bluuebunny/crossref_metadata_2025 huggingface dataset:
Diabetes: Rationale for Dipeptidyl Peptidase 4 Inhibitors: A New Class of Oral Agents for the Treatment of Type 2 Diabetes Mellitus
Authors: Campbell R Keith
Published: December 2006

Objective:

To review advances in understanding the pathophysiologic basis of type 2 diabetes mellitus and the pharmacology and mechanism of action of dipeptidyl peptidase 4 (DPP-4) inhibition in correcting the underlying defects in glycemic control.

Data Sources:

Articles were identified through MEDLINE for the period 1966 through November 2006. Abstracts and presentations from the American Diabetes Association Scientific Sessions and the European Association for the Study of Diabetes (2002–2006) were also searched for scientific reports on DPP-4 inhibitors.

Study Selection And Data Extraction:

Abstracts, original clinical and preclinical research reports, and review articles published in the English language were identified for review. Literature discussing glucose regulation, incretin hormones, type 2 diabetes pathophysiology, and DPP-4 inhibition were evaluated and selected based on consideration of their support for the proof of concept, mechanistic and in vivo findings, and timeliness.

Data Synthesis:

The search for new and effective therapies for type 2 diabetes has led to the identification of a novel therapeutic target, the incretin hormones, which play a role in mediating glucose homeostasis via effects on glucagon and insulin secretion from pancreatic islet α- and β-cells, respectively. The incretins' glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide are rapidly inactivated by the enzyme DPP-4. DPP-4 inhibitor agents act by blocking the active site of DPP-4, thereby preventing inactivation of and prolonging the duration of action of incretins, which in turn helps to correct the defective insulin and glucagon secretion that marks type 2 diabetes. Clinical studies to date indicate that DPP-4 inhibitors effectively stimulate insulin secretion, suppress glucagon release, and improve glucose control in patients with type 2 diabetes. These agents are well tolerated and have a low incidence of adverse effects.

Conclusions:

The DPP-4 inhibitors are novel agents for the treatment of type 2 diabetes. Compounds under development in this new class of oral antidiabetic drugs may be free of the limitations of current therapies.
Mesenchymal Hamartoma of the Liver in a Late-Term Equine Fetus
Authors: Brown D. L. , Anderson M. , Cullen J. M.
Published: December 2006

Mesenchymal hamartoma of the liver is a rare congenital disorder of biliary tract development. During the necropsy of a late-term equine fetus, a markedly enlarged liver of more than two times normal weight was found. Light microscopic review revealed that the normal hepatic parenchyma had been obliterated, replaced, and expanded by abnormal bile ducts surrounded by abundant, myxoid stroma. The lesion was diagnosed as a mesenchymal hamartoma. Small portions of the liver had bridging septa of fibrosis and proliferations of small-caliber abnormal bile ducts, resembling another congenital biliary abnormality termed congenital hepatic fibrosis.
Severe Granulomatous Lesions in Several Organs from Eustrongylides Larvae in a Free-ranging Dice Snake, Natrix tessellata
Authors: Mihalca A. D. , Fictum P. , Škorič M. , Sloboda M. , Kärvemo S. , Ghira I. , Carlsson M. , Modrý D.
Published: December 2006

During an extensive study regarding the epidemiology of larval Eustrongylides infestation in a free-ranging endangered population of dice snakes ( Natrix tessellata) from Histria, Romania, an adult female was euthanized to evaluate pathologic changes. Parasites appeared as nodules at various locations: in subcutaneous connective tissues, on the serosae of the intestines and liver. Histologic sections revealed nematode larvae surrounded by a capsule, forming a parasitic granuloma with 3 layers: macrophage layer, lymphocyte layer, and fibrous capsule. Differences between newly formed and mature granulomas consisted mainly in the eosinophilic infiltration. Other types of parasitic granulomas of reptiles are discussed in comparison with our findings.
Fatal Ulcerative and Hemorrhagic Typhlocolitis in a Pregnant Heifer Associated with Natural Bovine Enterovirus Type-1 Infection
Authors: Blas-Machado U. , Saliki J. T. , Boileau M. J. , Goens S. D. , Caseltine S. L. , Duffy J. C. , Welsh R. D.
Published: December 2006

One 2-year-old, 7.5 months pregnant Aberdeen Angus out of a herd of 100 apparently healthy cows, died within 10 hours of hospitalization. At necropsy, multiple foci of mucosal hemorrhage and ulceration were observed in the spiral colon and cecum. Virus isolation from intestinal lesions yielded a cytopathic virus, which was revealed by electron microscopy to be an approximately 27 nm, nonenveloped virus. Further characterization by reverse transcription-polymerase chain reaction (RT-PCR), sequencing of the 5′UTR and partial VP1 coding region, and phylogenetic analysis classified the virus isolate as bovine enterovirus type 1 (BEV-1). No other significant pathogens were detected. This is the first report of BEV-1 isolated in the USA from an animal with fatal enteric disease in more than 20 years. Further investigation is required to determine the prevalence of BEV in North America and to establish the clinical relevance of this understudied virus.
In vivo Endothelial Cell Infection by Anaplasma marginale
Authors: Carreño A. D. , Alleman A. R. , Barbet A. F. , Palmer G. H. , Noh S. M. , Johnson C. M.
Published: December 2006

