation and subsequent performance. This review provides an up-to-date overview of the metabolic impact of heat stress during endurance exercise, including proposed underlying mechanisms of altered substrate utilization. Against this metabolic backdrop, the current literature highlighting the role of heat stress in augmenting training adaptation and subsequent endurance performance will be presented with practical implications and opportunities for future research.


Subject(s)
Endurance Training , Humans , Heat-Shock Response/physiology , Acclimatization/physiology , Physical Endurance/physiology , Heat Stress Disorders/physiopathology , Heat Stress Disorders/metabolism , Adaptation, Physiological
5.
Cardiol Young ; : 1-6, 2024 Feb 27.
Article in English | MEDLINE | ID: mdl-38410052

ABSTRACT

OBJECTIVE: To describe a method of reducing the risk of sternal wound infection after sternotomy in children with a pre-existing tracheostomy. To report our outcomes using this method from 1 January, 2013 to 31 August, 2023. METHODS: We describe a method for temporarily occluding the tracheal stoma with a removable implant with the primary goal of reducing the risk of sternotomy wound infection by preventing soilage due to tracheostomal secretions. We then performed a retrospective review of all children who underwent temporary tracheostomal occlusion between 1 January, 2013 and 31 August, 2023 at our quaternary care children's hospital. Clinical variables were extracted from the hospital medical records. The rates of antibiotic use and minor and major complications during the period when the stoma plug was in place were recorded. RESULTS: Totally, 19 patients underwent tracheal stoma plugging prior to sternotomy and were included in our analysis. There were two cases of sternal wound infection; one case occurred while the stoma plug was in place, and one developed four days following plug removal. There was one minor complication, with one patient requiring stoma revision via serial dilation at bedside at the time of recannulation. There were no deaths. CONCLUSION: Temporary occlusion of the tracheal stoma with an impermeable plug is a viable option for reducing the risk of sternal wound infection in children with a pre-existing tracheostomy who are undergoing sternotomy.

6.
Exp Physiol ; 108(6): 838-851, 2023 06.
Article in English | MEDLINE | ID: mdl-36691850

ABSTRACT

NEW FINDINGS: What is the central question of this study? Whole-body substrate utilisation is altered during exercise in hot environments, characterised by increased glycolytic metabolism: does heat stress alter the serum metabolome in response to high intensity exercise? What are the main finding and its importance? Alongside increases in glycolytic metabolite abundance, circulating amino acid concentrations are reduced following exercise under heat stress. Prior research has overlooked the impact of heat stress on protein metabolism during exercise, raising important practical implications for protein intake recommendations in the heat. ABSTRACT: Using untargeted metabolomics, we aimed to characterise the systemic impact of environmental heat stress during exercise. Twenty-three trained male triathletes ( V ̇ O 2 peak ${\dot V_{{{\rm{O}}_2}{\rm{peak}}}}$  = 64.8 ± 9.2 ml kg min-1 ) completed a 30-min exercise test in hot (35°C) and temperate (21°C) conditions. Venous blood samples were collected immediately pre- and post-exercise, and the serum fraction was assessed via untargeted 1 H-NMR metabolomics. Data were analysed via uni- and multivariate analyses to identify differences between conditions. Mean power output was higher in temperate (231 ± 36 W) versus hot (223 ± 31 W) conditions (P < 0.001). Mean heart rate (temperate, 162 ± 10 beats min-1 , hot, 167 ± 9 beats min-1 , P < 0.001), peak core temperature (Trec ), core temperature change (ΔTrec ) (P < 0.001) and peak rating of perceived exertion (P = 0.005) were higher in hot versus temperate conditions. Change in metabolite abundance following exercise revealed distinct clustering following multivariate analysis. Six metabolites increased (2-hydroxyvaleric acid, acetate, alanine, glucarate, glucose, lactate) in hot relative to temperate (P < 0.05) conditions. Leucine and lysine decreased in both conditions but to a greater extent in temperate conditions (P < 0.05). Citrate (P = 0.04) was greater in temperate conditions whilst creatinine decreased in hot conditions only (P > 0.05). Environmental heat stress increased glycolytic metabolite abundance and led to distinct alterations in the circulating amino acid availability, including increased alanine, glutamine, leucine and isoleucine. The data highlight the need for additional exercise nutrition and metabolism research, specifically focusing on protein requirements for exercise under heat stress.


