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Oscillation of gap junction electrical coupling in the mouse pancreatic islets of Langerhans.
1. Pancreatic beta-cells oscillate synchronously when grouped in islets. Coupling seems essential to maintain this oscillatory behaviour, as isolated cells are unable to oscillate. This allows the islet to be used as a model system for studying the role of coupling in the generation of oscillatory patterns. 2. Pairs of beta-cells were intracellularly recorded in islets. beta-Cells oscillated synchronously. Propagated voltage deflections were observed as a function of glucose concentration and of the distance between the recording electrodes. Space constants were smaller in the silent than in the active phases, suggesting a higher intercellular connection in the active phases. 3. Coupling coefficients and estimated coupling conductances were larger in the active than in the silent phases. 4. Coupling coefficients and coupling conductances changed dynamically and in phase with the membrane potential oscillations, pointing to an active modulation of the gap junctions. 5. We hypothesize a role for coupling in the generation of the oscillatory events, providing different levels of permeability dependent on the state of conductance during the oscillatory phases.
Adverse effects of acid rain on the distribution of the Wood Thrush Hylocichla mustelina in North America.
Research into population declines of North American bird species has mainly focused on the fragmentation of habitat on the breeding or wintering grounds [Robinson, S. K., Thompson, F. R., Donovan, T. M., Whitehead, D. R. & Faaborg, J. (1995) Science 267, 1987-1990]. In contrast, research into declines of European species has mainly focused on intensification of agriculture [Donald, P. F., Green, R. E. & Heath, M. F. (2001) Proc. R. Soc. London Ser. B 268, 25-29] and the role played by the atmospheric deposition of pollutants, in particular, acid rain [Graveland, J. (1998) Environ. Rev. 6, 41-54]. However, despite widespread unexplained declines of bird populations in regions of heavy wet acid ion deposition [Sauer, J. R., Hines, J. E. & Fallon, J. (2001) The North American Breeding Bird Survey Results and Analysis 1966-2000 (Patuxent Wildlife Research Center, Laurel, MD)], no North American studies have presented evidence linking such widespread terrestrial bird declines to acid rain. To address the question of the role played by acid rain in population declines of eastern North American songbird species, we combine data from several sources. We use a multiple logistic regression model to test for adverse effects of acid rain on the Wood Thrush, while controlling for regional abundance, landscape-level habitat fragmentation, elevation, soil pH, and vegetation. We show a strong, highly significant, negative effect of acid rain on the predicted probability of breeding by this species, and interactions with elevation, low pH soils, and habitat fragmentation that worsen these negative effects. Our results suggest an important role for acid rain in recent declines of some birds breeding in the eastern United States, particularly in high elevation zones with low pH soils, and show the need to consider other large-scale influences, in addition to habitat fragmentation, when addressing bird population declines.
Molecular epidemiology of foodborne hepatitis a outbreaks in the United States, 2003.
BACKGROUND: Molecular epidemiologic investigations can link geographically separate foodborne hepatitis A outbreaks but have not been used while field investigations are in progress. In 2003, outbreaks of foodborne hepatitis A were reported in multiple states. METHODS: Case-control studies were conducted in 3 states. Hepatitis A virus was sequenced from serologic specimens from individuals associated with outbreaks and from individuals concurrently ill with hepatitis A in non-outbreak settings in the United States and Mexico. RESULTS: Case-control studies in Tennessee (TN), North Carolina (NC), and Georgia (GA) found green onions to be associated with illness among restaurant patrons (TN: odds ratio [OR], 65.5 [95% confidence interval {CI}, 8.9-482.5; NC: OR, 2.4 [95% CI, 0.3-21.9]; GA: OR, 20.9 [95% CI, 3.9-110.3]). Viral sequences from TN case patients differed by 2 nt, compared with those from case patients in NC and GA. A third sequence, differing from the TN and GA/NC sequences by 1 nt, was identified among case patients in a subsequent outbreak in Pennsylvania. Each outbreak sequence was identical to > or =1 sequence isolated from northern Mexican resident(s) with hepatitis A. The sources of green onions served in restaurants in TN and GA were 3 farms in northern Mexico. CONCLUSIONS: Ongoing viral strain surveillance facilitated the rapid implementation of control measures. Incorporation of molecular epidemiologic methods into routine hepatitis A surveillance would improve the detection of hepatitis A outbreaks and increase our understanding of hepatitis A epidemiology in the United States.
