The von Hippel-Lindau protein forms fibrillar amyloid assemblies that are mitigated by the anti-amyloid molecule Purpurin.

The von Hippel-Lindau protein (pVHL) is a tumor suppressor involved in oxygen regulation via dynamic nucleocytoplasmic shuttling. It plays a crucial role in cell survival by degrading hypoxia-inducible factors (HIFs). Mutations in the VHL gene cause angiogenic tumors, characterized as VHL syndrome. However, aggressive tumors involving wild-type pVHL have also been described but the underlying mechanism remains to be revealed. We have previously shown that pVHL possesses several short amyloid-forming motifs, making it aggregation-prone. In this study, using a series of biophysical assays, we demonstrated that a pVHL-derived fragment (pVHL104-140) that harbors the nuclear export motif and HIF binding site, forms amyloid-like fibrillar structures in vitro by following secondary-nucleation-based kinetics. The peptide also formed amyloids at acidic pH that mimics the tumor microenvironment. We, subsequently, validated the amyloid formation by pVHL in vitro. Using the Curli-dependent amyloid generator (C-DAG) expression system, we confirmed the amyloidogenesis of pVHL in bacterial cells. The pVHL amyloids are an attractive target for therapeutics of the VHL syndrome. Accordingly, we demonstrated in vitro that Purpurin is a potent inhibitor of pVHL fibrillation. The amyloidogenic behavior of wild-type pVHL and its inhibition provide novel insights into the molecular underpinning of the VHL syndrome and its possible treatment.

Altered Grooming Cycles in Transgenic Drosophila.

Head grooming in Drosophila consists of repeated sweeps of the legs across the head, comprising regular cycles. We used the GAL4-UAS system to study the effects of overexpressing shibirets1 and of Adar knockdown via RNA interference, on the period of head-grooming cycles in Drosophila. Overexpressing shibirets1 interferes with synaptic vesicle recycling and thus with cell communication, while Adar knockdown reduces RNA editing of neuronal transcripts for a large number of genes. All transgenic flies and their controls were tested at 22° to avoid temperature effects; in wild type, cycle frequency varied with temperature with a Q10 of 1.3. Two experiments were performed with transgenic shibirets1: (1) each fly was heat-shocked for 10 min at 30° immediately before testing at 22° and (2) flies were not heat shocked. In both experiments, cycle period was increased when shibirets1 was overexpressed in all neurons, but was not increased when shibirets1 was overexpressed in motoneurons alone. We hypothesize that grooming cycles in flies overexpressing shibirets1 are lengthened because of synaptic impairment in neural circuits that control head-grooming cycles. In flies with constitutive, pan-neuronal Adar knockdown, cycle period was more variable within individuals, but mean cycle period was not significantly altered. We conclude that RNA editing is essential for the maintenance of within-individual stereotypy of head-grooming cycles.

On the Measurement of Aging Anxiety: Comparative Validity of Two Popular Measures Among Older Adults.

Aging anxiety is a distinct form of fear characterized by negative feelings associated with growing older. This study directly compared two common measures of aging anxiety within an older adult sample. Participants completed the Anxiety about Aging Scale, the Personal Anxiety Toward Aging Scale and several related constructs including ageism, expectations regarding aging, dementia worry, and death anxiety. The two measures significantly and strongly associated with one another. The Anxiety about Aging Scale (AAS) showed evidence of convergent validity through significant and strong correlations with ageism, expectations regarding aging, and death anxiety, and a moderate correlation with dementia worry. The Personal Anxiety Toward Aging Scale (PAAS) also showed evidence of convergent validity through strong correlations with expectations regarding aging and death anxiety, and moderate correlations with ageism and dementia worry. Factor analysis showed a better model fit for the AAS. Key findings lend support for the AAS as a psychometrically stronger measure than the PAAS for older adult assessment.

Assessment of Personality Disorders in Older Adults. A Practice Guide.