Subject(s)
Amino Acids , Heat-Shock Response , Male , Humans , Leucine , Exercise/physiology , Alanine , Hot Temperature
7.
J Physiol ; 599(11): 2823-2849, 2021 06.
Article in English | MEDLINE | ID: mdl-33772787

ABSTRACT

KEY POINTS: Muscle glycogen and intramuscular triglycerides (IMTG, stored in lipid droplets) are important energy substrates during prolonged exercise. Exercise-induced changes in lipid droplet (LD) morphology (i.e. LD size and number) have not yet been studied under nutritional conditions typically adopted by elite endurance athletes, that is, after carbohydrate (CHO) loading and CHO feeding during exercise. We report for the first time that exercise reduces IMTG content in both central and peripheral regions of type I and IIa fibres, reflective of decreased LD number in both fibre types whereas reductions in LD size were exclusive to type I fibres. Additionally, CHO feeding does not alter subcellular IMTG utilisation, LD morphology or muscle glycogen utilisation in type I or IIa/II fibres. In the absence of alterations to muscle fuel selection, CHO feeding does not attenuate cell signalling pathways with regulatory roles in mitochondrial biogenesis. ABSTRACT: We examined the effects of carbohydrate (CHO) feeding on lipid droplet (LD) morphology, muscle glycogen utilisation and exercise-induced skeletal muscle cell signalling. After a 36 h CHO loading protocol and pre-exercise meal (12 and 2 g kg-1 , respectively), eight trained males ingested 0, 45 or 90 g CHO h-1 during 180 min cycling at lactate threshold followed by an exercise capacity test (150% lactate threshold). Muscle biopsies were obtained pre- and post-completion of submaximal exercise. Exercise decreased (P < 0.01) glycogen concentration to comparable levels (∼700 to 250 mmol kg-1 DW), though utilisation was greater in type I (∼40%) versus type II fibres (∼10%) (P < 0.01). LD content decreased in type I (∼50%) and type IIa fibres (∼30%) (P < 0.01), with greater utilisation in type I fibres (P < 0.01). CHO feeding did not affect glycogen or IMTG utilisation in type I or II fibres (all P > 0.05). Exercise decreased LD number within central and peripheral regions of both type I and IIa fibres, though reduced LD size was exclusive to type I fibres. Exercise induced (all P < 0.05) comparable AMPKThr172 (∼4-fold), p53Ser15 (∼2-fold) and CaMKIIThr268 phosphorylation (∼2-fold) with no effects of CHO feeding (all P > 0.05). CHO increased exercise capacity where 90 g h-1 (233 ± 133 s) > 45 g h-1 (156 ± 66 s; P = 0.06) > 0 g h-1 (108 ± 54 s; P = 0.03). In conditions of high pre-exercise CHO availability, we conclude CHO feeding does not influence exercise-induced changes in LD morphology, glycogen utilisation or cell signalling pathways with regulatory roles in mitochondrial biogenesis.


Subject(s)
AMP-Activated Protein Kinases , Lipid Droplets , Dietary Carbohydrates , Exercise Tolerance , Humans , Male , Muscle, Skeletal , Tumor Suppressor Protein p53
8.
Malar J ; 20(1): 409, 2021 Oct 18.
Article in English | MEDLINE | ID: mdl-34663359

