The formation of ubiquitin rich condensates triggers recruitment of the ATG9A lipid transfer complex to initiate basal autophagy.

Autophagy is an essential cellular recycling process that maintains protein and organelle homeostasis. ATG9A vesicle recruitment is a critical early step in autophagy to initiate autophagosome biogenesis. The mechanisms of ATG9A vesicle recruitment are best understood in the context of starvation-induced non-selective autophagy, whereas less is known about the signals driving ATG9A vesicle recruitment to autophagy initiation sites in the absence of nutrient stress. Here we demonstrate that loss of ATG9A or the lipid transfer protein ATG2 leads to the accumulation of phosphorylated p62 aggregates in the context of basal autophagy. Furthermore, we show that p62 degradation requires the lipid scramblase activity of ATG9A. Lastly, we present evidence that poly-ubiquitin is an essential signal that recruits ATG9A and mediates autophagy foci assembly in nutrient replete cells. Together, our data support a ubiquitin-driven model of ATG9A recruitment and autophagosome formation during basal autophagy.

A versatile, stimulus-responsive nanoparticle-based platform for use in both sonodynamic and photodynamic cancer therapy.

A PLGA-based multifunctional biodegradable nanoparticle platform co-harboring hematoporphyrin and indocyanine green has been developed. In vitro studies demonstrate ultrasound and light stimulated generation of cytotoxic reactive oxygen species. In vivo studies show that the ICG component facilitates nIR fluorescence imaging that demonstrates accumulation of IV- administered nanoparticles in tumours. In vivo studies also demonstrate ultrasound- and light-mediated inhibition of tumour growth in animals treated with the platform. Since the platform consists entirely of clinically-approved agents it could find use in sonodynamic- and photodynamic-based therapies for cancer. STATEMENT OF SIGNIFICANCE: We describe a biocompatible and biodegradable nanoparticle-based platform for use in sonodynamic and photodynamic therapeutic approaches for the treatment of cancer. The non-toxic nanoparticles produce cytotoxic reactive oxygen species when exposed to ultrasound and/or light at levels that have no impact on tissues. The system is unique in that it is accumulated by tumours within six hours and has the ability to release its sensitising capability while retaining its imaging capability within a therapeutic time frame. The former could enhance dispersion and sensitising capabilities in less permeable tumour tissues and the latter permits the design of therapeutic approaches that minimize collateral damage to normal tissues.

A position- and orientation-dependent element in the first intron is required for expression of the mouse hprt gene in embryonic stem cells.

The gene (hprt) coding for mouse HPRT (hypoxanthine phosphoribosyltransferase) is transcribed from a promoter lacking CAAT and TATAA boxes. It is expressed ubiquitously, albeit at different levels, in all tissues and cultured cells. During investigations to characterise hprt transcription control elements required in embryonic stem (ES) cells and to develop compact hprt minigenes for gene-targeting strategies, we discovered a requirement for intron-1 sequences for expression in ES cells. The essential intron-1 element, which is 420 bp long, is located 230 bp downstream from the transcription start point and is shown to increase transcription from the hprt promoter in a position- and orientation-dependent manner. We propose that this element is an integral downstream part of the hprt promoter.

Productivity management: applying it personally and professionally.

Productivity management is a major step in analyzing and documenting our professional tasks. Defining ratios, measuring, and evaluating are the first steps in accounting to consumers, employees, government bodies, and ourselves for our resources and services. Self-evaluation with empirical productivity data can provide the key information necessary for growth and change in the individual and, in turn, in the organization. Professional productivity management can be a managerial tool essential in documenting our professional worth. The significance of productivity management to the individual and her/his career needs to be self-examined by every dietetic professional. Well-defined goals and documented accomplishments are important, if not essential, to our existence as a profession. We can no longer afford not to accept the responsibility to manage and improve our professional lives.

Food item inventory instructional simulation using microcomputers.

The purpose of this study was to teach the management concepts of perpetual and periodic inventory systems to university students through a food item inventory instructional simulation using microcomputers. The objective of the study was to determine the simulation's effectiveness in enhancing students' understanding of inventory systems management. The participants were senior and graduate students enrolled in a foodservice procurement and inventory systems course at Oregon State University, Corvallis. The population consisted of 68 students, with 34 in the experimental group and 34 in the control group. All the participants completed a pretest to measure existing knowledge of inventory management concepts. This was followed by two classroom lectures, each 50 minutes long, on inventory systems management in foodservice facilities. Members of the experimental group participated in using the food item inventory simulation and study guide after attending both classroom lectures. All the participants of the experimental and control groups completed a post-test 3 weeks after the pretest. The difference in post-test adjusted mean scores between the experimental and control groups was significant (p less than or equal to .05) as determined by analysis of covariance. Therefore, the food item inventory instructional simulation using microcomputers was effective in enhancing students' understanding of the management of perpetual and periodic inventory systems.

