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PubMed2005

Some factors affecting reproductive success in crossbred dairy cows on smallholder farms in coastal north-east Tanzania.

A 2-year longitudinal survey was carried out to investigate factors affecting reproduction in crossbred cows on smallholder farms in and around an urban centre. Sixty farms were visited at approximately 2-week intervals and details of reproductive traits and body condition score (BCS) were collected. Fifteen farms were within the town (U), 23 farms were approximately 5 km from town (SU). and 22 farms approximately 10 km from town (PU). Sources of variation in reproductive traits were investigated using a general linear model (GLM) by a stepwise forward selection and backward elimination approach to judge important independent variables. Factors considered for the first step of formulation of the model included location (PU, SU and U), type of insemination, calving season, BCS at calving, at 3 months postpartum and at 6 months postpartum, calving year, herd size category, source of labour (hired and family labour), calf rearing method (bucket and partial suckling) and parity number of the cow. The effects of the independent variables identified were then investigated using a non-parametric survival technique. The number of days to first oestrus was increased on the U site (p = 0.045) and when family labour was used (p = 0.02). The non-parametric test confirmed the effect of site (p = 0.059), but effect of labour was not significant. The number of days from calving to conception was reduced by hiring labour (p = 0.003) and using natural service (p = 0.028). The non-parametric test confirmed the effects of type of insemination (p = 0.0001) while also identifying extended calving intervals on U and SU sites (p = 0.014). Labour source was again non-significant. Calving interval was prolonged on U and SU sites (p = 0.021), by the use of AI (p = 0.031) and by the use of family labour (p = 0.001). The nonparametric test confirmed the effect of site (p = 0.008) and insemination type (p > 0.0001) but not of labour source. It was concluded that under favourable conditions (PU site, hired labour and natural service) calving intervals of around 440 days could be achieved.

Animal Husbandry↗

PubMed1996

Dynamic remodeling of nuclear architecture during the cell cycle.

The nuclear matrix is an integral part of nuclear structure which undergoes a profound reorganization during the cell cycle reflecting major changes in functional requirements. This includes the processes of DNA replication and gene expression at interphase and partitioning of the nuclear contents during mitosis. Using a monoclonal antibody (mAb2A) which specifically stains a novel nuclear meshwork which reorganizes during the cell cycle in Drosophila, we have initiated a study to: 1) more closely analyze this structural reorganization; 2) clone and characterize the antigens recognized by this antibody; and 3) isolate other interacting proteins in order to gain insight into the regulation of this process. The mAb2A-labeled structure changes from what appears as a diffuse meshwork at interphase to a distinct spindle-like scaffold at prophase. Since at metaphase the microtubules of the mitotic apparatus co-localize with the mAb2A spindle structure, a model is considered whereby the nuclear mAb2A-labeled scaffolding reorganizes during the cell cycle to provide a guide for the establishment of the mitotic apparatus. The mAb2A has identified two separate antigens, each of which shows similar distribution patterns. One of these antigens has been partially cloned and contains an unusual tandem ser-thr kinase domain. The association of this kinase homologue with a nuclear scaffold which reorganizes during the cell cycle suggests that it may be involved in regulating changes in nuclear architecture during the cell cycle and/or in mediating the downstream consequences of such changes.

Animals↗

PubMed1981

Pancreatic secretions as a clue to the presence of pancreatic cancer.

Pancreatic secretory function is abnormal in at least 90% of patients with pancreatic cancer. These abnormalities may be due to direct involvement of the secretory cells by the malignant process and/or the effects of pancreatic duct obstruction. There is no specific stimulus (secretin and/or cholecystokinin, CCK, or CCK-like hormones) of pancreatic secretion that is clearly superior to any other as a test of pancreatic function. Pancreatic secretion is abnormal in animal models of pancreatic cancer and secretory abnormalities antedate the histologic appearance of the cancer. A decrease in protein secretion after CCK stimulation is the most significant finding in experimental partial pancreatic duct obstruction (the condition most commonly seen in pancreatic cancer). In the absence of any identifiable high-risk group within the population, it is unlikely that the testing of pancreatic function provides a means for the earlier diagnosis of pancreatic cancer.

