The beta-amyloid (Abeta) precursor protein (APP) is cleaved sequentially by beta-site of APP-cleaving enzyme (BACE) and gamma-secretase to release the Abeta peptides that accumulate in plaques in Alzheimer's disease (AD). GGA1, a member of the Golgi-localized gamma-ear-containing ARF-binding (GGA) protein family, interacts with BACE and influences its subcellular distribution. We now report that overexpression of GGA1 in cells increased the APP C-terminal fragment resulting from beta-cleavage but surprisingly reduced Abeta. GGA1 confined APP to the Golgi, in which fluorescence resonance energy transfer analyses suggest that the proteins come into close proximity. GGA1 blunted only APP but not notch intracellular domain release. These results suggest that GGA1 prevented APP beta-cleavage products from becoming substrates for gamma-secretase. Direct binding of GGA1 to BACE was not required for these effects, but the integrity of the GAT (GGA1 and TOM) domain of GGA1 was. GGA1 may act as a specific spatial switch influencing APP trafficking and processing, so that APP-GGA1 interactions may have pathophysiological relevance in AD. 相似文献
Parental and professional responses to questionnaires evaluating a paediatric disability service are reported and the viability of auditing structural, process, and outcome aspects of clinical practice are discussed. Expectations of waiting time to first appointment (met for only 52% of consumers) illustrate structural issues. Process issues are reflected in consumer reactions to outreach work (for example, 94% of parents and 84% of professionals found this supportive). Outcome measures such as consumer satisfaction with the service (76% of consumers reported being 'very satisfied' and 20% 'fairly satisfied') suggest that service aims are being met. Good concurrence of service aims with consumer needs is indicated by parental reasons for referral (for example, 75% for diagnostic help, 73% for a better understanding of the disorder, 88% for practical help), referrers' reasons (for example, 55% for a second diagnostic opinion, 45% due to lack of local expertise), and reports from most other professionals involved with the case that a similar service was not provided locally. 相似文献
AIMS: To study the effect of prone and supine sleep on infant behaviour, peripheral skin temperature, and cardiorespiratory parameters to aid understanding of why prone sleeping is associated with an increased risk of sudden infant death syndrome. METHODS: Of 33 enrolled infants, 32 were studied at 2.5 and 28 at 5 months of age. A computer aided multichannel system was used for polysomnographic recordings. Behaviour was charted separately. RESULTS: Prone REM (active) sleep was associated with lower frequencies of short arousals, body movements and sighs, and a shorter duration of apnoeas than supine REM sleep at both ages. At 2.5 months there were less frequent episodes of periodic breathing during prone sleep in non-REM (quiet) and REM sleep. Heart rate and peripheral skin temperature were higher in the prone position during both sleep states at both ages. CONCLUSIONS: The observation of decreased variation in behaviour and respiratory pattern, increased heart rate, and increased peripheral skin temperature during prone compared with supine sleep may indicate that young infants are less able to maintain adequate respiratory and metabolic homoeostasis during prone sleep. 相似文献
This review presents a critical analysis of covalently and ionically crosslinked chitosan hydrogels and related networks for medical or pharmaceutical applications. The structural basis of these hydrogels is discussed with reference to the specific chemical interactions, which dictate gel formation. The synthesis and chemistry of these hydrogels is discussed using specific pharmaceutical examples. Covalent crosslinking leads to formation of hydrogels with a permanent network structure, since irreversible chemical links are formed. This type of linkage allows absorption of water and/or bioactive compounds without dissolution and permits drug release by diffusion. pH-controlled drug delivery is made possible by the addition of another polymer. Ionically crosslinked hydrogels are generally considered as biocompatible and well-tolerated. Their non-permanent network is formed by reversible links. Ionically crosslinked chitosan hydrogels exhibit a higher swelling sensitivity to pH changes compared to covalently crosslinked chitosan hydrogels. This extends their potential application, since dissolution can occur in extreme acidic or basic pH conditions. 相似文献
Purpose: To review literature specific to the use of AAC with adults who have severe aphasia. Method: The authors reviewed studies involving AAC interventions for adults with severe aphasia. Results: Published data support the use of aided and unaided AAC with adults with severe aphasia in controlled treatment contexts. Reported gains in communication typically have not generalized to everyday settings. Conclusions: The application of AAC with persons with severe aphasia must address factors potentially limiting treatment success outside of training environments. 相似文献
Suicide is the second-leading cause of death in youth. We tested whether having a mentoring relationship associated with lower risks for suicidality, particularly among youth at higher risk due to cyberbullying.
Methods
This study pooled the 2017 Youth Risk Behavior Survey (YRBS) data from five jurisdictions that asked students if there was at least one teacher or other adult in their school that they could talk with, if they have a problem (mentorship). Students self-reported cyberbullying exposure and suicidality in the past 12 months. Odds of suicidal ideation, planning, and attempts were estimated using multivariable weighted logistic regression in overall and sex-stratified stepwise models. Interactions between mentorship and cyberbullying were also tested.
Results
Of the 25,527 student respondents, 87% reported having a mentoring relationship. Mentoring relationships were associated with lower odds of suicidal ideation (aOR, 0.44; 95% CI 0.33–0.57), planning (aOR, 0.59; 95% CI 0.41–0.85), and suicide attempts (aOR, 0.42; 95% CI 0.31–0.56). Stratified analyses showed a significant interaction between cyberbullying and mentorship with suicidal attempts among males, and a near-significant association between cyberbullying and mentorship with suicidal thoughts among females. Compared to male students with no cyberbullying and no mentorship, odds of attempting suicide were lower for males with no cyberbullying and mentorship (aOR, 0.55, 95% CI 0.32–0.92), higher for males with cyberbullying and no mentorship (aOR, 7.78, 95% CI 3.47–17.47), but not significantly different for males with cyberbullying and mentoring relationships (aOR, 1.49, 95% CI 0.86–2.48). Similarly, compared with females with no cyberbullying and no mentorship, odds of having suicidal thoughts were lower for females with no cyberbullying and mentorship (aOR, 0.40, 95% CI 0.28–0.57), and higher for females with cyberbullying and no mentorship (aOR, 2.54, 95% CI 1.59–4.07).
Conclusion
School-based mentoring may mitigate risk of suicidality among adolescents and limit the toxic effects of cyberbullying.