Assessment of personality disorders (PDs) in older adults is a nuanced trade of its own. The aim of this practice guide is to illustrate gerontological assessment challenges using 3 case vignettes. We argue that it is important to pay extra attention to the influence of cognitive and medical (somatic) disorders on personality functioning in older adults during personality assessment. We also note that information provided by informants contributes added value to personality assessment. Personality assessment should be sufficiently age-specific to prevent overdiagnosis or underdiagnosis in older adults. Furthermore, given the reduced psychological or somatic capacity of some older adults, phased or sequential personality assessment is recommended. This should be focused on the assessment questions to be answered, for example starting with short general screening of personality functioning, followed by more in-depth exploration. Personality assessment should be kept as brief and simple as possible in terms of formulation of the items.

Impact of self-reported cognitive dysfunction on the alternative model of personality disorders among older adults.

METHOD: Older adults (N = 202) completed the Levels of Personality Functioning Scale-Self-Report, Personality Inventory for DSM-5, and Coolidge Axis II Inventory with its six self-report cognitive dysfunction scales. RESULTS: Results suggested high correlational overlap between subjective cognitive problems with personality functioning and pathological personality, as measured by the AMPD. Hierarchical regressions revealed that subjective measures of executive functions, perceptual motor, and language difficulties were most strongly related to the AMPD's constructs. Results are discussed in the context of prior research on objective cognitive impairment among individuals with PDs. CONCLUSION: The degree of overlap found within the current older adult sample suggested an age-related problem or potential age-bias, with older adults being at-risk of (a) having their subjective cognitive problems being incorrectly interpreted as personality pathology under the AMPD or (b) having personality pathology being overlooked under the AMPD, with symptoms instead attributed to subjective cognitive issues. This study suggested that subjective cognitive dysfunction may be one mechanism that contributes to differential performance of the AMPD among older adults.

Relationship between anxiety and quality of life among older adults with self-reported polypharmacy in long-term care: A cross-sectional study.

AIMS: To investigate the relationship between anxiety and quality of life among older adults with self-reported polypharmacy living in the long-term care setting. DESIGN: A cross-sectional design was used. METHODS: Between July 2021 and August 2022, 92 older adults living in long-term care completed an anonymous one-time questionnaire packet. Polypharmacy was measured as self-reported five or more medications daily. Anxiety was measured using the Geriatric Anxiety Scale-Long Term Care tool. Quality of life was measured as health-related quality of life using two global questions from the RAND-36 and as medication-related quality of life using the Medication-Related Quality of Life Scale. RESULTS: The prevalence of polypharmacy was 89%. Among participants with polypharmacy, average age was 80.1 ± 7.9 years. The majority were female (70%) and white (85%). There was a moderate-to-strong correlation between anxiety and quality of life. Specifically, anxiety was negatively related to current health-related quality of life, perceived change in health-related quality of life and medication-related quality of life. Overall, anxiety explained 27-31% of the variance in both health-related and medication-related quality of life. CONCLUSION: The results of this study indicate that as anxiety increases, health-related and medication-related quality of life decreases in older adults living in long-term care who report consuming five or more medications daily. Advanced practice nurses can use these findings to guide practice, tailor interventions and improve care for these long-term care residents. IMPLICATIONS: Multiple medications are increasingly prescribed to treat multiple comorbidities in older adults. As a result, the prevalence of polypharmacy (≥5 medications per day) is rising and problematic. The main findings of this study highlight the negative relationship between anxiety and quality of life in this population and the need for adequate assessment of anxiety by advanced practice nurses in order to personalize care. REPORTING METHOD: In preparing the manuscript, the authors have adhered to relevant EQUATOR guidelines and the STROBE checklist for cross-sectional studies. PATIENT OR PUBLIC CONTRIBUTION: No patient or public contribution outside of participation in the actual study for purposes of data collection.

Relationships Between Diverse Forms of Anxiety With Intrapersonal Functioning Among Older Adults.

