Systematic Review and Meta-Analysis of Global Neuroma Incidence in Upper Extremity Amputees.

BACKGROUND: Neuromas substantially decrease a patient's quality of life and obstruct the use of prosthetics. This systematic review and meta-analysis aimed to determine the global incidence of neuroma formation in upper extremity amputees. METHODS: A literature search was performed using 3 databases: Web of Science, MEDLINE, and Cochrane. Inclusion criteria for the systematic review were those studies investigating only upper extremity amputees and reported postamputation neuroma. A random-effects, inverse-variance analysis was conducted to determine the pooled proportion of neuromas within the upper extremity amputation population. Critical appraisal using the JBI Checklist for Studies Reporting Prevalence Data of each individual article were performed for the systematic review. RESULTS: Eleven studies met the inclusion criteria collating a total of 1931 patients across 8 countries. More than three-fourth of patients are young men (77%; age range, 19-54 years) and had an amputation due to trauma. The random-effects analysis found the pooled combined proportion of neuromas to be 13% (95% confidence interval, 8%-18%). The treatment of neuroma is highly variable, with some patients receiving no treatment. CONCLUSIONS: The pooled proportion of neuroma incidence in the 1931 patients was 13%. With the known global prevalence of upper extremity amputees, this translates to nearly 3 million amputees suffering from a neuroma globally. Increasing training in preventative surgical methods could contribute to lowering this incidence and improving the outcomes of this patient population.

Synthesis of Pertyolides A, B, and C: A Synthetic Procedure to C17-Sesquiterpenoids and a Study of Their Phytotoxic Activity.

C17-sesquiterpenoids are a group of natural products that have been recently discovered. These compounds have the peculiarity of lacking the α,ß-methylene butyrolactone system, which is known to be quite relevant for many of the biological activities reported for sesquiterpene lactones. Unfortunately, the biological interest of C17-sesquiterpenoids has not been studied in-depth, mainly due to the poor isolation yields in which they can be obtained from natural sources. Therefore, in order to allow a deeper study of these novel molecules, we have worked out a synthetic pathway that provides C17-sesquiterpenoids in enough quantities from easily accessible sesquiterpene lactones to enable a more thorough investigation of their bioactivities. With this synthesis method, we have successfully synthesized, for the first time, three natural C17-sesquiterpenoids, pertyolides A, B, and C, with good overall yields. Furthermore, we have also evaluated their phytotoxicity against etiolated wheat coleoptiles and corroborated that pertyolides B and C present strong phytotoxic activity.

Synthesis of Vlasouliolides: A Pathway toward Guaiane-Eudesmane C17/C15 Dimers by Photochemical and Michael Additions.

Vladimiria souliei is a plant found in China used in traditional medicine. Recent isolation studies have led to the discovery of vlasouliolides, which are natural sesquiterpene dimers. However, the yields obtained from isolation have proven to be really low (<0.01%), greatly hindering the study of these molecules. In this work, we propose a simple synthetic route to obtain different vlasouliolides in good yields from dehydrocostuslactone and costunolide, which will lead to further bioactivity studies at a higher scale.

microRNA 193a-5p Regulates Levels of Nucleolar- and Spindle-Associated Protein 1 to Suppress Hepatocarcinogenesis.

