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1.
PLoS Biol ; 18(12): e3000621, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33351792

RESUMO

Neurons extend long axons that require maintenance and are susceptible to degeneration. Long-term integrity of axons depends on intrinsic mechanisms including axonal transport and extrinsic support from adjacent glial cells. The mechanisms of support provided by myelinating oligodendrocytes to underlying axons are only partly understood. Oligodendrocytes release extracellular vesicles (EVs) with properties of exosomes, which upon delivery to neurons improve neuronal viability in vitro. Here, we show that oligodendroglial exosome secretion is impaired in 2 mouse mutants exhibiting secondary axonal degeneration due to oligodendrocyte-specific gene defects. Wild-type oligodendroglial exosomes support neurons by improving the metabolic state and promoting axonal transport in nutrient-deprived neurons. Mutant oligodendrocytes release fewer exosomes, which share a common signature of underrepresented proteins. Notably, mutant exosomes lack the ability to support nutrient-deprived neurons and to promote axonal transport. Together, these findings indicate that glia-to-neuron exosome transfer promotes neuronal long-term maintenance by facilitating axonal transport, providing a novel mechanistic link between myelin diseases and secondary loss of axonal integrity.


Assuntos
Transporte Axonal/fisiologia , Neurônios/metabolismo , Oligodendroglia/metabolismo , Animais , Transporte Axonal/genética , Axônios/fisiologia , Exossomos/metabolismo , Exossomos/fisiologia , Vesículas Extracelulares/metabolismo , Vesículas Extracelulares/fisiologia , Feminino , Células HEK293 , Humanos , Manutenção , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Bainha de Mielina/metabolismo , Neuroglia , Neurônios/fisiologia , Oligodendroglia/fisiologia , Transdução de Sinais/fisiologia
2.
PLoS One ; 15(11): e0242873, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33227027

RESUMO

The animal-human relationship is essential for farm animal welfare and production. Generally, gentle tactile and vocal interactions improve the animal-human relationship in cattle. However, cows that are fearful of humans avoid their close presence and touch; thus, the animal-human relationship first has to be improved to a point where the animals accept stroking before their perception of the interactions and consequently the animal-human relationship can become positive. We tested whether the animal-human relationship of cows fearful of humans is improved more effectively by gentle interactions during restraint, allowing physical contact from the beginning, or if the gentle interactions are offered while the animals are free to move, giving them more control over the situation and thus probably a higher level of agency and a more positive perception of the interactions. Thirty-six dairy cows (median avoidance distance 1.6 m) were assigned to three treatments (each n = 12): gentle vocal and tactile interactions during restraint in the feeding rack (LOCK); gentle vocal and, if possible, tactile interactions while free in the barn (FREE); routine management without additional interactions (CON). Treatments were applied for 3 min per cow on 10 d per fortnight for 6 weeks (i.e., three periods). Avoidance and approach behaviour towards humans was tested before the start of the treatment period, and then at 2-week intervals. The recorded variables were reduced to one score by Principal Component Analysis. The resulting relationship score (higher values implying a better relationship with humans) increased in all groups; the increase was stronger in FREE than in CON, with the increase in LOCK being not significantly different from the other treatment groups. Thus, we recommend that gentle interactions with cows should take place while they are unrestrained, if possible.

3.
J Dairy Res ; 87(S1): 148-153, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33213569

RESUMO

In this Research Communication we address the hypotheses that reduced contact with humans during the first week of life would impair the relationship of dairy calves reared in dam-calf-contact systems to humans in comparison with artificially reared animals, but that this difference would vanish over time. Artificially reared calves (Artificial) that had been separated from their mother within 12 h after birth were bottle-fed with colostrum for 5 d and thereafter sucked milk from an automatic milk feeder. Animals reared with dam-calf contact (Dam-contact) were kept in the calving pen with their dam for 5 d, and then had permanent access to the cow barn and thus to their dam. Calves were weaned at an age of 12 weeks and kept in young stock groups mixed of both treatments until integration into the cow herd. We tested the animals' relationship with humans by assessing the animals' responses towards an unfamiliar person in an avoidance distance (AD) test in the home environment at 4 weeks of age, at 15 months and at 33 months. In calves, we additionally measured AD in a novel arena after a stationary person test. Artificial animals had lower AD, i.e. showed lower level of fear, than Dam-contact calves. However, the AD in Dam-contact calves decreased with increasing number of days they experienced assistance for suckling. Further, there was no significant difference in later ages. In conclusion, gentle human contact in combination with feeding during the first 5 d of life improved calves' relationship to humans leading to differences between the two treatments as well as within the Dam-contact calves. Potential effects under different conditions regarding quantity and quality of human-animal interactions need further research.

