Local mRNA translation mediates the adaptive responses of axons to extrinsic signals, but direct evidence that it occurs in mammalian CNS axons in vivo is scant. We developed an axon-TRAP-RiboTag ...approach in mouse that allows deep-sequencing analysis of ribosome-bound mRNAs in the retinal ganglion cell axons of the developing and adult retinotectal projection in vivo. The embryonic-to-postnatal axonal translatome comprises an evolving subset of enriched genes with axon-specific roles, suggesting distinct steps in axon wiring, such as elongation, pruning, and synaptogenesis. Adult axons, remarkably, have a complex translatome with strong links to axon survival, neurotransmission, and neurodegenerative disease. Translationally co-regulated mRNA subsets share common upstream regulators, and sequence elements generated by alternative splicing promote axonal mRNA translation. Our results indicate that intricate regulation of compartment-specific mRNA translation in mammalian CNS axons supports the formation and maintenance of neural circuits in vivo.
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•Dynamic translatome of retinal axons in vivo matches changing subcellular function•Adult CNS axons translate mRNAs for synaptic transmission and axon survival in vivo•Target mRNAs of key translation regulators show developmental co-regulation•Axon-specific sequence motifs link alternative splicing to axonal translation
Local mRNA translation in axons of developing and adult CNS neurons in vivo shows dynamic regulation, suggesting functional relevance for neural circuit formation and maintenance.
Extrinsic cues trigger the local translation of specific mRNAs in growing axons via cell surface receptors. The coupling of ribosomes to receptors has been proposed as a mechanism linking signals to ...local translation but it is not known how broadly this mechanism operates, nor whether it can selectively regulate mRNA translation. We report that receptor-ribosome coupling is employed by multiple guidance cue receptors and this interaction is mRNA-dependent. We find that different receptors associate with distinct sets of mRNAs and RNA-binding proteins. Cue stimulation of growing
retinal ganglion cell axons induces rapid dissociation of ribosomes from receptors and the selective translation of receptor-specific mRNAs. Further, we show that receptor-ribosome dissociation and cue-induced selective translation are inhibited by co-exposure to translation-repressive cues, suggesting a novel mode of signal integration. Our findings reveal receptor-specific interactomes and suggest a generalizable model for cue-selective control of the local proteome.
Sparse longitudinal data exist on how diet influences microalbuminuria and estimated GFR (eGFR) decline in people with well-preserved kidney function.
Of the 3348 women participating in the Nurses' ...Health Study who had data on urinary albumin to creatinine ratio in 2000, 3296 also had data on eGFR change between 1989 and 2000. Cumulative average intake of nutrients over 14 years was derived from semiquantitative food frequency questionnaires answered in 1984, 1986, 1990, 1994, and 1998. Microalbuminuria presence and eGFR decline > or = 30% were the outcomes of interest.
Compared with the lowest quartile, the highest quartile of animal fat (odds ratio (OR): 1.72; 95% confidence interval (CI): 1.12 to 2.64) and two or more servings of red meat per week (OR: 1.51; 95% CI: 1.01 to 2.26) were directly associated with microalbuminuria. After adjustment for other nutrients individually associated with eGFR decline > or = 30%, only the highest quartile of sodium intake remained directly associated (OR: 1.52; 95% CI: 1.10 to 2.09), whereas beta-carotene appeared protective (OR: 0.62, 95% CI: 0.43 to 0.89). Results did not vary by diabetes status for microalbuminuria and eGFR outcomes or in those without hypertension at baseline for eGFR decline. No significant associations were seen for other types of protein, fat, vitamins, folate, fructose, or potassium.
Higher dietary intake of animal fat and two or more servings per week of red meat may increase risk for microalbuminuria. Lower sodium and higher beta-carotene intake may reduce risk for eGFR decline.
