Exploring traumas in the development of talent: What are they, what do they do, and what do they require?

It has recently been argued that performers benefit from trauma (i.e., memorable challenges) during development. To deepen knowledge in this area, we explored perceived traumas in the development of twenty senior-international performers with a multi-methods, temporal-based design. Results showed perceived traumas were primarily sports-based, recognized from onset of investment, associated with immediately negative but ultimately positive impact, and negotiated through skills that were brought to, rather than generated by, these experiences. The findings provide an interesting contrast to messages in other early trauma-focused research and promote focus on the process and mechanisms of responding to and recovering from traumatic experiences

Factors that contribute to balance and mobility impairments in individuals with Huntington\u27s disease

Mobility and balance problems are common and often debilitating features of Huntington\u27s disease (HD). In this exploratory study we aimed to investigate the influence of disease severity, severity of motor deficits, lower limb muscle strength, cognition, executive function, lean muscle mass and reactivity on mobility and balance.Twenty-two individuals with HD were recruited from the North Metropolitan Area Mental Health Service, Perth, Australia. Pertinent demographic, genetic and disease progression information was recorded prior to testing. Balance was assessed using dynamic and static balance tasks. Mobility was assessed using self-paced and fast-paced mobility measures. Cognitive and executive measures were used to assess verbal learning and memory, information processing speed, attention, response inhibition and cognitive flexibility. Lower limb muscle strength was evaluated by maximal isokinetic and isometric voluntary contractions. Lean tissue mass was quantified using Dual-energy X-ray absorptiometry. Reactivity was measured using Moyart equipment.Univariate and multivariate linear regression statistical models were used to examine the influence of these measures on mobility and balance. Univariate analyses showed that disease severity as well as measures of information processing speed, attention, cognitive flexibility, response inhibition and lower limb strength, were strongly related with mobility and balance. Additionally multivariate analyses showed that disease severity, cognitive flexibility and knee flexion strength together were better able to explain mobility and balance performance than any single measure (50-85%).In conclusion, our preliminary results suggest that as well as disease severity, cognitive and executive impairment and reduced lower limb strength contribute significantly to mobility and balance problems

Factors that contribute to balance and mobility impairments in individuals with Huntington's disease

AbstractMobility and balance problems are common and often debilitating features of Huntington's disease (HD). In this exploratory study we aimed to investigate the influence of disease severity, severity of motor deficits, lower limb muscle strength, cognition, executive function, lean muscle mass and reactivity on mobility and balance.Twenty-two individuals with HD were recruited from the North Metropolitan Area Mental Health Service, Perth, Australia. Pertinent demographic, genetic and disease progression information was recorded prior to testing. Balance was assessed using dynamic and static balance tasks. Mobility was assessed using self-paced and fast-paced mobility measures. Cognitive and executive measures were used to assess verbal learning and memory, information processing speed, attention, response inhibition and cognitive flexibility. Lower limb muscle strength was evaluated by maximal isokinetic and isometric voluntary contractions. Lean tissue mass was quantified using Dual-energy X-ray absorptiometry. Reactivity was measured using Moyart equipment.Univariate and multivariate linear regression statistical models were used to examine the influence of these measures on mobility and balance. Univariate analyses showed that disease severity as well as measures of information processing speed, attention, cognitive flexibility, response inhibition and lower limb strength, were strongly related with mobility and balance. Additionally multivariate analyses showed that disease severity, cognitive flexibility and knee flexion strength together were better able to explain mobility and balance performance than any single measure (50–85%).In conclusion, our preliminary results suggest that as well as disease severity, cognitive and executive impairment and reduced lower limb strength contribute significantly to mobility and balance problems

Perspective, control, and confidence: perceived outcomes of using psycho-behavioural skills in the developmental trauma experience

While psycho-behavioural skills play a crucial role in negotiating and growing from developmental trauma, the precise outcomes which these skills enable has been underexplored. Accordingly, six senior international performers were interviewed to explore what such skills led to when negotiating and growing from traumatic experiences. It was subsequently found that psycho-behavioural skills supported a sense of perspective, control, and confidence in participants, all of which contributed to a predominantly constructive rather than illusory growth process. These findings add to our understanding of skills-based development by highlighting what psycho-behavioural skills can precisely help to facilitate in young performers, as part of their efforts to cope with and subsequently grow from traumatic experiences. Significantly, and, contrary to other research, the findings of this study also question the length of time which may be needed for constructive growth to be achieved

