Smaller lungs in women affect exercise hyperpnea

We subjected 29 healthy young women (age: 27 ± 1 yr) with a wide range of fitness levels [maximal oxygenuptake (O_{2 max}): 57 ± 6 ml · kg¹ · min¹;35-70ml · kg¹ · min¹]to a progressive treadmill running test. Our subjects had significantly smaller lung volumes and lower maximal expiratory flow rates, irrespective of fitness level, compared with predicted values for age-and height-matched men. The higher maximal workload in highly fit(O_{2 max} > 57 ml · kg¹ · min¹,n = 14) vs. less-fit(O_{2 max} < 56 ml · kg¹ · min¹,n = 15) women caused a higher maximalventilation (E) with increased tidal volume (VT)and breathing frequency (f_b) atcomparable maximal VT/vitalcapacity (VC). More expiratory flow limitation (EFL; 22 ± 4% ofVT) was also observed duringheavy exercise in highly fit vs. less-fit women, causing higherend-expiratory and end-inspiratory lung volumes and greater usage oftheir maximum available ventilatory reserves.HeO₂ (79% He-21%O₂) vs. room air exercise trialswere compared (with screens added to equalize external apparatusresistance). HeO₂ increasedmaximal expiratory flow rates (20-38%) throughout the range ofVC, which significantly reduced EFL during heavy exercise. When EFL wasreduced with HeO₂, VT,f_b, andE (+16 ± 2 l/min) weresignificantly increased during maximal exercise. However, in theabsence of EFL (during room air exercise),HeO₂ had no effect onE. We conclude that smaller lungvolumes and maximal flow rates for women in general, and especiallyhighly fit women, caused increased prevalence of EFL during heavyexercise, a relative hyperinflation, an increased reliance onf_b, and a greater encroachment onthe ventilatory "reserve." Consequently,VT andE are mechanically constrained duringmaximal exercise in many fit women because the demand for highexpiratory flow rates encroaches on the airways' maximum flow-volumeenvelope.

     

Discovery and SAR of isonicotinamide BACE-1 inhibitors that bind beta-secretase in a N-terminal 10s-loop down conformation

A series of low-molecular weight 2,6-diamino-isonicotinamide BACE-1 inhibitors containing an amine transition-state isostere were synthesized and shown to be highly potent in both enzymatic and cell-based assays. These inhibitors contain a trans-S,S-methyl cyclopropane P(3) which bind BACE-1 in a 10s-loop down conformation giving rise to highly potent compounds with favorable molecular weight and moderate to high susceptibility to P-glycoprotein (P-gp) efflux.     

A comparison of light-dependent RNA metabolism in wild-type Euglena with that of mutants impaired for chloroplast development

Summary The possibility that ³²PO ₄ ^3- (³²P_i) labeling of both chloroplast and non-chloroplast RNAs during light-induced chloroplast development in Euglena is due, in part, to the break-down of existing RNAs and their resynthesis into labeled RNAs has been examined by comparing the RNA content of dark-grown, non-dividing cells after completion of light-induced chloroplast development with that of identical cells maintained in darkness for the same period of time. The involvement of the photo-conversion of protochlorophyll to chlorophyll and other photoreceptor systems in the labeling of RNA during chloroplast development has been considered by comparing the labeling pattern obtained with wild-type cells with the patterns obtained with mutants of Euglena which either lack detectable amounts of protochlorophyll and chlorophyll or form only rudimentary chloroplasts upon light induction.No significant difference in RNA content between dark-grown, non-dividing cells containing fully developed chloroplasts and the same cells maintained in darkness for the development period can be detected. This observation is interpreted to mean that in non-dividing cells precursors for chloroplast-associated RNAs are derived from pools and pre-existing RNAs, including non-chloroplast RNAs, and that the matebolic entrapment of ³²P_i involves a light-dependent turnover and DNA-directed RNA synthesis in wild-type cells.The RNA profiles on sucrose gradients of mutants of Euglena show no remarkable deviation from the profile established for wild-type cells. The labeling patterns obtained after 24 hours of incubation in light and in darkness differ from that obtained for wild-type cells in that all mutants show less of a light-minus-dark difference than wild-type and that mutants lacking plastid-associated DNA and detectable amounts of chlorophyll incorporate considerably more ³²P_i into RNA in darkness than wild-type. One such mutant shows no significant difference in its light-dark labeling pattern.These observations indicate that cells possessing normal proplastids capable of forming functional chloroplasts regulate metabolism of RNA in darkness in a different manner than with either rudimentary chloroplasts or containing no detectable plastids structures. The possible involvement of more than one photoreceptor system in metabolic control is discussed.Supported by a grant from the National Institutes of Health, GM 14595     