Background Dietary patterns have been linked to such chronic diseases as cardiovascular disease, but sparse data currently are available for associations between dietary patterns and microalbuminuria ...or kidney function decline. Study Design Subgroup analysis from a prospective observational cohort study. Setting & Participants Female participants in the Nurses' Health Study who had dietary pattern data from food frequency questionnaires returned in 1984, 1986, 1990, 1994, and 1998 and urinary albumin-creatinine ratios from 2000 (n = 3,121); estimated glomerular filtration rate (eGFR) change between 1989 and 2000 was available for 3,071. Predictor Prudent (higher intake of fruits, vegetables, legumes, fish, poultry, and whole grains), Western (higher intake of red and processed meats, saturated fats, and sweets), and Dietary Approach to Stop Hypertension (DASH)-style dietary patterns (also greater intake of vegetables, fruits, and whole grains). Outcomes & Measurements Microalbuminuria (albumin-creatinine ratio, 25-354 μg/mg) in 2000 and change in kidney function using eGFR between 1989 and 2000. Results After multivariable adjustment, the highest quartile of Western pattern score compared with the lowest quartile was associated directly with microalbuminuria (OR, 2.17; 95% CI, 1.18-3.66; P for trend = 0.01) and rapid eGFR decline ≥3 mL/min/1.73 m2 /y (OR, 1.77; 95% CI, 1.03-3.03). Women in the top quartile of the DASH score had decreased risk of rapid eGFR decline (OR, 0.55; 95% CI, 0.38-0.80), but no association with microalbuminuria. These associations did not vary by diabetes status. The prudent dietary pattern was not associated with microalbuminuria or eGFR decline. Limitations Study cohort included primarily older white women and generalizability of results would benefit from validation in nonwhites and men. Conclusions A Western dietary pattern is associated with a significantly increased odds of microalbuminuria and rapid kidney function decrease, whereas a DASH-style dietary pattern may be protective against rapid eGFR decline.
Sugar-sweetened soda is reported to be associated with increased risk for diabetes and albuminuria, but there are currently limited data on how sugar or artificially sweetened soda may be related to ...kidney function decline.
This study identified 3318 women participating in the Nurses' Health Study with data on soda intake and albuminuria; of these, 3256 also had data on estimated GFR (eGFR) change between 1989 and 2000. Cumulative average beverage intake was derived from the 1984, 1986, 1990, 1994, and 1998 food frequency questionnaires. Serving categories included <1/mo (referent), 1 to 4/mo, 2 to 6/wk, 1 to 1.9/d, and ≥ 2/d. Microalbuminuria (MA) was considered a urinary albumin-to-creatinine ratio of 25 to 355 μg/mg. For kidney function change, the primary outcome was a ≥ 30% decline in eGFR over 11 years; rapid eGFR decline defined as ≥ 3 ml/min per 1.73 m(2) per year was also examined.
Consumption of ≥ 2 servings per day of artificially sweetened (diet) soda was independently associated with eGFR decline ≥ 30% (OR 2.02, 95% CI 1.36 to 3.01) and ≥ 3 ml/min per 1.73 m(2) per year (OR 2.20, 95% CI 1.36 to 3.55). No increased risk for eGFR decline was observed for <2 servings per day of diet soda. No associations were noted between diet soda and MA or sugar soda and MA or eGFR decline.
Consumption of ≥ 2 servings per day of artificially sweetened soda is associated with a 2-fold increased odds for kidney function decline in women.
This study assessed the relationship between initial responsiveness to darbepoetin alfa and outcomes in patients with chronic kidney disease and type 2 diabetes mellitus. A poor initial hematopoietic ...response was associated with an increased risk of death or cardiovascular events.
Erythropoiesis-stimulating agents (ESAs) have been credited with a reduced need for red-cell transfusion and improved quality of life for patients with end-stage kidney disease who have severe anemia.
1
In patients with chronic kidney disease who do not require dialysis and have moderate anemia, the use of ESAs remains substantial, despite little evidence of benefit and increased concern that these agents may confer harm.
2
–
4
Trials comparing lower and higher hemoglobin targets have been interpreted to suggest that targeting of a lower hemoglobin range would be a safer approach in these patients,
2
,
5
,
6
leading to recommendations for continued use of . . .
CDK9 is the kinase subunit of positive transcription elongation factor b (P-TEFb) that enables RNA polymerase (Pol) II's transition from promoter-proximal pausing to productive elongation. Although ...considerable interest exists in CDK9 as a therapeutic target, little progress has been made due to lack of highly selective inhibitors. Here, we describe the development of i-CDK9 as such an inhibitor that potently suppresses CDK9 phosphorylation of substrates and causes genome-wide Pol II pausing. While most genes experience reduced expression, MYC and other primary response genes increase expression upon sustained i-CDK9 treatment. Essential for this increase, the bromodomain protein BRD4 captures P-TEFb from 7SK snRNP to deliver to target genes and also enhances CDK9's activity and resistance to inhibition. Because the i-CDK9-induced MYC expression and binding to P-TEFb compensate for P-TEFb's loss of activity, only simultaneously inhibiting CDK9 and MYC/BRD4 can efficiently induce growth arrest and apoptosis of cancer cells, suggesting the potential of a combinatorial treatment strategy.