4.
J Dairy Res ; 87(S1): 144-147, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33213574

RESUMO

The aim of the study reported in this Research Communication was to compare play behaviour and social interactions of dairy calves either separated from their mother and reared in a calf group (Artificial) or with access to their mother and the cow herd (cow-calf contact: Contact). Contact calves had access to a calf area and also to the cow barn where they could suckle their dam. Artificial calves were fed whole milk up to 16 kg per day via an automatic milk feeder and were only kept in the calf area. We observed the animals on 3 d during the first three months of life. Contact calves showed solitary play, consisting predominantly of locomotor play, for longer than Artificial calves and mainly in the cow barn. This indicates higher welfare in Contact calves. In addition, Artificial calves hardly experienced any agonistic interaction, while Contact calves both initiated and received agonistic interactions, which might contribute to the development of higher social competence.

5.
J Dairy Res ; 87(S1): 108-114, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33213583

RESUMO

Due to increasing public concern regarding separation of the dairy cow and calf within the first days after birth, alternative systems, where cows and calves stay in contact for an extended period, are receiving increasing interest from a broad array of researchers and other stakeholders. With more research in the area, there is a risk of inconsistencies emerging in the use of terminology. To create a better consensus in further discussions, the aim of this Research Reflection is to provide definitions and propose a common terminology for cow-calf contact in dairy production. We also suggest definitions for various systems allowing cow-calf contact and describe the distinct phases of cow-calf contact systems.

6.
J Dairy Res ; 87(S1): 133-137, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33213585

RESUMO

In this research communication I show the effect of various cow-calf contact systems on milk yield and milk composition during the periods when calves where allowed to suckle their dams and after the calves were separated in comparison to cows that were only machine milked throughout their lactation. Analyses were based on four different experiments, but conducted at the same research station and under comparable housing and feeding conditions. Nursing dams had contact to their calves during the whole day, during night-time or only twice per day shortly before milking. A control group of cows that had no contact to their offspring was part of every experiment. Data of the regular monthly milk recordings were analysed with linear mixed models. Results showed a significant effect of the suckling system on the machine milk yield over the whole lactation. While cows with night-time contact reached the milk production level of the control cows, cows with whole day or short-time contact still produced less milk after the calves were separated. Fat content was always lower during the suckling period but not afterwards. The significantly higher milk protein content in dams with calf contact requires further investigation. Somatic cell count in milk of nursing dams was slightly increased, probably due to the exposure of the teats to frequent suckling in addition to machine milkings. In conclusion, cow-calf contact systems influence the performance of cows during and after the suckling period but to varying degrees depending on the system adopted.

7.
J Dairy Res ; 87(S1): 115-121, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33213593

RESUMO

In this Research Reflection we describe a common standpoint on suitable methodology for controlled and observational studies in cow-calf contact systems in dairy production. Different methods to assess behaviour, health and production in cow-calf contact systems are outlined. Knowledge and experience from researchers working in this field supplement scientific literature whenever relevant. Specific methods including study design, early behaviour of cow and calf, social behaviour relevant to cow-calf contact systems, human-animal relationships and aspects related to management (milking, weaning and separation, health) are reviewed, and recommendations formed. We expect that this paper can contribute to a better understanding of the complexity of cow-calf contact systems and help to advance research in this area of dairy production.

