Fine-grained food image classification and recipe extraction using a customized deep neural network and NLP.

Global eating habits cause health issues leading people to mindful eating. This has directed attention to applying deep learning to food-related data. The proposed work develops a new framework integrating neural network and natural language processing for classification of food images and automated recipe extraction. It address the challenges of intra-class variability and inter-class similarity in food images that have received shallow attention in the literature. Firstly, a customized lightweight deep convolution neural network model, MResNet-50 for classifying food images is proposed. Secondly, automated ingredient processing and recipe extraction is done using natural language processing algorithms: Word2Vec and Transformers in conjunction. Thirdly, a representational semi-structured domain ontology is built to store the relationship between cuisine, food item, and ingredients. The accuracy of the proposed framework on the Food-101 and UECFOOD256 datasets is increased by 2.4% and 7.5%, respectively, outperforming existing models in literature such as DeepFood, CNN-Food, Wiser, and other pre-trained neural networks.

Greek validation of the user version of the Mobile Application Rating Scale (uMARS).

OBJECTIVE: The original user version of the Mobile Application Rating Scale (uMARS) is an English-language questionnaire that was designed to allow non-expert app users to assess the quality of health apps. We aimed to translate into the Greek language and validate the uMARS. METHODS: This was a qualitative prospective study. The World Health Organization translation process was followed and a readily available and free-of-charge app was used for the validation process. Internal consistency and reliability were tested twice within one month by 91 Greek medical students. RESULTS: The total uMARS score showed excellent internal consistency (Cronbach's alpha = 0.86). The internal consistencies of its subscales were also very high (engagement alpha = 0.71; functionality alpha = 0.71; aesthetics alpha = 0.67; information alpha = 0.63), with the notable exception of the satisfaction alpha, which was 0.61. The uMARS total score demonstrated almost perfect agreement levels in most of the subscales according to the rWG index from baseline to 1 month. CONCLUSIONS: The Greek uMARS is a reliable and valid tool for assessing the quality of mobile apps.

Rescue of synaptic and cognitive functions in polysialic acid-deficient mice and dementia models by short polysialic acid fragments.

Dysregulated cortical expression of the neural cell adhesion molecule (NCAM) and deficits of its associated polysialic acid (polySia) have been found in Alzheimer's disease and schizophrenia. However, the functional role of polySia in cortical synaptic plasticity remains poorly understood. Here, we show that acute enzymatic removal of polySia in medial prefrontal cortex (mPFC) slices leads to increased transmission mediated by the GluN1/GluN2B subtype of N-methyl-d-aspartate receptors (NMDARs), increased NMDAR-mediated extrasynaptic tonic currents, and impaired long-term potentiation (LTP). The latter could be fully rescued by pharmacological suppression of GluN1/GluN2B receptors, or by application of short soluble polySia fragments that inhibited opening of GluN1/GluN2B channels. These treatments and augmentation of synaptic NMDARs with the glycine transporter type 1 (GlyT1) inhibitor sarcosine also restored LTP in mice deficient in polysialyltransferase ST8SIA4. Furthermore, the impaired performance of polySia-deficient mice and two models of Alzheimer's disease in the mPFC-dependent cognitive tasks could be rescued by intranasal administration of polySia fragments. Our data demonstrate the essential role of polySia-NCAM in the balancing of signaling through synaptic/extrasynaptic NMDARs in mPFC and highlight the therapeutic potential of short polySia fragments to restrain GluN1/GluN2B-mediated signaling.

Real-time mechanisms of exacerbated synaptic remodeling by microglia in acute models of systemic inflammation and tauopathy.

Remodeling of synapses by microglia is essential for synaptic plasticity in the brain. However, during neuroinflammation and neurodegenerative diseases, microglia can induce excessive synaptic loss, although the precise underlying mechanisms are unknown. To directly observe microglia-synapse interactions under inflammatory conditions, we performed in vivo two-photon time-lapse imaging of microglia-synapse interactions after bacterial lipopolysaccharide administration to model systemic inflammation, or after inoculation of Alzheimer's disease (AD) brain extracts to model disease-associated neuroinflammatory microglial response. Both treatments prolonged microglia-neuron contacts, decreased basal surveillance of synapses and promoted synaptic remodeling in response to synaptic stress induced by focal single-synapse photodamage. Spine elimination correlated with the expression of microglial complement system/phagocytic proteins and the occurrence of synaptic filopodia. Microglia were observed contacting spines, then stretching and phagocytosing spine head filopodia. Thus, in response to inflammatory stimuli microglia exacerbated spine remodeling through prolonged microglial contact and elimination of spines 'tagged' by synaptic filopodia.

