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1.
J Vet Intern Med ; 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34596276

RESUMO

BACKGROUND: Many medical conditions are thought to cause gastroduodenal ulceration or erosion (GUE) in dogs. However, evidence for the association between many of these conditions and GUE in dogs is lacking. OBJECTIVE: To identify medical conditions associated with GUE in dogs. ANIMALS: One hundred and sixty-eight dogs with GUE and 168 randomly selected control dogs without evidence of GUE identified on necropsy between January 2008 and September 2018. METHODS: Patient signalment, blood urea nitrogen (BUN) and serum creatinine concentrations, recently administered ulcerogenic drugs, as well as necropsy findings were recorded. The association between these findings and presence of GUE was assessed by univariable and multivariable analysis. RESULTS: In the final multivariable model, the following factors were associated with GUE: Nonsteroidal anti-inflammatory drug (NSAID) administration (odds ratio [OR], 6.3; 95% confidence interval [CI], 2.3-17.4; P = .0004), glucocorticoid administration (OR, 3.0; 95% CI, 1.5-5.9; P = .001), gastrointestinal neoplasia (OR, 13.5; 95% CI, 1.7-108.0; P = .01) and gastrointestinal mechanical disease (foreign bodies, gastric dilatation, and volvulus; OR, 4.8; 95% CI, 1.2-19.7; P = .03). Additionally, working dog breeds were predisposed to GUE compared to mixed breed dogs (OR, 2.8; 95% CI, 1.1-7.4; P = .04). Insufficient clinical data was available to either support or refute a role of other putative risk factors evaluated. CONCLUSION AND CLINICAL IMPORTANCE: Administration of NSAID or glucocorticoid and gastrointestinal neoplasia or mechanical disease were associated with GUE in dogs. The potential predisposition of working breed dogs for GUE requires further investigation.

2.
Curr Biol ; 31(1): 198-206.e8, 2021 01 11.
Artigo em Inglês | MEDLINE | ID: mdl-33125870

RESUMO

Extant Canis lupus genetic diversity can be grouped into three phylogenetically distinct clades: Eurasian and American wolves and domestic dogs.1 Genetic studies have suggested these groups trace their origins to a wolf population that expanded during the last glacial maximum (LGM)1-3 and replaced local wolf populations.4 Moreover, ancient genomes from the Yana basin and the Taimyr peninsula provided evidence of at least one extinct wolf lineage that dwelled in Siberia during the Pleistocene.35 Previous studies have suggested that Pleistocene Siberian canids can be classified into two groups based on cranial morphology. Wolves in the first group are most similar to present-day populations, although those in the second group possess intermediate features between dogs and wolves.67 However, whether this morphological classification represents distinct genetic groups remains unknown. To investigate this question and the relationships between Pleistocene canids, present-day wolves, and dogs, we resequenced the genomes of four Pleistocene canids from Northeast Siberia dated between >50 and 14 ka old, including samples from the two morphological categories. We found these specimens cluster with the two previously sequenced Pleistocene wolves, which are genetically more similar to Eurasian wolves. Our results show that, though the four specimens represent extinct wolf lineages, they do not form a monophyletic group. Instead, each Pleistocene Siberian canid branched off the lineage that gave rise to present-day wolves and dogs. Finally, our results suggest the two previously described morphological groups could represent independent lineages similarly related to present-day wolves and dogs.


Assuntos
DNA Antigo , Cães/genética , Genoma , Lobos/genética , Animais , Biodiversidade , DNA Mitocondrial/genética , Cães/anatomia & histologia , Extinção Biológica , Extremo Oriente , Fósseis , Geografia , Filogenia , Sibéria , Crânio/anatomia & histologia , Lobos/anatomia & histologia
3.
Haematologica ; 106(2): 437-445, 2021 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-32001533