This study assessed how clinical anxiety, anxiety about aging, and death anxiety related to one another and to intrapersonal functioning. Older adults completed the Geriatric Anxiety Scale, Anxiety About Aging Scale, Death Anxiety Scale-Extended, and Intrapersonal Problems Rating Scale. Clinical anxiety was strongly correlated with anxiety about aging (r = .50) and death anxiety (r = .59), and anxiety about aging and death anxiety were strongly positively correlated with each other (r = .51). Intrapersonal problems were significantly and strongly positively correlated with clinical anxiety (r = .79), anxiety about aging (r = .50), and death anxiety (r = .56). Multiple regression results showed that the three types of anxiety accounted for a large amount of variance in intrapersonal problems. Findings suggest strong comorbidities between diverse forms of anxiety with some unique features. Intrapersonal deficits may be prominent in the presence of diverse forms of anxiety. Screening should consider these relationships.

Assessing late-life anxiety in Japanese older adults: psychometric evaluation of the Japanese version of the Geriatric Anxiety Scale.

BACKGROUND: This study developed a Japanese version of the Geriatric Anxiety Scale (GAS-J) and its short form (GAS-10-J) to evaluate anxiety in Japanese older adults and assess its psychometric properties using a cross-sectional design. METHODS: A total of 331 community-dwelling older adult participants (208 men, 116 women, seven unknowns; mean age = 73.47 ± 5.17 years, range = 60-88 years) recruited from two Silver Human Resources Centres in the Kanto region, Japan, answered a set of self-report questionnaires. Of these respondents, 120 participated in a follow-up survey to evaluate test-retest reliability. RESULTS: Confirmatory factor analysis suggested that, as with the original GAS, the GAS-J had a three-factor structure and the GAS-10-J had a unifactor structure with high standardised factor loadings. Test-retest correlations and internal consistency analyses indicated that these scales were reliable. Correlations between the GAS-J/GAS-10-J with the Geriatric Anxiety Inventory, Generalised Anxiety Disorder-7, Geriatric Depression Scale-15, World Health Organization-Five Well-Being Index, and Kihon Checklist were mostly consistent with our hypotheses, thereby supporting the construct validity of the GAS-J/GAS-10-J. CONCLUSIONS: The findings indicate that the GAS-J and GAS-10-J have robust psychometric properties for assessing late-life anxiety in Japanese older adults. Further GAS-J studies are required for clinical groups.

Self-sustaining smouldering combustion for the treatment of industrial oily waste.

Significant onsite handling and offsite management costs are incurred by oilfield operators annually to properly manage hydrocarbon waste streams such as tank bottoms or other oily sludge or oil impacted soil generated during oil and gas production processes. The current study reports for the first-time technical results of a field trial on use of a smouldering combustion technology performed in an active oilfield. Two treatment batches with oily sludges, stabilized through blending with soil, resulted in permanent hydrocarbon removal (98-99.9% reduction) to create treated soil that met standards for reuse as clean backfill onsite. Emissions profile data collected pre- and post-thermal oxidizer indicated effective removal of volatile organic compounds, CO and SO2, but had increased NO and CO2 due to combustion of propane to affect the thermal oxidation. Regulatory, financial, environmental and safety considerations are discussed in context of future full-scale smouldering technology deployment. The technology has the potential to lower overall unit costs for management of hydrocarbon impacted waste and reduce waste sent to landfills, which can benefit more remote sites.

Development and Validation of a Short Form of the Geriatric Anxiety Scale (GAS-12) among Italian Older Adults.

OBJECTIVES: We developed a new Italian short version of the Geriatric Anxiety Scale (GAS-12) and evaluated its psychometric properties. The GAS-12 specifically screens for anxiety symptoms in the Italian older adult population by identifying items that best discriminate anxiety in this population. METHODS: In Study 1, we administered the full-length Italian translation of the GAS to 517 older adults and used item response theory to identify the most discriminating items and to develop the short form used in Study 2. In Study 2, we evaluated the functioning of the new short form of the questionnaire in a new sample of 427 older adults using Confirmatory factor analysis. RESULTS: Analyses indicated 12 items that discriminated well between anxious and non-anxious participants and distributed along the latent continuum of each trait. The GAS-12 fits a three-factor structure. There was also evidence for convergent and divergent validity. CONCLUSIONS: The Italian GAS-12 appears to be a useful instrument for the quantitative screening of anxiety in Italian older adults. CLINICAL IMPLICATIONS: Anxiety imposes significant impairment thus making imperative the screening and assessment of anxiety symptoms. The GAS-12 is particularly indicated with limited time and many scales in a clinical assessment or research protocols.