8.
EBioMedicine ; 60: 102989, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32920368

RESUMO

BACKGROUND: Stem cells` (SC) functional heterogeneity and its poorly understood aetiology impedes clinical development of cell-based therapies in regenerative medicine and oncology. Recent studies suggest a strong correlation between the SC migration potential and their therapeutic efficacy in humans. Designating SC migration as a denominator of functional SC heterogeneity, we sought to identify highly migrating subpopulations within different SC classes and evaluate their therapeutic properties in comparison to the parental non-selected cells. METHODS: We selected highly migrating subpopulations from mesenchymal and neural SC (sMSC and sNSC), characterized their features including but not limited to migratory potential, trophic factor release and transcriptomic signature. To assess lesion-targeted migration and therapeutic properties of isolated subpopulations in vivo, surgical transplantation and intranasal administration of MSCs in mouse models of glioblastoma and Alzheimer's disease respectively were performed. FINDINGS: Comparison of parental non-selected cells with isolated subpopulations revealed superior motility and migratory potential of sMSC and sNSC in vitro. We identified podoplanin as a major regulator of migratory features of sMSC/sNSC. Podoplanin engineering improved oncovirolytic activity of virus-loaded NSC on distantly located glioblastoma cells. Finally, sMSC displayed more targeted migration to the tumour site in a mouse glioblastoma model and remarkably higher potency to reduce pathological hallmarks and memory deficits in transgenic Alzheimer's disease mice. INTERPRETATION: Functional heterogeneity of SC is associated with their motility and migration potential which can serve as predictors of SC therapeutic efficacy. FUNDING: This work was supported in part by the Robert Bosch Stiftung (Stuttgart, Germany) and by the IZEPHA grant.

9.
EBioMedicine ; 60: 102987, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32942121

RESUMO

BACKGROUND: Limited knowledge of stem cell therapies` mechanisms of action hampers their sustainable implementation into the clinic. Specifically, the interactions of transplanted stem cells with the host vasculature and its implications for their therapeutic efficacy are not elucidated. We tested whether adhesion receptors and chemokine receptors on stem cells can be functionally modulated, and consequently if such modulation may substantially affect therapeutically relevant stem cell interactions with the host endothelium. METHODS: We investigated the effects of cationic molecule polyethylenimine (PEI) treatment with or without nanoparticles on the functions of adhesion receptors and chemokine receptors of human bone marrow-derived Mesenchymal Stem Cells (MSC). Analyses included MSC functions in vitro, as well as homing and therapeutic efficacy in rodent models of central nervous system´s pathologies in vivo. FINDINGS: PEI treatment did not affect viability, immunomodulation or differentiation potential of MSC, but increased the CCR4 expression and functionally blocked their adhesion receptors, thus decreasing their adhesion capacity in vitro. Intravenously applied in a rat model of brain injury, the homing rate of PEI-MSC in the brain was highly increased with decreased numbers of adherent PEI-MSC in the lung vasculature. Moreover, in comparison to untreated MSC, PEI-MSC featured increased tumour directed migration in a mouse glioblastoma model, and superior therapeutic efficacy in a murine model of stroke. INTERPRETATION: Balanced stem cell adhesion and migration in different parts of the vasculature and tissues together with the local microenvironment impacts their therapeutic efficacy. FUNDING: Robert Bosch Stiftung, IZEPHA grant, EU grant 7 FP Health.

