Tyrosine hydroxylase deficiency: a treatable disorder of brain catecholamine biosynthesis

Tyrosine hydroxylase deficiency is an autosomal recessive disorder resulting from cerebral catecholamine deficiency. Tyrosine hydroxylase deficiency has been reported in fewer than 40 patients worldwide. To recapitulate all available evidence on clinical phenotypes and rational diagnostic and therapeutic approaches for this devastating, but treatable, neurometabolic disorder, we studied 36 patients with tyrosine hydroxylase deficiency and reviewed the literature. Based on the presenting neurological features, tyrosine hydroxylase deficiency can be divided in two phenotypes: an infantile onset, progressive, hypokinetic-rigid syndrome with dystonia (type A), and a complex encephalopathy with neonatal onset (type B). Decreased cerebrospinal fluid concentrations of homovanillic acid and 3-methoxy-4-hydroxyphenylethylene glycol, with normal 5-hydroxyindoleacetic acid cerebrospinal fluid concentrations, are the biochemical hallmark of tyrosine hydroxylase deficiency. The homovanillic acid concentrations and homovanillic acid/5-hydroxyindoleacetic acid ratio in cerebrospinal fluid correlate with the severity of the phenotype. Tyrosine hydroxylase deficiency is almost exclusively caused by missense mutations in the TH gene and its promoter region, suggesting that mutations with more deleterious effects on the protein are incompatible with life. Genotype-phenotype correlations do not exist for the common c.698G>A and c.707T>C mutations. Carriership of at least one promotor mutation, however, apparently predicts type A tyrosine hydroxylase deficiency. Most patients with tyrosine hydroxylase deficiency can be successfully treated with l-dop

Suppression of p75 Neurotrophin Receptor Surface Expression with Intrabodies Influences Bcl-xL mRNA Expression and Neurite Outgrowth in PC12 Cells

Background: Although p75 neurotrophin receptor (p75NTR) is the first neurotrophin receptor isolated, its diverse physiological functions and signaling have remained elusive for many years. Loss-of-function phenotypic analyses for p75NTR were mainly focused at the genetic level; however these approaches were impacted by off-target effect, insufficient stability, unspecific stress response or alternative active splicing products. In this study, p75NTR surface expression was suppressed for the first time at the protein level by endoplasmic reticulum (ER) retained intrabodies. Results: Three monoclonal recombinant antibody fragments (scFv) with affinities in the low nanomolar range to murine p75NTR were isolated by antibody phage display. To suppress p75NTR cell surface expression, the encoding genes of these scFvs extended by the ER retention peptide KDEL were transiently transfected into the neuron-like rat pheochromocytoma cell line PC12 and the mouse neuroblastoma x mouse spinal cord hybrid cell line NSC19. The ER retained intrabody construct, SH325-G7-KDEL, mediated a downregulation of p75NTR cell surface expression as shown by flow cytometry. This effect was maintained over a period of at least eight days without activating an unfolded protein response (UPR). Moreover, the ER retention of p75NTR resulted in downregulation of mRNA levels of the anti-apoptotic protein Bcl-xL as well as in strong inhibition of NGF-induced neurite outgrowth in PC12 cells. Conclusion: The ER retained intrabody SH325-G7-KDEL not only induces phenotypic knockdown of this p75NTR but als

Isolation and Characterisation of a Human-Like Antibody Fragment (scFv) That Inactivates VEEV In Vitro and In Vivo

Venezuelan equine encephalitis virus (VEEV) belongs to the Alphavirus genus and several species of this family are pathogenic to humans. The viruses are classified as potential agents of biological warfare and terrorism and sensitive detection as well as effective prophylaxis and antiviral therapies are required

μ-PIV and ELDV wind tunnel investigations of the laminar separation bubble above a helicopter blade tip

Detailed studies of the boundary layer profile and the characteristics of the flow velocity distribution close to the leading edge of a helicopter blade profile were conducted using the embedded laser doppler velocimetry (ELDV) and stereo-PIV. The relatively small scales of flow structures related to dynamic stall, motivated an additional 2C-PIV study in which the flow field has been measured with a relatively high spatial resolution. The feasibility of PIV measurements utilizing a mirror telescope in a wind tunnel has been demonstrated successfully. The spatial resolution of approximately 50 μm allowed a judgment on the choice of turbulence models and damping coefficients for the improvement of CFD predictions

Ecologie rurali. Pratiche e forme della coesistenza

ECOLOGIE RURALI — PRATICHE E FORME DELLA COESISTENZA La ruralità è una condizione al tempo stesso delimitata e sconfinata, attiva e ricettiva, prodotta e produttiva, pacificata e conflittuale. Rendere esplicita la consistenza politica e ontologica del rurale, significa ridefinire i modi attraverso i quali, come architetti e urbanisti, ci confrontiamo con questa particolare dimensione operativa. Il rurale è un luogo spesso concepito come spazio da addomesticare, da proteggere, da sfruttare o da far fruttare: uno spazio subalterno. È tempo allora di politicizzare il nostro pensiero sul rurale, di decoloniarne il senso e il progetto, mettendo in discussione i tanti immaginari e approcci teorici, quasi sempre semplificanti, cioè ossificanti, attraverso cui oggi è pensato. Ciò che si cerca è una tensione cognitiva volta ad individuare e porre in relazione una complessa e spesso opaca varietà di ecologie sociali e spaziali al di fuori di qualsiasi operazione. Decolonizzare il pensiero rurale, significa farlo vibrare costantemente, dal momento che in campagna, più che altrove, il potere è ortopedico