Showing papers by "Daniel L. Segal published in 2019"

Workforce Analysis of Psychological Practice With Older Adults: Growing Crisis Requires Urgent Action.

Abstract: As the proportion and sheer number of older adults in the United States continues to increase, we need to plan for their behavioral health care. Access to accurate data about current workforce characteristics in psychology can provide essential information to inform workforce planning. In this paper, we present results of the American Psychological Association's Center for Workforce Studies survey of psychologists, with a focus on older adults. Participants (N = 4,109) were doctoral psychologists identified through state licensing boards. Only 1.2% of those surveyed described geropsychology as their specialty area, although 37.2% reported seeing older adults frequently or very frequently, most often from the specialties of rehabilitation psychology, clinical neuropsychology, and clinical health psychology. Frequent providers of aging services were more likely to be older, nonethnic minority, working in independent practice as their primary work setting, and self-employed as compared to other respondents. In addition, frequent providers of services to older adults were more likely to be in practices colocated with medical professionals and to accept Medicare as payment. Low reimbursement rates were cited as a reason for not accepting Medicare by those who did not. There was strong interest in further education in aging from all psychologists in areas including adjustment to medical illness/disability, depression, bereavement, dementia, anxiety, psychotherapy, and caregiver stress. The results of this survey suggest a continued urgent need to train psychologists across subfields in foundational geropsychology competencies that all psychologists should possess to be prepared for the rapidly growing and increasingly diverse population of older adults.

Novel Mannitol-Based Small Molecules for Inhibiting Aggregation of α-Synuclein Amyloids in Parkinson's Disease.

Abstract: The aggregation of the amyloidogenic protein α-synuclein (α-Syn) into toxic oligomers and mature fibrils is the major pathological hallmark of Parkinson's disease (PD). Small molecules that inhibit α-Syn aggregation thus may be useful therapeutics for PD. Mannitol and naphthoquinone-tryptophan (NQTrp) have been shown in the past to inhibit α-Syn aggregation by different mechanisms. Herein, we tested whether the conjugation of Mannitol and NQTrp may result in enhance efficacy toward α-Syn. The molecules were conjugated either by a click linker or via a PEG linker. The effect of the conjugate molecules on α-Syn aggregation in vitro was monitored using Thioflavin T fluorescence assay, circular dichroism, transmission electron microscopy, and Congo red birefringence assay. One of the conjugate molecules was found to be more effective than the two parent molecules and as effective as a mixture of the two. The conjugate molecules attenuated the disruptive effect of α-Syn on artificial membrane of Large Unilamellar Vesicles as monitored by dye leakage assay. The conjugates were found to be have low cytotoxicity and reduced toxicity of α-Syn toward SH-SY5Y neuroblastoma cells. These novel designed entities can be attractive scaffold for the development of therapeutic agents for PD.

Novel model of secreted human tau protein reveals the impact of the abnormal N-glycosylation of tau on its aggregation propensity.

Abstract: Alzheimer’s disease (AD) is the most common neurodegenerative disorder and has no disease-modifying treatment yet. The hallmarks of AD are two amyloidogenic proteins: tau and amyloid β (Aβ). Tau undergoes several posttranslational modifications, including N-glycosylation. Tau was reported to be N-glycosylated in AD brains, but not in healthy counterparts, which may affect AD etiology. Here, we aimed to examine the effect of N-glycosylation on aggregation propensity of tau. To that end, a novel SH-SY5Y cell-based model was generated in which recombinant human tau (htau) is forced to be secreted from the cells. Secreted htau was found to localize in the secretory pathway compartments and to undergo N-glycosylation. Following N-glycan cleavage of the secreted htau, various biophysical results collectively indicated that the untreated N-glycosylated secreted htau is markedly less aggregative, contains thinner and shorter fibrils, as compared to treated de-glycosylated secreted htau. This finding shows that N-glycans attached to htau may affect its aggregation. This could help to better understand the effect of N-glycosylated htau on AD progression.

Antagonistic Activity of Naphthoquinone-Based Hybrids toward Amyloids Associated with Alzheimer's Disease and Type-2 Diabetes.