ABSTRACT

BACKGROUND: Although malaria and Anopheles mosquito vectors are highly prevalent in Côte d'Ivoire, limited data are available to help understand the malaria vector density and transmission dynamics in areas bordering the country. To address this gap, the Anopheles mosquito species diversity, the members of the Anopheles gambiae complex and the transmission of malaria were assessed in four health districts along the borders of Côte d'Ivoire. METHODS: From July 2016 through December 2016 and July 2017 through December 2017, adult Anopheles mosquitoes were collected in four health districts of Côte d'Ivoire (Aboisso, Bloléquin, Odienné and Ouangolodougou) using standardized window exit trap (WET) and pyrethrum knockdown spray collection (PSC) methods. The collected mosquitoes were identified morphologically at species level and the members of the An. gambiae complex were separated using short interspersed nuclear element-based polymerase chain reaction (SINE-PCR). Anopheles gambiae sensu lato (s.l.), Anopheles funestus s.l. and Anopheles nili specimens were analysed for malaria Plasmodium parasite detection using the cytochrome oxidase I gene (COX-I), and malaria prevalence among human population through local Ministry of Health (MoH) statistical yearbooks. RESULTS: A total of 281 female Anopheles were collected in Aboisso, 754 in Bloléquin, 1319 in Odienné and 2443 in Ouangolodougou. Seven Anopheles species were recorded including An. gambiae s.l. (94.8-99.1%) as the main vector, followed by An. funestus s.l. (0.4-4.3%) and An. nili (0-0.7%). Among An. gambiae s.l., Anopheles coluzzii represented the predominant species in Aboisso (89.2%) and Bloléquin (92.2%), while An. gambiae sensu stricto (s.s.) was the major species in Odienné (96.0%) and Ouangolodougou (94.2%). The Plasmodium sporozoite infection rate in An. gambiae s.l. was highest in Odienné (11.0%; n = 100) followed by Bloléquin (7.8%, n = 115), Aboisso (3.1%; n = 65) and Ouangologoudou (2.5%; n = 120). In An. funestus s.l., Plasmodium falciparum sporozoite infection rate was estimated at 6.2% (n = 32) in Bloléquin, 8.7% (n = 23) in Odienné. No An. funestus s.l. specimens were found infected with P. falciparum sporozoite infection in Ouangolodougou and Aboisso. No P. falciparum sporozoite was detected in An. nili specimens in the four health districts. Among the local human populations, malaria incidence was higher in Odienné (39.7%; n = 45,376) and Bloléquin (37.6%; n = 150,205) compared to that in Ouangolodougou (18.3%; n = 131,629) and Aboisso (19.7%; n = 364,585). CONCLUSION: Anopheles vector species diversity, abundance and Plasmodium sporozoite infection were high within the health districts along the borders of the country of Côte d'Ivoire, resulting in high malaria transmission among the local populations. Anopheles gambiae s.l. and An. funestus s.l. were found to be highly infected with Plasmodium in the health districts of Bloléquin and Odienné where higher malaria incidence was observed than the other districts. This study provides important information that can be used to guide Côte d'Ivoire National Malaria Control Programme for vector control decision-making, mainly in districts that are at the country borders.


Subject(s)
Anopheles/parasitology , Malaria/transmission , Mosquito Vectors/parasitology , Animals , Anopheles/classification , Anopheles/genetics , Biodiversity , Cote d'Ivoire/epidemiology , Female , Malaria/epidemiology , Mosquito Vectors/classification , Mosquito Vectors/genetics , Plasmodium falciparum/isolation & purification
9.
Exp Physiol ; 105(11): 1882-1894, 2020 11.
Article in English | MEDLINE | ID: mdl-32862503

ABSTRACT

NEW FINDINGS: What is the central question of this study? What is the absolute level of pre-exercise glycogen concentration required to augment the exercise-induced signalling response regulating mitochondrial biogenesis? What is the main finding and its importance? Commencing high-intensity endurance exercise with reduced pre-exercise muscle glycogen concentrations confers no additional benefit to the early signalling responses that regulate mitochondrial biogenesis. ABSTRACT: We examined the effects of graded muscle glycogen on the subcellular location and protein content of AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) and mRNA expression of genes associated with the regulation of mitochondrial biogenesis and substrate utilisation in human skeletal muscle. In a repeated measures design, eight trained male cyclists completed acute high-intensity interval (HIT) cycling (8 × 5 min at 80% peak power output) with graded concentrations of pre-exercise muscle glycogen. Following initial glycogen-depleting exercise, subjects ingested  2 g kg-1  (L-CHO), 6 g kg-1 (M-CHO) or 14 g kg-1 (H-CHO) of carbohydrate during a 36 h period, such that exercise was commenced with graded (P < 0.05) muscle glycogen concentrations (mmol (kg dw)-1 : H-CHO, 531 ± 83; M-CHO, 332 ± 88; L-CHO, 208 ± 79). Exercise depleted muscle glycogen to <300 mmol (kg dw)-1 in all trials (mmol (kg dw)-1 : H-CHO, 270 ± 88; M-CHO, 173 ± 74; L-CHO, 100 ± 42) and induced comparable increases in nuclear AMPK protein content (∼2-fold) and PGC-1α (∼5-fold), p53 (∼1.5-fold) and carnitine palmitoyltransferase 1 (∼2-fold) mRNA between trials (all P < 0.05). The magnitude of increase in PGC-1α mRNA was also positively correlated with post-exercise glycogen concentration (P < 0.05). In contrast, neither exercise nor carbohydrate availability affected the subcellular location of PGC-1α protein or PPAR, SCO2, SIRT1, DRP1, MFN2 or CD36 mRNA. Using a sleep-low, train-low model with a high-intensity endurance exercise stimulus, we conclude that pre-exercise muscle glycogen does not modulate skeletal muscle cell signalling.