Ethnic/racial misidentification in death: a problem which may distort suicide statistics.
Since the majority of suicide studies are ex post facto studies of demographic data collected by pathologists anc coroner's investigators, the role of the forensic scientist in determining the accuracy of statistical analyses of death is extremely important. This paper discusses how two salient features of a decedent, surname and residence location, can be misleading in determining the ethnic/racial classification of the decreased. Because many Southern California Indians have Spanish Surnames and most do not reside on an Indian reservation it is shown that the suicide statistics may represent an over-estimation of actual Mexican-American suicidal deaths while simultaneously representing an under-estimation of the suicides among American Indians of the region.
SOL-1 is an auxiliary subunit that modulates the gating of GLR-1 glutamate receptors in Caenorhabditis elegans.
Most rapid excitatory synaptic signaling in the brain is mediated by postsynaptic ionotropic glutamate receptors (iGluRs) that are gated open by the neurotransmitter glutamate. In Caenorhabditis elegans, sol-1 encodes a CUB-domain transmembrane protein that is required for currents that are mediated by the GLR-1 iGluR. Mutations in sol-1 do not affect GLR-1 expression, localization, membrane insertion, or stabilization at synapses, suggesting that SOL-1 is required for iGluR function. Here, we provide evidence that SOL-1 is an auxiliary subunit that modulates the gating of GLR-1 receptors. We show that mutant variants of GLR-1 with altered gating partially restore glutamate-gated current and GLR-1-dependent behaviors in sol-1 mutants. Domain analysis of SOL-1 indicates that extracellular CUB domain 3 is required for function and that a secreted variant partially restores glutamate-gated currents and behavior. Also, we show that endogenous glutamatergic synaptic currents are absent in sol-1 mutants. Our data suggest that GLR-1 iGluRs are not simply stand-alone molecules and require the SOL-1 auxiliary protein to promote the open state of the receptor. Our analysis presents the possibility that glutamatergic signaling in other organisms may be similarly modified by SOL-1-like transmembrane proteins.
Reduced global cooperativity is a common feature underlying the amyloidogenicity of pathogenic lysozyme mutations.
One of the 20 or so human amyloid diseases is associated with the deposition in vital organs of full-length mutational variants of the antibacterial protein lysozyme. Here, we report experimental data that permit a detailed comparison to be made of the behaviour of two of these amyloidogenic variants, I56T and D67H, under identical conditions. Hydrogen/deuterium exchange experiments monitored by NMR and mass spectrometry reveal that, despite their different locations and the different effects of the two mutations on the structure of the native state of lysozyme, both mutations cause a cooperative destabilisation of a remarkably similar segment of the structure, comprising in both cases the beta-domain and the adjacent C-helix. As a result, both variant proteins populate transiently a closely similar, partially unstructured intermediate in which the beta-domain and the adjacent C-helix are substantially and simultaneously unfolded, whereas the three remaining alpha-helices that form the core of the alpha-domain still have their native-like structure. We show, in addition, that the binding of a camel antibody fragment, cAb-HuL6, which was raised against wild-type lysozyme, restores to both variant proteins the stability and cooperativity characteristic of the wild-type protein; as a consequence, it inhibits the formation of amyloid fibrils by both variants. These results indicate that the reduction in global cooperativity, and the associated ability to populate transiently a specific, partly unfolded intermediate state under physiologically relevant conditions, is a common feature underlying the behaviour of these two pathogenic mutations. The formation of intermolecular interactions between lysozyme molecules that are in this partially unfolded state is therefore likely to be the fundamental trigger of the aggregation process that ultimately leads to the formation and deposition in tissue of amyloid fibrils.
Protein tyrosine phosphatases in T cell physiology.
The molecular mechanisms of signal transduction have been the focus of intense research during the last decade. In T cells, much of the work has centered on protein tyrosine kinase-mediated signaling from the TCR and cytokine receptors, while the study of protein tyrosine phosphatases has lagged behind. Nevertheless, it has now become clear that many protein tyrosine phosphatases play equally important roles in T cell physiology and that no kinase-regulated system would work without the counterbalancing participation of phosphatases. In fact, we have learned that many processes are regulated primarily on the phosphatase side. This minireview summarizes the current state-of-the art in our understanding of the regulation and biology of protein tyrosine phosphatases in T lymphocyte physiology.