The effect of multidisciplinary rehabilitation on brain structure and cognition in Huntington\u27s disease: An exploratory study

Background: There is a wealth of evidence detailing gray matter degeneration and loss of cognitive function over time in individuals with Huntington\u27s disease (HD). Efforts to attenuate disease-related brain and cognitive changes have been unsuccessful to date. Multidisciplinary rehabilitation, comprising motor and cognitive intervention, has been shown to positively impact on functional capacity, depression, quality of life and some aspects of cognition in individuals with HD. This exploratory study aimed to evaluate, for the first time, whether multidisciplinary rehabilitation can slow further deterioration of disease-related brain changes and related cognitive deficits in individuals with manifest HD. Methods: Fifteen participants who manifest HD undertook a multidisciplinary rehabilitation intervention spanning 9 months. The intervention consisted of once-weekly supervised clinical exercise, thrice-weekly self-directed home based exercise and fortnightly occupational therapy. Participants were assessed using MR imaging and validated cognitive measures at baseline and after 9 months. Results: Participants displayed significantly increased gray matter volume in the right caudate and bilaterally in the dorsolateral prefrontal cortex after 9 months of multidisciplinary rehabilitation. Volumetric increases in gray matter were accompanied by significant improvements in verbal learning and memory (Hopkins Verbal Learning-Test). A significant association was found between gray matter volume increases in the dorsolateral prefrontal cortex and performance on verbal learning and memory. Conclusions: This study provides preliminary evidence that multidisciplinary rehabilitation positively impacts on gray matter changes and cognitive functions relating to verbal learning and memory in individuals with manifest HD. Larger controlled trials are required to confirm these preliminary findings

The N-terminus of hTERT contains a DNA-binding domain and is required for telomerase activity and cellular immortalization

Telomerase defers the onset of telomere damage-induced signaling and cellular senescence by adding DNA onto chromosome ends. The ability of telomerase to elongate single-stranded telomeric DNA depends on the reverse transcriptase domain of TERT, and also relies on protein:DNA contacts outside the active site. We purified the N-terminus of human TERT (hTEN) from Escherichia coli, and found that it binds DNA with a preference for telomeric sequence of a certain length and register. hTEN interacted with the C-terminus of hTERT in trans to reconstitute enzymatic activity in vitro. Mutational analysis of hTEN revealed that amino acids Y18 and Q169 were required for telomerase activity in vitro, but not for the interaction with telomere DNA or the C-terminus. These mutants did not reconstitute telomerase activity in cells, maintain telomere length, or extend cellular lifespan. In addition, we found that T116/T117/S118, while dispensable in vitro, were required for cellular immortalization. Thus, the interactions of hTEN with telomere DNA and the C-terminus of hTERT are functionally separable from the role of hTEN in telomere elongation activity in vitro and in vivo, suggesting other roles for the protein and nucleic acid interactions of hTEN within, and possibly outside, the telomerase catalytic core

The Glycosylation of AGP and Its Associations with the Binding to Methadone

Methadone remains the most common form of pharmacological therapy for opioid dependence; however, there is a lack ofexplanation for the reports of its relatively low success rate in achieving complete abstinence. One hypothesis is that in vivo bindingof methadone to the plasma glycoprotein alpha-1-acid glycoprotein (AGP), to a degree dependent on the molecular structure,may render the drug inactive. This study sought to determine whether alterations present in the glycosylation pattern of AGP inpatients undergoing various stages of methadone therapy (titration one anda half years) could affect the affinity of the glycoprotein to bind methadone. The composition of AGP glycosylation was determinedusing high pH anion exchange chromatography (HPAEC) and intrinsic fluorescence analysed to determine the extent of binding tomethadone. The monosaccharides galactose and N-acetyl-glucosamine were elevated in all methadone treatment groups indicatingalterations in AGP glycosylation. AGP from all patients receiving methadone therapy exhibited a greater degree of binding than thenormal population. This suggests that analysing the glycosylation of AGP in patients receiving methadone may aid in determiningwhether the therapy is likely to be effective

