Human PrimPol mutation associated with high myopia has a DNA replication defect

PrimPol is a primase-polymerase found in humans, and other eukaryotes, involved in bypassing lesions encountered during DNA replication. PrimPol employs both translesion synthesis and repriming mechanisms to facilitate lesion bypass by the replisome. PrimPol has been reported to be a potential susceptibility gene associated with the development of myopia. Mutation of tyrosine 89 to aspartic acid (PrimPolY89D) has been identified in a number of cases of high myopia, implicating it in the aetiology of this disorder. Here, we examined whether this mutation resulted in any changes in the molecular and cellular activities associated with human PrimPol. We show that PrimPolY89D has a striking decrease in primase and polymerase activities. The hydrophobic ring of tyrosine is important for retaining wild-type extension activity. We also demonstrate that the decreased activity of PrimPolY89D is associated with reduced affinities for DNA and nucleotides, resulting in diminished catalytic efficiency. Although the structure and stability of PrimPolY89D is altered, its fidelity remains unchanged. This mutation also reduces cell viability after DNA damage and significantly slows replication fork rates in vivo. Together, these findings establish that the major DNA replication defect associated with this PrimPol mutant is likely to contribute to the onset of high myopia

Proper Sterol Distribution Is Required for Candida albicans Hyphal Formation and Virulence

Candida albicans is an opportunistic fungus responsible for the majority of systemic fungal infections. Multiple factors contribute to C. albicans pathogenicity. C. albicans strains lacking CaArv1 are avirulent. Arv1 has a conserved Arv1 homology domain (AHD) that has a zinc-binding domain containing two cysteine clusters. Here, we explored the role of the CaAHD and zinc-binding motif in CaArv1-dependent virulence. Overall, we found that the CaAHD was necessary but not sufficient for cells to be virulent, whereas the zinc-binding domain was essential, as Caarv1/Caarv1 cells expressing the full-length zinc-binding domain mutants, Caarv1C3S and Caarv1C28S, were avirulent. Phenotypically, we found a direct correlation between the avirulence of Caarv1/Caarv1, Caarrv1AHD, Caarv1C3S, and Caarv1C28S cells and defects in bud site selection, septa formation and localization, and hyphal formation and elongation. Importantly, all avirulent mutant strains lacked the ability to maintain proper sterol distribution. Overall, our results have established the importance of the AHD and zinc-binding domain in fungal invasion, and have correlated an avirulent phenotype with the inability to maintain proper sterol distribution

Guideline for diagnosis and treatment of subacromial pain syndrome

Treatment of "subacromial impingement syndrome" of the shoulder has changed drastically in the past decade. The anatomical explanation as "impingement" of the rotator cuff is not sufficient to cover the pathology. "Subacromial pain syndrome", SAPS, describes the condition better. A working group formed from a number of Dutch specialist societies, joined by the Dutch Orthopedic Association, has produced a guideline based on the available scientific evidence. This resulted in a new outlook for the treatment of subacromial pain syndrome. The important conclusions and advice from this work are as follows: (1) The diagnosis SAPS can only be made using a combination of clinical tests. (2) SAPS should preferably be treated non-operatively. (3) Acute pain should be treated with analgetics if necessary. (4) Subacromial injection with corticosteroids is indicated for persistent or recurrent symptoms. (5) Diagnostic imaging is useful after 6 weeks of symptoms. Ultrasound examination is the recommended imaging, to exclude a rotator cuff rupture. (6) Occupational interventions are useful when complaints persist for longer than 6 weeks. (7) Exercise therapy should be specific and should be of low intensity and high frequency, combining eccentric training, attention to relaxation and posture, and treatment of myofascial trigger points (including stretching of the muscles) may be considered. (8) Strict immobilization and mobilization techniques are not recommended. (9) Tendinosis calcarea can be treated by shockwave (ESWT) or needling under ultrasound guidance (barbotage). (10) Rehabilitation in a specialized unit can be considered in chronic, treatment resistant SAPS, with pain perpetuating behavior. (11) There is no convincing evidence that surgical treatment for SAPS is more effective than conservature management. (12) There is no indication for the surgical treatment of asymptomatic rotator cuff tears

Platonic Forms and Unicorns: Plato\u27s Philosophy in Peter S. Beagle\u27s The Last Unicorn

Since its publication in 1968, Peter S. Beagle’s enduring fantasy novel The Last Unicorn has captured both the popular and critical imagination. While several critics have noted that Beagle seems to incorporate various aspects of Plato’s philosophy, none have dedicated a focused analysis to this specific textual feature. This thesis explores the way in which The Last Unicorn both invokes and subverts Plato’s dualistic conception of reality and truth , and concludes that it does so in order to construct a vision of reality that recognizes transient, human experiences and knowledge are just as true as transcendent, timeless experiences and knowledge. Special attention is paid to the presence of Plato’s theory of forms, in which he explores the nature of reality and knowledge; his famous Allegory of the Cave, frequently used to illustrate the theory of forms; and his idea of the philosopher-king

Subtractive Plasma-Assisted-Etch Process for Developing High Performance Nanocrystalline Zinc-Oxide Thin-Film-Transistors

Thin-Film-Transistors (TFTs) employing undoped zinc-oxide (ZnO) thin-films are currently being investigated by the Air Force for microwave switching applications. Since the on-resistance (R(on)) of the device scales with channel length (LC), ZnO TFT optimization should be focused on reducing LC, therefore minimizing the associated insertion losses. In this research, deep sub-micron scaling of ZnO TFTs was undertaken using a subtractive reactive-ion-etch (RIE) process. Under optimum processing conditions, ZnO TFTs with LC as small as 155 nm were successfully demonstrated. The active ZnO channels of the TFTs were patterned by selective SF6-RIE of a tungsten ohmic film through electron-beam defined openings in a polymethyl-methacrylate (PMMA) based resist. Through electrical testing, the width normalized R(on) of ZnO TFTs with 155 nm channels was extracted as 3.6 omega dot mm and the devices were found to operate at drain current densities and transconductance values of 830 mA/mm and 121 mS/mm, respectively. Additionally, a total width-normalized source and drain parasitic resistance of 2.1 omega dot mm was observed using a gated transfer length method (TLM), indicating the tungsten-ZnO interface is low resistance. This demonstration of high performance and low R(on) suggests the potential for ZnO TFTs in switching and microwave power applications

Tests of different coals in a Mercer residence-heating boiler (steam)

Thesis (B.S.)--University of Illinois, 1907.Typescript

Donigan Cumming : Continuité et rupture = Donigan Cumming : Continuity and Rupture

In this publication to accompany a series of video screenings, Cumming suggests that issues of continuity and rupture are central to his practice (and all forms of communication). Other topics discussed include: questions concerning the photographic model; issues of affect and place; and the technical transformations that shape Cumming’s work. Includes summaries by the artist on four tapes made between 1995-98. Text in French and English