RESUMO

Chitotriosidase activity and CCL18 concentration are interchangeably used for monitoring Gaucher disease (GD) activity, together with clinical assessment. However, comparative studies of these two biomarkers are scarce and of limited sample size. The aim of this systematic review with meta-analysis of individual participant data (IPD) was to compare the accuracy of chitotriosidase activity and CCL18 concentration for assessing type I GD severity. We identified cross-sectional and prospective cohort studies by searching Medline, EMBASE, and CENTRAL from 1995 to June 2017, and by contacting research groups. The primary outcome was a composite of liver volume >1.25 multiple of normal (MN), spleen volume >5 MN, hemoglobin concentration <11 g/dL, and platelet count <100x109/L. Overall, IPD included 1109 observations from 334 patients enrolled in nine primary studies, after excluding 111 patients with undocumented values and 18 patients with deficient chitotriosidase activity. IPD were unavailable for 14 eligible primary studies. The primary outcome was associated with a 5.3-fold (95% confidence interval [CI], 4.2 to 6.6) and 3.0-fold (95% CI, 2.6 to 3.6) increase of the geometric mean for chitotriosidase activity and CCL18 concentration, respectively. The corresponding areas under the receiver operating characteristics curves were 0.82 and 0.84 (summary difference, 0.02, 95% CI, -0.02 to 0.05). The addition of chitotriosidase activity did not improve the accuracy of CCL18 concentration. Estimates remained robust in the sensitivity analysis and consistent across subgroups. Neither chitotriosidase activity nor CCL18 concentration varied significantly according to a recent history of bone events among 97 patients. In conclusion, CCL18 concentration is as accurate as chitotriosidase activity in assessing hematological and visceral parameters of GD severity and can be measured in all GD patients. This meta-analysis supports the use of CCL18 rather than chitotriosidase activity for monitoring GD activity in routine practice.


Assuntos
Doença de Gaucher , Biomarcadores , Quimiocinas CC , Estudos Transversais , Doença de Gaucher/diagnóstico , Hexosaminidases , Humanos , Estudos Prospectivos , Índice de Gravidade de Doença
4.
Science ; 368(6498): 1495-1499, 2020 06 26.
Artigo em Inglês | MEDLINE | ID: mdl-32587022

RESUMO

Although sled dogs are one of the most specialized groups of dogs, their origin and evolution has received much less attention than many other dog groups. We applied a genomic approach to investigate their spatiotemporal emergence by sequencing the genomes of 10 modern Greenland sled dogs, an ~9500-year-old Siberian dog associated with archaeological evidence for sled technology, and an ~33,000-year-old Siberian wolf. We found noteworthy genetic similarity between the ancient dog and modern sled dogs. We detected gene flow from Pleistocene Siberian wolves, but not modern American wolves, to present-day sled dogs. The results indicate that the major ancestry of modern sled dogs traces back to Siberia, where sled dog-specific haplotypes of genes that potentially relate to Arctic adaptation were established by 9500 years ago.


Assuntos
Adaptação Fisiológica/genética , Cães/genética , Animais , Apolipoproteínas/genética , Regiões Árticas , Ácidos Graxos/metabolismo , Genoma , Groenlândia , Haplótipos , Proteínas de Transporte da Membrana Mitocondrial/genética , Seleção Artificial , Análise de Sequência de DNA , Sibéria , Triglicerídeos/metabolismo , Lobos/genética
5.
Stroke ; 51(3): 944-951, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31906829

RESUMO

Background and Purpose- Dexterous object manipulation, requiring generation and control of finger forces, is often impaired after stroke. This study aimed to describe recovery of precision grip force control after stroke and to determine clinical and imaging predictors of 6-month performance. Methods- Eighty first-ever stroke patients with varying degrees of upper limb weakness were evaluated at 3 weeks, 3 months, and 6 months after stroke. Twenty-three healthy individuals of comparable age were also studied. The Strength-Dexterity test was used to quantify index finger and thumb forces during compression of springs of varying length in a precision grip. The coordination between finger forces (CorrForce), along with Dexterity-score and Repeatability-score, was calculated. Anatomical magnetic resonance imaging was used to calculate weighted corticospinal tract lesion load (wCST-LL). Results- CorrForce, Dexterity-score, and Repeatability-score in the affected hand were dramatically lower at each time point compared with the less-affected hand and the control group, even in patients with mild motor impairment according to Fugl-Meyer assessment. Improved performance over time occurred in CorrForce and Dexterity-score but not in Repeatability-score. The Fugl-Meyer assessment hand subscale, sensory function, and wCST-LL best predicted CorrForce and Dexterity-score status at 6 months (R2=0.56 and 0.87, respectively). wCST-LL explained substantial variance in CorrForce (R2=0.34) and Dexterity-score (R2=0.50) at 6 months; two-point discrimination and Fugl-Meyer score accounted for considerable additional variance. Absence of recovery in CorrForce was predicted by wCST-LL >4 cc and in Dexterity-score by wCST-LL >6 cc. Conclusions- Findings highlight persisting deficits in the ability to grasp and control finger forces after stroke. wCST-LL was the strongest predictor of performance at 6 months, but early two-point discrimination and Fugl-Meyer score had substantial additional predictive value. Registration- URL: https://www.clinicaltrials.gov. Unique identifier: NCT02878304.