Job sharing at the managerial level.

Job sharing restructures a full-time position-two individuals share the responsibilities and the benefits of the position. If nurses are committed to making it work, this arrangement can succeed at the managerial level.

Total aneuploidy and age-related sex chromosome aneuploidy in cultured lymphocytes of normal men and women.

In PHA-cultured lymphocytes, about 8% of metaphases from 32 women were aneuploid compared to 4% of metaphases from 35 men. A significant part of this aneuploidy was characterized by sex chromosome involvement: in women, the loss of gain of X chromosomes; in men, the gain of X chromosomes and the loss or gain of Y chromosomes. The incidence of this aneuploidy was positively age-related for both sexes. Premature division of the X-chromosome centromere was closely associated with X-chromosome aneuploidy in women and men, and appeared to be the mechanism of non disjunction causing this aneuploidy. Premature centromere division (PCD) indicated a dysfunction of the X-chromosome centromere with aging, and this dysfunction was the basic cause of age-related aneuploidy. A similar mechanism of nondisjunction may operate for the Y chromosome of men, but could not be clearly demonstrated because of the low incidence of Y-chromosome aneuploidy. The balance of the aneuploidy was characterized by chromosome loss and the involvement of all chromosome groups. It was consistent with chromosome loss from metaphase cells damaged during preparation for cytogenetic examination.

Recent advances in medical imaging: surgery planning and simulation.

Three-dimensional display of medical image data has under gone rapid development since its introduction. This article explores the current state-of-the-art of 3-dimensional imaging applied to surgery planning and discusses the various image acquisition sources: computed tomography (CT), cine CT, magnetic resonance imaging, and ultrasound. Since increased physician involvement is the goal of the surgery planning software described, the future directions discussed emphasize the inclusion of "expert" knowledge and ways to facilitate realistic interaction for surgery simulation.

Lack of involvement of nucleotide excision repair gene polymorphisms in colorectal cancer.

DNA repair has an essential role in protecting the genome from damage by endogenous and environmental agents. Polymorphisms in DNA repair genes and differences in repair capacity between individuals have been widely documented. For colorectal cancer, the loss of mismatch repair gene activity is a key genetic determinant. Nucleotide excision repair (NER), recombination repair (RR) and base excision repair (BER) pathways have critical roles in protection against other cancers, and we wished to investigate their role in colorectal cancer. We have compared the frequency of polymorphisms in the NER genes, XPD, XPF, XPG, ERCC1; in the BER gene, XRCC1; and in the RR gene, XRCC3; in colorectal cancer patients and in a control group. No significant associations were found for any of the NER gene polymorphisms or for the XRCC1 polymorphism. The C allele (position 18067) of the XRCC3 gene was weakly but significantly associated with colorectal cancer (odds ratio 1.52, 95% confidence interval 1.04-2.22, P=0.03). For all patients who were heterozygous for any of the repair genes studied, tumour tissue was investigated for loss of heterozygosity (LOH). Only one example of LOH was found for all the genes examined. From the association and LOH data, we conclude that these genes do not have an important role in protection against colorectal carcinogenesis.

'Video, health education and the General Practitioner Contract'.

The 1990 General Practitioner Contract and the 1993 Contract Revision emphasised the role of health education/health promotion within primary care. In this paper, the authors suggest that a highly cost-effective approach is necessary given the premium on time available for general practitioners and members of the primary health care team to undertake such work. The views of general practitioners and the primary health care team in a random sample of general practices within all 15 Health Board areas in Scotland were sought between 1991 and 1993 regarding current experience and future potential in using video-based health education materials, with particular emphasis on the content, structure and parameters appropriate to running effective health education/health promotion programmes. This study has indicated the potential demand for high quality, appropriately targeted video-based materials for use by primary health care workers within a range of practice, community and home settings. Central to this is the need for a better system of information and dissemination of materials and a firmer evaluation framework for health education/health promotion programmes within primary care. The progress of several policy, management and research issues which arose from the findings of the study have been raised by the authors. These include implications for the NHS such as infrastructure resourcing and priority setting, programme development, information and dissemination, research and evaluation, and mechanism(s) whereby general practitioners can be better involved in this process.

Nitrogen-fixing aerobic bacteria have higher genomic GC content than non-fixing species within the same genus.

The genomic GC contents of both nitrogen-fixing and non-fixing members of eight genera of bacteria are investigated. Analysis by t-tests showed that in the two aerobic general investigated (Aquaspirillum and Vibrio) there is a significantly higher GC content in the nitrogen-fixing members of the genus than in those unable to fix nitrogen, whilst in aerobic genera there is either no GC bias, or in the case of two genera (Rhodospirillum and Clostridium) there is a significantly higher GC content in the non-fixing organisms. This suggests that, in many genera, directional mutational pressures are different in nitrogen-fixing and non-fixing organisms. These results are discussed in the light of known mechanisms of mutation pressure and their relation to environmental variables.

