Cryoelectron tomography reveals doublet-specific structures and unique interactions in the I1 dynein

Cilia and flagella are highly conserved motile and sensory organelles in eukaryotes, and defects in ciliary assembly and motility cause many ciliopathies. The two-headed I1 inner arm dynein is a critical regulator of ciliary and flagellar beating. To understand I1 architecture and function better, we analyzed the 3D structure and composition of the I1 dynein in Chlamydomonas axonemes by cryoelectron tomography and subtomogram averaging. Our data revealed several connections from the I1 dynein to neighboring structures that are likely to be important for assembly and/or regulation, including a tether linking one I1 motor domain to the doublet microtubule and doublet-specific differences potentially contributing to the asymmetrical distribution of dynein activity required for ciliary beating. We also imaged three I1 mutants and analyzed their polypeptide composition using 2D gel-based proteomics. Structural and biochemical comparisons revealed the likely location of the regulatory IC138 phosphoprotein and its associated subcomplex. Overall, our studies demonstrate that I1 dynein is connected to multiple structures within the axoneme, and therefore ideally positioned to integrate signals that regulate ciliary motility.     

Outcome and quality of life of elderly critically ill patients: an Italian prospective observational study

The demand of critical care admissions to intensive care unit (ICU) is projected to rise in the next decade. The aim of this study was to evaluate short and long-term mortality and quality of life (QoL) of elderly patients (80 years and older) admitted to two ICUs for medical conditions, abdominal surgery (planned and unplanned) and orthopedic surgery for hip fractures, over a 6-year period. Three months and one year after ICU discharge, patients or family members were contacted by telephone to obtain follow-up information using the EuroQoL questionnaire. The data were compared with an age-matched of the Italian population. Two hundred eighty-eight patients were included in the study. ICU mortality of medical (14.8%) and unplanned surgical patients (26.4%) was higher than that of planned surgical (5.0%) and orthopedic patients (2.5%), as was hospital mortality (27.7% vs. 50.0% vs. 5.0% vs. 14.3%). Three months and 12 months mortality rates after ICU discharge were 40.7% and 61.1% in medical patients, 70.5% and 76.4% in unplanned surgical patients, 20.0% and 30.0% in planned surgical patients, 36.2% and 46.2% in orthopedic patients. QoL measures revealed that, one year after ICU discharge, medical and orthopedic patients had significantly more severe problems vis-à-vis mobility, self-care and activity than abdominal surgical patients and control population. Type of admission was the independent risk factor associated with ICU and long-term mortality, whereas age 90 year and older was associated with long-term mortality. Orthopedic surgery for hip fractures seems to influence QoL similar to medical diseases.     

Age-related differences in lower extremity tissue compartments and associations with physical function in older adults

The lower extremities are important to performing physical activities of daily life. This study investigated lower extremity tissue composition, i.e. muscle and fat volumes, in young and older adults and the relative importance of individual tissue compartments to the physical function of older adults. A total of 43 older (age 78.3 ± 5.6 years) and 20 younger (age 23.8 ± 3.9 years) healthy men and women participated in the study. Older participants were further classified as either high- (HF) or low-functioning (LF) according to the Short Physical Performance Battery (SPPB). Magnetic resonance images were used to determine the volumes of skeletal muscle, subcutaneous fat (SAT), and intermuscular fat (IMAT) in the thigh (femoral) and calf (tibiofibular) regions. After adjusting for the sex of participants, younger participants had more femoral muscle mass than older adults (p < 0.001 for between group differences) as well as less femoral IMAT (p = 0.008) and tibiofibular IMAT (p < 0.001). Femoral muscle was the only tissue compartment demonstrating a significant difference between the two older groups, with HF participants having 31% more femoral muscle mass than LF participants (mean difference = 103.0 ± 34.0 cm³; p = 0.011). In subsequent multiple regression models including tissue compartments and demographic confounders, femoral muscle was the primary compartment associated with both SPPB score (r² = 0.264, p = 0.001) and 4-meter gait speed (r² = 0.187, p = 0.007). These data suggest that aging affects all lower extremity compartments, but femoral muscle mass is the major compartment associated with physical function in older adults.     

Reproductive factors and clinical features of Parkinson's disease

BackgroundLiterature suggests that sex steroid hormones may modify the risk for Parkinson's disease (PD). We investigated the potential effect of reproductive factors on the clinical features of idiopathic PD (IPD) patients.MethodsAll IPD female patients admitted to and evaluated at our Institute over a 12-month period were included in the present cross-sectional study. We investigated the effect of the following parameters by multivariate linear regression analysis: age at menarche, age at menopause, length of fertile life, duration of exposure to endogenous estrogens and cumulative length of pregnancies, use of contraceptives and hormonal replacement therapy.ResultsIn total, 579 patients were evaluated and 497 reported menopause before PD onset. In this population, age at PD onset was positively associated with age at menarche and at menopause, length of fertile life and duration of estrogen exposure. Moreover, UPDRS motor score was inversely associated with age at menopause, length of fertile life and duration of estrogen exposure. Increasing age at menarche was also associated with predominant resting tremor at PD onset. In models refitted on patients with early PD (disease duration <5 years; N = 226) all the associations found were confirmed. The relationship between surrogates of estrogen exposure and UPDRS motor score actually became more significant.ConclusionsOur observations support the concept that hormonal exposure of the nigro-striatal network during life may influence its susceptibility to degenerative stimuli in later life, but the association does not seem to be unique? unidirectional. In particular, increased severity of PD signs correlates with shorter duration of estrogen exposure. The underlying mechanisms need to be clarified.