Assuntos
Força da Mão , Acidente Vascular Cerebral/fisiopatologia , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Polegar/fisiopatologia , Fatores de Tempo
6.
Mol Ecol ; 29(9): 1596-1610, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-31840921

RESUMO

Grey wolves (Canis lupus) are one of the few large terrestrial carnivores that have maintained a wide geographical distribution across the Northern Hemisphere throughout the Pleistocene and Holocene. Recent genetic studies have suggested that, despite this continuous presence, major demographic changes occurred in wolf populations between the Late Pleistocene and early Holocene, and that extant wolves trace their ancestry to a single Late Pleistocene population. Both the geographical origin of this ancestral population and how it became widespread remain unknown. Here, we used a spatially and temporally explicit modelling framework to analyse a data set of 90 modern and 45 ancient mitochondrial wolf genomes from across the Northern Hemisphere, spanning the last 50,000 years. Our results suggest that contemporary wolf populations trace their ancestry to an expansion from Beringia at the end of the Last Glacial Maximum, and that this process was most likely driven by Late Pleistocene ecological fluctuations that occurred across the Northern Hemisphere. This study provides direct ancient genetic evidence that long-range migration has played an important role in the population history of a large carnivore, and provides insight into how wolves survived the wave of megafaunal extinctions at the end of the last glaciation. Moreover, because Late Pleistocene grey wolves were the likely source from which all modern dogs trace their origins, the demographic history described in this study has fundamental implications for understanding the geographical origin of the dog.


Assuntos
Evolução Biológica , DNA Antigo , Genoma Mitocondrial , Lobos , Animais , DNA Mitocondrial/genética , Cães , Fluxo Gênico , Filogenia , Lobos/genética
7.
Nature ; 570(7760): 182-188, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31168093

RESUMO

Northeastern Siberia has been inhabited by humans for more than 40,000 years but its deep population history remains poorly understood. Here we investigate the late Pleistocene population history of northeastern Siberia through analyses of 34 newly recovered ancient genomes that date to between 31,000 and 600 years ago. We document complex population dynamics during this period, including at least three major migration events: an initial peopling by a previously unknown Palaeolithic population of 'Ancient North Siberians' who are distantly related to early West Eurasian hunter-gatherers; the arrival of East Asian-related peoples, which gave rise to 'Ancient Palaeo-Siberians' who are closely related to contemporary communities from far-northeastern Siberia (such as the Koryaks), as well as Native Americans; and a Holocene migration of other East Asian-related peoples, who we name 'Neo-Siberians', and from whom many contemporary Siberians are descended. Each of these population expansions largely replaced the earlier inhabitants, and ultimately generated the mosaic genetic make-up of contemporary peoples who inhabit a vast area across northern Eurasia and the Americas.


Assuntos
Genoma Humano/genética , Migração Humana/história , Ásia/etnologia , DNA Antigo/análise , Europa (Continente)/etnologia , Pool Gênico , Haplótipos , História do Século XV , História Antiga , História Medieval , Humanos , Índios Norte-Americanos , Masculino , Sibéria/etnologia
8.
Hum Mol Genet ; 28(15): 2514-2530, 2019 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-31070736

RESUMO

A rare lysosomal disease resembling a mucopolysaccharidosis with unusual systemic features, including renal disease and platelet dysfunction, caused by the defect in a conserved region of the VPS33A gene on human chromosome 12q24.31, occurs in Yakuts-a nomadic Turkic ethnic group of Southern Siberia. VPS33A is a core component of the class C core vacuole/endosome tethering (CORVET) and the homotypic fusion and protein sorting (HOPS) complexes, which have essential functions in the endocytic pathway. Here we show that cultured fibroblasts from patients with this disorder have morphological changes: vacuolation with disordered endosomal/lysosomal compartments and-common to sphingolipid diseases-abnormal endocytic trafficking of lactosylceramide. Urine glycosaminoglycan studies revealed a pathological excess of sialylated conjugates as well as dermatan and heparan sulphate. Lipidomic screening showed elevated ß-D-galactosylsphingosine with unimpaired activity of cognate lysosomal hydrolases. The 3D crystal structure of human VPS33A predicts that replacement of arginine 498 by tryptophan will de-stabilize VPS33A folding. We observed that the missense mutation reduced the abundance of full-length VPS33A and other components of the HOPS and CORVET complexes. Treatment of HeLa cells stably expressing the mutant VPS33A with a proteasome inhibitor rescued the mutant protein from degradation. We propose that the disease is due to diminished intracellular abundance of intact VPS33A. Exposure of patient-derived fibroblasts to the clinically approved proteasome inhibitor, bortezomib, or inhibition of glucosylceramide synthesis with eliglustat, partially corrected the impaired lactosylceramide trafficking defect and immediately suggest therapeutic avenues to explore in this fatal orphan disease.