BACKGROUND & AIMS: We performed an integrated analysis to identify microRNAs (miRNAs) and messenger RNAs (mRNAs) with altered expression in liver tumors from 3 mouse models of hepatocellular carcinoma (HCC) and human tumor tissues. METHODS: We analyzed miRNA and mRNA expression profiles of liver tissues from mice with diethylnitrosamine-induced hepatocarcinogenesis, conditional expression of lymphotoxin alpha and lymphotoxin beta, or inducible expression of a Myc transgene (Tet-O-Myc mice), as well as male C57BL/6 mice (controls). miRNA mimics were expressed and miRNAs and mRNAs were knocked down in human (Huh7, Hep3B, JHH2) hepatoma cell lines; cells were analyzed for viability, proliferation, apoptosis, migration, and invasion. Cells were grown as xenograft tumors in nude mice and analyzed. We combined in silico target gene prediction with mRNA profiles from all 3 mouse models. We quantified miRNA levels in 146 fresh-frozen tissues from patients (125 HCCs, 17 matched nontumor tissues, and 4 liver samples from patients without cancer) and published human data sets and tested correlations with patient survival times using Kaplan-Meier curves and the log-rank test. Levels of NUSAP1 mRNA were quantified in 237 HCCs and 5 nontumor liver samples using the TaqMan assay. RESULTS: Levels of the miRNA 193a-5p (MIR193A-5p) were reduced in liver tumors from all 3 mouse tumor models and in human HCC samples, compared with nontumor liver tissues. Expression of a MIR193A-5p mimic in hepatoma cells reduced proliferation, survival, migration, and invasion and their growth as xenograft tumors in nude mice. We found nucleolar and spindle-associated protein 1 (NUSAP1) to be a target of MIR193A-5p; HCC cells and tissues with low levels of MIR193A-5p had increased expression of NUSAP1. Increased levels of NUSAP1 in HCC samples correlated with shorter survival times of patients. Knockdown of NUSAP1 in Huh7 cells reduced proliferation, survival, migration, and growth as xenograft tumors in nude mice. Hydrodynamic tail-vein injections of a small hairpin RNA against NUSAP1 reduced growth of Akt1-Myc-induced tumors in mice. CONCLUSIONS: MIR193A-5p appears to prevent liver tumorigenesis by reducing levels of NUSAP1. Levels of MIR193A-5p are reduced in mouse and human HCC cells and tissues, leading to increased levels of NUSAP1, associated with shorter survival times of patients. Integrated analyses of miRNAs and mRNAs in tumors from mouse models can lead to identification of therapeutic targets in humans. The currently reported miRNA and mRNA profiling data have been submitted to the Gene Expression Omnibus (super-series accession number GSE102418).

Intraocular Pressure as an Indicator of the Level of Induced Anxiety in Basketball.

SIGNIFICANCE: Our data demonstrate that intraocular pressure (IOP) is sensitive to anxiety manipulation in sport scenarios, specifically in a basketball free throw task. The present outcomes may be of special relevance because of its practical advantages for the objective control of athletes' anxiety levels. PURPOSE: Athletes experience high levels of anxiety during sport competition, and IOP has demonstrated to reflect autonomous nervous system changes during mentally demanding situations. We tested whether different levels of induced anxiety during basketball free throw shooting alter IOP. METHODS: We followed a repeated-measures design to test the effects of anxiety-induced manipulation during basketball free throw shooting on IOP, shooting performance, and perceived anxiety. Eighteen amateur basketball players performed three experimental sessions consisting of 100 free throws each. However, we gave three different instructions to participants regarding the score assigned to each free throw, allowing us to manipulate the level of induced anxiety (low, medium, and high). RESULTS: Confirming a successful anxiety manipulation, basketball players reported more perceived anxiety with higher levels of induced anxiety (P < .001, η = 0.37). Our data show that higher levels of induced anxiety provoke an acute IOP rise (P < .001, η = 0.44), with the low-, medium-, and high-anxiety-induced conditions promoting an average IOP rise of 0.21, 1.63, and 18.46%, respectively. Also, there was a linear IOP rise over time in the high-anxiety-induced condition (r = 0.82). Nevertheless, we found no effect of anxiety-induced manipulation on basketball free throw performance (P = .93). CONCLUSIONS: Intraocular pressure is sensitive to anxiety-induced manipulation during basketball free throw shooting, showing an increase in parallel with accumulated anxiety. Based on these findings, IOP may be considered a promising tool for the assessment of the level of anxiety in certain sport situations. Future studies are required to explore the generalizability of these results in other scenarios with different physical and mental demands.

miR-155 Predicts Long-Term Mortality in Critically Ill Patients Younger than 65 Years.

