Biomedical subjects

Nicole Müller

Publications and source records attributed to Nicole Müller.

10 recordsLinked to original sources

PubMed2006

Sustained JNK activation in response to tumor necrosis factor is mediated by caspases in a cell type-specific manner.

In most cell types, tumor necrosis factor (TNF) induces a transient activation of the JNK pathway. However, in NFkappaB-inhibited cells, TNF stimulates also a second sustained phase of JNK activation, which has been implicated in cell death induction. In the present study, we have analyzed the relationship of cell death induction, caspase activity, JNK, and NFkappaB stimulation in the context of TNF signaling in four different cellular systems. In all cases, NFkappaB inhibition enhanced TNF-induced cell death and primed most, but not all, cells for sustained JNK activation. The caspase inhibitor Benzyloxycarbonyl-Val-Ala-Asp(OMe)-fluoromethyl ketone (Z-VAD-fmk) and overexpression of the antiapoptotic proteins FLIP-L and Bcl2 differentially blocked transient and sustained JNK activation in NFkappaB-inhibited KB and HaCaT cells, indicating that the two phases of TNF-induced JNK activation occur at least in these cellular models by different pathways. Although the broad range caspase inhibitor Z-VAD-fmk and the antioxidant butylated hydroxyanisole interfered with TNF-induced cell death to a varying extent in a cell type-specific manner, inhibition of JNK signaling had no or only a very moderate effect. Notably, the JNK inhibitory effect of neither Z-VAD-fmk nor butylated hydroxyanisole was strictly correlated with the capability of these compounds to rescue cells from TNF-induced cell death. Thus, sustained JNK activation by TNF has no obligate role in TNF-induced cell death and is mediated by caspases and reactive oxygen species in a cell type-specific manner.

Animals↗

PubMed2006

A CD40-CD95L fusion protein interferes with CD40L-induced prosurvival signaling and allows membrane CD40L-restricted activation of CD95.

We analyzed a novel bifunctional fusion protein, CD40ed-CD95Led, consisting amino-terminally of the extracellular domain of CD40 and carboxy-terminally of the extracellular domain of CD95L. On cells lacking CD40L, this fusion protein is poorly active with respect to CD95 activation [median effective dose (ED50)>1 microg/ml], but it stimulates CD95 signaling with high efficiency upon binding to membrane-expressed CD40L (ED50<1 ng/ml). Thus, cell surface immobilization mediated by the CD40 part of the molecule unmasks the high-latent, CD95-stimulating capacity of the otherwise poorly active CD95L fusion protein. Moreover, interaction of the CD40 part of CD40ed-CD95Led with CD40L prevents the activation of cellular CD40. The CD40ed-CD95Led fusion protein therefore simultaneously blocks antiapoptotic CD40 activation and induces CD95-mediated apoptosis. Indeed, T47D cells displaying an antiapoptotic autocrine CD40-CD40L signaling loop were significantly more sensitive toward CD40ed-CD95Led than toward soluble CD95L artificially activated by crosslinking. Fusion proteins of RANK and CD95L (RANKed-CD95Led) and CD40 and tumor necrosis factor-related apoptosis inducing ligand (TRAIL) (CD40ed-TRAILed), with domain architectures similar to CD40ed-Cd95Led, displayed RANKL-dependent CD95 and CD40L-dependent TRAILR2 activation, respectively, indicating the principle feasibility of this fusion protein design.

Animals↗

PubMed2005

Reduction of spermatogenesis but not fertility in Creb3l4-deficient mice.

Creb3l4 belongs to the CREB/ATF family of transcription factors that are involved in mediating transcription in response to intracellular signaling. This study shows that Creb3l4 is expressed at low levels in all organs and in different stages of embryogenesis but is present at very high levels in the testis, particularly in postmeiotic male germ cells. In contrast to CREB3L4 in the human prostate, of which specific expression was detected, Creb3l4 transcripts in the mouse prostate could be detected only by RT-PCR. To identify the physiological function of Creb3l4, the murine gene was inactivated by replacement with the gene encoding green fluorescent protein. Surprisingly, Creb3l4-deficient mice were born at expected ratios, were healthy, and displayed normal long-term survival rates. Despite a significant reduction in the number of spermatozoa in the epididymis of Creb3l4(-)(/)(-) mice, the breeding of mutant males with wild-type females was productive and the average litter size was not significantly altered in comparison to wild-type littermates. Further analyses revealed that the seminiferous tubules of Creb3l4(-)(/)(-) mice contained all of the developmental stages, though there was evidence for increased apoptosis of meiotic/postmeiotic germ cells. These results suggest that Creb3l4 plays a role in male germ cell development, but its loss is insufficient to completely compromise the production of spermatozoa.