Anaplasma marginale has recently been shown to infect endothelial cells in vitro, but it remains unknown as to whether endothelial infection also occurs in vivo. In this report, we demonstrate through dual fluorescence microscopy that A marginale, detected by the monoclonal antibody ANAF16C1, co-localizes with the endothelial cell marker, von Willebrand factor, in tissue sections from an experimentally inoculated calf. The results indicate that A marginale infection includes endothelial cells and has implications for both pathogenesis and immune mechanisms.
Disseminated Mycobacterium avium subsp. avium infection in a pet Korean squirrel (Sciuris vulgaris coreae)
Authors: Moreno B. , Aduriz G. , Garrido J. M. , Sevilla I. , Juste R. A.
Published: December 2006

A disseminated Mycobacterium avium subsp. avium infection was diagnosed in a pet Korean squirrel. Grossly, multiple small nodules in the lung, liver, spleen, and skin were observed. Adrenal glands were very enlarged. The only tissue exhibiting necrosis and calcification was a very enlarged bronchial lymph node. The remaining lymph nodes were slightly enlarged. Moderate ascites was also observed. Microscopically, a disseminated granulomatous inflammation with numerous lymphocytes was seen. Acid-fast bacilli were detected in macrophages, in giant cells, free in the interstitium, and in some lymphatic vessels, both within cells and free in the lumen. M. avium subsp. avium was isolated and identified by polymerase chain reaction-restriction endonuclease analysis.
Epithelioid Variant of Hemangioma and Hemangiosarcoma in the Dog, Horse, and Cow
Authors: Warren A. L. , Summers B. A.
Published: December 2006

Epithelioid hemangiomas, hemangioendotheliomas, and angiosarcomas are well recognized histologic variants of endothelial tumors in humans that in the past have been confused with neoplasms of epithelial or histiocytic origin. We describe 12 epithelioid endothelial vascular tumors in 8 dogs, 3 horses, and 1 cow that share microscopic features with these tumors in humans. Ten tumors were located within the dermis and subcutis, 1 in the gastrocnemius tendon, and 1 in the skeletal muscle of the thigh. Key histologic features were the plump, epithelioid appearance of neoplastic endothelial cells and occasional cytoplasmic vacuolation, which rarely contained a single erythrocyte. Patterns of epithelioid endothelial cell growth ranged from conventional vasoformative structures to glandlike acini and short ducts to solid, sheetlike arrangements. All tumors were positive for endothelial markers: 12/12 (100%) were positive for von Willebrand factor with variable intensity and distribution and 9/9 (100%) were positive for CD31. All 12 were negative for cytokeratin. We subdivided these tumors into epithelioid hemangiomas (n = 3) and hemangiosarcomas (n = 9) based on conventional morphologic criteria, growth pattern (invasive or not), and metastasis (known in 1 case at the time of biopsy). Additional follow-up information obtained by a written questionnaire was available for 6/12 (50%) animals and revealed local recurrence in 3 animals (1 epithelioid hemangioma and 2 epithelioid hemangiosarcoma) and regional metastasis in 3 animals (all epithelioid hemangiosarcomas). This series represents a novel group of vascular tumors in domestic animals of which there are only 3 previous cases reported in the veterinary literature.
Myofasciitis in the Domestic Ferret
Authors: Garner M. M. , Ramsell K. , Schoemaker N. J. , Sidor I. F. , Nordhausen R. W. , Bolin S. , Evermann J. F. , Kiupel M.
Published: December 2006

Since late 2003, an inflammatory disease of muscle and fascia has been diagnosed in several ferrets at Northwest ZooPath, and this report describes the condition in 17 ferrets. It is a disease of young ferrets, characterized by rapid onset of clinical signs, high fever, neutrophilic leukocytosis, treatment failure, and death (or euthanasia). Gross lesions include atrophy of skeletal muscle; red and white mottling and dilatation of the esophagus; and splenomegaly. Histologically, moderate to severe suppurative to pyogranulomatous inflammation is in the skeletal muscle and the fascia at multiple sites, including esophagus, heart, limbs, body wall, head, and lumbar regions. Myeloid hyperplasia of spleen and/or bone marrow also is a prominent feature. Ultrastructural lesions include mitochondrial swelling, intracellular edema, disruption of myofibrils and Z bands. Bacterial and viral cultures, electron microscopy, immunohistochemistry, and polymerase chain reaction were negative for a variety of infectious agents. The clinical presentation and distribution of lesions suggests that polymyositis in domestic ferrets is likely a distinct entity. The etiopathogenesis if this condition is not known.
CNS Hypomyelination in Rat Terrier Dogs with Congenital Goiter and a Mutation in the Thyroid Peroxidase Gene
Authors: Pettigrew R. , Fyee J. C. , Gregory B. L. , Lipsitz D. , DeLahunta A. , Summers B. A. , Shelton G. D.
Published: December 2006

