THE ROLE OF THE MURINE HOMEOBOX GENE CUX-1 IN KIDNEY DEVELOPMENT AND POLYCYSTIC KIDNEY DISEASE

The murine homeobox gene cux-1 is evolutionarily conserved in drosophila, mice and humans. Cux-1 contains four DNA binding domains (3 cut repeat domains and a homeodomain) and functions as a transcription factor that represses the expression of the cyclin kinase inhibitor p27 during S-phase of the cell-cycle. Cux-1 is highly expressed in proliferating cells within the nephrogenic zone of developing kidneys. The role of Cux-1 during kidney development and Polycystic Kidney Disease (PKD) is unclear. Cux-1 is a transcription factor that binds to DNA when it is dephosphorylated. Calcineurin A (CnA) is a phosphatase that might be involved in regulating Cux-1 as both are expressed during early kidney development. Previous studies demonstrated that CnA knockout (-/-) mice display renal hypoplasia associated with ectopic expression of p27 in the nephrogenic zone. The opposite phenotype was observed when Cux-1 is overexpressed. Therefore metanephric kidney cultures, overexpressing Cux-1 were grown in the presence of cyclosporine A to inhibit Calcineurin. Overexpression of Cux-1 rescued growth inhibition due to Calcineurin inhibition. Calcineurin inhibition resulted in increased phospho-Cux-1 levels suggesting that Calcineurin may regulate Cux-1 and thus revealing a new pathway in kidney development. The cpk mouse model is the most widely characterized model for PKD. A hallmark of PKD is increased cell proliferation. The mechanism of cell proliferation in PKD is unclear although deregulation of cyclin kinase inhibitors appears to be involved. Cux-1 is highly expressed in cpk kidneys, however it is unclear if Cux-1 is required for PKD. The results here demonstrate that a mutation of Cux-1 (cux-1∆CR1) which lacks a Cathepsin-L proteolytic cleavage site, results in severe PKD when crossed onto cpk mice. Upregulation of Cux-1∆CR1 was observed and correlated with attenuated levels of p27 within cpk kidneys which suggests a potential mechanism for the acceleration of PKD. Alteration of the PKD phenotype by Cux-1 suggests that Cux-1 may act as a candidate modifier gene of PKD. The collection of studies presented within this body of work has helped to elucidate the importance of Cux-1 regulation by post-translational modification which requires further investigation as a critical factor in kidney development and PKD

A Bibliography for After Jews and Arabs

"Ammiel Alcalay’s groundbreaking work, After Jews and Arabs, published in 1993, redrew the geographic, political, cultural, and emotional map of relations between Jews and Arabs in the Levantine/Mediterranean world over a thousand-year period. Based on over a decade of research and fieldwork in many disciplines—including history and historiography; anthropology, ethnography, and ethnomusicology; political economy and geography; linguistics; philosophy; and the history of science and technology—the book presented a radically different perspective than that presented by received opinion. Given the radical and iconoclastic nature of Alcalay’s perspective, After Jews and Arabs met great resistance in attempts to publish it. Though completed and already circulating in 1989, it didn’t appear until 1993. In addition, when the book was published, there wasn’t enough space to include its original bibliography, a foundational part of the project. A Bibliography for After Jews and Arabs presents the original bibliography, as completed in 1992, without changes, as a glimpse into the historical record of a unique scholarly, political, poetic, and cultural journey. The bibliography itself had roots in research begun in the late 1970s and demonstrates a very wide arc. In addition to the bibliography, we include two accompanying texts here. In “Behind the Scenes: Before After Jews and Arabs,” Alcalay takes us behind the closed doors of the academic process, reprinting the original readers reports and his detailed rebuttals, and in “On a Bibliography for After Jews and Arabs,” Alcalay contextualizes his own path to the work he undertook, in methodological, historical, and political terms.

Comparing Multiple Stimulus Preference Assessments to the In-the-Moment Reinforcer Analysis

The provision of reinforcement to increase desired behaviors is a crucial element of behavior analytic intervention for individuals diagnosed with Autism Spectrum Disorder. Formal preference assessments, like the multiple stimulus without replacement procedure (MSWO), are often used to determine reinforcers used during intervention. While these types of assessments have been widely investigated, there is no empirical evidence to support that these rigorous methods of reinforcement identification produce higher rates of responding compared to the in-the-moment reinforcer analysis. The present study compared the average number of chips sorted per session on a sorting task when participants were reinforced with items selected based on an MSWO preference assessment versus items provided using in-the-moment reinforcer analysis. The results showed no significant difference in the average number of chips sorted, however there were differences in terms of efficiency