Subject(s)
AMP-Activated Protein Kinases , Glycogen , AMP-Activated Protein Kinases/metabolism , Exercise/physiology , Glycogen/metabolism , Humans , Male , Muscle, Skeletal/physiology , Nuclear Proteins/metabolism , Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/metabolism
10.
Angew Chem Int Ed Engl ; 59(51): 23283-23290, 2020 12 14.
Article in English | MEDLINE | ID: mdl-32857901

ABSTRACT

Tuning the dihedral angle (DA) of axially chiral compounds can impact biological activity, catalyst efficiency, molecular motor performance, or chiroptical properties. Herein, we report gradual, controlled, and reversible changes in molecular conformation of a covalently linked binaphthyl moiety within a 3D polymeric network by application of a macroscopic stretching force. We managed direct observation of DA changes by measuring the circular dichroism signal of an optically pure BINOL-crosslinked elastomer network. Stretching the elastomer resulted in a widening of the DA between naphthyl rings when the BINOL was doubly grafted to the elastomer network; no effect was observed when a single naphthyl ring of the BINOL was grafted to the elastomer network. We have determined that ca. 170 % extension of the elastomers led to the transfer of a mechanical force to the BINOL moiety of 2.5 kcal mol-1 Å-1 (ca. 175 pN) in magnitude and results in the opening of the DA of BINOL up to 130°.

11.
Environ Sci Technol ; 53(10): 6044-6052, 2019 05 21.
Article in English | MEDLINE | ID: mdl-31021077

ABSTRACT

Microplastics can affect biophysical properties of the soil. However, little is known about the cascade of events in fundamental levels of terrestrial ecosystems, i.e., starting with the changes in soil abiotic properties and propagating across the various components of soil-plant interactions, including soil microbial communities and plant traits. We investigated here the effects of six different microplastics (polyester fibers, polyamide beads, and four fragment types: polyethylene, polyester terephthalate, polypropylene, and polystyrene) on a broad suite of proxies for soil health and performance of spring onion ( Allium fistulosum). Significant changes were observed in plant biomass, tissue elemental composition, root traits, and soil microbial activities. These plant and soil responses to microplastic exposure were used to propose a causal model for the mechanism of the effects. Impacts were dependent on particle type, i.e., microplastics with a shape similar to other natural soil particles elicited smaller differences from control. Changes in soil structure and water dynamics may explain the observed results in which polyester fibers and polyamide beads triggered the most pronounced impacts on plant traits and function. The findings reported here imply that the pervasive microplastic contamination in soil may have consequences for plant performance and thus for agroecosystems and terrestrial biodiversity.


Subject(s)
Plastics , Soil , Biodiversity , Ecosystem , Plants
12.
Nature ; 483(7389): 341-4, 2012 Mar 07.
Article in English | MEDLINE | ID: mdl-22398443

ABSTRACT

Strigolactones were originally identified as stimulators of the germination of root-parasitic weeds that pose a serious threat to resource-limited agriculture. They are mostly exuded from roots and function as signalling compounds in the initiation of arbuscular mycorrhizae, which are plant-fungus symbionts with a global effect on carbon and phosphate cycling. Recently, strigolactones were established to be phytohormones that regulate plant shoot architecture by inhibiting the outgrowth of axillary buds. Despite their importance, it is not known how strigolactones are transported. ATP-binding cassette (ABC) transporters, however, are known to have functions in phytohormone translocation. Here we show that the Petunia hybrida ABC transporter PDR1 has a key role in regulating the development of arbuscular mycorrhizae and axillary branches, by functioning as a cellular strigolactone exporter. P. hybrida pdr1 mutants are defective in strigolactone exudation from their roots, resulting in reduced symbiotic interactions. Above ground, pdr1 mutants have an enhanced branching phenotype, which is indicative of impaired strigolactone allocation. Overexpression of Petunia axillaris PDR1 in Arabidopsis thaliana results in increased tolerance to high concentrations of a synthetic strigolactone, consistent with increased export of strigolactones from the roots. PDR1 is the first known component in strigolactone transport, providing new opportunities for investigating and manipulating strigolactone-dependent processes.