Serological Studies of the T and Tumor Antigens of the Oncogenic Simian Adenoviruses

Tumor-specific antigens and antisera were prepared for eight of the oncogenic simian adenoviruses. Complement-fixation tests revealed three distinct serological subgroups. This grouping was maintained in studies of virus-infected cells (T antigens) although high titered preparations were obtained for only the major subgroup I. The current grouping is as follows: (I) SV1, SV11, SV25, SV33, SV34, SV38; (II) SV20, SV23; (III) SA 7. Antigens from each subgroup were rapidly inactivated at 56 C, and group II and III antigens were also markedly inactivated at 37 C. One of the tumors (SV1) also contained SV40 T antigen, suggesting origin from a simian adenovirus-SV40 "hybrid."     

Mortality of Altitude-exposed Mice Infected with Pasturella tularensis

The influence of reduced barometric pressure equivalent to an altitude of 18,000 ft (5,486 m) on the susceptibility of mice to tularemia was investigated by exposing groups of animals to the test environment before, after, or before and after intraperitoneal inoculation of 225 colony-forming units of Pasteurella tularensis. Similarly infected control animals were not exposed to the experimental environment. Two measurements of mortality were employed: (i) the day on which 50% of the mice were dead; and (ii) the number of dead mice on the 8th day. Continuous altitude exposure for 14 days prior to infection had no effect on host susceptibility but exposure after infection significantly increased mortality (P < 0.001).     

Multiple Forms of Polyglucoside-Branching Enzyme in the Algae

Three isozymes specifically concerned with the “branching” of linear polyglucosides have been delected in algae. These enzymes were detected using two-dimensional polyacrylamide gel electrophoresis, and were found to be present in blue-green, red and in green algae. Two isozynies were found in Oscillatoria princeps; three enzymes were present in Spirogyra setiformis, and two and three such enzymes were detected in red algae of the Rhodymenia type. The significance of the multiple forms of this branching enzyme was assessed in light of the type of storage poly-glucosides formed by these plants. The “degree of branching” of the storage sugar appeared to be related to the evolutionary status of these algae.     

Reproductive Biology of the Introduced Mayan cichlid, Cichlasoma urophthalmus, Within an Estuarine Mangrove Habitat of Southern Florida

We investigated the reproductive biology of the Mayan cichlid, Cichlasoma urophthalmus, for twenty consecutive months in a southern Florida mangrove creek and compared it to that of available published accounts where this species is native. Mayan cichlid reproduction occurred during a period of the year when physical conditions facilitated the best growth and survival of the young, and was influenced more by changes in water level and salinity than by temperature. Most nests were observed along mangrove shorelines in April. The majority of reproduction and parental care of the young followed in May, and was completed by June when rising water levels flooded shallow habitats and dispersed young-of-year fish. Mayan cichlids in Florida became reproductively mature at a greater size than in native regions, but produced roughly the same number of eggs at a given body mass. The similarity of environmental conditions between southern Florida and areas where Mayan cichlids naturally occur imparts a very favorable reproductive potential for this species in southern Florida, and facilitates their continued presence within the ichthyofauna of the region.     

