Influenza A virus (IAV) infection leads to variable and imperfectly understood pathogenicity. We report that segment 3 of the virus contains a second open reading frame ("X-ORF"), accessed via ...ribosomal frameshifting. The frameshift product, termed PA-X, comprises the endonuclease domain of the viral PA protein with a C-terminal domain encoded by the X-ORF and functions to repress cellular gene expression. PA-X also modulates IAV virulence in a mouse infection model, acting to decrease pathogenicity. Loss of PA-X expression leads to changes in the kinetics of the global host response, which notably includes increases in inflammatory, apoptotic, and T lymphocyte-signaling pathways. Thus, we have identified a previously unknown IAV protein that modulates the host response to infection, a finding with important implications for understanding IAV pathogenesis.
Selenoprotein P (Se-P) contains most of the selenium in plasma. Its function is not known. Mice with the Se-P gene deleted (Sepp−/−) were generated. Two phenotypes were observed: 1) Sepp−/−mice lost ...weight and developed poor motor coordination when fed diets with selenium below 0.1 mg/kg, and 2) maleSepp−/− mice had sharply reduced fertility. Weanling male Sepp+/+,Sepp+/−, and Sepp−/−mice were fed diets for 8 weeks containing <0.02–2 mg selenium/kg.Sepp+/+ and Sepp+/−mice had similar selenium concentrations in all tissues except plasma where a gene-dose effect on Se-P was observed. Liver selenium was unaffected by Se-P deletion except that it increased when dietary selenium was below 0.1 mg/kg. Selenium in other tissues exhibited a continuum of responses to Se-P deletion. Testis selenium was depressed to 19% in mice fed an 0.1 mg selenium/kg diet and did not rise toSepp+/+ levels even with a dietary selenium of 2 mg/kg. Brain selenium was depressed to 43%, but feeding 2 mg selenium/kg diet raised it to Sepp+/+ levels. Kidney was depressed to 76% and reachedSepp+/+ levels on an 0.25 mg selenium/kg diet. Heart selenium was not affected. These results suggest that theSepp−/− phenotypes were caused by low selenium in testis and brain. They strongly suggest that Se-P from liver provides selenium to several tissues, especially testis and brain. Further, they indicate that transport forms of selenium other than Se-P exist because selenium levels of all tissues except testis responded to increases of dietary selenium inSepp−/− mice.
To revise the staging system for cutaneous melanoma under the auspices of the American Joint Committee on Cancer (AJCC).
The prognostic factors analysis described in the companion publication (this ...issue), as well as evidence from the published literature, was used to assemble the tumor-node-metastasis criteria and stage grouping for the melanoma staging system.
Major changes include (1) melanoma thickness and ulceration but not level of invasion to be used in the T category (except for T1 melanomas); (2) the number of metastatic lymph nodes rather than their gross dimensions and the delineation of clinically occult (ie, microscopic) versus clinically apparent (ie, macroscopic) nodal metastases to be used in the N category; (3) the site of distant metastases and the presence of elevated serum lactic dehydrogenase to be used in the M category; (4) an upstaging of all patients with stage I, II, and III disease when a primary melanoma is ulcerated; (5) a merging of satellite metastases around a primary melanoma and in-transit metastases into a single staging entity that is grouped into stage III disease; and (6) a new convention for defining clinical and pathologic staging so as to take into account the staging information gained from intraoperative lymphatic mapping and sentinel node biopsy.
This revision will become official with publication of the sixth edition of the AJCC Cancer Staging Manual in the year 2002.
The American Joint Committee on Cancer (AJCC) recently proposed major revisions of the tumor-node-metastases (TNM) categories and stage groupings for cutaneous melanoma. Thirteen cancer centers and ...cancer cooperative groups contributed staging and survival data from a total of 30,450 melanoma patients from their databases in order to validate this staging proposal.
There were 17,600 melanoma patients with complete clinical, pathologic, and follow-up information. Factors predicting melanoma-specific survival rates were analyzed using the Cox proportional hazards regression model. Follow-up survival data for 5 years or longer were available for 73% of the patients.