The application of liposuction for removal of hematomas and fat necrosis.

The standard liposuction apparatus with 1.5-mm spatula cannula has been used to aspirate hematomas early and to debride areas of fat necrosis. This technique has proved to be of great value in hematomas following face lifting and posttraumatic scalp hematomas and in fat necrosis generally.

How to involve hard to reach groups: a consumer-led project with lay carers of people with advanced HIV infection.

The identification and provision of support to lay carers is crucial if Health Authorities are to meet the identified health care needs of their populations. This paper outlines in Part One the process for recruiting a defined but potentially hard to reach group, namely lay carers of people with advanced HIV infection, into a project designed as part of an ongoing development in HIV/AIDS education, the specific difficulties encountered, and how these were overcome. Part Two describes how to make a video, highlighting the involvement of carers in all stages of the research and development of a health education video-based resource package. Crucial to overcoming many of the difficulties and in winning the confidence and trust of the carers was the overview throughout of a committed multi-disciplinary Steering Group, the emphasis on confidentiality, the support of colleagues in the six UK centres, and the sensitivity and skills of the university research and production facilitators. This process ensured that the carers as consumers were involved in a continuing and active dialogue through the project.

Richter's syndrome with identification of marker chromosomes.

A case is presented of a man with Richter's syndrome with diffuse histiocytic lymphoma following a ten-year history of untreated chronic lymphatic leukemia. He did not respond to therapy. The lymphoma cells had 61 chromosomes with aneuploidy of 13 chromosomes and 11 structurally altered chromosomes. Only chromosomes 8, 9, 12, 14, and 18 were diploid and without abnormality. Significantly, part of chromsome 1q was duplicated as in the partial trisomy of 1q reported to characterize a number of hematologic neoplasms. A large marker chromosome with subterminal centromere was a tandem duplication of chromosome 4q.

Expression of the mouse HPRT gene: deletional analysis of the promoter region of an X-chromosome linked housekeeping gene.

The mouse hypoxanthine phosphoribosyltransferase gene, like several other housekeeping genes, lacks many of the features associated with promoters of RNA polymerase II-transcribed genes. HPRT transcripts have multiple initiation sites and an HPRT minigene was used to show that only 49 bases of 5' flanking sequence was necessary for normal expression in cultured cells. The essential region, which occurs within a complex series of direct repeats, is homologous to sequences upstream of other housekeeping genes. When this sequence was deleted, cryptic upstream initiation sites were revealed. Similar aberrant patterns of initiation were seen with all minigenes assayed in Xenopus oocytes. We speculate that this region of the HPRT promoter is involved in a different interaction with the transcriptional machinery to that occurring at more conventional promoters.

Malignant melanoma of the conjunctiva.

The clinicopathological features of 37 patients with invasive melanoma of the conjunctiva have been studied. Prognosis was closely related to the subsite and size of the primary tumour. Twenty of 21 patients with small localized bulbar neoplasms (95%) and four of six patients with diffuse bulbar melanomas (67%) have survived with no evidence of secondary spread. By contrast, only one of six patients with neoplasms involving the fornix (17%) and two of four (50%) with caruncular melanomas have survived. Metastatic spread was very uncommon in patients with melanomas less than 1.5 mm in maximum thickness, but the outcome of the disease in patients with tumours greater than 1.5 mm was not always bad. Treatment by local excision biopsy was followed by a high rate of conjunctival recurrence (59%). Exenteration of the affected eye guarded against the development of further orbital disease, but was not infrequently followed by the appearance of metastases. Many (62%) of the tumours appeared to have arisen in a pre-existing melanotic lesion or pigmented naevus of long-standing. Histologically, the tumours could be divided into those with an adjacent intra-epithelial component, manifest as atypical melanocytic hyperplasia in the conjunctival epithelium adjacent to the invasive melanoma, and those without (nodular melanoma). However, clear separation of the former group into the subtypes described for cutaneous melanomas proved impossible. Prognosis was not related to the type of melanoma, mitotic rate, cell type or degree of pigmentation.

A complex Ph1 translocation in a patient with primary thrombocythaemia.

Routine blood examination of a 27-year-old female revealed a platelet count of 2000 X 10(9)/l. Bone marrow cells showed the Philadelphia chromosome which was one product of a complex rearrangement of chromosomes 9, 22 and X. Her platelet count was lowered by plateletphoresis and chemotherapy. She remains in good health 19 months later, but her thrombocythaemia is considered to be an early manifestation of chronic myeloid leukaemia.