INTRODUCTION: Alterations in miR-155 serum levels have been described in inflammatory and infectious diseases. Moreover, a role for miR-155 in aging and age-related diseases was recently suggested. We therefore analyzed a potential age-dependent prognostic value of circulating miR-155 as a serum-based marker in critical illness. METHODS: Concentrations of circulating miR-155 were determined in 218 critically ill patients and 76 healthy controls. RESULTS: By using qPCR, we demonstrate that miR-155 serum levels are elevated in patients with critical illness when compared to controls. Notably, levels of circulating miR-155 were independent on the severity of disease, the disease etiology, or the presence of sepsis. In the total cohort, miR-155 was not an indicator for patient survival. Intriguingly, when patients were subdivided according to their age upon admission to the ICU into those younger than 65 years, lower levels of miR-155 turned out as a strong marker, indicating patient mortality with a similar accuracy than other markers frequently used to evaluate critically ill patients on a medical ICU. CONCLUSION: In summary, the data provided within this study suggest an age-specific role of miR-155 as a prognostic biomarker in patients younger than 65 years. Our study is the first to describe an age-dependent miRNA-based prognostic biomarker in human diseases.

Acute intraocular pressure responses to high-intensity interval-training protocols in men and women.

We aimed (1) to test the acute impact of two high-intensity interval-training (HIIT) protocols differing in the level of effort on intraocular pressure (IOP) responses, and (2) to elucidate whether the IOP responses differ between men and women. Twenty-four physically active collegiate (12 men and 12 women) performed three protocols: low-fatigue HIIT (eight 30-m sprints with 60-s of rest), high-fatigue HIIT (eight 30-m sprints with 30-s of rest), and control (walking). IOP was taken at baseline, after sprints and recovery by rebound tonometry. Our data revealed an acute IOP reduction during both HIIT protocols compared to the control condition (effect size [ES]:0.81-1.65). The differences between both HIIT protocols were generally negligible (ES<0.30), however, the reduction of IOP was moderately higher for the low-fatigue HIIT protocol after the 7th (ES: 0.67) and 8th (ES: 0.74) sprints. Women showed a more prominent lowering effect on IOP during the control condition (ES: 0.42-1.02), and during the two first sprints of both HIIT protocols (ES: 0.54-1.03). These findings highlight that a time-efficient HIIT protocol may acutely reduce IOP levels, while low-fatigue HIIT protocol could be recommended since it induced a higher reduction on IOP than the high-fatigue HIIT protocol.

Muscular Strength Is Associated with Higher Intraocular Pressure in Physically Active Males.

SIGNIFICANCE: The positive association between intraocular pressure (IOP) and relative maximum force may have relevance for exercise recommendations when IOP is a concern. PURPOSE: The relationship between exercise and IOP has been approached in several studies. However, the influence of muscle function on IOP remains underexplored. This study aimed to determine the relationship between the maximal mechanical capabilities of muscles to generate force, velocity, and power with IOP. METHODS: Sixty-five physically active males participated in this cross-sectional study. Baseline IOP measures were obtained by rebound tonometry, and participants performed an incremental loading test in the ballistic bench press. RESULTS: Baseline IOP showed a strong positive correlation with relative maximum force (r65 = 0.85, P < .001) relative maximum power (r65 = 0.85, P < .001), and relative one-repetition maximum (r65 = 0.91, P < .001). Also, a moderate positive association was obtained between baseline IOP and maximum force (r65 = 0.74, P < .001), maximum power (r65 = 0.72, P < .001), and maximum dynamic strength (r65 = 0.80, P < .001). No significant correlations between IOP and maximal velocity were obtained (all P > .05). CONCLUSIONS: There is a positive association between greater upper-body power and strength with higher baseline IOP, which might have important implications in the management of ocular health and especially in individuals constantly involved in resistance training programs (e.g., military personnel, weightlifters). The possible protective effect of high fitness level on the acute IOP response to strength exercise needs to be addressed in future studies.