The Persian Version of the Mobile Application Rating Scale (MARS-Fa): Translation and Validation Study.

BACKGROUND: Approximately 110 million Farsi speakers worldwide have access to a growing mobile app market. Despite restrictions and international sanctions, Iran's internal mobile health app market is growing, especially for Android-based apps. However, there is a need for guidelines for developing health apps that meet international quality standards. There are also no tools in Farsi that assess health app quality. Developers and researchers who operate in Farsi could benefit from such quality assessment tools to improve their outputs. OBJECTIVE: This study aims to translate and culturally adapt the Mobile Application Rating Scale in Farsi (MARS-Fa). This study also evaluates the validity and reliability of the newly developed MARS-Fa tool. METHODS: We used a well-established method to translate and back translate the MARS-Fa tool with a group of Iranian and international experts in Health Information Technology and Psychology. The final translated version of the tool was tested on a sample of 92 apps addressing smartphone addiction. Two trained reviewers completed an independent assessment of each app in Farsi and English. We reported reliability and construct validity estimates for the objective scales (engagement, functionality, aesthetics, and information quality). Reliability was based on the evaluation of intraclass correlation coefficients, Cronbach α and Spearman-Brown split-half reliability indicators (for internal consistency), as well as Pearson correlations for test-retest reliability. Construct validity included convergent and discriminant validity (through item-total correlations within the objective scales) and concurrent validity using Pearson correlations between the objective and subjective scores. RESULTS: After completing the translation and cultural adaptation, the MARS-Fa tool was used to assess the selected apps for smartphone addiction. The MARS-Fa total scale showed good interrater reliability (intraclass correlation coefficient=0.83, 95% CI 0.74-0.89) and good internal consistency (Cronbach α=.84); Spearman-Brown split-half reliability for both raters was 0.79 to 0.93. The instrument showed excellent test-retest reliability (r=0.94). The correlations among the MARS-Fa subdomains and the total score were all significant and above r=0.40, suggesting good convergent and discriminant validity. The MARS-Fa was positively and significantly correlated with subjective quality (r=0.90, P<.001), and so were the objective subdomains of engagement (r=0.85, P<.001), information quality (r=0.80, P<.001), aesthetics (r=0.79, P<.001), and functionality (r=0.57, P<.001), indicating concurrent validity. CONCLUSIONS: The MARS-Fa is a reliable and valid instrument to assess mobile health apps. This instrument could be adopted by Farsi-speaking researchers and developers who want to evaluate the quality of mobile apps. While we tested the tool with a sample of apps addressing smartphone addiction, the MARS-Fa could assess other domains or issues since the Mobile App Rating Scale has been used to rate apps in different contexts and languages.

Development and validation of the Turkish version of the Mobile App Rating Scale - MARS-TR.

BACKGROUND: The number of mobile health apps (MHAs) is growing rapidly. MHAs have great potential to improve health and health care. However, the quality of available MHAs remains unknown due to the lack of quality assessment regulations and standards for MHAs. The Mobile Application Rating Scale (MARS) is the most widely used instrument to assess the quality of MHAs, and available in English, Italian, Spanish, German, French, Arabic and Japanese. However, the scale is currently not available in the Turkish language. OBJECTIVE: This study aimed to cross-culturally adapt the MARS into Turkish and evaluate the validity and reliability of the scale. METHODS: The MARS was translated and adapted into Turkish according to the international guidelines. A total of 52 pregnancy tracking apps were evaluated by two independent raters. Internal consistency (Cronbach's alpha), inter-rater reliability (Intraclass Correlation Coefficient [ICC]), convergent validity and concurrent validity were explored. Regarding convergent validity, MARS-TR scores were compared with the ENLIGHT scale. RESULTS: The MARS-TR was highly aligned with the original MARS. The MARS-TR showed excellent internal consistency (Cronbach's alpha of 0.95 for both raters) and excellent inter-rater reliability (ICC = 0.94; SEM = 0.02), with a smallest detectable change (95 % confidence level) of 0.05 points for the total score. Cronbach's alphas for the subscales ranged from 0.76 to 0.94 for the two raters. Correlations between the MARS-TR and ENLIGHT demonstrated adequate convergent validity (P < 0.05). No ceiling or floor effects were observed. CONCLUSION: The results provide evidence that the Turkish version of MARS is a valid and reliable tool for researchers and experts to assess the quality of MHAs in Turkey.

Development and validation of the Japanese version of the uMARS (user version of the mobile app rating system).