Subject(s)
ATP-Binding Cassette Transporters/metabolism , Arabidopsis/drug effects , Lactones/pharmacology , Petunia/metabolism , Plant Growth Regulators/pharmacology , Plant Proteins/metabolism , Signal Transduction/drug effects , Symbiosis/drug effects , ATP-Binding Cassette Transporters/genetics , Abscisic Acid/pharmacology , Arabidopsis/embryology , Arabidopsis/genetics , Arabidopsis/metabolism , Gene Expression Regulation, Plant , Germination , Molecular Sequence Data , Mycorrhizae/drug effects , Naphthaleneacetic Acids/pharmacology , Petunia/genetics , Phenotype , Plant Proteins/genetics , Plant Roots/drug effects , Plant Roots/metabolism , Plant Roots/microbiology
13.
J Clin Ultrasound ; 46(6): 415-418, 2018 Jul.
Article in English | MEDLINE | ID: mdl-29148580

ABSTRACT

Obturator hernia is a rare but clinically relevant cause of intestinal obstruction, usually found in elderly, thin, multiparous women. It is difficult to diagnose, leading to diagnostic delay with a high incidence of strangulation and a high mortality rate. Surgery is the only reported treatment. We report the case of an 86-year-old woman, in whom an early diagnosis of incarcerated obturator hernia was made with subsequent reduction by compression with an ultrasound transducer. When the risk of strangulation is presumed to be low, ultrasound-guided reduction of an obturator hernia is achievable and worth considering.


Subject(s)
Hernia, Obturator/diagnostic imaging , Hernia, Obturator/surgery , Intestinal Obstruction/diagnostic imaging , Intestinal Obstruction/surgery , Ultrasonography, Interventional/methods , Aged, 80 and over , Female , Hernia, Obturator/complications , Humans , Intestinal Obstruction/etiology
14.
Int J Mol Sci ; 19(9)2018 Aug 27.
Article in English | MEDLINE | ID: mdl-30150605

ABSTRACT

Pancreatic ß-cell dysfunction and death contribute to the onset of diabetes, and novel strategies of ß-cell function and survival under diabetogenic conditions need to be explored. We previously demonstrated that Isx9, a small molecule based on the isoxazole scaffold, drives neuroendocrine phenotypes by increasing the expression of genes required for ß-cell function and improves glycemia in a model of ß cell regeneration. We further investigated the role of Isx9 in ß-cell survival. We find that Isx9 drives the expression of Calbindin-D28K (D28K), a key regulator of calcium homeostasis, and plays a cytoprotective role through its calcium buffering capacity in ß cells. Isx9 increased the activity of the calcineurin (CN)/cytoplasmic nuclear factor of the activated T-cells (NFAT) transcription factor, a key regulator of D28K, and improved the recruitment of NFATc1, cAMP response element-binding protein (CREB), and p300 to the D28K promoter. We found that nutrient stimulation increased D28K plasma membrane enrichment and modulated calcium channel activity in order to regulate glucose-induced insulin secretion. Isx9-mediated expression of D28K protected ß cells against chronic stress induced by serum withdrawal or chronic inflammation by reducing caspase 3 activity. Consequently, Isx9 improved human islet function after transplantation in NOD-SCID mice in a streptozotocin-induced diabetes model. In summary, Isx9 significantly regulates expression of genes relevant to ß cell survival and function, and may be an attractive therapy to treat diabetes and improve islet function post-transplantation.