Animals↗

PubMed2002

Lifestyle interference and emotional distress in family caregivers of advanced cancer patients.

BACKGROUND: Providing end-of-life care at home to a family member with advanced cancer can have a negative impact on the emotional well-being of the family caregiver. The current study examined the impact of providing care on lifestyle and emotional well-being in a sample of caregivers to patients with advanced cancer. The mediation of lifestyle interference between the amount of care provided and emotional distress was specifically examined. METHODS: Forty-four family caregivers participated in a structured quantitative interview. Lifestyle interference was assessed by the Caregiving Impact Scale, amount of care provided was assessed by the Caregiver Assistance Scale, and emotional distress was assessed by the Profile of Mood States-Short Form. Pearson and partial correlations tested whether lifestyle interference mediated the relationship between caregiving assistance and emotional distress. Regression analyses determined overall correlates of emotional distress. RESULTS: Three criteria, required to substantiate mediation, were met for total mood disturbance and the depression and tension subscales. An overall regression model identified education level and lifestyle interference to be significant and unique correlates of emotional distress. CONCLUSIONS: The current results suggest that caregivers experience increased emotional distress, regardless of the amount of care provided, when limited in their ability to participate in valued activities and interests. In addition, caregivers with less than a high school education experience more emotional distress. Therefore, helping caregivers maintain valued aspects of their lifestyle should be an important element of home care.

Activities of Daily Living↗

PubMed2001

Homologues to the first gene for autosomal dominant polycystic kidney disease are pseudogenes.

PKD1 is the first gene identified to be causative for the condition of autosomal dominant polycystic kidney disease. There are several genes homologous to PKD1 that are located proximal to the master gene on the same chromosome. Two of these genes have been recently covered in a large sequencing work on chromosome 16, and their structure has been broadly analyzed. However, the major question whether homologous genes (HG) code for functionally active polypeptides has not been resolved so far. The current study identifies and partially characterizes four more homologues of PKD1, different from the previously published sequence, two of which were found by screening of a BAC library and the other two contained in available databases. Analysis of HG transcripts shows that they are not translated in the model cell line T98G. Taken together, these findings suggest that homologues to PKD1 form a family of pseudogenes.

Base Sequence↗

PubMed1991

Suppression of low dose streptozotocin induced diabetes in mice by administration of a nitric oxide synthase inhibitor.

Nitric oxide has recently been identified as the primary toxic effector molecule in the lysis of islet cells by inflammatory macrophages. We show here that N-nitro-L-arginine-methylester (NAME), an inhibitor of endothelial and macrophage NO synthase partially suppresses diabetes development in the low dose streptozotocin induced diabetes model in C57BL/6J mice. Mean blood glucose levels were lower in the group receiving NAME throughout the observation period of 30d (p less than 0.05-0.001). Similar concentrations of NAME as expected in vivo were tested in vitro in macrophage-islet cell cocultures and were found to partially suppress NO production and islet cell lysis. We conclude that NO synthase activity is a pathogenetic factor in diabetes development.

Amino Acid Oxidoreductases↗

PubMed2004

Study of a loop heat pipe using neutron radiography.

An explanation is given of what a loop heat pipe (LHP) is, and how it works. It is then shown that neutron imaging (both real time neutron radioscopy and single exposure neutron radiography) is an effective experimental tool for the study of LHPs. Specifically, neutron imaging has helped to identify and correct a cooling water distribution problem in the condenser, and has enabled visualization of two-phase flow (liquid and vapor) in various components of the LHP. In addition, partial wick dry-out, a phenomenon of great importance in the effective operation of LHPs, is potentially identifiable with neutron imaging. It is anticipated that neutron radioscopy and radiography will greatly contribute to our understanding of LHP operation, and will lead to improvement of LHP modeling and design.

