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Abstract: Mammals survive starvation by activating proteolysis and lipolysis in many different tissues. These responses are triggered, at least in part, by changing hormonal and neural statuses during starvation. Pathways of proteolysis that are activated during starvation are surprisingly diverse, depending on tissue type and duration of starvation. The ubiquitin-proteasome system is primarily responsible for increased skeletal muscle protein breakdown during starvation. However, in most other tissues, lysosomal pathways of proteolysis are stimulated during fasting. Short-term starvation activates macroautophagy, whereas long-term starvation activates chaperone-mediated autophagy. Lipolysis also increases in response to starvation, and the breakdown of triacylglycerols provides free fatty acids to be used as an energy source by skeletal muscle and other tissues. In addition, glycerol released from triacylglycerols can be converted to glucose by hepatic gluconeogenesis. During long-term starvation, oxidation of free fatty acids by the liver leads to the production of ketone bodies that can be used for energy by skeletal muscle and brain. Tissues that cannot use ketone bodies for energy respond to these small molecules by activating chaperone-mediated autophagy. This is one form of interaction between proteolytic and lipolytic responses to starvation. [Copyright &y& Elsevier]

Abstract: The purpose of this study was to investigate the nature of recovery from stuttering based on the experiences of adults who recovered without treatment. Using a semi-structured, open-ended interview format, 15 speakers verified as persons who recovered without treatment were asked to describe their status as everyday speakers. Seven speakers reported that they no longer stuttered and eight reported that they still stuttered on occasion. Interview material was coded and analyzed by the investigators and checked by independent judges. Results suggested that complete recovery was possible for speakers who reported that they no longer stuttered; whereas, those who still stuttered occasionally appeared to no longer be handicapped by stuttering, but required some vigilance to maintain their relatively fluent speech. Educational objectives: After completing this activity, the learner will be able to: (1) describe the relevance of self-report data for evaluating the nature of recovery from stuttering without treatment; (2) describe the differences in self-perception concerning the nature of recovery for those who no longer have any tendency to stutter compared to those who still have an occasional tendency to stutter; and (3) suggest the possible implications for understanding the nature of recovery from persistent stuttering based on investigations of late recovery without treatment. [Copyright &y& Elsevier]

Chaperone-mediated autophagy (CMA) is a selective lysosomal protein degradative process that is activated in higher organisms under conditions of prolonged starvation and in cell culture by the removal of serum. Ketone bodies are comprised of three compounds (β-hydroxybutyrate, acetoacetate, and acetone) that circulate during starvation, especially during prolonged starvation. Here we have investigated the hypothesis that ketone bodies induce CMA. We found that physiological concentrations of β-hydroxybutyrate (BOH) induced proteolysis in cells maintained in media with serum and without serum; however, acetoacetate only induced proteolysis in cells maintained in media with serum. Lysosomes isolated from BOH-treated cells displayed an increased ability to degrade both glyceraldehyde.3.phosphato dehydrogenase and ribonuclease A, substrates for CMA. Isolated lysosomes from cells maintained in media without serum also demonstrated an increased ability to degrade glyceraldehyde-3-phosphate dehydrogenase and ribonuclease A when the reaction was supplemented with BOH. Such treatment did not affect the levels of lysosome-associated membrane protein 2a or lysosomal heat shock cognate protein of 70 kDa, two rate-limiting proteins in CMA. However, pretreatment of glyceraldehyde-3-phosphate and ribonuclease A with BOH increased their rate of degradation by isolated lysosomes. Lysosomes pretreated with BOH showed no increase in proteolysis, suggesting that BOH acts on the substrates to increase their rates of proteolysis. Using OxyBlot™ analysis to detect carbonyl formation on proteins, one common marker of protein oxidation, we showed that treatment of substrates with BOH increased their oxidation. Neither glycerol, another compound that increases in circulation during prolonged starvation, nor butanol or butanone, compounds closely related to BOH, had an effect on CMA. The induction of CMA by ketone bodies may provide an important physiological mechanism for the activation of CMA during prolonged starvation. [ABSTRACT FROM AUTHOR]