BACKGROUND: Although the global market of Mobile Health Apps (mHealth apps) continues to grow dramatically, most mHealth apps still not only lack evidence base but have even not been evaluated for the basic usability or functionality. The User Version of the Mobile App Rating Scale (uMARS) was developed to allow end users to assess mHealth apps objectively and subjectively. However, there is no Japanese version of uMARS to date. OBJECTIVE: The purpose of this study is (1) to develop a validated Japanese version of uMARS and (2) to assess the translated version's reliability and validity in evaluating mHealth apps. METHODS: The original uMARS was adapted for Japanese use by four specialists using universalist cross-cultural methods. Translation/back-translation was reviewed by the author of the original version of uMARS, and confirmed. Its reliability and validity were further evaluated as part of a prospective cohort study of postoperative patients using a new mHealth app. RESULTS: Conceptual equivalence was analyzed and all items in all subcategories of the original uMARS were included in the Japanese version. Internal consistency was deemed acceptable for all subscales of objective and subjective quality with a Cronbach's alpha of 0.75-0.85. Test-retest reliability of all subscales was also acceptable with intraclass correlation coefficients (ICCs) of 0.57-0.88. Convergent/divergent validity and concurrent validity were also considered acceptable. CONCLUSION: A Japanese version of uMARS was cross-culturally validated and found to be as reliable as the original uMARS. This Japanese version of uMARS is expected to become a standard tool in assessing the quality of mHealth apps in Japan.

Turkish Validation of the User Version of the Mobile Application Rating Scale.

OBJECTIVE: As the number of mobile health applications increases, quality assessment becomes a capital feature of any mobile application design. Besides the professional evaluation conducted before marketing the app, the perceptions of the subjects to whom is intended will determine the successful widespread dis- semination. Hence, the implementation of a given app may be impaired by the lack of a validated transla- tion and cross-cultural adaptation. We aimed to validate in the Turkish language the User Version of the Mobile Application Rating Scale, an English original scale designed to assess the quality of mobile health applications. MATERIALS AND METHODS: A well-established and predefined process of cross-cultural adaptation and transla- tion to Turkish of the User Version of the Mobile Application Rating Scale according to the World Health Organization guidelines was performed using a common, readily available, free-of-charge application. Internal consistency and reliability were tested in a population sample by Cronbach's α and rWG index, respectively. RESULTS: The total User Version of the Mobile Application Rating Scale score had good internal consistency (Cronbach's α = 0.87). Internal consistencies of its subscales were also acceptable: with Cronbach's α of 0.71, 0.78, 0.71, and 0.73 for engagement, functionality, aesthetics, and information, respectively. Cronbach's α of the satisfaction subscale was 0.46. The User Version of the Mobile Application Rating Scale total and sub- scales scores had a strong within-group agreement, all of them with rwg indexes between 0.78 and 0.87 over baseline to 1 month. CONCLUSION: The Turkish version of the User Version of the Mobile Application Rating Scale is consistent with the English original version and is a reliable and valid tool to assess the quality of mobile applications by Turkish users.

Pan-European phylogeography of the European roe deer (Capreolus capreolus).

To provide the most comprehensive picture of species phylogeny and phylogeography of European roe deer (Capreolus capreolus), we analyzed mtDNA control region (610 bp) of 1469 samples of roe deer from Central and Eastern Europe and included into the analyses additional 1541 mtDNA sequences from GenBank from other regions of the continent. We detected two mtDNA lineages of the species: European and Siberian (an introgression of C. pygargus mtDNA into C. capreolus). The Siberian lineage was most frequent in the eastern part of the continent and declined toward Central Europe. The European lineage contained three clades (Central, Eastern, and Western) composed of several haplogroups, many of which were separated in space. The Western clade appeared to have a discontinuous range from Portugal to Russia. Most of the haplogroups in the Central and the Eastern clades were under expansion during the Weichselian glacial period before the Last Glacial Maximum (LGM), while the expansion time of the Western clade overlapped with the Eemian interglacial. The high genetic diversity of extant roe deer is the result of their survival during the LGM probably in a large, contiguous range spanning from the Iberian Peninsula to the Caucasus Mts and in two northern refugia.

Validation of a Korean version of mobile app rating scale (MARS) for apps targeting disease management.