Journal Article↗

PubMed2003

Drug recognition and stabilisation of the parallel-stranded DNA quadruplex d(TTAGGGT)4 containing the human telomeric repeat.

The NMR structure of the parallel-stranded DNA quadruplex d(TTAGGGT)(4), containing the human telomeric repeat, has been determined in solution in complex with a fluorinated pentacyclic quino[4,3,2-kl]acridinium cation (RHPS4). RHPS4 has been identified as a potent inhibitor of telomerase at submicromolar levels (IC(50) value of 0.33(+/-0.13)microM), exhibiting a wide differential between telomerase inhibition and acute cellular toxicity. All of the data point to RHPS4 exerting its chemotherapeutic potency through interaction with, and stabilisation of, four-stranded G-quadruplex structures. RHPS4 forms a dynamic interaction with d(TTAGGGT)(4), as evident from 1H and 19F linewidths, with fast exchange between binding sites induced at 318 K. Perturbations to DNA chemical shifts and 24 intermolecular nuclear Overhauser effects (NOEs) identify the 5'-ApG and 5'-GpT steps as the principle intercalation sites; a structural model has been refined using NOE-restrained molecular dynamics. The central G-tetrad core remains intact, with drug molecules stacking at the ends of the G-quadruplex. The partial positive charge on position 13-N of the acridine ring appears to act as a "pseudo" potassium ion and is positioned above the centre of the G-tetrad in the region of high negative charge density. In both ApG and GpT intercalation sites, the drug is seen to converge to the same orientation in which the pi-system of the drug overlaps primarily with two bases of each G-tetrad. The drug is held in place by stacking interactions with the G-tetrads; however, there is some evidence for a more dynamic, weakly stabilised A-tetrad that stacks partially on top of the drug at the 5'-end of the sequence. Together, the interactions of RHPS4 increase the t(m) of the quadruplex by approximately 20 degrees C. There is no evidence for drug intercalation within the G-quadruplex; however, the structural model strongly supports end-stacking interactions with the terminal G-tetrads.

Acridines↗

PubMed2006

A structural core within apolipoprotein C-II amyloid fibrils identified using hydrogen exchange and proteolysis.

Plasma apolipoproteins show alpha-helical structure in the lipid-bound state and limited conformational stability in the absence of lipid. This structural instability of lipid-free apolipoproteins may account for the high propensity of apolipoproteins to aggregate and accumulate in disease-related amyloid deposits. Here, we explore the properties of amyloid fibrils formed by apolipoproteins using human apolipoprotein (apo) C-II as a model system. Hydrogen-deuterium exchange and NMR spectroscopy of apoC-II fibrils revealed core regions between residues 19-37 and 57-74 with reduced amide proton exchange rates compared to monomeric apoC-II. The C-terminal core region was also identified by partial proteolysis of apoC-II amyloid fibrils using endoproteinase GluC and proteinase K. Complete tryptic hydrolysis of apoC-II fibrils followed by centrifugation yielded a single peptide in the pellet fraction identified using mass spectrometry as apoC-II(56-76). Synthetic apoC-II(56-76) readily formed fibrils, albeit with a different morphology and thioflavinT fluorescence yield compared to full-length apoC-II. Studies with smaller peptides narrowed this fibril-forming core to a region within residues 60-70. We postulate that the ability of apoC-II(60-70) to independently form amyloid fibrils drives fibril formation by apoC-II. These specific amyloid-forming regions within apolipoproteins may underlie the propensity of apolipoproteins and their peptide derivatives to accumulate in amyloid deposits in vivo.

Amino Acid Motifs↗

PubMed2004

Initial study of honey adulteration by sugar solutions using midinfrared (MIR) spectroscopy and chemometrics.