A Bibliography for After Jews and Arabs

"Ammiel Alcalay’s groundbreaking work, After Jews and Arabs, published in 1993, redrew the geographic, political, cultural, and emotional map of relations between Jews and Arabs in the Levantine/Mediterranean world over a thousand-year period. Based on over a decade of research and fieldwork in many disciplines—including history and historiography; anthropology, ethnography, and ethnomusicology; political economy and geography; linguistics; philosophy; and the history of science and technology—the book presented a radically different perspective than that presented by received opinion. Given the radical and iconoclastic nature of Alcalay’s perspective, After Jews and Arabs met great resistance in attempts to publish it. Though completed and already circulating in 1989, it didn’t appear until 1993. In addition, when the book was published, there wasn’t enough space to include its original bibliography, a foundational part of the project. A Bibliography for After Jews and Arabs presents the original bibliography, as completed in 1992, without changes, as a glimpse into the historical record of a unique scholarly, political, poetic, and cultural journey. The bibliography itself had roots in research begun in the late 1970s and demonstrates a very wide arc. In addition to the bibliography, we include two accompanying texts here. In “Behind the Scenes: Before After Jews and Arabs,” Alcalay takes us behind the closed doors of the academic process, reprinting the original readers reports and his detailed rebuttals, and in “On a Bibliography for After Jews and Arabs,” Alcalay contextualizes his own path to the work he undertook, in methodological, historical, and political terms.

Experimental study of scattering in atom- surface collisions with atom energies of the order of eV

Supersonic molecular beams applied to study of interactions of neutral-particle beams with solid surface

Precision medicine in Parkinson’s disease: emerging treatments for genetic Parkinson’s disease

In recent years, numerous clinical trials for disease modification in Parkinson’s disease (PD) have failed, possibly because of a “one-size-fits all” approach. Alternatively, a precision medicine approach, which customises treatments based on patients’ individual genotype, may help reach disease modification. Here, we review clinical trials that target genetic forms of PD, i.e., GBA-associated and LRRK2-associated PD. In summary, six ongoing studies which explicitely recruit GBA-PD patients, and two studies which recruit LRRK2-PD patients, were identified. Available data on mechanisms of action, study design, and challenges of therapeutic trials are discussed. Parkinson’s disease (PD) is the second most common neurodegenerative disorder, affecting more than 6 million people worldwide [1]. Numerous drugs for the treatment of PD are avilable on the market. While drugs targeting the dopaminergic pathway treat motor symptoms, there is no evidence that they modify disease progression. This “one-size-fits all” approach may very well explain why clinical trials for disease modification in PD have failed. Treatments that target the underlying pathophysiology are required. Since the pathophysiology of PD may be different in different patients, studies should be designed that assess PD treatment on a more individual basis. Therefore, a precision medicine approach in PD is very timely

Effect of psoralens and ultraviolet radiation on murine dendritic epidermal cells

AbstractMonofunctional psoralens produce less phototoxicity than bifunctional psoralens after ultraviolet A (UVA) irradiation. We investigated the effect of repetitive treatments with angelicin (isopsoralen), a monofunctional psoralen, plus UVA radiation (IPUVA) on the number and morphology of dendritic epidermal cells (dEC). This effect was compared with that of 8-methoxypsoralen plus UVA radiation (PUVA), UVA alone, and UVB radiation. C3H/HeN mice were treated topically with the drugs three times/wk for 4 consecutive wk; followed each time by 1 or 2.5 J/cm2 of UVA radiation. Other groups of mice were treated with the drugs alone, UVA alone, or 0.81 J/cm2 of UVB. Epidermal sheets were stained for ATPase, Ia, and Thy-1 markers. Mice treated with PUVA and UVB exhibited severe phototoxicity, whereas no overt phototoxicity was observed in mice treated with IPUVA, UVA alone, or the drugs alone. Early during the PUVA and UVA treatments the ATPase marker was lost from dEC, followed by loss of the Ia marker; the Ia marker was lost before the ATPase marker from dEC in animals treated with IPUVA. At the end of the treatment, however, nearly total depletion of ATPase+, Ia+, and Thy-1+ dEC was observed in mice treated with PUVA and IPUVA. UVB radiation caused rapid depletion of Thy-1+ dEC as well as ATPase+ and Ia+ cells. During treatments with IPUVA, PUVA, UVA, and UVB, the Langerhans cells became rounded and lost their dendrites. These changes were quantitated by image analysis. We conclude that alterations of cutaneous immune cells can occur in the absence of overt phototoxicity, and that monofunctional and bifunctional psoralens plus low dose of UVA radiation may have different effects on dEC markers

Emerging Targeted Therapeutics for Genetic Subtypes of Parkinsonism

In recent years, a precision medicine approach, which customizes medical treatments based on patients' individual profiles and incorporates variability in genes, the environment, and lifestyle, has transformed medical care in numerous medical fields, most notably oncology. Applying a similar approach to Parkinson's disease (PD) may promote the development of disease-modifying agents that could help slow progression or possibly even avert disease development in a subset of at-risk individuals. The urgent need for such trials partially stems from the negative results of clinical trials where interventions treat all PD patients as a single homogenous group. Here, we review the current obstacles towards the development of precision interventions in PD. We also review and discuss the clinical trials that target genetic forms of PD, i.e., GBA-associated and LRRK2-associated PD