A test-retest assessment of the effects of mental load on ratings of affect, arousal and perceived exertion during submaximal cycling.

This study aimed to test the effects of mental (i.e. executive) load during a dual physical-mental task on ratings of perceived exertion (RPE), affective valence, and arousal. The protocol included two dual tasks with matched physical demands but different executive demands (2-back and oddball), carried out on different days. The procedure was run twice to assess the sensitivity and stability of RPE, valence and arousal across the two trials. Linear mixed-effects analyses showed less positive valence (-0.44 points on average in a 1-9 scale; Rß2 = 0.074 [CI90%, 0.052-0.098]), and heightened arousal (+0.13 points on average in a 1-9 scale; Rß2 = 0.006 [CI90%, 0.001-0.015]), for the high executive load condition, but showed no effect of mental load on RPE. Separated analyses for the two task trials yielded best-fitting models that were identical across trials for RPE and valence, but not for arousal. Model fitting was improved by assuming a 1-level autoregressive covariance structure for all analyses. In conclusion, executive load during a dual physical-mental task modulates the emotional response to effort, but not RPE. The autoregressive covariance suggests that people tend to anchor estimates on prior ones, which imposes certain limits on scales' usability.

Measuring mental workload: ocular astigmatism aberration as a novel objective index.

This study assessed the effect of two perceptually matched mental tasks with different levels of mental demand on ocular aberrations in a group of young adults. We measured ocular aberration with a wavefront sensor, and total, internal and corneal RMS (root mean square) aberrations were calculated from Zernike coefficients, considering natural and scaled pupils (5, 4.5, and 4 mm). We found that total, internal and corneal astigmatism RMS showed significant differences between mental tasks with natural pupils (p < .05), and this effect was maintained with 5 mm scaled pupils (total RMS astigmatism, p < .05). Consistently, pupil size, intraocular pressure, perceived mental load and cognitive performance were influenced by the level of mental complexity (p < .05 for all). The findings suggest that ocular astigmatism aberration, mediated by intraocular pressure, could be an objective, valid reliable index to evaluate the impact of cognitive processing in conjunction with others physiological markers in real world contexts. Practitioner Summary: The search continues for a valid, reliable, convenient method of measuring mental workload. In this study we found ocular astigmatism aberration is sensitive to the cumulative effect of mental effort. It shows promise of being a novel ocular index which may help to assess mental workload in real situations.

Diversity and functional convergence of small noncoding RNAs in male germ cell differentiation and fertilization.

The small noncoding RNAs (sncRNAs) are considered as post-transcriptional key regulators of male germ cell development. In addition to microRNAs (miRNAs) and PIWI-interacting RNAs (piRNAs), other sncRNAs generated from small nucleolar RNAs (snoRNAs), tRNAs, or rRNAs processing may also play important regulatory roles in spermatogenesis. By next-generation sequencing (NGS), we characterized the sncRNA populations detected at three milestone stages in male germ differentiation: primordial germ cells (PGCs), pubertal spermatogonia cells, and mature spermatozoa. To assess their potential transmission through the spermatozoa during fertilization, the sncRNAs of mouse oocytes and zygotes were also analyzed. Both, microRNAs and snoRNA-derived small RNAs are abundantly expressed in PGCs but transiently replaced by piRNAs in spermatozoa and endo-siRNAs in oocytes and zygotes. Exhaustive analysis of miRNA sequence variants also shows an increment of noncanonical microRNA forms along male germ cell differentiation. RNAs-derived from tRNAs and rRNAs interacting with PIWI proteins are not generated by the ping-pong pathway and could be a source of primary piRNAs. Moreover, our results strongly suggest that the small RNAs-derived from tRNAs and rRNAs are interacting with PIWI proteins, and specifically with MILI. Finally, computational analysis revealed their potential involvement in post-transcriptional regulation of mRNA transcripts suggesting functional convergence among different small RNA classes in germ cells and zygotes.

