Effects of oligomer toxicity, fibril toxicity and fibril spreading in synucleinopathies; 35244787

Protein misfolding is a general hallmark of protein deposition diseases, such as Alzheimer’s disease or Parkinson’s disease, in which different types of aggregated species (oligomers, protofibrils and fibrils) are generated by the cells. Despite widespread interest, the relationship between oligomers and fibrils in the aggregation process and spreading remains elusive. A large variety of experimental evidences supported the idea that soluble oligomeric species of different proteins might be more toxic than the larger fibrillar forms. Furthermore, the lack of correlation between the presence of the typical pathological inclusions and disease sustained this debate. However, recent data show that the ß-sheet core of the a-Synuclein (aSyn) fibrils is unable to establish persistent interactions with the lipid bilayers, but they can release oligomeric species responsible for an immediate dysfunction of the recipient neurons. Reversibly, such oligomeric species could also contribute to pathogenesis via neuron-to-neuron spreading by their direct cell-to-cell transfer or by generating new fibrils, following their neuronal uptake. In this Review, we discuss the various mechanisms of cellular dysfunction caused by aSyn, including oligomer toxicity, fibril toxicity and fibril spreading. © 2022, The Author(s)

Psychological Outcomes in Children and Early Adolescents With Type 1 Diabetes Following Pediatric Diabetes Summer Camp: A 3-Month Follow-Up Study

Objective: The aim of this study was to assess general psychosocial adjustment to diabetes and perceived disease management among patients with type 1 diabetes (T1D) and their parents before and after patients' participation in a diabetes summer camp. Methods: In this follow-up study, 20 children and adolescents with T1D (eight boys; mean age = 11.01 ± 0.94 years; mean diabetes duration = 3.02 ± 2.27) attending a southern Italian diabetic center, along with their parents, were assessed prior to and 3 months after the youths participated in a 1 week camp-based intervention involving didactic and interactive child-centered education and recreational activities. Patients and their parents completed measures assessing patients' quality of life and strategies employed by patients to cope with pain. Patients also completed measures evaluating their diabetes psychosocial adjustment, diabetes self-efficacy management, and illness perception; also, their parents completed measures of caregivers' perceived diabetes burden and treatment satisfaction. Youths' glycated hemoglobin (HbA1c) and standardized body mass index (z-BMI) values were also assessed. Within-subjects repeated-measures analyses of variance evaluated pre- and post-camp changes. Results: Camp attendance showed no beneficial effects on glycemic control, as indicated by HbA1c values both before (7.02%) and after (7.28%) camp being lower than 7.5%. HbA1c values were found to have increased after camp (pre-camp = 7.02%, post-camp = 7.28%; p = 0.010), but since they still fell within an acceptable range, they did not reveal clinically relevant changes in glycemic control. No substantial significant improvement in psychosocial measures was observed in children or parents (all p > 0.05). According to the parents' evaluation, social support-seeking as a patient pain-coping strategy was slightly increased (p = 0.044) after attending the camp. Conclusions: This study does not provide empirical evidence of benefits of participating in a diabetes camp for either patients or their parents. These findings suggest that healthcare providers rethink such camps as an experience for youths with T1D that actively involves parents and that includes both youth- and parent-focused psychological interventions

Body Image Problems in Individuals with Type 1 Diabetes: A Review of the Literature

Despite type 1 diabetes' (T1D) potential influence on adolescents' physical development, the occurrence of body image problems of adolescents with diabetes remains unclear. No research synthesis has yet addressed this issue. This study aims to systematically evaluate the empirical evidence concerning body image in individuals with T1D in order to provide an overview of the existing literature. Using PRISMA methodology, 51 relevant studies that fulfilled the eligibility criteria were found, the majority of them (N = 48) involving youth. The findings varied across studies: 17 studies indicated that in youth with T1D, body dissatisfaction was common and that body concerns were generally greater in youth with T1D than in controls; nine studies did not find any differences in body image problems between participants with and without T1D; three studies described higher body satisfaction in youth with diabetes than in controls; and three studies reported mixed results. Body concerns in individuals with T1D were often found to be associated with negative medical and psychological functioning. The variability and limits in assessment tools across studies, the overrepresentation of female subjects, and the fact that most research in this field is based on cross-sectional data are stressed in the interpretation of these mixed findings. Future research directions that could improve the understanding of body image concerns and clinical implications are discussed

Eating Problems in Youths with Type 1 Diabetes During and After Lockdown in Italy: An 8-Month Follow-Up Study

Eighty-five youths with T1D and 176 controls aged 8–19 years were asked to complete online questionnaires (ChEAT and EAT-26) measuring disordered eating behaviors (DEBs) during (baseline) and after (8-month follow-up) the lockdown. DEB symptoms in all participants (especially younger than 13 years), glycemic control, and zBMI were found unchanged from baseline to follow-up (all p >.05). After 8 months, the ChEAT/EAT-26 critical score frequency decreased significantly in controls (p =.004), as was the score for the ChEAT/EAT-26’s Oral Control subscale in both groups (T1D: p =.005; controls: p =.01). Participants with T1D, especially those older than 13 years, had higher ChEAT/EAT-26 Dieting scores (p =.037) and lower ChEAT/EAT-26 Oral Control scores (p =.046) than controls. Unchanged DEB symptoms suggest that the COVID-19 restrictions did not significantly affect participants’ eating behaviors and that a general adaptation to the challenges of lockdown and other pandemic containment measures occurred in both T1D and control participants