9.
Science ; 361(6397): 81-85, 2018 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-29976825

RESUMO

Dogs were present in the Americas before the arrival of European colonists, but the origin and fate of these precontact dogs are largely unknown. We sequenced 71 mitochondrial and 7 nuclear genomes from ancient North American and Siberian dogs from time frames spanning ~9000 years. Our analysis indicates that American dogs were not derived from North American wolves. Instead, American dogs form a monophyletic lineage that likely originated in Siberia and dispersed into the Americas alongside people. After the arrival of Europeans, native American dogs almost completely disappeared, leaving a minimal genetic legacy in modern dog populations. The closest detectable extant lineage to precontact American dogs is the canine transmissible venereal tumor, a contagious cancer clone derived from an individual dog that lived up to 8000 years ago.


Assuntos
Evolução Biológica , Doenças do Cão/transmissão , Cães , Domesticação , Neoplasias/veterinária , Doenças Sexualmente Transmissíveis/veterinária , América , Animais , Núcleo Celular/genética , Doenças do Cão/genética , Cães/classificação , Cães/genética , Genoma Mitocondrial , Migração Humana , Humanos , Filogenia , Doenças Sexualmente Transmissíveis/transmissão , Sibéria , Lobos/classificação , Lobos/genética
10.
J Mot Behav ; 50(2): 134-143, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-28524811

RESUMO

The authors sought to explore the impact of tactile sensation on manual dexterity and the validity of the strength-dexterity test in subjects with chronic impairments after stroke in a cross-sectional study of 24 patients with impaired hand function after stroke. Dexterity was assessed by the strength-dexterity test, Box and Blocks, and Nine-Hole Peg Test, and the ABILHAND questionnaire. Sensation was measured by pinprick, cotton-wool, graphesthesia, and 2-point discrimination tests. Sensation in the paretic hand had strong association with paretic hand performance in the strength-dexterity test and Nine-Hole Peg Test and explained 13% of the variance. Sensation in the nonparetic hand was associated with the results of the ABILHAND questionnaire. Among sensory tests, 2-point discrimination had the strongest association with dexterity tests. No significant correlations between sensation, pinch force, and dexterity tests were found for the nonparetic hand. The strength-dexterity test exhibited strong correlations with the other dexterity measures and with pinch force. There is an association between tactile sensation and dexterous performance in the paretic hand; activity level performance is associated with sensation in the nonparetic hand. The study supports the validity of the strength-dexterity test when applied in subjects in the chronic stage after stroke.


Assuntos
Força da Mão/fisiologia , Mãos/fisiopatologia , Destreza Motora/fisiologia , Acidente Vascular Cerebral/fisiopatologia , Tato/fisiologia , Idoso , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Inquéritos e Questionários
11.
Artigo em Inglês | MEDLINE | ID: mdl-29233783