The acute effect of strength exercises at different intensities on intraocular pressure.

BACKGROUND: This study aimed to determine the effect of two basic strength exercises with progressive loads on intraocular pressure (IOP). METHODS: Seventeen (out of 20 recruited) physically active male military officers (46 ± 4.77 years) performed the jump squat and the ballistic bench press exercises, in counterbalanced order, with four and five progressive loads, respectively. IOP was measured with a rebound tonometer before and after each of the corresponding loads. RESULTS: IOP linearly increases with heavier loads for the jump squat (r = 0.976) and the ballistic bench press (r = 0.991) exercises. A significant IOP elevation was observed during the jump squat test (p < 0.001), and Bonferroni-Holm correction revealed that ~75% of one repetition maximum (RM) was able to promote significant changes in IOP with respect to the other three loads (all corrected p values <0.05), whereas the load corresponding to ~65%RM and ~60%RM induced a significant IOP rise when compared with the load of ~50%RM (corrected p-values of 0.43 in both cases). For its part, IOP significantly increases with the bench press test (p < 0.001), and performing the ~50%RM load was enough to induce significant IOP changes (corrected p-value <0.01). CONCLUSIONS: Acute performance of jump squat and ballistic bench press lead to a significant increase of IOP, and 5 min of rest are enough to recover baseline IOP values. There is a strong linear association between the increase in load and the IOP rise for both exercises, and bench press execution produces a significantly higher IOP increase when compared with the jump squat for the same relative loads.

Simultaneous Physical and Mental Effort Alters Visual Function.

PURPOSE: Perceptual processing is sensitive to physiological changes. Thus, the homeostatic disturbances during and after exercise may alter the visual function. Here, we investigated the effect of simultaneous physical effort and two levels of cognitive demand on skills related to the visuoperceptual and motor processing. METHODS: Eighteen male regular exercisers performed 60 minutes of simultaneous physical exercise (cycling at 60 ± 5% of reserve heart rate) and cognitive effort (mental workload). The same protocol was performed with a mental workload and an oddball condition of this task on different days in a counterbalanced manner. We assessed the near point of convergence, near stereoacuity, accommodative facility (Hart Charts), and eye-hand coordination before and after the two dual-tasking sessions. Also, we calculated cognitive-performance scores and subjective measures of mental load. RESULTS: We found that the near point of convergence (break and recovery) is significantly (P ≤ .05) reduced after physical and mental effort independently of the mental level administered. Only the condition of mental workload with simultaneous constant-intensity cycling promoted a significant impairment in the near stereoacuity and the eye-hand coordination (P = .006 and P = .018, respectively); however, these two parameters did not significantly change under the oddball condition. The accommodative facility showed an improvement in the oddball and mental workload conditions (P < .001 and P = .006, respectively). Confirming a successful experimental manipulation, participants experienced higher mental demand and arousal and achieved lower scores on cognitive performance during the mental workload task (both P < .001). CONCLUSIONS: The visual function is affected by simultaneous physical and mental effort, the manipulation of mental-task complexity being an important modulator of this effect. Both dual tasks, physical with or without mental workload demands, may enhance or impair visual and motor processing depending on the visual parameter tested, and those changes could be related to the activation state of the nervous system.

Global characterization and target identification of piRNAs and endo-siRNAs in mouse gametes and zygotes.

A set of small RNAs known as rasRNAs (repeat-associated small RNAs) have been related to the down-regulation of Transposable Elements (TEs) to safeguard genome integrity. Two key members of the rasRNAs group are piRNAs and endo-siRNAs. We have performed a comparative analysis of piRNAs and endo-siRNAs present in mouse oocytes, spermatozoa and zygotes, identified by deep sequencing and bioinformatic analysis. The detection of piRNAs and endo-siRNAs in the spermatozoa and revealed also in zygotes, hints to their potential delivery to oocytes during fertilization. However, a comparative assessment of the three cell types indicates that both piRNAs and endo-siRNAs are mainly maternally inherited. Finally, we have assessed the role of the different rasRNA molecules in connection with amplification processes by way of the "ping-pong cycle". Our results suggest that the ping-pong cycle can act on other rasRNAs, such as tRNA- and rRNA-derived fragments, thus not only being restricted to TEs during gametogenesis.