Topoisomerase 1 Inhibition in MYC-Driven Cancer Promotes Aberrant R-Loop Accumulation to Induce Synthetic Lethality

CRISPR screening reveals topoisomerase 1 as an immediately actionable vulnerability in cancers harboring MYC as a driver oncoprotein that can be targeted with clinically approved inhibitors. MYC is a central regulator of gene transcription and is frequently dysregulated in human cancers. As targeting MYC directly is challenging, an alternative strategy is to identify specific proteins or processes required for MYC to function as a potent cancer driver that can be targeted to result in synthetic lethality. To identify potential targets in MYC-driven cancers, we performed a genome-wide CRISPR knockout screen using an isogenic pair of breast cancer cell lines in which MYC dysregulation is the switch from benign to transformed tumor growth. Proteins that regulate R-loops were identified as a potential class of synthetic lethal targets. Dysregulated MYC elevated global transcription and coincident R-loop accumulation. Topoisomerase 1 (TOP1), a regulator of R-loops by DNA topology, was validated to be a vulnerability in cells with high MYC activity. Genetic knockdown of TOP1 in MYC-transformed cells resulted in reduced colony formation compared with control cells, demonstrating synthetic lethality. Overexpression of RNaseH1, a riboendonuclease that specifically degrades R-loops, rescued the reduction in clonogenicity induced by TOP1 deficiency, demonstrating that this vulnerability is driven by aberrant R-loop accumulation. Genetic and pharmacologic TOP1 inhibition selectively reduced the fitness of MYC-transformed tumors in vivo. Finally, drug response to TOP1 inhibitors (i.e., topotecan) significantly correlated with MYC levels and activity across panels of breast cancer cell lines and patient-derived organoids. Together, these results highlight TOP1 as a promising target for MYC-driven cancers.Significance: CRISPR screening reveals topoisomerase 1 as an immediately actionable vulnerability in cancers harboring MYC as a driver oncoprotein that can be targeted with clinically approved inhibitors

Pore dynamics and asymmetric cargo loading in an encapsulin nanocompartment

Encapsulins are protein nanocompartments that house various cargo enzymes, including a family of decameric ferritin-like proteins. Here, we study a recombinant Haliangium ochraceum encapsulin:encapsulated ferritin complex using cryo–electron microscopy and hydrogen/deuterium exchange mass spectrometry to gain insight into the structural relationship between the encapsulin shell and its protein cargo. An asymmetric single-particle reconstruction reveals four encapsulated ferritin decamers in a tetrahedral arrangement within the encapsulin nanocompartment. This leads to a symmetry mismatch between the protein cargo and the icosahedral encapsulin shell. The encapsulated ferritin decamers are offset from the interior face of the encapsulin shell. Using hydrogen/deuterium exchange mass spectrometry, we observed the dynamic behavior of the major fivefold pore in the encapsulin shell and show the pore opening via the movement of the encapsulin A-domain. These data will accelerate efforts to engineer the encapsulation of heterologous cargo proteins and to alter the permeability of the encapsulin shell via pore modifications

Mammary molecular portraits reveal lineage-specific features and progenitor cell vulnerabilities.

The mammary epithelium depends on specific lineages and their stem and progenitor function to accommodate hormone-triggered physiological demands in the adult female. Perturbations of these lineages underpin breast cancer risk, yet our understanding of normal mammary cell composition is incomplete. Here, we build a multimodal resource for the adult gland through comprehensive profiling of primary cell epigenomes, transcriptomes, and proteomes. We define systems-level relationships between chromatin-DNA-RNA-protein states, identify lineage-specific DNA methylation of transcription factor binding sites, and pinpoint proteins underlying progesterone responsiveness. Comparative proteomics of estrogen and progesterone receptor-positive and -negative cell populations, extensive target validation, and drug testing lead to discovery of stem and progenitor cell vulnerabilities. Top epigenetic drugs exert cytostatic effects; prevent adult mammary cell expansion, clonogenicity, and mammopoiesis; and deplete stem cell frequency. Select drugs also abrogate human breast progenitor cell activity in normal and high-risk patient samples. This integrative computational and functional study provides fundamental insight into mammary lineage and stem cell biology