Arrested physical development and neurologic abnormalities were identified in 3 of 5 Rat Terrier puppies at 9 weeks of age. Bilaterally firm symmetrical masses were palpated in the region of the thyroid glands. Low serum total (T4) and free thyroxine (FT4, by equilibrium dialysis) and markedly elevated thyroid stimulating hormone (TSH) concentrations supported the diagnosis of hypothyroidism. At necropsy, the thyroid gland was grossly enlarged and histologically exhibited severe, diffuse hyperplasia of the follicular epithelium. Gross examination of the central nervous system revealed a myelin deficiency, most evident in the corpus callosum. Regional distribution of hypomyelination was confirmed histologically, affecting the corpus callosum and, to a lesser degree, the corona radiata, the longitudinal fibers of the pons, the pyramids, and the lateral funiculi of the spinal cord. Myelin reduction was paralleled by axon reduction, suggesting that hypomyelination was a consequence of reduced axonal formation. A homozygous nonsense mutation in the thyroid peroxidase gene was identified in the affected puppies. The dam and a clinically normal litter mate were heterozygous for this mutation, confirming simple autosomal recessive inheritance of the disease trait. The same mutation, causing congenital hypothyroidism with a goiter was previously described in the Toy Fox Terrier breed. Given the ongoing practice of introducing the Toy Fox Terrier genetic background into some Rat Terrier breeding programs to obtain a smaller stature and the apparent relative incidence of the disorder in the 2 breeds, it is likely that this mutation crossed into the Rat Terrier breed from Toy Fox Terriers fairly recently.
Morphometric Analysis of the Retina from Horses Infected with the Borna Disease Virus
Authors: Dietzel J. , Kuhrt H. , Stahl T. , Kacza J. , Seeger J. , Weber M. , Uhlig A. , Reichenbach A. , Grosche A. , Pannicke T.
Published: December 2006

Borna disease (BD) is a fatal disorder of horses, often characterized by blindness. Although degeneration of retinal neurons has been demonstrated in a rat model, there are controversial data concerning whether a similar degeneration occurs in the retina of infected horses. To investigate whether BD may cause degeneration of photoreceptors and possibly of other neuronal cells at least at later stages of the disease, we performed a detailed quantitative morphologic study of retinal tissue from Borna-diseased horses. BD was diagnosed by detection of pathognomonic Joest-Degen inclusion bodies in the postmortem brains. Paraffin sections of paraformaldehyde-fixed retinae were used for histologic and immunohistochemical stainings. Numbers of neurons and Müller glial cells were counted, and neuron-to-Müller cell ratios were calculated. Among tissues from 9 horses with BD, we found retinae with strongly altered histologic appearance as well as retinae with only minor changes. The neuron-to-Müller cell ratio for the whole retina was significantly smaller in diseased animals (8.5 ± 0.4; P < .01) as compared with controls (17.6 ± 0.8). It can be concluded that BD in horses causes alterations of the retinal histology of a variable degree. The study provides new data about the pathogenesis of BD concerning the retina and demonstrates that a loss of photoreceptors may explain the observed blindness in infected horses.
Experimental Infection of C3H/HeJ Mice with the NY18 Isolate of Anaplasma phagocytophilum
Authors: Blas-Machado U. , De La Fuente J. , Blouin E. F. , Almazan C. , Kocan K. M. , Mysore J. V.
Published: December 2006

Human granulocytic anaplasmosis (HGA), an emerging disease of public health concern in many areas of the world, is caused by Anaplasma phagocytophilum. Small animal models of A phagocytophilum in laboratory mice have been developed and used to study the pathogenesis of HGA. In this study, we characterized the pathologic changes in acute infection of C3H/HeJ mice experimentally infected with the NY18 isolate of A phagocytophilum. Although no clinical signs were noted, acute infection was associated with gross splenomegaly, microscopic inflammatory lesions in the lung and liver, hyperplastic lesions on the spleen, and clinical pathology abnormalities including neutropenia and monocytosis. This study emphasizes the use of well-defined animal models as a valuable tool for the study of A phagocytophilum infections.
Immunohistochemical Detection of Protein Gene Product 9.5 (PGP 9.5) in Canine Epitheliotropic T-Cell Lymphoma (Mycosis Fungoides)
Authors: Ramos-Vara J. A. , Miller M. A.
Published: December 2006

Protein gene product 9.5 (PGP 9.5), a ubiquitin COOH-terminal hydrolase initially considered specific for neural and neuroendocrine tissues, is expressed in a variety of epithelial and mesenchymal tumors. During immunohistochemical evaluation of a cutaneous epitheliotropic T-cell lymphoma (mycosis fungoides [MF]) in a dog, strong reactivity for PGP 9.5 was observed. This unexpected result prompted us to examine PGP 9.5 immunoreactivity in 13 additional cases of canine mycosis fungoides. All tumors were confirmed as T-cell epitheliotropic lymphoma by histopathology and immunohistochemistry for CD3. Eight of 14 cases were positive for PGP 9.5, with reactivity mainly in the cytoplasm and less commonly in the nucleus. One case had strong reactivity in the cell membrane, sometimes with concurrent paranuclear staining. Immunoreactivity did not correlate with location (epidermal, dermal, and adnexal) of tumor cells. Disease outcome did not vary between PGP 9.5-positive and negative tumors. Although PGP 9.5 immunoreactivity in MF did not predict tumor behavior in these dogs, it has had prognostic value in certain human carcinomas. This unexpected staining of lymphocytes in mycosis fungoides with an antibody to PGP 9.5 demonstrates its presence in nonneuroendocrine tumors and precludes its use as the sole diagnostic marker in discrete cell tumors in the skin.
An Immunohistochemical and Polymerase Chain Reaction Evaluation of Feline Plasmacytic Pododermatitis
Authors: Bettenay S. V. , Lappin M. R. , Mueller R. S.
Published: December 2006