Fourier transform infrared (FTIR) spectroscopy and attenuated total reflection (ATR) sampling have been used to detect adulteration of honey samples. The sample set comprised 320 spectra of authentic (n = 99) and adulterated (n = 221) honeys. Adulterants used were solutions containing both d-fructose and d-glucose prepared in the following respective weight ratios: 0.7:1.0, 1.2:1.0 (typical of honey composition), and 2.3:1.0. Each adulterant solution was added to individual honeys at levels of 7, 14, and 21% w/w. Spectral data were compressed and analyzed using k-nearest neighbors (kNN) and partial least squares (PLS) regression techniques. A number of data pretreatments were explored. Best classification models were achieved with PLS regression on first derivative spectra giving an overall correct classification rate of 93%, with 99% of samples adulterated at levels of 14% w/w or greater correctly identified. This method shows promise as a rapid screening technique for detection of this type of honey adulteration.

Carbohydrates↗

PubMed1996

A genome-wide search for chromosomal loci linked to bipolar affective disorder in the Old Order Amish.

The most characteristic features of bipolar affective disorder (manic-depressive illness) are episodes of mania (bipolar I, BPI) or hypomania (bipolar II, BPII) interspersed with periods of depression. Manic-depressive illness afflicts about one percent of the population, and if untreated, is associated with an approximately 20% risk of suicide. Twin, family and adoption studies provide compelling evidence for a partial genetic aetiology, but the mode(s) of inheritance has not been identified. Nonetheless, the majority of genetic linkage studies have assumed classical mendelian inheritance attributable to a single major gene. Although segregation analyses have yielded inconsistent results (with most studies rejecting a single locus inheritance model), the best single gene model is dominant inheritance if only BPI is considered. Reported linkages of bipolar affective disorder on chromosomes 11, 18, 21 and X have been difficult to substantiate, and additional studies are required for replication or exclusion of these regions. We now present the results of our genome-wide linkage analyses that provide evidence that regions on chromosomes 6, 13 and 15 harbour susceptibility loci for bipolar affective disorder, suggesting that bipolar affective disorder in the Old Order Amish is inherited as a complex trait.

Alleles↗

PubMed2001

Competence development by Haemophilus influenzae is regulated by the availability of nucleic acid precursors.

DNA uptake by naturally competent bacteria provides cells with both genetic information and nucleotides. In Haemophilus influenzae, competence development requires both cAMP and an unidentified signal arising under starvation conditions. To investigate this signal, competence induction was examined in media supplemented with nucleic acid precursors. The addition of physiological levels of AMP and GMP reduced competence 200-fold and prevented the normal competence-induced transcription of the essential competence genes comA and rec-2. The rich medium normally used for growth allows only limited competence. Capillary electrophoresis revealed only a subinhibitory amount of AMP and no detectable GMP, and the addition of AMP or GMP to this medium also reduced competence 20- to 100-fold. Neither a functional stringent response system nor a functional phosphoenolpyruvate:glycose phosphotransferase system (PTS) was found to be required for purine-mediated repression. Added cAMP partially restored both transcription of competence genes and competence development, suggesting that purines may reduce the response to cAMP. Potential binding sites for the PurR repressor were identified in several competence genes, suggesting that competence is part of the PUR regulon. These observations are consistent with models of competence regulation, in which depleted purine pools signal the need for nucleotides, and support the hypothesis that competence evolved primarily for nucleotide acquisition.

Adenosine Monophosphate↗

PubMed2000

Murine guanylate-binding protein: incomplete geranylgeranyl isoprenoid modification of an interferon-gamma-inducible guanosine triphosphate-binding protein.

Farnesylation of Ras proteins is necessary for transforming activity. Although farnesyl transferase inhibitors show promise as anticancer agents, prenylation of the most commonly mutated Ras isoform, K-Ras4B, is difficult to prevent because K-Ras4B can be alternatively modified with geranylgeranyl (C20). Little is known of the mechanisms that produce incomplete or inappropriate prenylation. Among non-Ras proteins with CaaX motifs, murine guanylate-binding protein (mGBP1) was conspicuous for its unusually low incorporation of [(3)H]mevalonate. Possible problems in cellular isoprenoid metabolism or prenyl transferase activity were investigated, but none that caused this defect was identified, implying that the poor labeling actually represented incomplete prenylation of mGBP1 itself. Mutagenesis indicated that the last 18 residues of mGBP1 severely limited C20 incorporation but, surprisingly, were compatible with farnesyl modification. Features leading to the expression of mutant GBPs with partial isoprenoid modification were identified. The results demonstrate that it is possible to alter a protein's prenylation state in a living cell so that graded effects of isoprenoid on function can be studied. The C20-selective impairment in prenylation also identifies mGBP1 as an important model for the study of substrate/geranylgeranyl transferase I interactions.