Lack of SARS transmission and U.S. SARS case-patient.
In early April 2003, severe acute respiratory syndrome (SARS) was diagnosed in a Pennsylvania resident after his exposure to persons with SARS in Toronto, Canada. To identify contacts of the case-patient and evaluate the risk for SARS transmission, a detailed epidemiologic investigation was performed. On the basis of this investigation, 26 persons (17 healthcare workers, 4 household contacts, and 5 others) were identified as having had close contact with this case-patient before infection-control practices were implemented. Laboratory evaluation of clinical specimens showed no evidence of transmission of SARS-associated coronavirus (SARS-CoV) infection to any close contact of this patient. This investigation documents that, under certain circumstances, SARS-CoV is not readily transmitted to close contacts, despite ample unprotected exposures. Improving the understanding of risk factors for transmission will help focus public health control measures.
Acellular mineral deposition in collagen-based biomaterials incubated in cell culture media.
Rapid developments in tissue engineering have renewed interest in biodegradable three-dimensional structures such as collagen-based biomaterials. Collagen matrices seeded in vitro with fibroblasts, osteoblasts, and chondrocytes can form tissues resembling skin, bone, and cartilage that could be used as functional substitutes for damaged tissues. Collagen is associated with both dystrophic calcification of collagenous implants and bone mineralization. We report here the calcification properties of collagen sponges incubated in cell-free media. Mineral deposited in sponges was identified by X-ray and electron diffraction, Fourier transform infrared spectroscopy, and the molar ratio of calcium:phosphorus (Ca:P) as a poorly crystalline apatite similar to bone. The degree of calcification increased with length of incubation and the Ca and P content of the media, with 10-15% Ca (dry weight) after 21 days' incubation in media containing 1.6-3 mM Ca and a Ca x P molar product of 2-3 mM(2), but only 2% Ca after incubation in medium with 1.33 mM Ca and a 1.7 mM(2) Ca x P molar product. Mineral deposition was completely inhibited in sponges that were washed extensively and initially contained less than 0.01% P. Readdition of phosphate in these sponges and subsequent freeze drying and sterilization restore their mineralization capacity, suggesting that collagen per se cannot initiate calcification and that the inorganic phosphate content associated with the collagen preparation process is in the solid state a potential nucleator. Addition of chondroitin 4-sulfate to the sponges partially or totally inhibited mineral deposition, even though 80-90% of the compound was released within 24 hours. These results indicate that acellular calcification of collagen-based biomaterials can occur under the culture conditions currently used in tissue engineering.
The Gabriella Miller Kids First Data Resource for genomic research in pediatric cancer and congenital anomalies.
Nine-year-old brain tumor patient Gabriella Miller challenged members of Congress to "stop talking and start doing" when providing federal funding for research into cures for pediatric cancer and congenital anomalies. Though she ultimately lost her life to that cancer, her advocacy efforts resulted in the 2014 Gabriella Miller Kids First Research Act, launching the Gabriella Miller Kids First Pediatric Research Program at the National Institutes of Health (NIH). The overarching goal of the Gabriella Miller Kids First Pediatric Research Program is to help researchers uncover new insights into the biology of childhood cancer and congenital anomalies. Following the signing of the Gabriella Miller Kids First Research Act 2.0 in January 2025, the program has been extended at NIH through 2028 to advance the groundwork laid in the program's first ten years. The Gabriella Miller Kids First Data Resource Center has since honored her legacy by building a comprehensive data resource for genomic research into pediatric conditions. Data from more than 30,000 participants annotated with demographic and clinical information related to their diagnoses have been released for secondary research and analysis using the center's web-based platforms. This paper analyzes the outcomes of the initiative and highlights breakthroughs made by the larger research community resulting from the availability of this data resource. We explore the future expansion of the data resource to include new modalities and tools for supporting life-saving research for children like Gabriella Miller.
Results of a prospective study of acute liver failure at 17 tertiary care centers in the United States.