RESUMO

BACKGROUND: Transcranial direct current stimulation (tDCS) can be an effective treatment for depression, however, the duration of the stimulation session, among other parameters, needs to be optimized. METHODS: 69 mild to moderately depressed patients (age 37.6±10.5years, 19 men) were randomized into three groups - 30-, 20-minute or sham tDCS. 10 daily sessions of anodal/sham tDCS of the left DLPFC (0.5mA; electrode 3,5×7cm) combined with 50mg/day of sertraline were performed. Mood, cognition and BDNF level were assessed before and after the treatment. RESULTS: A significant difference between groups was observed in the percent change of the Hamilton Depression Rating Scale (F(2, 66)=10.1; p<0.001). Sham group (43.4%±18.1) had a smaller improvement compared to the 30-minute (63.8%±13.4; 95% CI: 11.23-29.44; p=0.00003) and 20-minute group (53.2%±15.3; 95% CI: 0.21-19.26; p=0.045). 30-minute group had significantly greater percent improvement than 20-minute group (95% CI: 1.74-19.46; p=0.02). Responders constituted 89%, 68%, and 50% and remitters - 70%, 27%, and 35% in the 30-, 20-minute and sham groups, respectively. A significant difference in the number of responders was observed between 30-minute vs. sham group (odds ratio=8; 95% CI, 2.59-24.69; p=0.001), in remission rate - between 30-minute vs. sham (odds ratio=4.40; 95% CI, 2.02-9.57; p=0.02) and vs. 20-minute (odds ratio=6.33; 95% CI, 2.85-14.10; p=0.003) groups. Two hypomania cases and one case of blood pressure elevation were detected in the 20-minute group. Among neuropsychological tests, only the change in Digit Span Backwards test showed a significant interaction between groups (TIME*GROUP; F(2, 65)=6,6, p=0.002); a greater improvement was observed in both active groups compared to sham (p<0.05). The change in BDNF level after the treatment did not show the significant difference between groups. CONCLUSIONS: tDCS of 20- or 30-minutes combined with sertraline are efficient for the treatment of mild and moderate depression; the effect of 30min stimulation exceeds the one obtained from 20min.


Assuntos
Antidepressivos/uso terapêutico , Transtorno Depressivo/terapia , Sertralina/uso terapêutico , Estimulação Transcraniana por Corrente Contínua , Adulto , Afeto , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Cognição , Terapia Combinada , Feminino , Humanos , Masculino , Córtex Pré-Frontal , Método Simples-Cego , Fatores de Tempo , Estimulação Transcraniana por Corrente Contínua/métodos , Resultado do Tratamento
12.
Restor Neurol Neurosci ; 35(3): 307-317, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28506002

RESUMO

BACKGROUND: Recent studies exploring the combined effect of motor learning and transcranial direct current stimulation (tDCS) for stroke rehabilitation have shown partially conflicting results. OBJECTIVE: To test the efficacy of an optimized hand training approach combined with tDCS in stroke patients. METHODS: In the present pilot study we investigated motor effects of four-week training with a visuomotor grip force tracking task combined with tDCS in 11 chronic stroke patients. Anodal (0.5 mA) or sham tDCS was applied over the primary motor cortex of the lesioned side for 20 minutes, twice a day, during training. RESULTS: No difference between the Active and Sham groups in the total upper extremity (UE) Fugl-Meyer Assessment (FMA) score was found. The most prominent recovery occurred in the shoulder-elbow FMA sub-score; in this segment a significantly greater improvement in the Active compared to the Sham group was observed up to two months after the intervention. Mean hold force during the first treatment session predicted the change in the total UE FMA score after treatment. CONCLUSION: Four-week visuo-motor training combined with tDCS showed no difference between the Active and Sham groups in the total UE FMA score, which may be explained by heterogeneity of the degree of recovery in the Active group. However, the shoulder-elbow FMA sub-score improved significantly more in the Active compared to the Sham group, which deserves further study.


Assuntos
Terapia por Exercício/métodos , Córtex Motor/fisiopatologia , Avaliação de Resultados em Cuidados de Saúde , Desempenho Psicomotor/fisiologia , Reabilitação do Acidente Vascular Cerebral/métodos , Acidente Vascular Cerebral/terapia , Estimulação Transcraniana por Corrente Contínua/métodos , Extremidade Superior/fisiopatologia , Adulto , Idoso , Doença Crônica/reabilitação , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Recuperação de Função Fisiológica/fisiologia
13.
Syst Rev ; 6(1): 87, 2017 04 20.
Artigo em Inglês | MEDLINE | ID: mdl-28427477