Optimal Use of Tumor-Based Molecular Assays for Localized Prostate Cancer.

PURPOSEOF REVIEW: The use of genomic testing for prostate cancer continues to grow; however, utilization remains institutionally dependent. Herein, we review current tissue-based markers and comment on current use with active surveillance and prostate MRI. RECENT FINDINGS: While data continues to emerge, several studies have shown a role for genomic testing for treatment selection. Novel testing options include ConfirmMDx, ProMark, Prolaris, and Decipher, which have shown utility in select patients. The current body of literature on this specific topic remains very limited; prospective trials with long-term follow-up are needed to improve our understanding on how these genomic tests fit when combined with our current clinical tools. As the literature matures, it is likely that newer risk calculators that combine our classic clinical variables with genomic and imaging data will be developed to bring about standard protocols for prostate cancer decision-making.

Differential effects of putative N-glycosylation sites in human Tau on Alzheimer's disease-related neurodegeneration.

Amyloid assemblies of Tau are associated with Alzheimer's disease (AD). In AD Tau undergoes several abnormal post-translational modifications, including hyperphosphorylation and glycosylation, which impact disease progression. N-glycosylated Tau was reported to be found in AD brain tissues but not in healthy counterparts. This is surprising since Tau is a cytosolic protein whereas N-glycosylation occurs in the ER-Golgi. Previous in vitro studies indicated that N-glycosylation of Tau facilitated its phosphorylation and contributed to maintenance of its Paired Helical Filament structure. However, the specific Tau residue(s) that undergo N-glycosylation and their effect on Tau-engendered pathology are unknown. High-performance liquid chromatography and mass spectrometry (LC-MS) analysis indicated that both N359 and N410 were N-glycosylated in wild-type (WT) human Tau (hTau) expressed in human SH-SY5Y cells. Asparagine to glutamine mutants, which cannot undergo N-glycosylation, at each of three putative N-glycosylation sites in hTau (N167Q, N359Q, and N410Q) were generated and expressed in SH-SY5Y cells and in transgenic Drosophila. The mutants modulated the levels of hTau phosphorylation in a site-dependent manner in both cell and fly models. Additionally, N359Q ameliorated, whereas N410Q exacerbated various aspects of hTau-engendered neurodegeneration in transgenic flies.

Distinctions between depression and anxiety with fear of being a burden in late life.

Objectives: The perception of being a burden is a well-known risk factor for dying by suicide. Research on factors that precede the state of perceived burdensomeness, such as fearing being a burden, is necessary. We investigated the extent to which health status, elevated depressive symptoms, and elevated anxiety symptoms are associated with fear of being a burden in late life.Method: Older adult participants (N = 155) completed the Geriatric Anxiety Scale (GAS), Patient Health Questionnaire (PHQ-8), and demographic and health questions. Fear of being a burden, assessed with a supplemental item on the GAS, was categorically grouped as 'no fear' or 'some fear'. Using logistic regression, we examined predictors of fear of being a burden.Results: In the first step, elevated depression was associated with fear of being a burden (OR = 2.30, 95% CI: 1.09, 4.89, p = .03), but health status was not significant. In the second step, elevated anxiety was significant (OR = 2.63, 95% CI: 1.15, 5.99, p = .02); depression was no longer significant.Conclusion: Contrary to expectations, anxiety more strongly predicted fear of being a burden than depression. Future research should further investigate the role of anxiety in fear of being a burden and ways of intervening.

Inhibitor-Mediated Structural Transition in a Minimal Amyloid Model.