Sections of 14 skin biopsies of cats with plasmacytic pododermatitis and a clinical follow-up of 12–36 months were stained with a polyclonal anti- Mycobacterium bovis (Bacille Calmette-Guerin = BCG) antibody cross-reactive to a broad spectrum of fungi and bacteria. All sections were negative for organisms within the actual footpad tissue with the anti-BCG antibody stains. Polymerase chain reaction (PCR) assays that amplify the DNA of Bartonella spp., Ehrlichia spp., Anaplasma phagocytophilum, Chlamydophila felis, Mycoplasma spp., Toxoplasma gondii, and feline herpesvirus 1 (FHV-1) were applied to tissue digests. DNA of those pathogens assessed was not amplified from tissue.
Maxillary Ameloblastic Carcinoma in an Alaskan Malamute
Authors: Jiménez M. A. , Castejón A. , San Román F. , Castaño M. , Rodríguez-Bertos A.
Published: December 2006

A 3-year-old female Alaskan Malamute was submitted to the Veterinary Teaching Hospital of Madrid with a mass in the right maxilla. It was ulcerated, covered by a yellowish infected membrane, and painful. The histologic examination showed a neoplastic proliferation of palisading cells distributed irregularly in cords. The tumor was diagnosed as an ameloblastic carcinoma because of the histologic signs of malignancy, the aggressive behavior, and the absence of distal metastasis. This is the first description of an ameloblastic carcinoma in a dog.
Escherichia coli Septicemia Associated with Lack of Maternally Acquired Immunity in a Bottlenose Dolphin Calf
Authors: van Elk C. E. , van dep Bildt M. W. G. , Martina B. E. E. , Osterhaus A. D. M. E. , Kuiken T.
Published: December 2006

Stillbirth and neonatal mortality are substantial problems in captive bottlenose dolphins ( Tursiops truncatus). The cause of these problems often is unknown. We report a case of Escherichia coli septicemia in a male 3-day-old bottlenose dolphin calf. Lesions included omphalitis, synovitis, and hepatic necrosis associated with the presence of Gram-negative bacilli. E. coli was isolated in pure culture from multiple organs. A serum gammaglobulin level of 1.5 g/L indicated a lack of maternally acquired immunity. The observed failure to nurse may have resulted from brain injury due to perinatal asphyxia. Evidence for perinatal asphyxia was the diffuse presence of a moderate amount of meconium in the lungs.
Solitary Biliary Hamartoma with Cholelithiasis in a Domestic Rabbit (Oryctolagus cuniculus)
Authors: Starost M. F.
Published: December 2006

Hamartomas of the liver and biliary system are extremely rare entities in both animals and humans. Biliary hamartomas in humans are usually multiple and constitute the von Meyenburg complexes. This report describes the presence of a large solitary mass arising from the edge of the right medial liver lobe of a domestic rabbit. Histologically, the mass was composed of an extensive network of large varying sized cystic structures lined by simple cuboidal to columnar epithelium within an abundant fibrous stroma. Within many of the cyst lumina were varying sized, pale white to greenish hard concretions identified as choleliths and were analyzed and found to be composed of calcium carbonate. This is the first known report of biliary hamartoma with cholelithiasis in rabbits.
Histologic and Ultrastructural Studies of Juvenile Onset Renal Disease in Four Rottweiler Dogs
Authors: Wakamatsu N. , Surdyk K. , Carmichael K. P. , Brown C. A.
Published: December 2006

Juvenile onset renal disease is described in 2 male and 2 female young Rottweiler dogs. Histologic changes in all dogs were cystic dilatation of Bowman's space, mesangial hypercellularity, and glomerulosclerosis. Three dogs also had glomerular crescents and moderate to severe interstitial fibrosis. Electron microscopy revealed glomerular basement membranes of variable thickness, with extensive splitting or lamellation of the lamina densa. These ultrastructural findings are similar to those found in people and in other breeds of dogs with inherited defects in type IV collagen.
Temporal Discontiguity Is neither Necessary nor Sufficient for Learning-Induced Effects on Adult Neurogenesis
Authors: Leuner Benedetta , Waddell Jaylyn , Gould Elizabeth , Shors Tracey J.
Published: December 2006

Some, but not all, types of learning and memory can influence neurogenesis in the adult hippocampus. Trace eyeblink conditioning has been shown to enhance the survival of new neurons, whereas delay eyeblink conditioning has no such effect. The key difference between the two training procedures is that the conditioning stimuli are separated in time during trace but not delay conditioning. These findings raise the question of whether temporal discontiguity is necessary for enhancing the survival of new neurons. Here we used two approaches to test this hypothesis. First, we examined the influence of a delay conditioning task in which the duration of the conditioned stimulus (CS) was increased nearly twofold, a procedure that critically engages the hippocampus. Although the CS and unconditioned stimulus are contiguous, this very long delay conditioning procedure increased the number of new neurons that survived. Second, we examined the influence of learning the trace conditioned response (CR) after having acquired the CR during delay conditioning, a procedure that renders trace conditioning hippocampal-independent. In this case, trace conditioning did not enhance the survival of new neurons. Together, these results demonstrate that associative learning increases the survival of new neurons in the adult hippocampus, regardless of temporal contiguity.
Luminance-Evoked Inhibition in Primary Visual Cortex: A Transient Veto of Simultaneous and Ongoing Response
Authors: Tucker Thomas R. , Fitzpatrick David
Published: December 2006