Abstract: Protein misfolding and amyloid formation are associated with various human diseases including Alzheimer's disease (AD), Parkinson's disease (PD), and Type-2 Diabetes mellitus (T2DM). No disease-modifying therapeutics are available for them. Despite the lack of sequence homology between the corresponding proteins, aromatic residues are recognized as common key motifs in the formation and stabilization of amyloid structures via π-π stacking. Thus, targeting aromatic recognition interfaces could be a useful approach for inhibiting amyloid formation as well as disrupting the preformed amyloid fibrils. Combining experimental and computational approaches, we demonstrated the anti-amyloidogenic effect of naphthoquinone-tryptophan-based hybrid molecules toward PHF6 (τ-derived aggregative peptide), Amyloid β (Aβ42), and human islet amyloid polypeptide (hIAPP) implicated in AD and T2DM, respectively. These hybrid molecules significantly inhibited the aggregation and disrupted their preformed fibrillar aggregates in vitro, in a dose-dependent manner as evident from Thioflavin T/S binding assay, CD spectroscopy, and electron microscopy. Dye leakage assay from LUVs and cell-based experiments indicated that the hybrid molecules inhibit membrane disruption and cytotoxicity induced by these amyloids. Furthermore, in silico studies provided probable mechanistic insights into the interaction of these molecules with the amyloidogenic proteins in their monomeric or aggregated forms, including the role of hydrophobic interaction, hydrogen bond formation, and packing during inhibition of aggregation and fibril disassembly. Our findings may help in designing novel therapeutics toward AD, T2DM, and other proteinopathies based on the naphthoquinone derived hybrid molecules.

Suicide Risk Factors Among Older Adults: Exploring Thwarted Belongingness and Perceived Burdensomeness in Relation to Personality and Self-Esteem.

Abstract: The objective of this study was to explore the role of personality and self-esteem in later life within two established risk factors for suicidal ideation (SI)—Thwarted Belongingness (TB) and Perce...

Naphthoquinone Tryptophan Hybrids: A Promising Small Molecule Scaffold for Mitigating Aggregation of Amyloidogenic Proteins and Peptides.

Abstract: A current challenge faced by researchers is the lack of disease-modifying therapeutics for amyloid formation that is associated with several human diseases. Although the monomeric proteins or peptides involved in various amyloidogenic diseases do not have amino acid sequence homology, there appears to be a structural correlation among the amyloid assemblies, which are responsible for distinct pathological conditions. Here, we review our work on Naphthoquinone Tryptophan (NQTrp) hybrids, a small molecule scaffold that can generically modulate neuronal and non-neuronal amyloid aggregation both in vitro and in vivo. NQTrp reduces the net amyloid load by inhibiting the process of amyloid formation and disassembling the pre-formed fibrils, both in a dose-dependent manner. As a plausible mechanism of action, NQTrp effectively forms hydrogen bonding and hydrophobic interactions, such as π-π stacking, with the vital residues responsible for the initial nucleation of protein/peptide aggregation. This review highlights the effectiveness of the NQTrp hybrid scaffold for developing novel small molecule modulators of amyloid aggregation.

Continuity Between DSM-5 Section II and III Personality Disorders in a Dutch Clinical Sample.

Abstract: The goal of this study was to evaluate the continuity across the Section II personality disorders (PDs) and the proposed Section III model of PDs in the Diagnostic and Statistical Manual of Mental ...

Arginine refolds, stabilizes, and restores function of mutant pVHL proteins in animal model of the VHL cancer syndrome.

Abstract: The von Hippel-Lindau (VHL) syndrome is a rare inherited cancer, caused by mutations in the VHL gene, many of which render the VHL protein (pVHL) unstable pVHL is a tumor-suppressor protein implicated in a variety of cellular processes, most notably in response to changes in oxygen availability, due to its role as part of an E3-ligase complex which targets the hypoxia-inducible factor (HIF) for degradation Previously we reported, using in silico and in vitro analyses, that common oncogenic VHL mutations render pVHL less stable than the wild-type protein, distort its core domain and as a result reduce the ability of the protein to bind its target HIF-1α Among various chemical chaperones tested, arginine was the most effective in refolding mutant of pVHL Here we examined the consequences of administering L- or D-arginine to a Drosophila VHL model and to human renal carcinoma cells, both expressing misfolded versions of human pVHL Arginine treatment increased pVHL solubility in both models and increased the half-life of the mutant pVHL proteins in the cell culture In both models, L- as well as D-arginine enhanced the ability of wild-type pVHL and certain misfolded mutant versions of pVHL to bind ODD, the HIF-derived target peptide, reflecting restoration of pVHL function Moreover, continuous feeding of Drosophila expressing misfolded versions of pVHL either L- or D-arginine rich diet rescued their lethal phenotype Collectively, these in vivo results suggest that arginine supplementation should be examined as a potential novel treatment for VHL cancer syndrome

Basics and Beyond in Clinical and Diagnostic Interviewing

Abstract: The ability to conduct an efficient and effective clinical and diagnostic interview is arguably one of the most valued skills among mental health professionals. It is during the interview that the clinician learns about the difficulties and challenges experienced by the client and begins to form the foundations of a healing professional therapeutic relationship. Although the metaphor is not a novel one, the job of the interviewer may be likened to that of a detective trying to collect enough data and organize the clues to “solve the mystery,” in this example, the presenting problem and diagnosis of the client. The most important aspect of this detective metaphor is that effective interviewers (detectives) are served well by their natural curiosity (truly wanting to understand all aspects of the client’s experiences, no matter how painful or uncomfortable) and the thoughtfulness of their approach (being guided by strategies and principles for gathering data while also forming an emotional connection with the client).