RESUMO

BACKGROUND: Gaucher disease (GD) is an autosomal recessive lysosomal storage disorder caused by deficiency in acid beta-glucosidase. GD exhibits a wide clinical spectrum of disease severity with an unpredictable natural course. Plasma chitotriosidase activity and CC chemokine ligand 18 (CCL18) have been exchangeably used for monitoring GD activity and response to enzyme replacement therapy in conjunction with clinical assessment. Yet, a large-scale head-to-head comparison of these two biomarkers is currently lacking. We propose a collaborative systematic review with meta-analysis of individual participant data (IPD) to compare the accuracy of plasma chitotriosidase activity and CCL18 in assessing type I (i.e., non-neuropathic) GD severity. METHODS: Eligible studies include cross-sectional, cohort, and randomized controlled studies recording both plasma chitotriosidase activity and CCL18 level at baseline and/or at follow-up in consecutive children or adult patients with type I GD. Pre-specified surrogate outcomes reflecting GD activity include liver and spleen volume, hemoglobin concentration, platelet count, and symptomatic bone events with imaging confirmation. Primary studies will be identified by searching Medline (1995 onwards), EMBASE (1995 onwards), and Cochrane Central Register of Controlled Trials (CENTRAL). Electronic search will be complemented by contacting research groups in order to identify unpublished relevant studies. Where possible, IPD will be extracted from published articles. Corresponding authors will be invited to collaborate by supplying IPD. The methodological quality of retrieved studies will be appraised for each study outcome, using a checklist adapted from the Quality Assessment of Diagnostic Accuracy Studies-2 tool. The primary outcome will be a composite of liver volume >1.25 multiple of normal (MN), spleen volume >5 MN, hemoglobin concentration <11 g/dL, or platelet count <100 × 109/L. Effect size estimates for biomarker comparative accuracy in predicting outcomes will be reported as differences in areas under receiver operating characteristic curves along with 95% confidence intervals. Effect size estimates will be reported as (weighted) mean differences along with 95% confidence intervals for each biomarker according to outcomes. IPD meta-analysis will be conducted with both one- and two-stage approaches. DISCUSSION: Valid and precise accuracy estimates will be derived for CCL18 relative to plasma chitotriosidase activity in discriminating patients according to GD severity. SYSTEMATIC REVIEW REGISTRATION: PROSPERO 2015 CRD42015027243.


Assuntos
Quimiocinas CC/sangue , Doença de Gaucher/sangue , Doença de Gaucher/enzimologia , Hexosaminidases/sangue , Revisões Sistemáticas como Assunto , Anemia/etiologia , Biomarcadores/sangue , Doença de Gaucher/complicações , Hepatomegalia/etiologia , Humanos , Metanálise como Assunto , Projetos de Pesquisa , Índice de Gravidade de Doença , Esplenomegalia/etiologia , Trombocitopenia/etiologia
14.
FEBS Open Bio ; 6(9): 902-13, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27642553

RESUMO

Gaucher disease is caused by inherited deficiency of lysosomal glucocerebrosidase. Proteome analysis of laser-dissected splenic Gaucher cells revealed increased amounts of glycoprotein nonmetastatic melanoma protein B (gpNMB). Plasma gpNMB was also elevated, correlating with chitotriosidase and CCL18, which are established markers for human Gaucher cells. In Gaucher mice, gpNMB is also produced by Gaucher cells. Correction of glucocerebrosidase deficiency in mice by gene transfer or pharmacological substrate reduction reverses gpNMB abnormalities. In conclusion, gpNMB acts as a marker for glucosylceramide-laden macrophages in man and mouse and gpNMB should be considered as candidate biomarker for Gaucher disease in treatment monitoring.

15.
Glob Chang Biol ; 22(5): 1710-21, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-26919067

RESUMO

Recent palaeogenetic studies indicate a highly dynamic history in collared lemmings (Dicrostonyx spp.), with several demographical changes linked to climatic fluctuations that took place during the last glaciation. At the western range margin of D. torquatus, these changes were characterized by a series of local extinctions and recolonizations. However, it is unclear whether this pattern represents a local phenomenon, possibly driven by ecological edge effects, or a global phenomenon that took place across large geographical scales. To address this, we explored the palaeogenetic history of the collared lemming using a next-generation sequencing approach for pooled mitochondrial DNA amplicons. Sequences were obtained from over 300 fossil remains sampled across Eurasia and two sites in North America. We identified five mitochondrial lineages of D. torquatus that succeeded each other through time across Europe and western Russia, indicating a history of repeated population extinctions and recolonizations, most likely from eastern Russia, during the last 50 000 years. The observation of repeated extinctions across such a vast geographical range indicates large-scale changes in the steppe-tundra environment in western Eurasia during the last glaciation. All Holocene samples, from across the species' entire range, belonged to only one of the five mitochondrial lineages. Thus, extant D. torquatus populations only harbour a small fraction of the total genetic diversity that existed across different stages of the Late Pleistocene. In North American samples, haplotypes belonging to both D. groenlandicus and D. richardsoni were recovered from a Late Pleistocene site in south-western Canada. This suggests that D. groenlandicus had a more southern and D. richardsoni a more northern glacial distribution than previously thought. This study provides significant insights into the population dynamics of a small mammal at a large geographical scale and reveals a rather complex demographical history, which could have had bottom-up effects in the Late Pleistocene steppe-tundra ecosystem.