Large-scale changes in luminance are known to exert a significant suppressive or masking effect on visual perception, but the neural substrate for this effect remains unclear. In this report, we describe the results of experiments usingin vivointracellular recording to explore the impact of luminance transients on the responses of orientation-selective neurons in layer 2/3 of tree shrew primary visual cortex. By measuring changes in excitatory and inhibitory conductances, we find that instantaneous changes in luminance evoke strong cortical inhibition. When combined with visual stimuli that would otherwise yield strong excitatory responses, luminance transients produce significant reductions in excitation as well as increases in inhibition. As a result, luminance transients significantly delay the emergence of orientation tuned cortical responses, and virtually eliminate ongoing responses to effective stimuli. We conclude that cortical inhibition is a critical factor in luminance-evoked cortical suppression and the likely substrate for luminance-induced visual masking phenomenon.
Large Functional Variability in Cockroach Photoreceptors: Optimization to Low Light Levels
Authors: Heimonen Kyösti , Salmela Iikka , Kontiokari Panu , Weckström Matti
Published: December 2006

The compound eyes of insects contain photoreceptors in small eyelets, ommatidia. The photoreceptors generally vary very little from ommatidium to ommatidium. However, in the large compound eyes of the cockroach (Periplaneta americana), previous studies have shown large differences in the optical structure between the ommatidia. The anatomy suggests pooling of 6–20 photoreceptor signals into one second-order cell in the first synapse. Here, we show and characterize an unexpectedly large and seemingly random functional variability in the cockroach photoreceptors in terms of sensitivity, adaptation speed, angular sensitivity, and signal-to-noise ratio. We also investigate the implications of action potentials, triggered by the light-induced membrane depolarization in the photoreceptor axons. The combination of the functional features reported here is unique among the compound eyes. Recordings from the proximal parts of the thin and long photoreceptor axons or small and distant second-order neurons are not practical with the present methods. To alleviate this lack of data, we used computer simulations mimicking the functional variability, spike coding, and pooling of 12 photoreceptor signals, on the basis of our recordings from the photoreceptor somata and distal axons. The predicted responses of a simulated second-order cell follow surprisingly reliably the simulated light stimuli when compared with a simulation of functionally identical photoreceptors. We hypothesize that cockroach photoreceptors use action potential coding and a kind of population coding scheme for making sense of the inherently unreliable light signals at low luminance and for optimization of vision in its mainly dim living conditions.
Receptive Field Properties of the Macaque Second Somatosensory Cortex: Nonlinear Mechanisms Underlying the Representation of Orientation Within a Finger Pad
Authors: Thakur Pramodsingh H. , Fitzgerald Paul J. , Lane John W. , Hsiao Steven S.
Published: December 2006

We investigate the position invariant receptive field properties of neurons in the macaque second somatosensory (SII) cortical region. Previously we reported that many SII region neurons show orientation tuning in the center of multiple finger pads of the hand and further that the tuning is similar on different pads, which can be interpreted as position invariance. Here we study the receptive field properties of a single finger pad for a subset (n= 61) of those 928 neurons, using a motorized oriented bar that we positioned at multiple locations across the pad. We calculate both vector fields and linear receptive fields of the finger pad to characterize the receptive field properties that give rise to the tuning, and we perform an additional regression analysis to quantify linearity, invariance, or both in individual neurons. We show that orientation tuning of SII region neurons is based on a variety of mechanisms. For some neurons, the tuning is explained by simple excitatory regions, simple inhibitory regions, or some combination of these structures. However, a large fraction of the neurons (n= 20 of 61, 33%) show position invariance that is not explained well by their linear receptive fields. Finding invariance within a finger pad, coupled with the previous result of similar tuning on different pads, indicates that some SII region neurons may exhibit similar tuning throughout large regions of the hand. We hypothesize that invariant neurons play an important role in tactile form recognition.
Regulation of Rod Phototransduction Machinery by Ciliary Neurotrophic Factor
Authors: Wen Rong , Song Ying , Kjellstrom Sten , Tanikawa Atsuhiro , Liu Yun , Li Yiwen , Zhao Lian , Bush Ronald A. , Laties Alan M. , Sieving Paul A.
Published: December 2006

Ciliary neurotrophic factor (CNTF) promotes photoreceptor survival but also suppresses electroretinogram (ERG) responses. This has caused concerns about whether CNTF is detrimental to the function of photoreceptors because it is considered to be a potential treatment for retinal degenerative disorders. Here we report that the suppression of ERG responses is attributable to negative regulation of the phototransduction machinery in rod photoreceptors. Intravitreal injection of recombinant human CNTF protein in rat results in a series of biochemical and morphological changes in rod photoreceptors. CNTF induces a decrease in rhodopsin expression and an increase in arrestin level. Morphologically, CNTF treatment causes a shortening of rod outer segments (ROS). All of these changes are fully reversible. The lower rhodopsin level and shortened ROS reduce the photon catch of rods. Less rhodopsin and more arrestin dramatically increase the arrestin-to-rhodopsin ratio so that more arrestin molecules are available to quench the photoexcited rhodopsin. The overall effect of CNTF is to negatively regulate the phototransduction machinery, which reduces the photoresponsiveness of rods, resulting in lower ERG amplitude at a given intensity of light stimulus. The CNTF-induced changes in rods are similar to those in light-induced photoreceptor plasticity. Whether CNTF-induced changes in rods are through the same mechanism that mediates light-induced photoreceptor plasticity remains to be answered.
An Oculomotor Decision Process Revealed by Functional Magnetic Resonance Imaging
Authors: Heinen Stephen J. , Rowland Jess , Lee Byeong-Taek , Wade Alex R.
Published: December 2006