In light of emerging findings concerning untreated recovery and neural plasticity, this paper re-examines the viability of an NIH conference recommendation [Cooper, J. A. (1990). Research directions in stuttering: Consensus and conflict. In Cooper, I. A. (Ed.), Research needs in stuttering: Roadblocks and future directions (pp. 98-100). Rockville, MD: American Speech-Language-Hearing Association.] that adults who have recovered from stuttering might inform our understanding of the nature and treatment of persistent stuttering. It is suggested that those who have recovered could constitute a behavioral, cognitive, and neurophysiologic benchmark for evaluating stuttering treatment for adolescents and adults, while helping to identify the limits of recovery from a persistent disorder. This possibility seems especially promising because of findings from recent studies investigating untreated recovery during childhood and adulthood, the emerging evidence concerning neural plasticity and reorganization, and reports of neural system changes during stuttering treatment. Potential obstacles to applying findings from unassisted recovery to treatment do exist, but the benefits of attempts to fully understand stuttering certainly outweigh the difficulties. [ABSTRACT FROM AUTHOR]

An evidence-based framework can be described as an empirically-driven, measurement-based, client-sensitive approach for selecting treatments. It is believed that using such a framework is more likely to result in a clinically significant outcome. For this paper, a clinically significant outcome was defined as a meaningful treatment change. It was suggested that there are at least three groups for whom a treatment’s outcome is meaningful. These groups include clinicians/clinical researchers, the clients, and relevant others who have some interest in the outcome (e.g., parents of a child who stutters). The meaning and measurement of clinical significance was discussed for each of these three groups, based on research from the behavioral stuttering treatment literature.Educational objectives: The reader will learn about and be able to (1) broadly define a clinically significant outcome and identify some of the groups who are interested in such an outcome and (2) describe how clinical significance has been evaluated in stuttering treatment within an evidence-based framework. [Copyright &y& Elsevier]

Generalization and maintenance are a widely recognized challenge for stuttering treatment. There are many reasons why this is the case. First, there is no accepted model of recovery, though self-efficacy may be a helpful construct and, secondly, the client’s age, stuttering severity, and negative attitudes may be complicating factors.Three strategies for promoting generalization and maintenance in school settings are suggested based on current research evidence. They include probing and training for generalization, incorporating real-life elements into therapy, and training clients to self-regulate their behavior. These strategies appear to be viable and practical, but further research is needed to fully evaluate their effectiveness for school settings.: Learning outcomesReaders will learn about (1) typical approaches to managing stuttering in the school setting, (2) barriers to generalization and maintenance of stuttering treatment gains, and (3) three strategies for promoting generalization and maintenance. [Copyright &y& Elsevier]

• Collective intelligence methods conducted with students and educators for scale item generation. • Exploratory and confirmatory factor analysis conducted across two independent samples for factor structure identification. • Convergent and predictive validity tests indicated relationships between CT dispositions and other constructs and outcomes, including conspiracy and paranormal beliefs. • The SENCTDS is a 21-item instrument, measuring six dispositions: reflection, attentiveness, open-mindedness, organisation, perseverance, and intrinsic goal motivation. Although many conceptualisations of critical thinking (CT) exist, the vast majority acknowledge the importance of both skill-based and disposition-based components. There is, however, a notable lack of agreement regarding what constitutes CT dispositions and how best to approach the measurement of CT dispositions. The current study reports on the development and validation of a new Student-Educator Negotiated CT Dispositions scale (SENCTDS). Using collective intelligence methods for scale item generation and both exploratory and confirmatory factor analysis across two independent samples for factor structure identification, a six-factor CT disposition scale was developed. Convergent and predictive validity tests indicated relationships between CT dispositions and other constructs and outcomes, including Need for Cognition (NCS), Motivated Strategies for Learning (MSLQ), Real World Outcomes of Critical Thinking (RWO), and both conspiracy and paranormal beliefs. Given the limited availability of measures of CT dispositions, the development of the SENCTDS is a valuable contribution to the field, which may prove useful in future research that seeks to examine predictors and outcomes of both skill-based and disposition-based aspects of CT. [ABSTRACT FROM AUTHOR]

