Predicting changes in brain metabolism and progression from mild cognitive impairment to dementia using multitask Deep Learning models and explainable AI.

BACKGROUND: The prediction of Alzheimer's disease (AD) progression from its early stages is a research priority. In this context, the use of Artificial Intelligence (AI) in AD has experienced a notable surge in recent years. However, existing investigations predominantly concentrate on distinguishing clinical phenotypes through cross-sectional approaches. This study aims to investigate the potential of modeling additional dimensions of the disease, such as variations in brain metabolism assessed via [18F]-fluorodeoxyglucose positron emission tomography (FDG-PET), and utilize this information to identify patients with mild cognitive impairment (MCI) who will progress to dementia (pMCI). METHODS: We analyzed data from 1,617 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) who had undergone at least one FDG-PET scan. We identified the brain regions with the most significant hypometabolism in AD and used Deep Learning (DL) models to predict future changes in brain metabolism. The best-performing model was then adapted under a multi-task learning framework to identify pMCI individuals. Finally, this model underwent further analysis using eXplainable AI (XAI) techniques. RESULTS: Our results confirm a strong association between hypometabolism, disease progression, and cognitive decline. Furthermore, we demonstrated that integrating data on changes in brain metabolism during training enhanced the models' ability to detect pMCI individuals (sensitivity=88.4%, specificity=86.9%). Lastly, the application of XAI techniques enabled us to delve into the brain regions with the most significant impact on model predictions, highlighting the importance of the hippocampus, cingulate cortex, and some subcortical structures. CONCLUSION: This study introduces a novel dimension to predictive modeling in AD, emphasizing the importance of projecting variations in brain metabolism under a multi-task learning paradigm.

The Alternative Model of Personality Disorders: Assessment, Convergent and Discriminant Validity, and a Look to the Future.

The Alternative Model of Personality Disorders (AMPD) is a dimensional, empirically based diagnostic system developed to overcome the serious limitations of traditional categories. We review the mounting evidence on its convergent and discriminant validity, with an incursion into the less-studied ICD-11 system. In the literature, the AMPD's Pathological Trait Model (Criterion B) shows excellent convergence with normal personality traits, and it could be useful as an organizing framework for mental disorders. In contrast, Personality Functioning (Criterion A) cannot be distinguished from personality traits, lacks both discriminant and incremental validity, and has a shaky theoretical background. We offer some suggestions with a view to the future. These include removing Criterion A, using the real-life consequences of traits as indicators of severity, delving into the dynamic mechanisms underlying traits, and furthering the integration of currently disengaged psychological paradigms that can shape a sounder clinical science. Expected final online publication date for the Annual Review of Clinical Psychology, Volume 20 is May 2024. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Biomarkers of Alzheimer's disease and neurodegeneration in dried blood spots-A new collection method for remote settings.

BACKGROUND: We aimed to evaluate the precision of Alzheimer's disease (AD) and neurodegeneration biomarker measurements from venous dried plasma spots (DPSv enous) for the diagnosis and monitoring of neurodegenerative diseases in remote settings. METHODS: In a discovery (n = 154) and a validation cohort (n = 115), glial fibrillary acidic protein (GFAP); neurofilament light (NfL); amyloid beta (Aß) 40, Aß42; and phosphorylated tau (p-tau181 and p-tau217) were measured in paired DPSvenous and ethylenediaminetetraacetic acid plasma samples with single-molecule array. In the validation cohort, a subset of participants (n = 99) had cerebrospinal fluid (CSF) biomarkers. RESULTS: All DPSvenous and plasma analytes correlated significantly, except for Aß42. In the validation cohort, DPSvenous GFAP, NfL, p-tau181, and p-tau217 differed between CSF Aß-positive and -negative individuals and were associated with worsening cognition. DISCUSSION: Our data suggest that measuring blood biomarkers related to AD pathology and neurodegeneration from DPSvenous extends the utility of blood-based biomarkers to remote settings with simplified sampling conditions, storage, and logistics. HIGHLIGHTS: A wide array of biomarkers related to Alzheimer's disease (AD) and neurodegeneration were detectable in dried plasma spots (DPSvenous). DPSvenous biomarkers correlated with standard procedures and cognitive status. DPSvenous biomarkers had a good diagnostic accuracy discriminating amyloid status. Our findings show the potential interchangeability of DPSvenous and plasma sampling. DPSvenous may facilitate remote and temperature-independent sampling for AD biomarker measurement. Innovative tools for blood biomarker sampling may help recognizing the earliest changes of AD.

