Disordered regions of human eIF4B orchestrate a dynamic self-association landscape.

Eukaryotic translation initiation factor eIF4B is required for efficient cap-dependent translation, it is overexpressed in cancer cells, and may influence stress granule formation. Due to the high degree of intrinsic disorder, eIF4B is rarely observed in cryo-EM structures of translation complexes and only ever by its single structured RNA recognition motif domain, leaving the molecular details of its large intrinsically disordered region (IDR) unknown. By integrating experiments and simulations we demonstrate that eIF4B IDR orchestrates and fine-tunes an intricate transition from monomers to a condensed phase, in which large-size dynamic oligomers form before mesoscopic phase separation. Single-molecule spectroscopy combined with molecular simulations enabled us to characterize the conformational ensembles and underlying intra- and intermolecular dynamics across the oligomerization transition. The observed sensitivity to ionic strength and molecular crowding in the self-association landscape suggests potential regulation of eIF4B nanoscopic and mesoscopic behaviors such as driven by protein modifications, binding partners or changes to the cellular environment.

Education as Risk Factor of Mild Cognitive Impairment: The Link to the Gut Microbiome.

BACKGROUND: With differences apparent in the gut microbiome in mild cognitive impairment (MCI) and dementia, and risk factors of dementia linked to alterations of the gut microbiome, the question remains if gut microbiome characteristics may mediate associations of education with MCI. OBJECTIVES: We sought to examine potential mediation of the association of education and MCI by gut microbiome diversity or composition. DESIGN: Cross-sectional study. SETTING: Luxembourg, the Greater Region (surrounding areas in Belgium, France, Germany). PARTICIPANTS: Control participants of the Luxembourg Parkinson's Study. MEASUREMENTS: Gut microbiome composition, ascertained with 16S rRNA gene amplicon sequencing. Differential abundance, assessed across education groups (0-10, 11-16, 16+ years of education). Alpha diversity (Chao1, Shannon and inverse Simpson indices). Mediation analysis with effect decomposition was conducted with education as exposure, MCI as outcome and gut microbiome metrics as mediators. RESULTS: After exclusion of participants below 50, or with missing data, n=258 participants (n=58 MCI) were included (M [SD] Age=64.6 [8.3] years). Higher education (16+ years) was associated with MCI (Odds ratio natural direct effect=0.35 [95% CI 0.15-0.81]. Streptococcus and Lachnospiraceae-UCG-001 genera were more abundant in higher education. CONCLUSIONS: Education is associated with gut microbiome composition and MCI risk without clear evidence for mediation. However, our results suggest signatures of the gut microbiome that have been identified previously in AD and MCI to be reflected in lower education and suggest education as important covariate in microbiome studies.

More than constipation - bowel symptoms in Parkinson's disease and their connection to gut microbiota.

BACKGROUND AND PURPOSE: The majority of Parkinson's disease (PD) patients suffer from gastrointestinal symptoms of which constipation is considered the most prominent. Recently, in addition to constipation, a diagnosis of irritable bowel syndrome (IBS) was also found to be associated with increased PD risk. Gut microbiota alterations have been reported in IBS and recently also in PD. IBS-like bowel symptoms in PD and their possible connection to other non-motor symptoms and faecal microbiota were assessed. METHODS: This case-control study compared 74 PD patients with 75 controls without any signs of parkinsonism or potential premotor symptoms. IBS-like symptoms were assessed using the Rome III questionnaire. The non-motor symptoms were assessed using the Non-Motor Symptoms Questionnaire and Non-Motor Symptom Scale. Faecal microbiota were assessed by pyrosequencing of the V1-V3 regions of the bacterial 16S ribosomal RNA gene. RESULTS: Symptoms that were IBS-like were significantly more prevalent in PD patients than in controls (24.3% vs. 5.3%; P = 0.001). Criteria for functional constipation were met by 12.2% of PD patients and 6.7% of controls (P = 0.072). PD patients with IBS-like symptoms had more non-motor symptoms and a lower faecal abundance of Prevotella bacteria than those without IBS-like symptoms. CONCLUSION: Our results indicate that PD patients may suffer from colonic dysfunction beyond pure constipation. Therefore, a more comprehensive assessment of bowel symptoms could provide valuable information. The lower abundance of Prevotella bacteria in PD patients with IBS-like symptoms suggests that the microbiota-gut-brain axis may be implicated in the gastrointestinal dysfunction of PD patients.

TRIB1 constitutes a molecular link between regulation of sleep and lipid metabolism in humans.

Epidemiological studies show association between sleep duration and lipid metabolism. In addition, inactivation of circadian genes induces insulin resistance and hyperlipidemia. We hypothesized that sleep length and lipid metabolism are partially controlled by the same genes. We studied the association of total sleep time (TST) with 60 genetic variants that had previously been associated with lipids. The analyses were performed in a Finnish population-based sample (N = 6334) and replicated in 2189 twins. Finally, RNA expression from mononuclear leucocytes was measured in 10 healthy volunteers before and after sleep restriction. The genetic analysis identified two variants near TRIB1 gene that independently contributed to both blood lipid levels and to TST (rs17321515, P = 8.92(*)10(-5), Bonferroni corrected P = 0.0053, ß = 0.081 h per allele; rs2954029, P = 0.00025, corrected P = 0.015, ß = 0.076; P<0.001 for both variants after adjusting for blood lipid levels or body mass index). The finding was replicated in the twin sample (rs17321515, P = 0.022, ß = 0.063; meta-analysis of both samples P = 8.1(*)10(-6), ß = 0.073). After the experimentally induced sleep restriction period TRIB1 expression increased 1.6-fold and decreased in recovery phase (P = 0.006). In addition, a negative correlation between TRIB1 expression and slow wave sleep was observed in recovery from sleep restriction. These results show that allelic variants of TRIB1 are independently involved in regulation of lipid metabolism and sleep. The findings give evidence for the pleiotropic nature of TRIB1 and may reflect the shared roots of sleep and metabolism. The shared genetic background may at least partially explain the mechanism behind the well-established connection between diseases with disrupted metabolism and sleep.