It is not known how the brain decides to act on moving objects. We demonstrated previously that neurons in the macaque supplementary eye field (SEF) reflect the rule of ocular baseball, a go/nogo task in which eye movements signal the rule-guided interpretation of the trajectory of a target. In ocular baseball, subjects must decide whether to pursue a moving spot target with an eye movement after discriminating whether the target will cross a distal, visible line segment. Here we identify cortical regions active during the ocular baseball task using event-related human functional magnetic resonance imaging (fMRI) and concurrent eye-movement monitoring. Task-related activity was observed in the SEF, the frontal eye field (FEF), the superior parietal lobule (SPL), and the right ventrolateral prefrontal cortex (VLPFC). The SPL and right VLPFC showed heightened activity only during ocular baseball, despite identical stimuli and oculomotor demands in the control task, implicating these areas in the decision process. Furthermore, the right VLPFC but not the SPL showed the greatest activation during the nogo decision trials. This suggests both a functional dissociation between these areas and a role for the right VLPFC in rule-guided inhibition of behavior. In the SEF and FEF, activity was similar for ocular baseball and a control eye-movement task. We propose that, although the SEF reflects the ocular baseball rule, both areas in humans are functionally closer to motor processing than the SPL and the right VLPFC. By recording population activity with fMRI during the ocular baseball task, we have revealed the cortical substrate of an oculomotor decision process.
An Extension of the Transmission Disequilibrium Test Incorporating Imprinting
Authors: Hu Yue-Qing , Zhou Ji-Yuan , Fung Wing K
Published: December 2006

The recombination rates in meioses of females and males are often different. Some genes that affect development and behavior in mammals are known to be imprinted, and >1% of all mammalian genes are believed to be imprinted. When the gene is imprinted and the recombination fractions are sex specific, the conventional transmission disequilibrium test (TDT) is shown to be still valid for testing for linkage. The power function of the TDT is derived, and the effect of the degree of imprinting on the power of the TDT is investigated. It is learned that imprinting has little effect on the power when the female and male recombination rates are equal. On the basis of case–parents trios, the transmissions from the heterozygous fathers/mothers to their affected children are separated as paternal and maternal, and two TDT-like statistics, TDTp and TDTm, are consequently constructed. It is found that the TDTp possesses a higher power than the TDT for maternal imprinting genes, and the TDTm is more powerful than the TDT for paternal imprinting genes. On the basis of the parent-of-origin effects test statistic (POET), a novel statistic, TDT incorporating imprinting (TDTI) is proposed to test for linkage in the presence of linkage disequilibrium, which is shown to be more powerful than the TDT when parent-of-origin effects are significant but slightly less powerful than the TDT when parent-of-origin effects are negligible. The validity of the TDT and TDTI is assessed by simulation. The power approximation formulas for the TDT and TDTI are derived and the simulation results show that they are accurate. The simulation study on power comparison shows that the TDTI outperforms the TDT for imprinted genes. The improvement can be substantial in the case of complete paternal/maternal imprinting.
The Structure of Linkage Disequilibrium Around a Selective Sweep
Authors: McVean Gil
Published: December 2006

The fixation of advantageous mutations by natural selection has a profound impact on patterns of linked neutral variation. While it has long been appreciated that such selective sweeps influence the frequency spectrum of nearby polymorphism, it has only recently become clear that they also have dramatic effects on local linkage disequilibrium. By extending previous results on the relationship between genealogical structure and linkage disequilibrium, I obtain simple expressions for the influence of a selective sweep on patterns of allelic association. I show that sweeps can increase, decrease, or even eliminate linkage disequilibrium (LD) entirely depending on the relative position of the selected and neutral loci. I also show the importance of the age of the neutral mutations in predicting their degree of association and describe the consequences of such results for the interpretation of empirical data. In particular, I demonstrate that while selective sweeps can eliminate LD, they generate patterns of genetic variation very different from those expected from recombination hotspots.
Rmd9p Controls the Processing/Stability of Mitochondrial mRNAs and Its Overexpression Compensates for a Partial Deficiency of Oxa1p in Saccharomyces cerevisiae
Authors: Nouet Cécile , Bourens Myriam , Hlavacek Otakar , Marsy Sophie , Lemaire Claire , Dujardin Geneviève
Published: December 2006

Oxa1p is a key component of the general membrane insertion machinery of eukaryotic respiratory complex subunits encoded by the mitochondrial genome. In this study, we have generated a respiratory-deficient mutant, oxa1-E65G-F229S, that contains two substitutions in the predicted intermembrane space domain of Oxa1p. The respiratory deficiency due to this mutation is compensated for by overexpressing RMD9. We show that Rmd9p is an extrinsic membrane protein facing the matrix side of the mitochondrial inner membrane. Its deletion leads to a pleiotropic effect on respiratory complex biogenesis. The steady-state level of all the mitochondrial mRNAs encoding respiratory complex subunits is strongly reduced in the Δrmd9 mutant, and there is a slight decrease in the accumulation of two RNAs encoding components of the small subunit of the mitochondrial ribosome. Overexpressing RMD9 leads to an increase in the steady-state level of mitochondrial RNAs, and we discuss how this increase could suppress the oxa1 mutations and compensate for the membrane insertion defect of the subunits encoded by these mRNAs.
Genetic Dissection of Ethanol Tolerance in the Budding Yeast Saccharomyces cerevisiae
Authors: Hu X H , Wang M H , Tan T , Li J R , Yang H , Leach L , Zhang R M , Luo Z W
Published: December 2006