Time-calibrated phylogenies reveal mediterranean and pre-mediterranean origin of the thermophilous vegetation of the Canary Islands.

BACKGROUND AND AIMS: The Canary Islands have strong floristic affinities with the Mediterranean Basin. One of the most characteristic and diverse vegetation belts of the archipelago is the thermophilous woodland (between 200 and 900 m.a.s.l.). This thermophilous plant community consists of many non-endemic species shared with the Mediterranean Floristic Region together with Canarian endemic species. Consequently, phytogeographic studies have historically proposed the hypothesis of an origin of the Canarian thermophilous species following the establishment of the summer-dry mediterranean climate in the Mediterranean Basin around 2.8 million years ago. METHODS: Time-calibrated phylogenies for 39 plant groups including Canarian thermophilous species were primarily analysed to infer colonization times. In particular, we used 26 previously published phylogenies together with 13 new time-calibrated phylogenies (including newly generated plastid and nuclear DNA sequence data) to assess whether the time interval between stem and crown ages of Canarian thermophilous lineages postdates 2.8 Ma. For lineages postdating this time threshold, we additionally conducted ancestral area reconstructions to infer the potential source area for colonization. KEY RESULTS: A total of 43 Canarian thermophilous lineages were identified from 39 plant groups. Both mediterranean (16) and pre-mediterranean (9) plant lineages were found. However, we failed to determine the temporal origin for 18 lineages because a stem-crown time interval overlaps with the 2.8-Ma threshold. The spatial origin of thermophilous lineages was also heterogeneous, including ancestral areas from the Mediterranean Basin (nine) and other regions (six). CONCLUSIONS: Our findings reveal an unexpectedly heterogeneous origin of the Canarian thermophilous species in terms of colonization times and mainland source areas. A substantial proportion of the lineages arrived in the Canaries before the summer-dry climate was established in the Mediterranean Basin. The complex temporal and geographic origin of Canarian thermophilous species challenges the view of the Canary Islands (and Madeira) as a subregion within the Mediterranean Floristic Region.

Parallel Parkin: Cdc20 Takes a New Partner.

CDC20 and CDH1 are well-established substrate receptors for the Anaphase Promoting Complex/Cyclosome (APC/C). In this issue of Molecular Cell, Lee et al. (2015) show that these adaptors can also target cell cycle proteins for destruction through a second ubiquitin ligase, Parkin.

The Synergic Effect of AT(N) Profiles and Depression on the Risk of Conversion to Dementia in Patients with Mild Cognitive Impairment.

Few studies have addressed the impact of the association between Alzheimer's disease (AD) biomarkers and NPSs in the conversion to dementia in patients with mild cognitive impairment (MCI), and no studies have been conducted on the interaction effect of these two risk factors. AT(N) profiles were created using AD-core biomarkers quantified in cerebrospinal fluid (CSF) (normal, brain amyloidosis, suspected non-Alzheimer pathology (SNAP) and prodromal AD). NPSs were assessed using the Neuropsychiatric Inventory Questionnaire (NPI-Q). A total of 500 individuals with MCI were followed-up yearly in a memory unit. Cox regression analysis was used to determine risk of conversion, considering additive and multiplicative interactions between AT(N) profile and NPSs on the conversion to dementia. A total of 224 participants (44.8%) converted to dementia during the 2-year follow-up study. Pathologic AT(N) groups (brain amyloidosis, prodromal AD and SNAP) and the presence of depression and apathy were associated with a higher risk of conversion to dementia. The additive combination of the AT(N) profile with depression exacerbates the risk of conversion to dementia. A synergic effect of prodromal AD profile with depressive symptoms is evidenced, identifying the most exposed individuals to conversion among MCI patients.

Cardiac MRI in Patients with Acute Chest Pain.