BACKGROUND: Because acute liver failure is rare, related data have been sparse. Studies have suggested that viral hepatitis is the most common underlying cause of this condition. OBJECTIVE: To describe the clinical features, presumed causes, and short-term outcomes of acute liver failure. DESIGN: Prospective cohort study. SETTING: 17 tertiary care centers participating in the U.S. Acute Liver Failure Study Group. PATIENTS: 308 consecutive patients with acute liver failure, admitted over a 41-month period. MEASUREMENTS: Detailed clinical and laboratory data collected during hospitalization, including outcome 3 weeks after study admission. RESULTS: 73% of patients were women; median age was 38 years. Acetaminophen overdose was the most common apparent cause of acute liver failure, accounting for 39% of cases. Idiosyncratic drug reactions were the presumptive cause in 13% of cases, viral hepatitis A and B combined were implicated in 12% of cases, and 17% of cases were of indeterminate cause. Overall patient survival at 3 weeks was 67%. Twenty-nine percent of patients had liver transplantation, and 43% survived without transplantation. Short-term transplant-free survival varied greatly, from 68% for patients with acetaminophen-related liver failure to 25% and 17% for those with other drug reactions and liver failure of indeterminate cause, respectively. Coma grade at admission appeared to be associated with outcome, but age and symptom duration did not. CONCLUSIONS: Acetaminophen overdose and idiosyncratic drug reactions have replaced viral hepatitis as the most frequent apparent causes of acute liver failure. Apparent cause and coma grade at admission were associated with outcome. Although transplantation may improve patient survival, it was unavailable or unnecessary for most patients.
Predictors of progression from impaired glucose tolerance to NIDDM: an analysis of six prospective studies.
Risk factors associated with the progression from impaired glucose tolerance (IGT) to NIDDM were examined in data from six prospective studies. IGT and NIDDM were defined in all studies by World Health Organization (WHO) criteria, and baseline risk factors were measured at the time of first recognition of IGT. The studies varied in size from 177 to 693 participants with IGT, and included men and women followed from 2 to 27 years after the recognition of IGT. Across the six studies, the incidence rate of NIDDM was 57.2/1,000 person-years and ranged from 35.8/1,000 to 87.3/1,000 person-years. Although baseline measures of fasting and 2-h postchallenge glucose levels were both positively associated with NIDDM incidence, incidence rates were sharply higher for those in the top quartile of fasting plasma glucose levels, but increased linearly with increasing 2-h postchallenge glucose quartiles. Incidence rates were higher among the Hispanic, Mexican-American, Pima, and Nauruan populations than among Caucasians. The effect of baseline age on NIDDM incidence rates differed among the studies; the rates did not increase or rose only slightly with increasing baseline age in three of the studies and formed an inverted U in three studies. In all studies, estimates of obesity (including BMI, waist-to-hip ratio, and waist circumference) were positively associated with NIDDM incidence. BMI was associated with NIDDM incidence independently of fasting and 2-h post challenge glucose levels in the combined analysis of all six studies and in three cohorts separately, but not in the three studies with the highest NIDDM incidence rates. Sex and family history of diabetes were generally not related to NIDDM progression. This analysis indicates that persons with IGT are at high risk and that further refinement of risk can be made by other simple measurements. The ability to identify persons at high risk of NIDDM should facilitate clinical trials in diabetes prevention.
Tandem function of nucleotide binding domains confers competence to sulfonylurea receptor in gating ATP-sensitive K+ channels.
Fundamental to the metabolic sensor function of ATP-sensitive K(+) (K(ATP)) channels is the sulfonylurea receptor. This ATP-binding cassette protein, which contains nucleotide binding domains (NBD1 and NBD2) with conserved Walker motifs, regulates the ATP sensitivity of the pore-forming Kir6.2 subunit. Although NBD2 hydrolyzes ATP, a property essential in K(ATP) channel gating, the role of NBD1, which has limited catalytic activity, if at all, remains less understood. Here, we provide functional evidence that cooperative interaction, rather than the independent contribution of each NBD, is critical for K(ATP) channel regulation. Gating of cardiac K(ATP) channels by distinct conformations in the NBD2 ATPase cycle, induced by gamma-phosphate analogs, was disrupted by point mutation not only of the Walker motif in NBD2 but also in NBD1. Cooling membrane patches to decelerate the intrinsic ATPase activity counteracted ATP-induced K(ATP) channel inhibition, an effect that mimicked stabilization of the MgADP-bound posthydrolytic state at NBD2 by the gamma-phosphate analog orthovanadate. Temperature-induced channel activation was abolished by mutations that either prevent stabilization of MgADP at NBD2 or ATP at NBD1. These findings provide a paradigm of K(ATP) channel gating based on integration of both NBDs into a functional unit within the multimeric channel complex.
[Role of the hemostasis laboratory in the etiologic approach to deep vein thrombosis].