Assuntos
Arvicolinae/genética , Extinção Biológica , Variação Genética , Animais , Regiões Árticas , DNA Antigo/análise , DNA Mitocondrial/análise , Europa (Continente) , Fósseis , Pradaria , América do Norte , Filogenia , Dinâmica Populacional , Federação Russa , Análise de Sequência de DNA , Tundra
16.
Science ; 351(6270): 260-3, 2016 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-26816376

RESUMO

Archaeological evidence for human dispersal through northern Eurasia before 40,000 years ago is rare. In west Siberia, the northernmost find of that age is located at 57°N. Elsewhere, the earliest presence of humans in the Arctic is commonly thought to be circa 35,000 to 30,000 years before the present. A mammoth kill site in the central Siberian Arctic, dated to 45,000 years before the present, expands the populated area to almost 72°N. The advancement of mammoth hunting probably allowed people to survive and spread widely across northernmost Arctic Siberia.


Assuntos
Atividades Humanas , Migração Humana , Mamutes/lesões , Animais , Antropologia , Regiões Árticas , Osso e Ossos/anatomia & histologia , Osso e Ossos/lesões , Europa (Continente) , Humanos , Mamutes/anatomia & histologia , Paleontologia , Sibéria
17.
J Lipid Res ; 57(3): 451-63, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26724485

RESUMO

The membrane lipid glucosylceramide (GlcCer) is continuously formed and degraded. Cells express two GlcCer-degrading ß-glucosidases, glucocerebrosidase (GBA) and GBA2, located in and outside the lysosome, respectively. Here we demonstrate that through transglucosylation both GBA and GBA2 are able to catalyze in vitro the transfer of glucosyl-moieties from GlcCer to cholesterol, and vice versa. Furthermore, the natural occurrence of 1-O-cholesteryl-ß-D-glucopyranoside (GlcChol) in mouse tissues and human plasma is demonstrated using LC-MS/MS and (13)C6-labeled GlcChol as internal standard. In cells, the inhibition of GBA increases GlcChol, whereas inhibition of GBA2 decreases glucosylated sterol. Similarly, in GBA2-deficient mice, GlcChol is reduced. Depletion of GlcCer by inhibition of GlcCer synthase decreases GlcChol in cells and likewise in plasma of inhibitor-treated Gaucher disease patients. In tissues of mice with Niemann-Pick type C disease, a condition characterized by intralysosomal accumulation of cholesterol, marked elevations in GlcChol occur as well. When lysosomal accumulation of cholesterol is induced in cultured cells, GlcChol is formed via lysosomal GBA. This illustrates that reversible transglucosylation reactions are highly dependent on local availability of suitable acceptors. In conclusion, mammalian tissues contain GlcChol formed by transglucosylation through ß-glucosidases using GlcCer as donor. Our findings reveal a novel metabolic function for GlcCer.


Assuntos
Colesterol/metabolismo , beta-Glucosidase/metabolismo , Animais , Células COS , Chlorocebus aethiops , Feminino , Doença de Gaucher/metabolismo , Glicosilação , Humanos , Masculino , Camundongos , Doenças de Niemann-Pick/metabolismo , Células RAW 264.7
18.
PLoS One ; 10(5): e0125759, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26018528

RESUMO

Modern Arctic Siberia provides a wealth of resources for archaeological, geological, and paleontological research to investigate the population dynamics of faunal communities from the Pleistocene, particularly as the faunal material coming from permafrost has proven suitable for genetic studies. In order to examine the history of the Canid species in the Siberian Arctic, we carried out genetic analysis of fourteen canid remains from various sites, including the well-documented Upper Paleolithic Yana RHS and Early Holocene Zhokhov Island sites. Estimated age of samples range from as recent as 1,700 years before present (YBP) to at least 360,000 YBP for the remains of the extinct wolf, Canis cf. variabilis. In order to examine the genetic affinities of ancient Siberian canids species to the domestic dog and modern wolves, we obtained mitochondrial DNA control region sequences and compared them to published ancient and modern canid sequences. The older canid specimens illustrate affinities with pre-domestic dog/wolf lineages while others appear in the major phylogenetic clades of domestic dogs. Our results suggest a European origin of domestic dog may not be conclusive and illustrates an emerging complexity of genetic contribution of regional wolf breeds to the modern Canis gene pool.