Acute chest pain is a common reason for visits to the emergency department. It is important to distinguish among the various causes of acute chest pain, because treatment and prognosis are substantially different among the various conditions. It is critical to exclude acute coronary syndrome (ACS), which is a major cause of hospitalization, death, and health care costs worldwide. Myocardial ischemia is defined as potential myocyte death secondary to an imbalance between oxygen supply and demand due to obstruction of an epicardial coronary artery. Unobstructed coronary artery disease can have cardiac causes (eg, myocarditis, myocardial infarction with nonobstructed coronary arteries, and Takotsubo cardiomyopathy), and noncardiac diseases can manifest with acute chest pain and increased serum cardiac biomarker levels. In the emergency department, cardiac MRI may aid in the identification of patients with non-ST-segment elevation myocardial infarction or unstable angina or ACS with unobstructed coronary artery disease, if the patient's clinical history is known to be atypical. Also, cardiac MRI is excellent for risk stratification of patients for adverse left ventricular remodeling or major adverse cardiac events. Cardiac MRI should be performed early in the course of the disease (<2 weeks after onset of symptoms). Steady-state free-precession T2-weighted MRI with late gadolinium enhancement is the mainstay of the cardiac MRI protocol. Further sequences can be used to analyze the different pathophysiologic subjacent mechanisms of the disease, such as microvascular obstruction or intramyocardial hemorrhage. Finally, cardiac MRI may provide several prognostic biomarkers that help in follow-up of these patients. Online supplemental material is available for this article. ©RSNA, 2020.

Diagnosis of Alzheimer's disease and behavioural variant frontotemporal dementia with machine learning-aided neuropsychological assessment using feature engineering and genetic algorithms.

BACKGROUND: Neuropsychological assessment is considered a valid tool in the diagnosis of neurodegenerative disorders. However, there is an important overlap in cognitive profiles between Alzheimer's disease (AD) and behavioural variant frontotemporal dementia (bvFTD), and the usefulness in diagnosis is uncertain. We aimed to develop machine learning-based models for the diagnosis using cognitive tests. METHODS: Three hundred and twenty-nine participants (170 AD, 72 bvFTD, 87 healthy control [HC]) were enrolled. Evolutionary algorithms, inspired by the process of natural selection, were applied for both mono-objective and multi-objective classification and feature selection. Classical algorithms (NativeBayes, Support Vector Machines, among others) were also used, and a meta-model strategy. RESULTS: Accuracies for the diagnosis of AD, bvFTD and the differential diagnosis between them were higher than 84%. Algorithms were able to significantly reduce the number of tests and scores needed. Free and Cued Selective Reminding Test, verbal fluency and Addenbrooke's Cognitive Examination were amongst the most meaningful tests. CONCLUSIONS: Our study found high levels of accuracy for diagnosis using exclusively neuropsychological tests, which supports the usefulness of cognitive assessment in diagnosis. Machine learning may have a role in improving the interpretation and test selection.

Cardiac MRI in Pulmonary Hypertension: From Magnet to Bedside.

Pulmonary hypertension (PH) is a disease characterized by progressive rise of pulmonary artery (PA) pressure, which can lead to right ventricular (RV) failure. It is usually diagnosed late because of the nonspecificity of its symptoms. RV performance and adaptation to an increased afterload, reflecting the interaction of the PA and RV as a morphofunctional unit, constitute a critical determinant of morbidity and mortality in these patients. Therefore, early detection of dysfunction may prevent treatment failure. Cardiac MRI constitutes one of the most complete diagnostic modalities for diagnosing PH. It allows evaluation of the morphology and hemodynamics of the PA and RV. Several cine steady-state free-precession (SSFP)-derived parameters (indexed RV end-diastolic volume or RV systolic volume) and phase-contrast regional area change have been suggested as powerful biomarkers for prognosis and treatment. Recently, new cardiac MRI sequences have been added to clinical protocols for PH evaluation, providing brand-new information. Strain analysis with myocardial feature tracking can help detect early RV dysfunction, even with preserved ejection fraction. Four-dimensional flow cardiac MRI can enhance assessment of advanced RV and PA hemodynamics. Late gadolinium enhancement (LGE) imaging may allow detection of replacement fibrosis in PH patients, which is associated with poor outcome. T1 mapping may help detect interstitial fibrosis, even with normal LGE imaging results. The authors analyze the imaging workup of PH with a focus on the role of morphologic and functional cardiac MRI in diagnosis and management of PH, including some of the newer techniques. Online supplemental material is available for this article. ©RSNA, 2020.

High rates of severe disease and death due to SARS-CoV-2 infection in rheumatic disease patients treated with rituximab: a descriptive study.