Alkyl and Aryl Transferases↗

PubMed2005

Lessons for glaucoma from other neurodegenerative diseases: can one treatment suit them all?

The past decade has seen growing acceptance that glaucoma should be viewed as a slowly progressive neurodegenerative disease. According to this view, in glaucoma (as in other such diseases), whatever the primary risk factors, at any given time some neurons are still healthy but are threatened with destruction owing to the toxicity emanating from the degenerating neurons. It follows that any intervention that protects surviving neurons and rescues the marginally damaged ones should slow down progression of the disease. This novel view of glaucoma prompted scientists to compare glaucoma with other neurodegenerative diseases with respect to mediators of disease progression and ways in which the spread of damage, or 'secondary degeneration', can be attenuated. Studies of partial crush injury of the rat optic nerve, a model of secondary degeneration established in our laboratory, led us to conceptualize the 'enemy within' as a flood of neurotoxic self-compounds issuing from the degenerating nerve. With this model, pharmacological and molecular approaches were employed to identify and test potentially therapeutic neuroprotective compounds and methodologies, leading us ultimately to the serendipitous discovery of protective autoimmunity as the body's defense against destructive self-compounds. Mediators of self-perpetuating acute and chronic degeneration identified in the injured optic nerve were also detected in other sites of central nervous system (CNS) damage. This finding led scientists to screen drugs that had proven to be beneficial in other disease models for their use in glaucoma therapy. It also opened the way to studies of the direct effects of these toxic mediators on retinal ganglion cell survival and ways to prevent the degenerative outcome. Although no single model can fully simulate human glaucoma or any other neurodegenerative disease, the availability of different models of optic nerve damage and the similarity of findings in the optic nerve and in other parts of the CNS have led to significant progress toward development of a cure for glaucoma.

Animals↗

PubMed2004

A role for semaphorin 3A signaling in the degeneration of hippocampal neurons during Alzheimer's disease.

Among the earliest invariant neuropathological changes in Alzheimer's disease (AD) is the degeneration of vulnerable hippocampal CA1 and subicular pyramidal neurons. Semaphorin 3A (Sema3A) is a secreted protein that functions in signaling growth cone collapse, chemorepulsion and neuronal apoptosis during early development of the central nervous system. In this report we show that accumulation of an internalized form of Sema3A is associated with degeneration of neurons in vulnerable fields of the hippocampus during AD. Accumulation of Sema3A overlaps the appearance of phosphorylated MAP1B and tau in many neurons, suggesting that Sema3A signaling at some level may be coupled to these previously identified cytoskeletal markers of neurodegeneration. Consistent with this, we isolated and partially characterized a multiprotein complex from the hippocampus of patients with AD that contains phosphorylated MAP1B, collapsin-response mediator protein 2 (CRMP-2), Plexins A1 and A2, and a processed form of Sema3A. A model is presented in which aberrant release of Sema3A from expressing neurons in the subiculum during AD results in the internalization and transport of Sema3A from this field to CA1. Within the context of the myriad of potential insults that contribute to Alzheimer's and other neurodegenerative diseases, the bioactivity of Sema3A may contribute either directly to neurodegeneration by inducing neuronal collapse, or indirectly by abrogating the recovery capabilities of adult neurons faced with these insults.

Aged↗

PubMed2025

Homoploid Hybrid Speciation in a Marine Pelagic Fish.