Long-term results after treatment of basal cell carcinoma of the eyelid in South-Western Finland.

PURPOSE: Basal cell carcinoma (BCC) is the most common skin cancer of the eyelid, showing an increasing incidence in the white population. The authors studied the clinical characteristics and the treatment results of BCC of the eyelid in southwestern Finland during 1977-1997. METHODS: The authors reviewed the case records of 191 patients with BCC of the eyelids treated at the Turku University Eye Clinic during 1977-1997. The mean follow-up period after the treatment was 8.6+/-5.2 years. RESULTS: The 191 patients had altogether 194 BCC tumors of the eyelid with the mean diameter of the tumor being smaller than 10 mm in 77.3% of cases. Of the 194 BCC tumors of the eyelid 16.0% showed recurrence, and the recurrence rate of all surgically treated tumors was 13.7%. In this study 61 patients (31.9%) developed other malignancies than the BCC of the eyelid including 28 patients (14.7 %) with carcinoma in other locations than skin. CONCLUSIONS: Incompletely removed BCCs of the eyelid showed only 18.9% recurrence rate during the follow-up time. On the other hand, BCCs of the eyelid should not be underestimated because of the rather high total recurrence rate. The frequency of 31.9% of other malignancies than BCC of the eyelid is remarkably high and requires special attention from the ophthalmologist taking care of the patient with BCC of the eyelid.

Crosslinked poly(epsilon-caprolactone/D,L-lactide)/bioactive glass composite scaffolds for bone tissue engineering.

A series of elastic polymer and composite scaffolds for bone tissue engineering applications were designed. Two crosslinked copolymer matrices with 90/10 and 30/70 mol % of epsilon-caprolactone (CL) and D,L-lactide (DLLA) were prepared with porosities from 45 to 85 vol % and their mechanical and degradation properties were tested. Corresponding composite scaffolds with 20-50 wt % of particulate bioactive glass (BAG) were also characterized. Compressive modulus of polymer scaffolds ranged from 190+/-10 to 900+/-90 kPa. Lactide rich scaffolds absorbed up to 290 wt % of water in 4 weeks and mainly lost their mechanical properties. Caprolactone rich scaffolds absorbed no more than 110 wt % of water in 12 weeks and kept their mechanical integrity. Polymer and composite scaffolds prepared with P(CL/DLLA 90/10) matrix and 60 vol % porosity were further analyzed in simulated body fluid and in osteoblast culture. Cell growth was compromised inside the 2 mm thick three-dimensional scaffold specimens as a static culture model was used. However, composite scaffolds with BAG showed increased osteoblast adhesion and mineralization when compared to neat polymer scaffolds.

Group II phospholipase A2 content of tears in patients with senile cataract and primary open-angle glaucoma.

PURPOSE: To determine the group II phospholipase A2 (PLA2) content of tears in patients with senile cataract or primary open-angle glaucoma (POAG) and to compare it with the PLA2 content of tears in age-matched healthy controls. METHODS: The PLA2 concentration of tears was measured with time-resolved fluoroimmunoassay in 21 patients with senile cataract, 23 patients with POAG and in 40 healthy controls. RESULTS: The PLA2 content of tears was 38.3+/-30.1 microg/ml in patients with senile cataract, 32.1+/-22.3 microg/ml in patients with POAG, and 36.6+/-31.1 microg/ml in healthy controls. There were no significant differences between the patient and the control groups. CONCLUSIONS: We conclude that neither senile cataract nor POAG has any effect on the PLA2 content of tears.

Group II PLA(2) content of tears in normal subjects.

PURPOSE: To determine the concentration of group II phospholipase (PL) A(2), an antimicrobial molecule, in tears of normal subjects in different age and sex groups. METHODS: PLA(2) content of tears was measured in 122 healthy volunteers with ages ranging from 20 to 89 years (mean, 49.5 years) by a time-resolved fluoroimmunoassay using a polyclonal rabbit antibody to recombinant human PLA(2). RESULTS: The mean concentration of PLA(2) in tears was 54.5 +/- 33.9 microg/ml. It was highest in the age group 20 to 29 years (81.6 +/- 32.0 microg/ml), and a decrease of concentration occurred with an increase of age. PLA(2) values were statistically significantly lower in the age group 60 to 69 years (P = 0.0013) and 70 years or more (P = 0.0001) than in the age group 20 to 29 years. There were no statistically significant differences in PLA(2) content of tears between the genders in any age group (P = 0.798). CONCLUSIONS: The results indicate that tears contain a high concentration of PLA(2) and that PLA(2) levels decrease with an increase of age and/or reflex tear component of the sample analyzed.