Despite the fundamental clinical importance of amyloid fibril formation, its mechanism is still enigmatic. Crystallography of minimal amyloid models was a milestone in the understanding of the architecture and biological activities of amyloid fibers. However, the crystal structure of ultimate dipeptide-based amyloids is not yet reported. Herein, we present the crystal structure of a typical amyloid-forming minimal dipeptide, Ac-Phe-Phe-NH2 (Ac-FF-NH2 ), showing a canonical ß-sheet structure at the atomic level. The simplicity of the structure helped in investigating amyloid-inhibition using crystallography, never previously reported for larger peptide models. Interestingly, in the presence of an inhibitor, the supramolecular packing of Ac-FF-NH2 molecules rearranged into a supramolecular 2-fold helix (21 helix). This study promotes our understanding of the mechanism of amyloid formation and of the structural transitions that occur during the inhibition process in a most fundamental model.

Purpurin modulates Tau-derived VQIVYK fibrillization and ameliorates Alzheimer's disease-like symptoms in animal model.

Neurofibrillary tangles of the Tau protein and plaques of the amyloid ß peptide are hallmarks of Alzheimer's disease (AD), which is characterized by the conversion of monomeric proteins/peptides into misfolded ß-sheet rich fibrils. Halting the fibrillation process and disrupting the existing aggregates are key challenges for AD drug development. Previously, we performed in vitro high-throughput screening for the identification of potent inhibitors of Tau aggregation using a proxy model, a highly aggregation-prone hexapeptide fragment 306VQIVYK311 (termed PHF6) derived from Tau. Here we have characterized a hit molecule from that screen as a modulator of Tau aggregation using in vitro, in silico, and in vivo techniques. This molecule, an anthraquinone derivative named Purpurin, inhibited ~ 50% of PHF6 fibrillization in vitro at equimolar concentration and disassembled pre-formed PHF6 fibrils. In silico studies showed that Purpurin interacted with key residues of PHF6, which are responsible for maintaining its ß-sheets conformation. Isothermal titration calorimetry and surface plasmon resonance experiments with PHF6 and full-length Tau (FL-Tau), respectively, indicated that Purpurin interacted with PHF6 predominantly via hydrophobic contacts and displayed a dose-dependent complexation with FL-Tau. Purpurin was non-toxic when fed to Drosophila and it significantly ameliorated the AD-related neurotoxic symptoms of transgenic flies expressing WT-FL human Tau (hTau) plausibly by inhibiting Tau accumulation and reducing Tau phosphorylation. Purpurin also reduced hTau accumulation in cell culture overexpressing hTau. Importantly, Purpurin efficiently crossed an in vitro human blood-brain barrier model. Our findings suggest that Purpurin could be a potential lead molecule for AD therapeutics.

Relationships between pathological narcissism and maladaptive personality traits among older adults.

Objectives: The Pathological Narcissism Inventory (PNI) is a measure of narcissism, with two domains of Vulnerability and Grandiosity, that has limited evidence of validity among older adults. Subsequently, the objective of the present study was to examine relationships between the PNI and measures of diverse pathological personality features.Method: Participants consisted of 125 community-dwelling older adults (M age = 71.8 years) who completed the PNI, the Personality Inventory for DSM-5 (PID-5), and the Coolidge Axis II Inventory (CATI).Results: Total Narcissism, Vulnerability, and Grandiosity were significantly correlated with every PD scale, with the exception of Grandiosity with Schizotypal PD. Regression analyses revealed that Narcissistic and Avoidant PDs had the strongest relationships with the PNI. Total Narcissism was also significantly correlated with all five PID-5 domains, with regression indicating Negative Affect and Antagonism as the strongest predictors.Conclusions: Findings generally support the convergent validity of the PNI for use among older adults and suggest that pathological narcissism may be related to general personality pathology in later life.

Severity Indices of Personality Problems-Short Form in Old-Age Psychiatry: Reliability and Validity.