Assuntos
Canidae/genética , DNA Mitocondrial , Fósseis , Animais , Regiões Árticas , DNA Mitocondrial/genética , Cães/genética , Filogenia , Sibéria
19.
Brain Res ; 1620: 98-106, 2015 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-25998541

RESUMO

OBJECTIVE: To study whether a temporary block of the tactile afferents from the fingers causes altered activity in the neural network for dexterous manipulation. METHODS: Whole-brain functional Magnetic Resonance Imaging (fMRI) was conducted in 18 healthy subjects, while they compressed an unstable spring between the thumb and index finger of the right hand. Two sensory conditions--with and without tactile input from the fingers--were employed. In the latter condition the digital nerves were blocked by local anesthesia. RESULTS: Compression of the unstable spring was associated with activity in an earlier described network for object manipulation. We found that this entire network remained active after a nerve block, and the activity was increased in the dorsal premotor cortex. CONCLUSIONS: The neural network for dexterous manipulation is robust with only minor alterations after acute loss of tactile information from the fingers. There was no loss of activity, but, unexpectedly, an increased activity in some parts of the network. SIGNIFICANCE: This study gives new insights to possible neural compensatory mechanisms that make fine motor control possible after acute disruption of tactile information in natural situations like cold weather or wearing surgical gloves.


Assuntos
Dedos/fisiologia , Atividade Motora/fisiologia , Córtex Motor/fisiologia , Percepção do Tato/fisiologia , Tato/fisiologia , Adulto , Anestésicos Locais/farmacologia , Mapeamento Encefálico , Feminino , Força da Mão/fisiologia , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Bloqueio Nervoso , Vias Neurais/efeitos dos fármacos , Vias Neurais/fisiologia , Tato/efeitos dos fármacos , Percepção do Tato/efeitos dos fármacos , Adulto Jovem
20.
J Pathol ; 235(1): 113-24, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25256118

RESUMO

Clonal B-cell proliferation is a frequent manifestation of Gaucher disease - a sphingolipidosis associated with a high risk of multiple myeloma and non-Hodgkin lymphoma. Gaucher disease is caused by genetic deficiency of acid ß-glucosidase, the natural substrates of which (ß-d-glucosylceramide and ß-d-glucosylsphingosine) accumulate, principally in macrophages. Mice with inducible deficiency of ß-glucosidase [Gba(tm1Karl/tm1Karl)Tg(MX1-cre)1Cgn/0] serve as an authentic model of human Gaucher disease; we have recently reported clonal B-cell proliferation accompanied by monoclonal serum paraproteins and cognate tumours in these animals. To explore the relationship between B-cell malignancy and the biochemical defect, we treated Gaucher mice with eliglustat tartrate (GENZ 112638), a potent and selective inhibitor of the first committed step in glycosphingolipid biosynthesis. Twenty-two Gaucher mice received 300 mg/kg of GENZ 112638 daily for 3-10 months from 6 weeks of age. Plasma concentrations of ß-d-glucosylceramide and the unacylated glycosphingolipid, ß-d-glucosylsphingosine, declined. After administration of GENZ 112638 to Gaucher mice for 3-10 months, serum paraproteins were not detected and there was a striking reduction in the malignant lymphoproliferation: neither lymphomas nor plasmacytomas were found in animals that had received the investigational agent. In contrast, 14 out of 60 Gaucher mice without GENZ 112638 treatment developed these tumours; monoclonal paraproteins were detected in plasma from 18 of the 44 age-matched mice with Gaucher disease that had not received GENZ 112638. Long-term inhibition of glycosphingolipid biosynthesis suppresses the development of spontaneous B-cell lymphoma and myeloma in Gaucher mice.


Assuntos
Doença de Gaucher/complicações , Glucosiltransferases/antagonistas & inibidores , Linfoma de Células B/patologia , Pirrolidinas/farmacologia , Animais , Modelos Animais de Doenças , Feminino , Doença de Gaucher/metabolismo , Glucosiltransferases/metabolismo , Linfoma de Células B/etiologia , Masculino , Camundongos , Difosfato de Uridina/metabolismo
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