Prevalence of disordered eating behaviors in adolescents with type 1 diabetes: Results of multicenter Italian Nationwide study

Objective: To assess the prevalence of disordered eating behaviors (DEBs) in a large sample of Italian adolescents with type 1 diabetes and to explore potential demographic, clinical, and psychological differences (understood as emotional and behavioral problems) among adolescents with and without DEBs. Method: Adolescents (11–19 years) with type 1 diabetes completed the Diabetes Eating Problems Survey-revised (DEPS-r) and the Youth Self Report (YSR). Demographic and clinical data were also collected. Results: Of 690 adolescents with type 1 diabetes (mean age 14.97 ± 1.81, n = 337 girls) assessed in this study, 28.1% (21% boys, 35% girls) were DEPS-r positive (score ≥ 20). Girls had higher DEPS-r total scores (p <.0001, d =.42) than boys, although no age differences were found in mean DEPS-r total scores (p =.961). In both genders, adolescents with DEBs had significantly higher zBMI (p <.0001, d =.52) and HbA1c values (p <.0001, d =.54) and showed more emotional and behavioral problems (both as internalizing and externalizing problems) than those without DEBs (all p <.0001). These differences were largely confirmed in all age groups. Adolescents reporting insulin misuse had higher HbA1c values (p =.001, d =.26), higher DEPS-r mean scores (p <.0001, d = 1.07), and greater psychological problems (all p <.001) than those who did not. Discussion: DEBs are prevalent among adolescents with type 1 diabetes, and those with eating problems showed adverse clinical and psychological conditions. Routine screening for DEBs and of general psychological condition should be a fundamental part of diabetes care, especially during adolescence. Public significance statement: This nationwide study indicated that DEBs are common in adolescents with T1D, and those suffering from them show poorer clinical conditions and higher emotional and behavioral problems. As such, it offers important contributions for those working with EDs and in the T1D field, as it provides a deeper understanding of the co-occurring DEBs–emotional/behavioral problems in youths with T1D and highlights the importance of continuous monitoring of their psychological condition by a multidisciplinary team

Influence of conformational fluctuations on enzymatic activity: modelling the functional motion of beta-secretase

Considerable insight into the functional activity of proteins and enzymes can be obtained by studying the low-energy conformational distortions that the biopolymer can sustain. We carry out the characterization of these large scale structural changes for a protein of considerable pharmaceutical interest, the human $\beta$-secretase. Starting from the crystallographic structure of the protein, we use the recently introduced beta-Gaussian model to identify, with negligible computational expenditure, the most significant distortion occurring in thermal equilibrium and the associated time scales. The application of this strategy allows to gain considerable insight into the putative functional movements and, furthermore, helps to identify a handful of key regions in the protein which have an important mechanical influence on the enzymatic activity despite being spatially distant from the active site. The results obtained within the Gaussian model are validated through an extensive comparison against an all-atom Molecular Dynamics simulation.Comment: To be published in a special issue of J. Phys.: Cond. Mat. (Bedlewo Workshop

The release of toxic oligomers from a-synuclein fibrils induces dysfunction in neuronal cells

The self-assembly of a-synuclein (aS) into intraneuronal inclusion bodies is a key characteristic of Parkinson’s disease. To define the nature of the species giving rise to neuronal damage, we have investigated the mechanism of action of the main aS populations that have been observed to form progressively during fibril growth. The aS fibrils release soluble prefibrillar oligomeric species with cross-ß structure and solvent-exposed hydrophobic clusters. aS prefibrillar oligomers are efficient in crossing and permeabilize neuronal membranes, causing cellular insults. Short fibrils are more neurotoxic than long fibrils due to the higher proportion of fibrillar ends, resulting in a rapid release of oligomers. The kinetics of released aS oligomers match the observed kinetics of toxicity in cellular systems. In addition to previous evidence that aS fibrils can spread in different brain areas, our in vitro results reveal that aS fibrils can also release oligomeric species responsible for an immediate dysfunction of the neurons in the vicinity of these species

Single-hit resolution measurement with MEG II drift chamber prototypes

Drift chambers operated with helium-based gas mixtures represent a common solution for tracking charged particles keeping the material budget in the sensitive volume to a minimum. The drawback of this solution is the worsening of the spatial resolution due to primary ionisation fluctuations, which is a limiting factor for high granularity drift chambers like the MEG II tracker. We report on the measurements performed on three different prototypes of the MEG II drift chamber aimed at determining the achievable single-hit resolution. The prototypes were operated with helium/isobutane gas mixtures and exposed to cosmic rays, electron beams and radioactive sources. Direct measurements of the single hit resolution performed with an external tracker returned a value of 110 $\mu$m, consistent with the values obtained with indirect measurements performed with the other prototypes.Comment: 18 pages, 18 figure