This analysis demonstrated that (1) in the T category, tumor thickness and ulceration were the most powerful predictors of survival, and the level of invasion had a significant impact only within the subgroup of thin (< or = 1 mm) melanomas; (2) in the N category, the following three independent factors were identified: the number of metastatic nodes, whether nodal metastases were clinically occult or clinically apparent, and the presence or absence of primary tumor ulceration; and (3) in the M category, nonvisceral metastases was associated with a better survival compared with visceral metastases. A marked diversity in the natural history of pathologic stage III melanoma was demonstrated by five-fold differences in 5-year survival rates for defined subgroups. This analysis also demonstrated that large and complex data sets could be used effectively to examine prognosis and survival outcome in melanoma patients.
The results of this evidence-based methodology were incorporated into the AJCC melanoma staging as described in the companion publication.
The body image concern (BIC) continuum ranges from a healthy and positive body image, to clinical diagnoses of abnormal body image, like body dysmorphic disorder (BDD). BDD and non-clinical, yet ...high-BIC participants have demonstrated a local visual processing bias, characterised by reduced inversion effects. To examine whether this bias is a potential marker of BDD, the visual processing of individuals across the entire BIC continuum was examined. Dysmorphic Concern Questionnaire (DCQ; quantified BIC) scores were expected to correlate with higher discrimination accuracy and faster reaction times of inverted stimuli, indicating reduced inversion effects (occurring due to increased local visual processing). Additionally, an induced global or local processing bias via Navon stimulus presentation was expected to alter these associations. Seventy-four participants completed the DCQ and upright-inverted face and body stimulus discrimination task. Moderate positive associations were revealed between DCQ scores and accuracy rates for inverted face and body stimuli, indicating a graded local bias accompanying increases in BIC. This relationship supports a local processing bias as a marker for BDD, which has significant assessment implications. Furthermore, a moderate negative relationship was found between DCQ score and inverted face accuracy after inducing global processing, indicating the processing bias can temporarily be reversed in high BIC individuals. Navon stimuli were successfully able to alter the visual processing of individuals across the BIC continuum, which has important implications for treating BDD.
Abstract
Background
This study assessed the prevalence of suicidal behavior and associated risk factors in public primary health care in Mozambique.
Methods
The Mini International Neuropsychiatric ...Interview was used to evaluate suicidal behavior among 502 adults attending three Primary Health Care (PHC) settings.
Results
In the past month, 13% (
n
= 63) of PHC attendees expressed suicidal ideation, 8% (
n
= 40) had made a suicide plan, 4% (
n
= 20) had made a suicide attempt, and 5% (
n
= 25) reported a lifetime suicide attempt. Females had 2.8-fold increased odds of suicide plan (95% CI: 1.5, 5.5) and 3.3-fold increased odds of suicide attempt in the past month (95% CI: 1.2, 9.1). Each 10-year increase in age was associated with 0.61-fold the odds of suicide plan (95% CI: 0.38, 0.98) and 0.09-fold the odds of suicide attempt (95% CI: 0.01, 0.69) in the past month. People living with HIV (PLWHA) had 2.2-fold increased adjusted odds of past month suicide attempt (CI: 1.1, 4.1).
Conclusion
Suicidal behaviors are common among adults attending PHC clinics in Mozambique. Screening and linkage to effective preventive interventions are urgently needed in PHC settings. Females, younger individuals, and PLWHA are at elevated risk for suicidal behavior in PHC.