Impacts of epitope expression kinetics and class I downregulation on the antiviral activity of human immunodeficiency virus type 1-specific cytotoxic T lymphocytes

The determinants of CD8(+) cytotoxic T-lymphocyte (CTL) antiviral activity against human immunodeficiency virus type 1 (HIV-1) remain poorly defined. Although recent technological advances have markedly enhanced the ability to detect HIV-1-specific T cells, commonly used assays do not reveal their direct interaction with virus. We investigated two determinants of CTL antiviral efficiency by manipulating HIV-1 and measuring the effects on CTL suppression of viral replication in acutely infected cells. Translocation of a Gag epitope into the early protein Nef markedly increased the activity of CTL recognizing that epitope, in comparison to HIV-1 expressing the epitope normally in the late protein Gag. Because this epitope translocation resulted not only in earlier expression but also in loss of major histocompatibility complex class I downregulation by Nef, the activities of CTL against a panel of viral constructs differing in kinetics of epitope expression and class I downmodulation were compared. The results indicated that both the timing of epitope expression and the reduction of class I have profound effects on the ability of CTL to suppress HIV-1 replication in acutely infected cells. The epitope targeting of CTL and viral control of class I therefore likely play important roles in the ability of CTL to exert pressure on HIV-1.     

Chroman and tetrahydroquinoline ureas as potent TRPV1 antagonists

Novel chroman and tetrahydroquinoline ureas were synthesized and evaluated for their activity as TRPV1 antagonists. It was found that aryl substituents on the 7- or 8-position of both bicyclic scaffolds imparted the best in vitro potency at TRPV1. The most potent chroman ureas were assessed in chronic and acute pain models, and compounds with the ability to cross the blood-brain barrier were shown to be highly efficacious. The tetrahydroquinoline ureas were found to be potent CYP3A4 inhibitors, but replacement of bulky substituents at the nitrogen atom of the tetrahydroisoquinoline moiety with small groups such as methyl can minimize the inhibition.     

Polyamines and Ca2+ Mediate Hyperosmolal Opening of the Blood-Brain Barrier: In Vitro Studies in Isolated Rat Cerebral Capillaries

We recently presented evidence that the reversible opening of the blood-brain barrier (BBB) by the infusion of 1.6 M mannitol into the rat internal carotid artery is mediated by a rapid stimulation of ornithine decarboxylase (ODC) activity and putrescine synthesis in cerebral capillaries. We have now investigated this hypothesis further, using isolated rat cerebral capillaries as an in vitro model of the BBB. The ODC activity of cerebral capillary preparations was enriched up to 15-fold over that of the cerebral homogenate. Hyperosmolal mannitol in physiological buffer evoked a rapid (less than 15 s), concentration- and time-dependent increase in capillary ODC activity and an accumulation of putrescine and spermidine which was blocked by the specific ODC inhibitor, alpha-difluoromethylornithine (DFMO, 10 mM). Mannitol (1 M), as well as 2 M urea, evoked a two- to fivefold increase in the temperature-sensitive influx of 45Ca2+ and uptake of horseradish peroxidase (HRP) and 2-deoxy-D-[1-3H]glucose (DG), but not alpha-[1-14C]aminoisobutyrate, during a 2-min incubation. DFMO (10 mM) abolished 1 M mannitol-mediated stimulation of 45Ca2+ influx and uptake of HRP and DG, whereas 1 mM putrescine replenished capillary polyamines and reversed the DFMO effects. Mannitol (1 M)-induced stimulation of ODC activity and membrane transport processes was Ca2+-dependent and verapamil- and nisoldipine-sensitive. Phorbol myristate acetate (PMA, 10 nM), a protein kinase C activator, also evoked a two- to threefold stimulation of 45Ca2+ transport and HRP and DG uptake. This PMA effect was abolished by DFMO, suggesting involvement of rapid, ODC-controlled polyamine synthesis.(ABSTRACT TRUNCATED AT 250 WORDS)