The Severity Indices of Personality Problems (SIPP; Verheul et al., 2008) is a popular self-report questionnaire that measures severity of maladaptive personality functioning. Two studies demonstrated the utility of the short form (SIPP-SF) among older adults but validation in clinical settings is lacking. Therefore, we examined the psychometric properties of the SIPP-SF in a large sample of older adult Dutch outpatients (N = 124; age range = 60-85 years, M = 69.8, SD = 5.3). The SIPP-SF domains showed good to excellent internal reliability (Cronbach's α = .75-.91) and effectively discriminated between participants with and without a personality disorder, as assessed with the Structured Clinical Interview for DSM-IV Axis II Personality Disorders (SCID-II). Convergent validity of the SIPP-SF was examined with instruments for measuring personality pathology among older adults (Informant Personality questionnaire [HAP]; Gerontological Personality Disorders Scale [GPS]). The GPS generally correlated with the SIPP-SF domains in expected directions, with small to large effect sizes. For the HAP, only 1 scale correlated with all SIPP-SF domains. No associations were found between the SIPP-SF and psychiatric symptomatology as measured by the Brief Symptom Inventory (BSI). The SIPP-SF appears to be a promising instrument for assessing maladaptive personality functioning among older adult outpatients.

An Empirical Evaluation of the DSM-5 Alternative Model of Personality Disorders in Later Life.

Personality disorders (PDs) in the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) are conceptualized as distinct clinical syndromes. However, debate persists about the clinical utility of this categorical model, with many researchers supporting a dimensional model that focuses on pathological personality traits and personality dysfunction. This model was published in Section III of DSM-5 and named the Alternative Model of Personality Disorders (AMPD). This study evaluated the AMPD by examining relationships between traits and dysfunction with traditional categorical PD constructs among older adults. Older adults (N = 202) completed the Personality Inventory for DSM-5, Levels of Personality Functioning Scale-Self-Report, and Coolidge Axis II Inventory. Results indicated that pathological personality traits do not relate to categorical PDs in directions predicted by the AMPD. Personality functioning related to categorical PDs in expected theoretical patterns according to the AMPD but lacked incremental validity above pathological personality traits. An implication of these findings is that the AMPD does not fully resolve the age-related issues with the traditional categorical PD model.

Relationships Among Executive Dysfunction, Constructive Worrying, and Worry Responses in Older Adults.

Worry is a ubiquitous human experience and core symptom of anxiety. The present study examined the extent to which specific aspects of worry are related to perceived executive dysfunction in older adults. A total of 100 older adult participants (M age = 68.82 years; range = 65-79 years) completed the Worry Behaviors Inventory, the Coolidge Axis II Inventory Executive Dysfunctions Scale, and the Constructive and Unconstructive Worry Questionnaire. Multiple regression analyses found that worry constructiveness and response behaviors were predictive of executive dysfunction. Specifically, greater avoidance behaviors and unconstructive worry were uniquely predictive of greater executive dysfunctions. Thus, findings indicate that worry constructiveness and approaches to worry management are significantly related to cognitive functioning in older adults. These findings imply a need to assess both worry and executive dysfunction to more accurately determine causal factors regarding anxiety and cognitive decline in older adults.

Assessment of Anxiety in Long-Term Care Residents: Issues and Strategies.

The experience of clinically significant anxiety and anxiety disorders represent significant and often debilitating problems for many residents in long-term care (LTC) settings. However, anxiety problems often go undetected and untreated in this growing population. The purposes of this paper are to examine the prevalence and impact of anxiety problems among residents in LTC facilities, describe the efficacy of the current instruments that are used to detect anxiety in these settings, and provide clinical guidance for the thorough assessment of anxiety. Regarding measurement tools, the GAI, GAI-SF, GAS-LTC, and the BADS are the only self-report measures designed for older adults that have been successfully validated for use with older adults living in LTC settings. Clinicians should focus on ways to educate LTC directors and staff to emphasize the importance of screening and assessing for anxiety, using validated measures, to improve the assessment and treatment of anxiety in their residents.