Homoploid hybrid speciation (HHS) is an enigmatic evolutionary process where new species arise through hybridisation of divergent lineages without changes in chromosome number. Although increasingly documented in various taxa and ecosystems, convincing cases of HHS in marine fishes have been lacking. This study presents a possible case of HHS in a pelagic marine fish based on comprehensive genomic, morphological, and ecological analyses. Population genomics, species tree estimation, and tests of introgression and admixture identified three sympatric clusters in Megalaspis cordyla in the western Pacific and the admixed nature of one cluster between the others. Moreover, model-based demographic inference favoured a hybrid speciation scenario over introgression for the origin of the admixed cluster. While contemporary gene flow suggested partial reproductive isolation, examination of occurrence data and ecologically relevant morphological characters suggested ecological differences between the clusters, potentially contributing to the reproductive isolation and niche partitioning in sympatry. The clusters are also morphologically distinguishable and thus can be taxonomically recognised as separate species. The hybrid cluster is restricted to the coasts of Taiwan and Japan, where all three clusters coexist. The parental clusters are additionally found in lower latitudes, where they display non-overlapping distributions. Given the geographical distributions, estimated times of species formation, and patterns of historical demographic changes, we propose that the Pleistocene glacial cycles were the primary driver of HHS in this system. We also develop an ecogeographic model of HHS in marine coastal ecosystems, including a novel hypothesis to explain the initial stages of HHS.

Animals↗

PubMed2006

Proximal 19q trisomy: a new syndrome of morbid obesity and mental retardation.

AIMS: To report on the clinical and metabolic characteristic and the unique chromosomal defect of a mentally retarded and morbidly obese patient. METHODS: A 13-year follow-up, including insulin sensitivity, lipid profile and polysomnography studies and various therapeutic interventions are described. The presence of a supernumerary marker in karyotype preparation was further studied by fluorescence in situ hybridization (FISH). Comparative genomic hybridization (CGH) was used to identify the source of the chromosomal marker. RESULTS: Insulin resistance was found by the homeostatic model assessment (HOMA) and the quantitative insulin sensitivity check index (QUICKI). M-FISH identified euchromatin derived from chromosome 19, and CGH confirmed the FISH results and demonstrated that the supernumerary marker derived from 19q12 to 19q13.2. CONCLUSION: The clinical and metabolic characteristics in association with partial chromosomal trisomy differ our patient from the currently known syndromes of obesity and mental retardation. The metabolic impairments in this case can derive from unbalanced expression of several genes in the 19q12-19q13.2 region, genes that are related to adipose tissue homeostasis and insulin resistance. The clinical and genetic similarities to a previously reported case may suggest that partial 19q trisomy is a new syndrome of obesity and mental retardation.

Adolescent↗

PubMed2000

Corticolimbic interactions associated with performance on a short-term memory task are modified by age.

Aging has been associated with a decline in memory abilities dependent on hippocampal processing. We investigated whether the functional interactions between the hippocampus and related cortical areas were modified by age. Young and old subjects' brain activity was measured using positron emission tomography (PET) while they performed a short-term memory task (delayed visual discrimination) in which they determined which of two successively presented sine-wave gratings had the highest spatial frequency. Behavioral performance was equal for the two groups. Partial least squares (PLS) analysis of PET images identified a hippocampal voxel whose activity was similarly correlated with performance across groups. Using this voxel as a seed, a second PLS analysis identified cortical regions functionally connected to the hippocampus. Quantification of the neural interactions with structural equation modeling suggested that a different hippocampal network supported performance in the elderly. Unlike the neural network engaged by the young, which included prefrontal cortex Brodmann's area (BA) 10, fusiform gyrus, and posterior cingulate gyrus, the network recruited by the old included more anterior areas, i.e., dorsolateral prefrontal cortex (BA 9/46), middle cingulate gyrus, and caudate nucleus. Recruitment of a distinct corticolimbic network for visual memory in the elderly suggests that age-related neurobiological deterioration not only results in focal changes but also in the modification of large-scale network operations.

Adult↗