Uncovering genetic control of variation in ethanol tolerance in natural populations of yeast Saccharomyces cerevisiae is essential for understanding the evolution of fermentation, the dominant lifestyle of the species, and for improving efficiency of selection for strains with high ethanol tolerance, a character of great economic value for the brewing and biofuel industries. To date, as many as 251 genes have been predicted to be involved in influencing this character. Candidacy of these genes was determined from a tested phenotypic effect following gene knockout, from an induced change in gene function under an ethanol stress condition, or by mutagenesis. This article represents the first genomics approach for dissecting genetic variation in ethanol tolerance between two yeast strains with a highly divergent trait phenotype. We developed a simple but reliable experimental protocol for scoring the phenotype and a set of STR/SNP markers evenly covering the whole genome. We created a mapping population comprising 319 segregants from crossing the parental strains. On the basis of the data sets, we find that the tolerance trait has a high heritability and that additive genetic variance dominates genetic variation of the trait. Segregation at five QTL detected has explained ∼50% of phenotypic variation; in particular, the major QTL mapped on yeast chromosome 9 has accounted for a quarter of the phenotypic variation. We integrated the QTL analysis with the predicted candidacy of ethanol resistance genes and found that only a few of these candidates fall in the QTL regions.
Background Selection in Single Genes May Explain Patterns of Codon Bias
Authors: Loewe Laurence , Charlesworth Brian
Published: December 2006

Background selection involves the reduction in effective population size caused by the removal of recurrent deleterious mutations from a population. Previous work has examined this process for large genomic regions. Here we focus on the level of a single gene or small group of genes and investigate how the effects of background selection caused by nonsynonymous mutations are influenced by the lengths of coding sequences, the number and length of introns, intergenic distances, neighboring genes, mutation rate, and recombination rate. We generate our predictions from estimates of the distribution of the fitness effects of nonsynonymous mutations, obtained from DNA sequence diversity data in Drosophila. Results for genes in regions with typical frequencies of crossing over in Drosophila melanogaster suggest that background selection may influence the effective population sizes of different regions of the same gene, consistent with observed differences in codon usage bias along genes. It may also help to cause the observed effects of gene length and introns on codon usage. Gene conversion plays a crucial role in determining the sizes of these effects. The model overpredicts the effects of background selection with large groups of nonrecombining genes, because it ignores Hill–Robertson interference among the mutations involved.
Natural Genetic Variation in Cuticular Hydrocarbon Expression in Male and Female Drosophila melanogaster
Authors: Foley Brad , Chenoweth Stephen F , Nuzhdin Sergey V , Blows Mark W
Published: December 2006

Cuticular hydrocarbons (CHCs) act as contact pheromones in Drosophila melanogaster and are an important component of several ecological traits. Segregating genetic variation in the expression of CHCs at the population level in D. melanogaster is likely to be important for mate choice and climatic adaptation; however, this variation has never been characterized. Using a panel of recombinant inbred lines (RILs) derived from a natural population, we found significant between-line variation for nearly all CHCs in both sexes. We identified 25 QTL in females and 15 QTL in males that pleiotropically influence CHC expression. There was no evidence of colocalization of QTL for homologous traits across the sexes, indicating that sexual dimorphism and low intersex genetic correlations between homologous CHCs are a consequence of largely independent genetic control. This is consistent with a pattern of divergent sexual and natural selection between the sexes.
Phylogenetic Mapping of Recombination Hotspots in Human Immunodeficiency Virus via Spatially Smoothed Change-Point Processes
Authors: Minin Vladimir N , Dorman Karin S , Fang Fang , Suchard Marc A
Published: December 2006

We present a Bayesian framework for inferring spatial preferences of recombination from multiple putative recombinant nucleotide sequences. Phylogenetic recombination detection has been an active area of research for the last 15 years. However, only recently attempts to summarize information from several instances of recombination have been made. We propose a hierarchical model that allows for simultaneous inference of recombination breakpoint locations and spatial variation in recombination frequency. The dual multiple change-point model for phylogenetic recombination detection resides at the lowest level of our hierarchy under the umbrella of a common prior on breakpoint locations. The hierarchical prior allows for information about spatial preferences of recombination to be shared among individual data sets. To overcome the sparseness of breakpoint data, dictated by the modest number of available recombinant sequences, we a priori impose a biologically relevant correlation structure on recombination location log odds via a Gaussian Markov random field hyperprior. To examine the capabilities of our model to recover spatial variation in recombination frequency, we simulate recombination from a predefined distribution of breakpoint locations. We then proceed with the analysis of 42 human immunodeficiency virus (HIV) intersubtype gag recombinants and identify a putative recombination hotspot.
A Distinct Type of Heterochromatin Within Drosophila melanogaster Chromosome 4
Authors: Haynes Karmella A , Gracheva Elena , Elgin Sarah C R
Published: December 2006