Acrosome Reaction↗

PubMed2004

Owning up to complexity: a sociocultural orientation to attention deficit hyperactivity disorder.

To enrich our conception of attention deficit hyperactivity disorder (ADHD), it is necessary to take a wider orientation to this disability category than has been advocated traditionally. Over the past decade, there has been an emerging conception of ADHD from a sociocultural perspective, and this orientation, when linked to the traditional biomedical perspective, provides a more accurate and authentic construct of ADHD. In this article, we advocate that speech-language pathologists approach ADHD with a mindset that is open to the complexities of context-bound human functioning at all levels. Four sources of data demonstrating the richness of the sociocultural orientation are presented and clinical implications are detailed

Attention Deficit Disorder with Hyperactivity↗

PubMed2002

Smad4 induces the tumor suppressor E-cadherin and P-cadherin in colon carcinoma cells.

Smad4 is an intracellular transmitter of TGF-beta signals and its tumor suppressor function is presumed to reside in its capacity to mediate TGF-beta-induced growth inhibition. However, there is accumulating evidence that this hypothesis may be too simple. The roles of TGF-beta in carcinogenesis are complex and also comprise tumor promoting functions particularly in late stage carcinogenesis. Importantly, functional inactivation of Smad4 in colon carcinomas frequently occurs at late stages when tumors acquire invasive and metastatic capabilities. We have previously reported that stable re-expression of Smad4 in SW480 human colon carcinoma cells was adequate to suppress tumor growth in nude mice. However, it did not affect cell growth in vitro nor did it restore TGF-beta responsiveness. Here, we report that Smad4 transcriptionally induced classical cadherins including the invasion suppressor E-cadherin, presumably re-establishing epithelial morphology. Smad4-induced cadherins were able to recruit catenins to the plasma membrane and were functionally active in cell-cell adhesion. These results indicate a novel pathway of Smad4-mediated tumor suppression and suggest that Smad4 in colon cells may be involved in the maintenance of epithelial traits.

Animals↗

PubMedDate not supplied

Transcribing discourse: interactions with Alzheimer's disease.

This paper illustrates the use of a 'discourse line' in transcribing spoken interaction between a person with Alzheimer's disease, and a visitor. Discourse is here interpreted as a metacategory, or an analytic level of interaction. We view transcribing as an integral part of 'doing discourse', and use two sub-layers of the discourse line, dedicated to speech acts and conversation analysis, respectively. The prosody and voice layer is used to show the analysis of a speaker's use of a specific voice quality in discourse terms.

Adult↗

PubMedDate not supplied

A transcription toolkit: theoretical and clinical considerations.

This paper discusses theoretical and clinical aspects of transcription practices in clinical linguistics and phonetics, and speech-language pathology. We consider the purpose of transcribing and transcripts, and distinguish between the transcript as a product and transcribing as a complex, cyclical process that forms an integral part of data analysis. Operational relationships between transcriber, data and data source, and the reader are addressed. We suggest a multi-layered toolkit approach to transcribing, based on six guiding principles.

Communication↗

PubMedDate not supplied

Electronic publishing: opportunities and challenges for clinical linguistics and phonetics.

This paper discusses the contributions of informatics technology to the field of clinical linguistics and phonetics. The electronic publication of research reports and books has facilitated both the dissemination and the retrieval of scientific information. Electronic archives of speech and language corpora, too, stimulate research efforts. Although technology provides many opportunities, there remain significant challenges. Establishment and maintenance of scientific archives is largely dependent upon volunteer efforts, and there are few standards to ensure long-term access. Coordinated efforts and peer review are necessary to ensure utility and quality.

Humans↗

PubMedDate not supplied

Intelligibility and negotiated meaning in interaction.

Intelligibility is discussed in terms of the process of realizing a potential for mutual understanding, or intersubjectivity. The local management of mutual understanding, and its emergent properties within the context of an interaction are emphasized. Clinical applications of conceptualizing intelligibility as a potential rather than a property of speaker or interaction are discussed.

Acoustics↗

PubMedDate not supplied

Order and disorder in conversation: encounters with dementia of the Alzheimer's type.

After a brief introduction to Dementia of the Alzheimer's Type (DAT), its behavioral diagnostic symptom complex and a summary of communicative implications, we present data from two conversations involving participants with and without DAT. We discuss the concept of "order" in conversation, and the central importance of interactional monitoring. Conversational success and problems in interactions with persons with DAT are seen as emergent from situationally embedded conversations in the presence of cognitive and linguistic impairments on the part of the person with DAT, and of contextually situated communicative impairment resulting therefrom.

Aged↗