Subject(s)
Calbindins/genetics , Gene Expression Regulation, Neoplastic/drug effects , Insulin-Secreting Cells/drug effects , Isoxazoles/pharmacology , Thiophenes/pharmacology , Animals , Calbindins/metabolism , Cell Line, Tumor , Cell Survival/drug effects , Cell Survival/genetics , Diabetes Mellitus, Experimental/metabolism , Humans , Insulin-Secreting Cells/metabolism , Insulin-Secreting Cells/pathology , Islets of Langerhans/drug effects , Islets of Langerhans/metabolism , Islets of Langerhans Transplantation , Mice, Inbred NOD , Mice, SCID , NFATC Transcription Factors/genetics , NFATC Transcription Factors/metabolism , Rats
15.
Fordham Law Rev ; 86(4): 1889-921, 2018 Mar.
Article in English | MEDLINE | ID: mdl-29993206

ABSTRACT

While approximately one in ten Americans suffers from a rare disease, only 5 percent of rare diseases have a U.S. Food and Drug Administration (FDA) approved treatment. Congressional and regulatory efforts to stimulate the development of rare-disease treatments, while laudable, have not resolved the fundamental issues surrounding rare-disease treatment development. Indeed, small patient populations, incomplete scientific understanding of rare diseases, and high development costs continually limit the availability of rare-disease treatments. To illustrate the struggle of developing and approving safe rare-disease treatments, this Note begins by discussing the approval of Eteplirsen, the first drug approved for treating a rare disease called Duchenne muscular dystrophy. After exploring the current drug regulation system and how this impacts the availability of rare-disease treatments, this Note examines the 21st Century Cures Act's patient experience data provisions and the currently pending Trickett Wendler Right to Try Act. Ultimately, the unmet therapeutic needs of rare-disease patients can be met while protecting patient safety. This Note reasons that, if carefully implemented, the 21st Century Cures Act and the Trickett Wendler Right to Try Act could work in tandem to safely facilitate patient access to rare-disease treatments.


Subject(s)
Drug Approval/legislation & jurisprudence , Drugs, Investigational/therapeutic use , Health Services Accessibility/legislation & jurisprudence , Investigational New Drug Application/legislation & jurisprudence , Orphan Drug Production/legislation & jurisprudence , Patient Safety , Rare Diseases/drug therapy , Clinical Trials as Topic , Humans , United States , United States Food and Drug Administration
16.
New Phytol ; 215(2): 851-864, 2017 Jul.
Article in English | MEDLINE | ID: mdl-28631322

ABSTRACT

The embryology of basal angiosperm lineages (Amborella, Nymphaeales and Austrobaileyales) is central to reconstructing the early evolution of flowering plants. Previous studies have shown that mature seeds in Austrobaileyales are albuminous, with a small embryo surrounded by a substantial diploid endosperm. However, little is known of seed ontogeny and seedling germination in Austrobaileya scandens, sister to all other extant Austrobaileyales. Standard histochemical techniques were used to study ovule/seed development and germination of Austrobaileya. Early development of the endosperm in Austrobaileya is ab initio cellular with pronounced cell proliferation. The nucellus transiently accumulates some starch, but is obliterated by expansion of a massive endosperm, where all embryo-nourishing reserves are ultimately stored. Twelve months elapse from fertilization to fruit abscission. Seeds are dispersed with a minute embryo, requiring 12 additional months for seedling establishment. The 2 yr required for seedling establishment is an apomorphic feature of Austrobaileya, probably related to germination in extremely dark understory conditions. Remarkably, although Austrobaileya seeds are nearly 50 times larger (by length) than the smallest seeds of extinct and extant members of early divergent angiosperm lineages, the embryo to seed ratio (E : S) falls squarely within the narrow range that characterizes the albuminous seeds of ancient flowering plant lineages.


Subject(s)
Biological Evolution , Magnoliopsida/physiology , Seeds/growth & development , Australia , Flowers/physiology , Germination , Magnoliopsida/growth & development , Seed Dispersal , Seedlings/growth & development , Seedlings/physiology , Seeds/physiology
18.
J Am Chem Soc ; 137(45): 14256-9, 2015 Nov 18.
Article in English | MEDLINE | ID: mdl-26536147

ABSTRACT

Five-coordinate geometry is the standard binding mode of zinc porphyrins with pyridine ligands. Here we show that pseudo-octahedral six-coordinate zinc porphyrin complexes can also be formed in solution, by taking advantage of the chelate effect. UV-vis-NIR titrations indicate that the strength of this second coordination is ca. 6-8 kJ mol(-1). We have used the formation of six-coordinate zinc porphyrin complexes to achieve the template-directed synthesis of a 3D π-conjugated spiro-fused array of 11 porphyrin units, covalently connected in a nontrivial topology. Time-resolved fluorescence anisotropy experiments show that electronic excitation delocalizes between the two perpendicular nanorings of this spiro-system within the experimental time-resolution of 270 fs.