The objective of this study is to describe the characteristics and outcomes of rheumatic and musculoskeletal disease (RMD) patients who were treated with rituximab and had suspected or confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. In this descriptive study, RMD patients who were treated with rituximab in the last 12 months at the Rheumatology Department of our hospital were screened for SARS-CoV-2 infection via telephone interview and a comprehensive review of clinical health records (01/02/2020-26/05/2020). Those with probable or confirmed SARS-CoV-2 infection were included. In total, 76 patients were screened. Of these, 13 (17.1%) had suspected or confirmed SARS-CoV-2 infection. With regard to these 13 patients, the median age at coronavirus disease (COVID-19) diagnosis was 68 years (range 28-76 years) and 8 (61.5%) were female. Five patients had rheumatoid arthritis, three had systemic vasculitis, two had Sjögren syndrome, and two had systemic lupus erythematosus. Additionally, seven patients (53.8%) had pulmonary involvement secondary to RMD. Eight patients (61.5%) developed severe disease leading to hospitalization, and seven developed bilateral pneumonia and respiratory insufficiency. Of the eight hospitalized patients, five (62.5%) fulfilled the acute respiratory distress syndrome criteria and three developed a critical disease and died. Our cohort had a high rate of severe disease requiring hospitalization (61.5%), with bilateral pneumonia and hyperinflammation leading to a high mortality rate (23.1%). Treatment with rituximab should be considered a possible risk factor for unfavorable outcomes in COVID-19 patients with RMD. However, further study is required to confirm this association.

International Assessment of DSM-5 and ICD-11 Personality Disorder Traits: Toward a Common Nosology in DSM-5.1.

INTRODUCTION: The DSM-5 Alternative Model of Personality Disorders (AMPD) and the ICD-11 classification of personality disorders (PD) are largely commensurate and, when combined, they delineate 6 trait domains: negative affectivity, detachment, antagonism/dissociality, disinhibition, anankastia, and psychoticism. OBJECTIVE: The present study evaluated the international validity of a brief 36-item patient-report measure that portrays all 6 domains simultaneously including 18 primary subfacets. METHODS: We developed and employed a modified version of the Personality Inventory for DSM-5 - Brief Form Plus (PID5BF+). A total of 16,327 individuals were included, 2,347 of whom were patients. The expected 6-factor structure of facets was initially investigated in samples from Denmark (n = 584), Germany (n = 1,271), and the USA (n = 605) and subsequently replicated in both patient- and community samples from Italy, France, Switzerland, Belgium, Norway, Portugal, Spain, Poland, Czech Republic, the USA, and Brazil. Associations with interview-rated DSM-5 PD categories were also investigated. RESULTS: Findings generally supported the empirical soundness and international robustness of the 6 domains including meaningful associations with familiar interview-rated PD types. CONCLUSIONS: The modified PID5BF+ may be employed internationally by clinicians and researchers for brief and reliable assessment of the 6 combined DSM-5 and ICD-11 domains, including 18 primary subfacets. This 6-domain framework may inform a future nosology for DSM-5.1 that is more reasonably aligned with the authoritative ICD-11 codes than the current DSM-5 AMPD model. The 36-item modified PID5BF+ scoring key is provided in online supplementary Appendix A see www.karger.com/doi/10.1159/000507589 (for all online suppl. material).

Approach to Pulmonary Hypertension: From CT to Clinical Diagnosis.

Pulmonary hypertension (PH) is a condition characterized by increased pressure in the pulmonary circulation. It may be idiopathic or arise in the setting of other clinical conditions. Patients with PH tend to present with nonspecific cardiovascular or respiratory symptoms. The clinical classification of PH was recently revised at the World Health Organization symposium in Nice, France, in 2013. That consensus statement provided an updated classification based on the shared hemodynamic characteristics and management of the different categories of PH. Some features seen at computed tomography (CT) can suggest a subtype or probable cause of PH that may facilitate placing the patient in the correct category. These features include findings in the pulmonary arteries (peripheral calcification, peripheral dilatation, eccentric filling defects, intra-arterial soft tissue), lung parenchyma (centrilobular nodules, mosaic attenuation, interlobular septal thickening, bronchiectasis, subpleural peripheral opacities, ground-glass opacities, diffuse nodules), heart (congenital lesions, left heart disease, valvular disease), and mediastinum (hypertrophied bronchial arteries). An approach based on identification of these CT features in patients with PH will allow the radiologist to play an important role in diagnosis and help guide the clinician in management of PH. ©RSNA, 2018.

Personality Disorders Are Not as We Thought: Hierarchical Factor Structure at the Criterion Level.