Studies of transcriptional gene silencing in Drosophila melanogaster suggest that most of chromosome 4 resembles pericentric heterochromatin. However, some modifiers of position-effect variegation, including chromosome 4 dosage and loss of SU(VAR)3-9, have different effects on silencing in pericentric vs. distal arm chromosome 4 heterochromatin, distinguishing these two heterochromatin types.
Comparative Genomics and Adaptive Selection of the ATP-Binding-Cassette Gene Family in Caenorhabditis Species
Authors: Zhao Zhongying , Thomas James H , Chen Nansheng , Sheps Jonathan A , Baillie David L
Published: December 2006

ABC transporters constitute one of the largest gene families in all species. They are mostly involved in transport of substrates across membranes. We have previously demonstrated that the Caenorhabditis elegans ABC family shows poor one-to-one gene orthology with other distant model organisms. To address the evolution dynamics of this gene family among closely related species, we carried out a comparative analysis of the ABC family among the three nematode species C. elegans, C. briggsae, and C. remanei. In contrast to the previous observations, the majority of ABC genes in the three species were found in orthologous trios, including many tandemly duplicated ABC genes, indicating that the gene duplication took place before speciation. Species-specific expansions of ABC members are rare and mostly observed in subfamilies A and B. C. briggsae and C. remanei orthologous ABC genes tend to cluster on trees, with those of C. elegans as an outgroup, consistent with their proposed species phylogeny. Comparison of intron/exon structures of the highly conserved ABCE subfamily members also indicates a closer relationship between C. briggsae and C. remanei than between either of these species and C. elegans. A comparison between insect and mammalian species indicates lineage-specific duplications or deletions of ABC genes, while the family size remains relatively constant. Sites undergoing positive selection within subfamily D, which are implicated in very-long-chain fatty acid transport, were identified. The evolution of these sites might be driven by the changes in food source with time.
Consistent Patterns of Rate Asymmetry and Gene Loss Indicate Widespread Neofunctionalization of Yeast Genes After Whole-Genome Duplication
Authors: Byrne Kevin P , Wolfe Kenneth H
Published: December 2006

We investigated patterns of rate asymmetry in sequence evolution among the gene pairs (ohnologs) formed by whole-genome duplication (WGD) in yeast species. By comparing three species (Saccharomyces cerevisiae, Candida glabrata, and S. castellii) that underwent WGD to a nonduplicated outgroup (Kluyveromyces lactis), and by using a synteny framework to establish orthology and paralogy relationships at each duplicated locus, we show that 56% of ohnolog pairs show significantly asymmetric protein sequence evolution. For ohnolog pairs that remain duplicated in two species there is a strong tendency for the faster-evolving copy in one species to be orthologous to the faster copy in the other species, which indicates that the evolutionary rate differences were established before speciation and hence soon after the WGD. We also present evidence that in cases where one ohnolog has been lost from the genome of a post-WGD species, the lost copy was likely to have been the faster-evolving member of the pair prior to its loss. These results suggest that a significant fraction of the retained ohnologs in yeast species underwent neofunctionalization soon after duplication.
Power to Detect Higher-Order Epistatic Interactions in a Metabolic Pathway Using a New Mapping Strategy
Authors: Stich Benjamin , Yu Jianming , Melchinger Albrecht E , Piepho Hans-Peter , Utz H Friedrich , Maurer Hans P , Buckler Edward S
Published: December 2006

Epistatic interactions among quantitative trait loci (QTL) contribute substantially to the variation in complex traits. The main objectives of this study were to (i) compare three- vs. four-step genome scans to identify three-way epistatic interactions among QTL belonging to a metabolic pathway, (ii) investigate by computer simulations the power and proportion of false positives (PFP) for detecting three-way interactions among QTL in recombinant inbred line (RIL) populations derived from a nested mating design, and (iii) compare these estimates to those obtained for detecting three-way interactions among QTL in RIL populations derived from diallel and different partial diallel mating designs. The single-nucleotide polymorphism haplotype data of B73 and 25 diverse maize inbreds were used to simulate the production of various RIL populations. Compared to the three-step genome scan, the power to detect three-way interactions was higher with the four-step genome scan. Higher power to detect three-way interactions was observed for RILs derived from optimally allocated distance-based designs than from nested designs or diallel designs. The power and PFP to detect three-way interactions using a nested design with 5000 RILs were for both the 4-QTL and the 12-QTL scenario of a magnitude that seems promising for their identification.
Drosophila ATR in Double-Strand Break Repair
Authors: LaRocque Jeannine R , Jaklevic Burnley , Su Tin Tin , Sekelsky Jeff
Published: December 2006

The ability of a cell to sense and respond to DNA damage is essential for genome stability. An important aspect of the response is arrest of the cell cycle, presumably to allow time for repair. Ataxia telangiectasia mutated (ATM) and ATR are essential for such cell-cycle control, but some observations suggest that they also play a direct role in DNA repair. The Drosophila ortholog of ATR, MEI-41, mediates the DNA damage-dependent G2-M checkpoint. We examined the role of MEI-41 in repair of double-strand breaks (DSBs) induced by P-element excision. We found that mei-41 mutants are defective in completing the later steps of homologous recombination repair, but have no defects in end-joining repair. We hypothesized that these repair defects are the result of loss of checkpoint control. To test this, we genetically reduced mitotic cyclin levels and also examined repair in grp (DmChk1) and lok (DmChk2) mutants. Our results suggest that a significant component of the repair defects is due to loss of MEI-41-dependent cell cycle regulation. However, this does not account for all of the defects we observed. We propose a novel role for MEI-41 in DSB repair, independent of the Chk1/Chk2-mediated checkpoint response.