Abstract
Purpose
In acute respiratory distress syndrome (ARDS), dead space fraction has been independently associated with mortality. We hypothesized that early measurement of the difference between ...arterial and end-tidal CO
2
(arterial-ET difference), a surrogate for dead space fraction, would predict mortality in mechanically ventilated patients with ARDS.
Methods
We performed two separate exploratory analyses. We first used publicly available databases from the ALTA, EDEN, and OMEGA ARDS Network trials (
N
= 124) as a derivation cohort to test our hypothesis. We then performed a separate retrospective analysis of patients with ARDS using University of Chicago patients (
N
= 302) as a validation cohort.
Results
The ARDS Network derivation cohort demonstrated arterial-ET difference, vasopressor requirement, age, and APACHE III to be associated with mortality by univariable analysis. By multivariable analysis, only the arterial-ET difference remained significant (
P
= 0.047). In a separate analysis, the modified Enghoff equation ((P
a
CO
2
–P
ET
CO
2
)/P
a
CO
2
) was used in place of the arterial-ET difference and did not alter the results. The University of Chicago cohort found arterial-ET difference, age, ventilator mode, vasopressor requirement, and APACHE II to be associated with mortality in a univariate analysis. By multivariable analysis, the arterial-ET difference continued to be predictive of mortality (
P
= 0.031). In the validation cohort, substitution of the arterial-ET difference for the modified Enghoff equation showed similar results.
Conclusion
Arterial to end-tidal CO
2
(ETCO
2
) difference is an independent predictor of mortality in patients with ARDS.
BACKGROUND: Diet represents a potentially important target for intervention in nephropathy, yet data on this topic are scarce. OBJECTIVES: The objective was to investigate associations between ...dietary fats and early kidney disease. DESIGN: We examined cross-sectional associations between dietary fats and the presence of high albuminuria (an established independent predictor of kidney function decline, cardiovascular disease, and mortality) or estimated glomerular filtration rate (eGFR) <60 mL · min⁻¹ · 1.73 m⁻² at baseline in 19,256 participants of the REGARDS (Reasons for Geographic and Racial Differences in Stroke) study, an ongoing cohort study in US adults aged ≥45 y at time of enrollment. We used logistic regression to assess associations between quintiles of total fat and subtypes of dietary fat (saturated, monounsaturated, polyunsaturated, and trans fat) and presence of high albuminuria or eGFR <60 mL · min⁻¹ · 1.73 m⁻². RESULTS: After multivariable adjustment, only saturated fat intake was significantly associated with high albuminuria for quintile 5 compared with quintile 1, odds ratio (OR): 1.33; 95% CI: 1.07, 1.66; P for trend = 0.04. No significant associations between any type of fat and eGFR <60 mL · min⁻¹ · 1.73 m⁻² were observed. ORs between the highest quintile of saturated fat and eGFR <60 mL · min⁻¹ · 1.73 m⁻² varied by race with a borderline significant interaction term (ORs: 1.24 in whites compared with 0.74 in blacks; P for interaction = 0.05) in multivariable-adjusted models, but no other associations were significantly modified by race or diabetes status. CONCLUSION: Higher saturated fat intake is significantly associated with the presence of high albuminuria, but neither total nor other subtypes of dietary fat are associated with high albuminuria or eGFR <60 mL · min⁻¹ · 1.73 m⁻².
The dataset includes thermal videos of various hand gestures captured by the FLIR Lepton Thermal Camera. A large dataset is created to accurately classify hand gestures captured from eleven different ...individuals. The dataset consists of 9 classes corresponding to various hand gestures from different people collected at different time instances with complex backgrounds. This data includes flat/leftward, flat/rightward, flat/contract, spread/ leftward, spread/rightward, spread/contract, V-shape/leftward, V-shape/rightward, and V-shape/contract. There are 110 videos in the dataset for each gesture and a total of 990 videos corresponding to 9 gestures. Each video has data of three different (15/10/5) frame lengths.
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