The use of personality disorder (PD) categories persists, despite the evidence against them. An often overlooked reason for this is the fact that the true structure underlying the Diagnostic and Statistical Manual of Mental Disorders (DSM) taxonomy is still unknown: We cannot be certain which disorders are valid, and which ones are arbitrary mixtures of heterogeneous traits. To address this gap, we factor analyzed the Personality Diagnostic Questionnaire (PDQ-4+; Hyler, 1994 ) at the criterion level in a mixed clinical and nonclinical sample of 2,519 individuals. The resulting structure was more similar to current dimensional taxonomies than to the DSM classification at all hierarchical levels. Whereas paranoid and antisocial PDs-and to a lesser extent avoidant, dependent, depressive, and schizoid PDs-were fairly homogeneous, all other disorders turned out to be combinations of 2 or 3 unrelated dimensions. Our results strongly support the structure of empirically based dimensional taxonomies and relocate DSM criteria within this emerging framework, thus contributing to preserving much of the knowledge accumulated to date.

Dimensional Personality Assessment among a Chronic Fatigue Syndrome (CFS) sample with Personality Inventory for DSM-5 (PID-5).

INTRODUCTION: Personality Disorders (PD) are highly prevalent among Chronic Fatigue Syndrome (CFS) patients, but studies based on the DSM-5 are still scarce. Validated instruments have not yet been specifically used in CFS patients. Therefore, our aim was to analyze the differences in personality facets and domains profiles among CFS patients with and without a PD using the Personality Inventory for DSM-5 (PID-5). Additionally, we analyzed the ability of this instrument to predict PD in a sample of CFS patients. This instrument is validated for PDs, but not for CFS. METHODS: All of the 84 CFS patients were evaluated through a clinical interview and underwent psychopathological evaluation with the SCID I and SCID II. Dimensional personality facets and domains were evaluated with the PID-5, according to DSM-5. RESULTS: In our sample, 54 (64%) of the patients fulfilled the criteria of a PD. The most significant facets in CFS with PD in comparison to those patients without a PD were Separation Insecurity, Perseveration, Withdrawal, Depressivity, Rigid Perfectionism, Unusual Beliefs and Experiences. Negative Affectivity and Detachment were the two significant domains in CFS-PD patients. In the regression analyses, only Detachment and Rigid Perfectionism constituted a prognostic factor leading to high probability of an endorsed PD. Conclussion. According to these results, the PID-5 domains and facets could be adequate and useful to differentiate between PD and non-PD patients in clinical samples and suggest a more frequent dimensional personality profile in CFS patients.

Efficient and automated large-scale detection of structural relationships in proteins with a flexible aligner.

BACKGROUND: The total number of known three-dimensional protein structures is rapidly increasing. Consequently, the need for fast structural search against complete databases without a significant loss of accuracy is increasingly demanding. Recently, TopSearch, an ultra-fast method for finding rigid structural relationships between a query structure and the complete Protein Data Bank (PDB), at the multi-chain level, has been released. However, comparable accurate flexible structural aligners to perform efficient whole database searches of multi-domain proteins are not yet available. The availability of such a tool is critical for a sustainable boosting of biological discovery. RESULTS: Here we report on the development of a new method for the fast and flexible comparison of protein structure chains. The method relies on the calculation of 2D matrices containing a description of the three-dimensional arrangement of secondary structure elements (angles and distances). The comparison involves the matching of an ensemble of substructures through a nested-two-steps dynamic programming algorithm. The unique features of this new approach are the integration and trade-off balancing of the following: 1) speed, 2) accuracy and 3) global and semiglobal flexible structure alignment by integration of local substructure matching. The comparison, and matching with competitive accuracy, of one medium sized (250-aa) query structure against the complete PDB database (216,322 protein chains) takes about 8 min using an average desktop computer. The method is at least 2-3 orders of magnitude faster than other tested tools with similar accuracy. We validate the performance of the method for fold and superfamily assignment in a large benchmark set of protein structures. We finally provide a series of examples to illustrate the usefulness of this method and its application in biological discovery. CONCLUSIONS: The method is able to detect partial structure matching, rigid body shifts, conformational changes and tolerates substantial structural variation arising from insertions, deletions and sequence divergence, as well as structural convergence of unrelated proteins.

Hematological toxicity of carboplatin for gynecological cancer according to body mass index.