Thrombophilia is characterized by an inherited or acquired defect in the blood coagulation pathway leading to an increased risk for thrombosis. The etiological approach following confirmed venous thrombotic events should rule out medical or chirurgical risk factors. Thrombophilia should be sought by laboratory tests. The recent discovery of a blood coagulation defect: inherited resistance to activated protein C which is found to 20% of patients with former thrombotic events has changed current laboratory approach. Deficiencies of one of the anticoagulant proteins (antithrombin III, protein C, protein S) are found in 10% of the patients, similar to the frequency of antiphospholipid antibodies. These tests may be difficult to interpret immediately after the thrombotic event because of various factors such as inflammatory states or anticoagulant treatments. Therefore this abnormal tests should be confirmed on a later sample analysis far from the event. The discovery of an inherited blood coagulation pathway defect may affect the duration of treatment, prophylaxis in situations with circumstantial risk factors and requires familial analysis. Inherited resistance to activated protein C may be associated with another inherited defect leading to an increased risk for thrombosis.
The nucleotide sequence of Saccharomyces cerevisiae chromosome IV.
The complete DNA sequence of the yeast Saccharomyces cerevisiae chromosome IV has been determined. Apart from chromosome XII, which contains the 1-2 Mb rDNA cluster, chromosome IV is the longest S. cerevisiae chromosome. It was split into three parts, which were sequenced by a consortium from the European Community, the Sanger Centre, and groups from St Louis and Stanford in the United States. The sequence of 1,531,974 base pairs contains 796 predicted or known genes, 318 (39.9%) of which have been previously identified. Of the 478 new genes, 225 (28.3%) are homologous to previously identified genes and 253 (32%) have unknown functions or correspond to spurious open reading frames (ORFs). On average there is one gene approximately every two kilobases. Superimposed on alternating regional variations in G+C composition, there is a large central domain with a lower G+C content that contains all the yeast transposon (Ty) elements and most of the tRNA genes. Chromosome IV shares with chromosomes II, V, XII, XIII and XV some long clustered duplications which partly explain its origin.
PHYSIOLAB: a cardiovascular laboratory.
PHYSIOLAB is a cardio-vascular laboratory designed by CNES in cooperation with IMBP, with double scientific and medical goals: -a better understanding of the basic mechanisms involved in blood pressure and heart rate regulation, in order to predict and control the phenomenon of cardio-vascular deconditionning. -a real-time monitoring of cosmonauts during functional tests. Launched to the MIR station in 1996, this laboratory was set up and used for the first time by Claudie Andre-Deshays during the French mission "Cassiopeia". The scientific program is performed pre, post and in-flight to study phenomena related to the transition to microgravity as well as the return to the earth conditions. Particular emphasis was placed on the development of the real-time telemetry to monitor LBNP test. This function was successful during the Cassiopeia mission, providing the medical team at TSOUP (MIR Control Center in Moscow) with efficient means to control the physiological state of the cosmonaut. Based on the results of this first mission, IMBP and CNES will go on using Physiolab with Russian crews. CNES will take advantage of the upcoming French missions on MIR to improve the system, and intends to develop a new laboratory for the International Space Station.
Hormone-dependent nuclear localization of the tyrosine kinase iyk in the normal human breast epithelium and loss of expression during carcinogenesis.
iyk, a member of the frk family of non-receptor tyrosine kinases, was originally isolated from normal mouse mammary glands and is characterized by a nuclear localizing signal within the SH2 domain. We have investigated the expression and subcellular localization of iyk in the normal human breast and in malignant breast diseases. Immuno-histochemical analyses revealed that in normal tissue iyk localizes to both cytoplasmic and nuclear compartments of breast epithelial cells. The subcellular distribution was dependent on the hormonal state, being mostly cytoplasmic during the follicular, proliferative phase of the menstrual cycle, whereas frequent nuclear staining was observed in the resting stages during the luteal phase and, most prominently, after menopause. Strikingly, invasive carcinomas, irrespective of tumor type or hormonal status of the patient, exhibited almost complete loss of iyk expression in both the cytoplasm and the nucleus. In contrast, in situ breast carcinomas from post-menopausal patients showed a clear reduction of the nuclear iyk localization while retaining cytoplasmic staining. Our results indicate that iyk expression is gradually lost during carcinogenesis; thus, iyk may be classified as a tumor-suppressor gene.