A completely revised staging system for cutaneous melanoma was implemented in 2003. The changes were validated with a prognostic factors analysis involving 17,600 melanoma patients from prospective ...databases. This major collaborative study of predicting melanoma outcome was conducted specifically for this project, and the results were used to finalize the criteria for this evidence-based staging system. In fact, this was the largest prognostic factors analysis of prospectively followed melanoma patients ever conducted. Important results that shaped the staging criteria involved both the tumor-node-metastasis (TNM) criteria and stage grouping for all four stages of melanoma. Major changes in the staging include: (1) melanoma thickness and ulceration are the dominant predictors of survival in patients with localized melanoma (Stages I and II); deeper level of invasion (ie, IV and V) was independently associated with reduced survival only in patients with thin or T1 melanomas. (2) The number of metastatic lymph nodes and the tumor burden were the most dominant predictors of survival in patients with Stage III melanoma; patients with metastatic nodes detected by palpation had a shorter survival compared with patients whose nodal metastases were first detected by sentinel node excision of clinically occult or "microscopic" metastases. (3) The site of distant metastases (nonvisceral versus lung versus all other visceral metastatic sites) and the presence of elevated serum lactate dehydrogenase (LDH) were the dominant predictors of outcome in patients with Stage IV or distant metastases. (4) An upstaging was implemented for all patients with Stage I, II, and III disease when a primary melanoma is ulcerated by histopathological criteria. (5) Satellite metastases around a primary melanoma and in-transit metastases were merged into a single staging entity that is grouped into Stage III disease. (6) A new convention was implemented for defining clinical and pathological staging so as to take into account the new staging information gained from lymphatic mapping and sentinel node biopsy.
Programmed ribosomal frameshifting is an essential mechanism used for the expression of
orf1b in coronaviruses. Comparative analysis of the frameshift region reveals a universal shift site U_UUA_AAC, ...followed by a predicted downstream RNA structure in the form of either a pseudoknot or kissing stem loops. Frameshifting in SARS-CoV has been characterized in cultured mammalian cells using a dual luciferase reporter system and mass spectrometry. Mutagenic analysis of the SARS-CoV shift site and mass spectrometry of an affinity tagged frameshift product confirmed tandem tRNA slippage on the sequence U_UUA_AAC. Analysis of the downstream pseudoknot stimulator of frameshifting in SARS-CoV shows that a proposed RNA secondary structure in loop II and two unpaired nucleotides at the stem I–stem II junction in SARS-CoV are important for frameshift stimulation. These results demonstrate key sequences required for efficient frameshifting, and the utility of mass spectrometry to study ribosomal frameshifting.
Current literature describes several methods for the design of efficient siRNAs with 19 perfectly matched base pairs and 2 nt overhangs. Using four independent databases totaling 3336 experimentally ...verified siRNAs, we compared how well several of these methods predict siRNA cleavage efficiency. According to receiver operating characteristics (ROC) and correlation analyses, the best programs were BioPredsi, ThermoComposition and DSIR. We also studied individual parameters that significantly and consistently correlated with siRNA efficacy in different databases. As a result of this work we developed a new method which utilizes linear regression fitting with local duplex stability, nucleotide position-dependent preferences and total G/C content of siRNA duplexes as input parameters. The new method's discrimination ability of efficient and inefficient siRNAs is comparable with that of the best methods identified, but its parameters are more obviously related to the mechanisms of siRNA action in comparison with BioPredsi. This permits insight to the underlying physical features and relative importance of the parameters. The new method of predicting siRNA efficiency is faster than that of ThermoComposition because it does not employ time-consuming RNA secondary structure calculations and has much less parameters than DSIR. It is available as a web tool called 'siRNA scales'.
Programmed ribosomal frameshifting is used in the expression of many virus genes and some cellular genes. In eukaryotic systems, the most well-characterized mechanism involves –1 tandem tRNA slippage ...on an X_XXY_YYZ motif. By contrast, the mechanisms involved in programmed +1 (or −2) slippage are more varied and often poorly characterized. Recently, a novel gene, PA-X, was discovered in influenza A virus and found to be expressed via a shift to the +1 reading frame. Here, we identify, by mass spectrometric analysis, both the site (UCC_UUU_CGU) and direction (+1) of the frameshifting that is involved in PA-X expression. Related sites are identified in other virus genes that have previously been proposed to be expressed via +1 frameshifting. As these viruses infect insects (chronic bee paralysis virus), plants (fijiviruses and amalgamaviruses) and vertebrates (influenza A virus), such motifs may form a new class of +1 frameshift-inducing sequences that are active in diverse eukaryotes.
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