19.
PLoS Genet ; 8(7): e1002838, 2012.
Article in English | MEDLINE | ID: mdl-22844253

ABSTRACT

The evolutionary transition from outcrossing to self-fertilization (selfing) through the loss of self-incompatibility (SI) is one of the most prevalent events in flowering plants, and its genetic basis has been a major focus in evolutionary biology. In the Brassicaceae, the SI system consists of male and female specificity genes at the S-locus and of genes involved in the female downstream signaling pathway. During recent decades, much attention has been paid in particular to clarifying the genes responsible for the loss of SI. Here, we investigated the pattern of polymorphism and functionality of the female specificity gene, the S-locus receptor kinase (SRK), in allotetraploid Arabidopsis kamchatica. While its parental species, A. lyrata and A. halleri, are reported to be diploid and mainly self-incompatible, A. kamchatica is self-compatible. We identified five highly diverged SRK haplogroups, found their disomic inheritance and, for the first time in a wild allotetraploid species, surveyed the geographic distribution of SRK at the two homeologous S-loci across the species range. We found intact full-length SRK sequences in many accessions. Through interspecific crosses with the self-incompatible and diploid congener A. halleri, we found that the female components of the SI system, including SRK and the female downstream signaling pathway, are still functional in these accessions. Given the tight linkage and very rare recombination of the male and female components on the S-locus, this result suggests that the degradation of male components was responsible for the loss of SI in A. kamchatica. Recent extensive studies in multiple Brassicaceae species demonstrate that the loss of SI is often derived from mutations in the male component in wild populations, in contrast to cultivated populations. This is consistent with theoretical predictions that mutations disabling male specificity are expected to be more strongly selected than mutations disabling female specificity, or the female downstream signaling pathway.


Subject(s)
Arabidopsis , Fertilization , Plant Proteins/genetics , Protein Kinases/genetics , Self-Incompatibility in Flowering Plants/genetics , Arabidopsis/genetics , Arabidopsis/physiology , Crosses, Genetic , Diploidy , Fertilization/genetics , Fertilization/physiology , Mutation , Plant Proteins/physiology , Polymorphism, Genetic , Protein Kinases/physiology , Self-Incompatibility in Flowering Plants/physiology , Signal Transduction , Tetraploidy
20.
J Chem Phys ; 140(20): 204301, 2014 May 28.
Article in English | MEDLINE | ID: mdl-24880274

ABSTRACT

The excited state dynamics of isolated sulfur dioxide molecules have been investigated using the time-resolved photoelectron spectroscopy and time-resolved photoelectron-photoion coincidence techniques. Excited state wavepackets were prepared in the spectroscopically complex, electronically mixed (B̃)(1)B1/(Ã)(1)A2, Clements manifold following broadband excitation at a range of photon energies between 4.03 eV and 4.28 eV (308 nm and 290 nm, respectively). The resulting wavepacket dynamics were monitored using a multiphoton ionisation probe. The extensive literature associated with the Clements bands has been summarised and a detailed time domain description of the ultrafast relaxation pathways occurring from the optically bright (B̃)(1)B1 diabatic state is presented. Signatures of the oscillatory motion on the (B̃)(1)B1/(Ã)(1)A2 lower adiabatic surface responsible for the Clements band structure were observed. The recorded spectra also indicate that a component of the excited state wavepacket undergoes intersystem crossing from the Clements manifold to the underlying triplet states on a sub-picosecond time scale. Photoelectron signal growth time constants have been predominantly associated with intersystem crossing to the (c̃)(3)B2 state and were measured to vary between 750 and 150 fs over the implemented pump photon energy range. Additionally, pump beam intensity studies were performed. These experiments highlighted parallel relaxation processes that occurred at the one- and two-pump-photon levels of excitation on similar time scales, obscuring the Clements band dynamics when high pump beam intensities were implemented. Hence, the Clements band dynamics may be difficult to disentangle from higher order processes when ultrashort laser pulses and less-differential probe techniques are implemented.

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