11.
BMC Health Serv Res ; 9: 145, 2009 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-19671164

RESUMO

BACKGROUND: Multimorbidity is a highly frequent condition in older people, but well designed longitudinal studies on the impact of multimorbidity on patients and the health care system have been remarkably scarce in numbers until today. Little is known about the long term impact of multimorbidity on the patients' life expectancy, functional status and quality of life as well as health care utilization over time. As a consequence, there is little help for GPs in adjusting care for these patients, even though studies suggest that adhering to present clinical practice guidelines in the care of patients with multimorbidity may have adverse effects. METHODS/DESIGN: The study is designed as a multicentre prospective, observational cohort study of 3.050 patients aged 65 to 85 at baseline with at least three different diagnoses out of a list of 29 illnesses and syndromes. The patients will be recruited in approx. 120 to 150 GP surgeries in 8 study centres distributed across Germany. Information about the patients' morbidity will be collected mainly in GP interviews and from chart reviews. Functional status, resources/risk factors, health care utilization and additional morbidity data will be assessed in patient interviews, in which a multitude of well established standardized questionnaires and tests will be performed. DISCUSSION: The main aim of the cohort study is to monitor the course of the illness process and to analyse for which reasons medical conditions are stable, deteriorating or only temporarily present. First, clusters of combinations of diseases/disorders (multimorbidity patterns) with a comparable impact (e.g. on quality of life and/or functional status) will be identified. Then the development of these clusters over time will be analysed, especially with regard to prognostic variables and the somatic, psychological and social consequences as well as the utilization of health care resources. The results will allow the development of an instrument for prediction of the deterioration of the illness process and point at possibilities of prevention. The practical consequences of the study results for primary care will be analysed in expert focus groups in order to develop strategies for the inclusion of the aspects of multimorbidity in primary care guidelines.


Assuntos
Comorbidade/tendências , Atenção Primária à Saúde , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Alemanha , Humanos , Entrevistas como Assunto , Masculino , Estudos Prospectivos
12.
J Gen Virol ; 84(Pt 5): 1253-1259, 2003 May.
Artigo em Inglês | MEDLINE | ID: mdl-12692291

RESUMO

It was demonstrated using self-replicating hepatitis C virus (HCV) RNAs that both types of interferons (IFNs) (in particular IFN-alpha and IFN-gamma) are potent inhibitors of HCV replication in Huh-7 cells. Because IFN-gamma and tumour necrosis factor (TNF)-alpha trigger a partially overlapping set of antiviral defence mechanisms, it is tempting to speculate that TNF-alpha also inhibits HCV replication. However, this study shows that TNF-alpha does not affect HCV protein and RNA synthesis, nor does it synergistically enhance the inhibitory effect of IFN-gamma. Taken together, these results demonstrate that HCV replication in Huh-7 cells is highly resistant to TNF-alpha. It is, therefore, unlikely that the increased production of TNF-alpha, which is seen in many hepatitis C patients, contributes to HCV clearance by inducing antiviral defence mechanisms in infected hepatocytes.


Assuntos
Hepacivirus/patogenicidade , RNA Viral/biossíntese , Fator de Necrose Tumoral alfa/farmacologia , Replicação Viral/efeitos dos fármacos , Antivirais/farmacologia , Farmacorresistência Viral , Hepacivirus/genética , Hepacivirus/fisiologia , Humanos , Interferon gama/farmacologia , Células Tumorais Cultivadas
13.
Hepatology ; 35(3): 694-703, 2002 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-11870386

RESUMO

Persistent infection with hepatitis C virus (HCV) is a major cause of chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma. All treatments known so far rely on the antiviral activity of interferon alfa (IFN-alpha) that is given alone or in combination with ribavirin. Unfortunately, only a fraction of the patients clear the virus during therapy and for those who do not respond there is currently no alternative treatment. Selectable subgenomic HCV RNAs (replicons) have been recently used to investigate the effect of IFN-alpha on HCV replication. However, it has not yet been analyzed whether other cytokines also play a role in the innate immune response against HCV. Here we show that IFN-gamma inhibits protein synthesis and RNA replication of subgenomic and genomic HCV replicons. We further show that the inhibitory action of IFN-gamma does not rely on the production of nitric oxide or the depletion of tryptophan. In conclusion, our results suggest that cytotoxic T cells and natural killer cells may contribute to HCV clearance not only by cell killing but also by producing IFN-gamma, thereby enhancing the intracellular inhibition of viral replication.


Assuntos
Hepacivirus/efeitos dos fármacos , Interferon gama/farmacologia , RNA Viral/biossíntese , Replicação Viral/efeitos dos fármacos , Hepacivirus/genética , Humanos , Interferon Tipo I/biossíntese , Óxido Nítrico/biossíntese , Óxido Nítrico Sintase/fisiologia , Óxido Nítrico Sintase Tipo II , Replicon/efeitos dos fármacos , Triptofano/metabolismo , Células Tumorais Cultivadas , Proteínas não Estruturais Virais/metabolismo
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