Elevated miR-122 serum levels are an independent marker of liver injury in inflammatory diseases.

BACKGROUND & AIMS: Serum concentrations of miR-122 were proposed as a marker for various inflammatory diseases, but the mechanisms driving alterations in miR-122 serum levels are unknown. METHODS: We analysed miR-122 serum levels and hepatic miR-122 expression in mice after hepatic ischaemia and reperfusion (I/R) injury. These data were compared with data from mice after caecal pole ligation and puncture (CLP) procedure. To translate these data into the human, we analysed miR-122 serum concentrations in a cohort of 223 patients with critical illness and 57 patients with cirrhosis. RESULTS: We detected strongly elevated levels of miR-122 in mice after hepatic I/R injury. miR-122-concentrations correlated with the degree of liver damage according to AST/ALT and were associated with the presence of hepatic cell death detected by TUNEL staining. miR-122 levels were elevated in the cellular supernatants in an in vitro model of hepatocyte injury, supporting the hypothesis that the passive release of miR-122 represents a surrogate for hepatocyte death in liver injury. Moreover, miR-122 levels were almost normal in patients with cirrhosis without ongoing liver damage, but were elevated when liver injury was present. In contrast to previous assumptions, miR-122-concentrations were independent of the presence of infection/sepsis in mice or human patients. miR-122 levels did not correlate with disease severity or mortality in critically ill patients. In contrast, serum miR-122 levels strictly correlated with the presence of hepatic injury in these patients. CONCLUSION: In mice and humans, miR-122 levels represent an independent and potent marker of ongoing liver injury and hepatic cell death regardless of the underlying disease.

Persistently elevated osteopontin serum levels predict mortality in critically ill patients.

INTRODUCTION: Inflammatory, autoimmune and metabolic disorders have been associated with alterations in osteopontin (OPN) serum levels. Furthermore, elevated serum levels of OPN were reported from a small cohort of patients with sepsis. We therefore analyzed OPN serum concentrations in a large cohort of critically ill medical patients. METHODS: A total of 159 patients (114 with sepsis, 45 without sepsis) were studied prospectively upon admission to the medical intensive care unit (ICU) as well as after 3 days of ICU treatment and compared to 50 healthy controls. Clinical data, various laboratory parameters as well as investigational inflammatory cytokine profiles were assessed. Patients were followed for approximately 1 year. RESULTS: We found significantly elevated serum levels of OPN at admission to the ICU and after 3 days of treatment in critically ill patients compared to healthy controls. OPN concentrations were related to disease severity and significantly correlated with established prognosis scores and classical as well as experimental markers of inflammation and multi-organ failure. In the total cohort, OPN levels decreased from admission to day 3 of ICU treatment. However, persistently elevated OPN levels at day 3 of ICU treatment were a strong independent predictor for an unfavorable prognosis, with similar or better diagnostic accuracy than routinely used markers of organ failure or prognostic scoring systems such as SAPS2 or APACHE II score. CONCLUSIONS: Persistently elevated OPN serum concentrations are associated with an unfavourable outcome in patients with critical illness, independent of the presence of sepsis. Besides a possible pathogenic role of OPN in critical illness, our study indicates a potential value for OPN as a prognostic biomarker in critically ill patients during the early course of ICU treatment.

The hidden cost of coaching: intentional training of shot adequacy discrimination in basketball hampers utilization of informative incidental cues.