PURPOSE: The aim of the present study was to analyze how patient weight affects the hematological toxicity of carboplatin and whether this toxicity is more prevalent in overweight patients. METHODS: We performed a retrospective 2-year study of patients diagnosed with a gynecological cancer and whose treatment regimen contained carboplatin (AUC dose = 5 or 6) and paclitaxel (dose = 175 mg/m(2)) every 3 weeks (CP scheme). We recorded all severe hematological events (thrombocytopenia, neutropenia, and/or anemia grade III/IV) according to the CTCAE v4.03, as well as treatment modifications and the need for granulocyte colony-stimulating factors (G-CSF) and/or erythropoietin (EPO) or packed red blood cells (PRBC). Patients with a body mass index (BMI) ≥27 kg/m(2) were considered as overweight (OW) and those with a BMI <27 kg/m(2) were considered as normal weight (NW). RESULTS: Fifty-two patients met the inclusion criteria (21 patients in the OW group, 31 patients in the NW group). The OW group showed a higher incidence of thrombocytopenia (95% confidence intervals (CI) 1.51-27.72; p < 0.02) and anemia (95% CI 1.06-33.63; p < 0.05). Moreover, this was reflected in a greater number of changes in the usual CP regimen (95% CI 2.19-44.32; p < 0.01). The need for G-CSF and/or EPO/PRBC was also significantly higher in the OW group (95% CI 1.08-12.16; p < 0.04). CONCLUSIONS: Carboplatin dosing based on real weight in obese patients resulted in increased hematologic toxicity, mainly thrombocytopenia. Dose adjustment based on other descriptors of weight, such as adjusted weight, may be better tolerated by patients. However, future studies are needed to demonstrate not only better safety of carboplatin but also improved survival rates.

Borderline Personality Disorder and Personality Inventory for DSM-5 (PID-5): Dimensional personality assessment with DSM-5.

INTRODUCTION: Borderline personality disorder (BPD) diagnosis has been considered highly controversial. The Diagnostic and Statistical Manual of Mental Disorders 5th edition (DSM-5) proposes an alternative hybrid diagnostic model for personality disorders (PD), and the Personality Inventory for DSM-5 (PID-5) has adequate psychometric properties and has been widely used for the assessment of the dimensional component. METHODS: Our aim was to analyze the utility of the personality traits presented in Section III of the DSM-5 for BPD diagnosis in an outpatient clinical sample, using the Spanish version of the PID-5. Two clinical samples were studied: BPD sample (n=84) and non-BPD sample (n=45). Between-sample differences in PID-5 scores were analyzed. RESULTS: The BPD sample obtained significantly higher scores in most PID-5 trait facets and domains. Specifically and after regression logistic analyses, in BPD patients, the domains of Negative Affectivity and Disinhibition, and the trait facets of emotional lability, [lack of] restricted affectivity, and impulsivity were more significantly associated with BPD. CONCLUSIONS: Although our findings are only partially consistent with the algorithm proposed by DSM-5, we consider that the combination of the PID-5 trait domains and facets could be useful for BPD dimensional diagnosis, and could further our understanding of BPD diagnosis complexity.

How temperament and character affect our career, relationships, and mental health.

BACKGROUND: On the way toward an agreed dimensional taxonomy for personality disorders (PD), several pivotal questions remain unresolved. We need to know which dimensions produce problems and in what domains of life; whether impairment can be found at one or both extremes of each dimension; and whether, as is increasingly advocated, some dimensions measure personality functioning whereas others reflect style. METHOD: To gain this understanding, we administered the Temperament and Character Inventory to a sample of 862 consecutively attended outpatients, mainly with PDs (61.2%). Using regression analysis, we examined the ability of personality to predict 39 variables from the Life Outcome Questionnaire concerning career, relationships, and mental health. RESULTS: Persistence stood out as the most important dimension regarding career success, with 24.2% of explained variance on average. Self-directedness was the best predictor of social functioning (21.1%), and harm avoidance regarding clinical problems (34.2%). Interpersonal dimensions such as reward dependence and cooperativeness were mostly inconsequential. In general, dimensions were detrimental only in one of their poles. CONCLUSIONS: Although personality explains 9.4% of life problems overall, dimensions believed to measure functioning (character) were not better predictors than those measuring style (temperament). The notion that PD diagnoses can be built upon the concept of "personality functioning" is unsupported.

Prb1 Protease Activity Is Required for Its Recognition by the F-Box Protein Saf1.

The SCF ubiquitin ligase associates with substrates through its F-box protein adaptor. Substrates are typically recognized through a defined phosphodegron. Here, we characterize the interaction of the F-box protein Saf1 with Prb1, one of its vacuolar protease substrates. We show that Saf1 binds the mature protein but ubiquitinates only the zymogen precursor. The ubiquitinated lysine was found to be in a peptide eliminated from the mature protein. Mutations that eliminate the catalytic activity of Prb1, or the related substrate Prc1, block Saf1 targeting of the zymogen precursor. Our data suggest that Saf1 does not require a conventional degron as do other F-box proteins but instead recognizes the catalytic site itself.