A large amount of low grade heat is wasted at temperatures below 100 °C but its quantity remains mostly unknown. Therefore, the identification and quantitation of low grade heat availability enables further assessments on whether or not the recovery of this fraction of heat is convenient. By considering the countries composing the European Union (EU), this work quantifies the low grade heat from power generation and industrial sectors (mining, minerals, metals, chemicals, pulp and paper, food) with a particular focus on the faction of heat below 100 °C. The analysis shows that, in the year 2018, 8774.4∙106 GJ (2437.3 TWh) of heat was available in the EU below 100 °C, with the power generation sector accounting for 95% of the total low grade heat emitted. In addition, around 96% of the waste heat was in the temperature range from 25 °C to 80 °C, being of ultralow grade. Similar conclusions were obtained in terms of exergy loss, which was essentially from the power generation sector, especially in the range of temperatures between 40 °C and 60 °C. These results suggest that ultralow waste heat is an untapped source of energy which can be conveniently exploited by the same point-source emitters, primarily in the power generation sector or in wider industrial areas where infrastructure is present. • 8774.4∙106 GJ of heat below 100 °C in EU are from power generation and industrial sectors. • Largest fraction (7847.2⋅106 GJ) of ultralow heat in EU is between 40 °C and 60 °C. • The greatest contributor to ultralow grade waste heat is the power generation sector. • An exergy amount of 733.5∙106 GJ is available from ultralow grade waste heat. [ABSTRACT FROM AUTHOR]

Due to the lack of acid α-glucosidase (GAA) activity, Pompe mice develop glycogen storage pathology and progressive skeletal muscle dysfunction with age. Applying either gene or enzyme therapy to reconstitute GAA levels in older, symptomatic Pompe mice effectively reduces glycogen storage in skeletal muscle but provides only modest improvements in motor function. As strategies to stimulate muscle hypertrophy, such as by myostatin inhibition, have been shown to improve muscle pathology and strength in mouse models of muscular dystrophy, we sought to determine whether these benefits might be similarly realized in Pompe mice. Administration of a recombinant adeno-associated virus serotype 8 vector encoding follistatin, an inhibitor of myostatin, increased muscle mass and strength but only in Pompe mice that were treated before 10 months of age. Younger Pompe mice showed significant muscle fiber hypertrophy in response to treatment with follistatin, but maximal gains in muscle strength were achieved only when concomitant GAA administration reduced glycogen storage in the affected muscles. Despite increased grip strength, follistatin treatment failed to improve rotarod performance. These findings highlight the importance of treating Pompe skeletal muscle before pathology becomes irreversible, and suggest that adjunctive therapies may not be effective without first clearing skeletal muscle glycogen storage with GAA. [ABSTRACT FROM AUTHOR]

Abstract: Tissue turnover during wound healing, regeneration or integration of biomedical materials depends on the rate and extent of materials trafficking into and out of cells involved in extracellular matrix (ECM) remodeling. To exploit these processes, we report the first model for matrix trafficking in which these issues are quantitatively assessed for cells grown on both native collagen (normal tissue) and denatured collagen (wound state) substrates. Human fibroblasts more rapidly remodeled denatured versus normal collagen type I to form new ECM. Fluxes to and from the cells from the collagen substrates and the formation of new ECM were quantified using radioactively labeled substrates. The model can be employed for the systematic and quantitative study of the impact of a broad range of physiological factors and disease states on tissue remodeling, integrating extracellular matrix structures and cell biology. [Copyright &y& Elsevier]

This paper overviews recent developments in an ongoing program of brain imaging research on developmental stuttering that is being conducted at the University of Texas Health Science Center, San Antonio. This program has primarily used H215O PET imaging of different speaking tasks by right-handed adult male and female persistent stutterers, recovered stutterers and controls in order to isolate the neural regions that are functionally associated with stuttered speech. The principal findings have emerged from studies using condition contrasts and performance correlation techniques. The emerging findings from these studies are reviewed and referenced to a neural model of normal speech production recently proposed by Ju¨rgens [Neurosci. Biobehav. Rev. 26 (2002) 235]. This paper will report (1) the reconfiguration of previous findings within the Ju¨rgens Model; (2) preliminary findings of an investigation with late recovered stutterers; (3) an investigation of neural activations during a treatment procedure designed to produce a sustained improvement in fluency; and (4) an across-studies comparison that seeks to isolate neural regions within the Ju¨rgens Model that are consistently associated with stuttering. Two regions appear to meet this criterion: right anterior insula (activated) and anterior middle and superior temporal gyri (deactivated) mainly in right hemisphere. The implications of these findings and the direction of future imaging investigations are discussed.Educational objectives: The reader will learn about (1) recent uses of H215O PET imaging in stuttering research; (2) the use of a new neurological model of speech production in imaging research on stuttering; and (3) initial findings from PET imaging investigations of treated and recovered stutterers. [Copyright &y& Elsevier]