The goal was to identify the advantages and disadvantages of using intentional guidance to teach to discriminate between good and bad circumstances to shoot in basketball. A simulated shot-adequacy learning task was developed, in which participants were asked to decide, in each trial, whether the player in possession of the ball should shoot or not. After each decision, they received feedback on their response (determined by five cues: Opposition, Rebound, Balance, Alternative, and Distance). 65 naïve participants (M age = 18.6 yr., SD = 1.3) were divided into two groups. The Incidental group received no guiding instructions. The Intentional group was instructed to utilize four of the five cues. The Distance cue was kept incidental for both groups. Participants effectively incorporated the cues into their decisions. Guidance had a markedly different effect across cues. The Intentional group utilized Distance less efficiently than the Incidental group, i.e., intentional instructions on the other four cues nearly blocked the utilization of Distance.

Levels of circulating miR-133a are elevated in sepsis and predict mortality in critically ill patients.

OBJECTIVE: Serum levels of microRNA have been proposed as biomarkers in various inflammatory diseases. However, up to now, their clinical relevance in critical illness and sepsis is unclear. DESIGN: Single-center clinical study. SETTING: Fourteen-bed medical ICU of the University Hospital Aachen, university laboratory research unit. SUBJECTS AND PATIENTS: Experimental sepsis model in C57Bl/6 mice; 223 critically ill patients in comparison with 76 healthy volunteers. INTERVENTIONS: We used the model of cecal pole ligation and puncture for induction of polymicrobial sepsis in mice and measured alterations in serum levels of six different microRNAs with a known function in inflammatory diseases upon induction of septic disease. These results from mice were translated into a large and well-characterized cohort of critically ill patients admitted to the medical ICU. MEASUREMENTS AND MAIN RESULTS: Serum miR-133a was then measured in 223 critically ill patients (138 with sepsis and 85 without sepsis) and 76 controls and associated with disease severity, organ failure, and prognosis. Significant alterations of miR-133a, miR-150, miR-155, and miR-193b* were found in mice after cecal pole ligation and puncture-induced sepsis. Among all regulated microRNAs, miR-133a displayed the most prominent and concordant up-regulation in sepsis, and this microRNA was therefore chosen for further investigation in the human. Here, significantly elevated miR-133a levels were found in critically ill patients at ICU admission, when compared with healthy controls, especially in patients with sepsis. Correlation analyses revealed significant correlations of miR-133a with disease severity, classical markers of inflammation and bacterial infection, and organ failure. Strikingly, high miR-133a levels were predictive for an unfavorable prognosis and represented a strong independent predictor for both ICU and long-term mortality in critically ill patients. CONCLUSIONS: miR-133a serum levels were significantly elevated in critical illness and sepsis. High miR-133a levels were associated with the severity of disease and predicted an unfavorable outcome of critically ill patients.

P1 and P2 protein heterodimer binding to the P0 protein of Saccharomyces cerevisiae is relatively non-specific and a source of ribosomal heterogeneity.

The ribosomal stalk is formed by four acidic phosphoproteins in Saccharomyces cerevisiae, P1α, P1ß, P2α and P2ß, which form two heterodimers, P1α/P2ß and P1ß/P2α, that preferentially bind to sites A and B of the P0 protein, respectively. Using mutant strains carrying only one of the four possible P1/P2 combinations, we found a specific phenotype associated to each P1/P2 pair, indicating that not all acidic P proteins play the same role. The absence of one P1/P2 heterodimer reduced the rate of cell growth by varying degrees, depending on the proteins missing. Synthesis of the 60S ribosomal subunit also decreased, particularly in strains carrying the unusual P1α-P2α or P1ß-P2ß heterodimers, although the distinct P1/P2 dimers are bound with similar affinity to the mutant ribosome. While in wild-type strains the B site bound P1ß/P2α in a highly specific manner and the A site bound the four P proteins similarly, both the A and B binding sites efficiently bound practically any P1/P2 pair in mutant strains expressing truncated P0 proteins. The reported results support that while most ribosomes contain a P1α/P2ß-P0-P1ß/P2α structure in normal conditions, the stalk assembly mechanism can generate alternative compositions, which have been previously detected in the cell.