Progressive familial intrahepatic cholestasis type 3 (PFIC3) is a rare lethal autosomal recessive liver disorder caused by loss-of-function variations of the ABCB4 gene, encoding a phosphatidylcholine transporter (ABCB4/MDR3). Currently, no effective treatment exists for PFIC3 outside of liver transplantation. We have produced and screened chemically and genetically modified mRNA variants encoding human ABCB4 (h ABCB4 mRNA) encapsulated in lipid nanoparticles (LNPs). We examined their pharmacological effects in a cell-based model and in a new in vivo mouse model resembling human PFIC3 as a result of homozygous disruption of the Abcb4 gene in fibrosis-susceptible BALB/c. Abcb4 -/- mice. We show that treatment with liver-targeted h ABCB4 mRNA resulted in de novo expression of functional hABCB4 protein and restored phospholipid transport in cultured cells and in PFIC3 mouse livers. Importantly, repeated injections of the h ABCB4 mRNA effectively rescued the severe disease phenotype in young Abcb4 -/- mice, with rapid and dramatic normalisation of all clinically relevant parameters such as inflammation, ductular reaction, and liver fibrosis. Synthetic mRNA therapy also promoted favourable hepatocyte-driven liver regeneration to restore normal homeostasis, including liver weight, body weight, liver enzymes, and portal vein blood pressure. Our data provide strong preclinical proof-of-concept for h ABCB4 mRNA therapy as a potential treatment option for patients with PFIC3. This report describes the development of an innovative mRNA therapy as a potential treatment for PFIC3, a devastating rare paediatric liver disease with no treatment options except liver transplantation. We show that administration of our mRNA construct completely rescues severe liver disease in a genetic model of PFIC3 in mice. [Display omitted] • Synthetic liver-targeted h ABCB4 mRNA therapy was designed for PFIC3, a devastating rare paediatric liver disease. • Single injection restores hepatocyte ABCB4 expression and biliary phosphatidylcholine secretion in a genetic model of PFIC3. • Repeated administration rapidly and completely rescues PFIC3 disease in young Abcb4 -/- mice. • Treatment ameliorated liver injury, inflammation, ductular reaction, fibrosis, portal hypertension and 'failure to thrive'. [ABSTRACT FROM AUTHOR]

• Techniques for late spontaneous recovery from stuttering clustered into six strategies. • The strategies reflect components of established treatments and naïve explanations. • Causal attributions of recovery clustered into three implicit theories about recovery. • Knowledge about strategies and implicit theories may help to improve treatment. (1) To survey the employed techniques and the reasons/occasions which adults who had recovered from stuttering after age 11 without previous treatment reported as causal to overcome stuttering, (2) to investigate whether the techniques and causal attributions can be reduced to coherent (inherently consistent) dimensions, and (3) whether these dimensions reflect common therapy components. 124 recovered persons from 8 countries responded by SurveyMonkey or paper-and-pencil to rating scale questions about 49 possible techniques and 15 causal attributions. A Principal Component Analysis of 110 questionnaires identified 6 components (dimensions) for self-assisted techniques (Speech Restructuring; Relaxed/Monitored Speech; Elocution; Stage Performance; Sought Speech Demands; Reassurance; 63.7% variance explained), and 3 components of perceived causal attributions of recovery (Life Change, Attitude Change, Social Support; 58.0% variance explained). Two components for self-assisted techniques (Speech Restructuring; Elocution) reflect treatment methods. Another component (Relaxed/Monitored Speech) consists mainly of items that reflect a common, non-professional understanding of effective management of stuttering. The components of the various perceived reasons for recovery reflect differing implicit theories of causes for recovery from stuttering. These theories are considered susceptible to various biases. This identification of components of reported techniques and of causal attributions is novel compared to previous studies who just list techniques and attributions. The identified dimensions of self-assisted techniques and causal attributions to reduce stuttering as extracted from self-reports of a large, international sample of recovered formerly stuttering adults may guide the application of behavioral stuttering therapies. [ABSTRACT FROM AUTHOR]