The mobile app rating scale (MARS) is a widely used instrument for evaluating smartphone app quality. We aimed to examine the reliability and validity of the Korean version of MARS (MARS-K). Two independent raters performed the assessment using the translated 23-item questionnaire. We applied intraclass correlation coefficient analysis (ICC) to examine inter-rater reliability, Omega, and item-total correlation for internal consistency, and Pearson's r for test-retest reliability and correlation between subscales and the total score of MARS-K. Most items showed moderate to good ICC (0.447-1.000). The MARS-K showed excellent internal consistency and all subscales exceeded the acceptable level of omega. Results indicated MARS-K to be a valid and reliable instrument for evaluating disease management apps offered in the Korean app store. However, upgrades are recommended to further improve MARS-K's rating accuracy and reliability.

Japanese Version of the Mobile App Rating Scale (MARS): Development and Validation.

BACKGROUND: The number of mobile health (mHealth) apps continues to rise each year. Widespread use of the Mobile App Rating Scale (MARS) has allowed objective and multidimensional evaluation of the quality of these apps. However, no Japanese version of MARS has been made available to date. OBJECTIVE: The purposes of this study were (1) to develop a Japanese version of MARS and (2) to assess the translated version's reliability and validity in evaluating mHealth apps. METHODS: To develop the Japanese version of MARS, cross-cultural adaptation was used using a universalist approach. A total of 50 mental health apps were evaluated by 2 independent raters. Internal consistency and interrater reliability were then calculated. Convergent and divergent validity were assessed using multitrait scaling analysis and concurrent validity. RESULTS: After cross-cultural adaptation, all 23 items from the original MARS were included in the Japanese version. Following translation, back-translation, and review by the author of the original MARS, a Japanese version of MARS was finalized. Internal consistency was acceptable by all subscales of objective and subjective quality (Cronbach α=.78-.89). Interrater reliability was deemed acceptable, with the intraclass correlation coefficient (ICC) ranging from 0.61 to 0.79 for all subscales, except for "functionality," which had an ICC of 0.40. Convergent/divergent validity and concurrent validity were also considered acceptable. The rate of missing responses was high in several items in the "information" subscale. CONCLUSIONS: A Japanese version of MARS was developed and shown to be reliable and valid to a degree that was comparable to the original MARS. This Japanese version of MARS can be used as a standard to evaluate the quality and credibility of mHealth apps.

Metabolic Profiles, Genetic Diversity, and Genome Size of Bulgarian Population of Alkanna tinctoria.

Alkanna tinctoria (L.) Tausch Boraginaceae is a medicinal plant whose root is used for its antimicrobial and anti-inflammatory properties. A. tinctoria roots have been subject to numerous studies. However, the aerial parts have been explored less. The objective of the present study was to compare the chemical profile of aerial parts and roots as well as the total alkannin content in roots of 11 populations of the species from different floristic regions of Bulgaria. Methanolic extracts from 22 samples were analyzed by GC/MS. Phenolic, fatty, and organic acids, sterols, polyols, fatty alcohols, and sugars were identified. Ononitol (4-O-methyl-myo-inositol) was found as the main compound in the aerial parts. The total alkannin content in the roots was evaluated by the spectrophotometric method and compared with that of the commercial product. Populations with high alkannin content and rich in other bioactive compounds were identified. A relatively low genetic diversity in the studied populations was observed. The present study is the first comprehensive study on metabolite profiles and genetic diversity of the Bulgarian populations of A. tinctoria. The occurrence of ononitol in the aerial parts of the species is reported for the first time, as well as the phenolic acid profiles of the species in both aerial parts and roots. The results showed that aerial parts of the plant are also promising for use as a source of valuable biologically active substances.

Context value updating and multidimensional neuronal encoding in the retrosplenial cortex.

The retrosplenial cortex (RSC) has diverse functional inputs and is engaged by various sensory, spatial, and associative learning tasks. We examine how multiple functional aspects are integrated on the single-cell level in the RSC and how the encoding of task-related parameters changes across learning. Using a visuospatial context discrimination paradigm and two-photon calcium imaging in behaving mice, a large proportion of dysgranular RSC neurons was found to encode multiple task-related dimensions while forming context-value associations across learning. During reversal learning requiring increased cognitive flexibility, we revealed an increased proportion of multidimensional encoding neurons that showed higher decoding accuracy for behaviorally relevant context-value associations. Chemogenetic inactivation of RSC led to decreased behavioral context discrimination during learning phases in which context-value associations were formed, while recall of previously formed associations remained intact. RSC inactivation resulted in a persistent positive behavioral bias in valuing contexts, indicating a role for the RSC in context-value updating.

Translation and validation of the Italian version of the user version of the Mobile Application Rating Scale (uMARS).

BACKGROUND: Health sciences are steadily developing apps to help people to adopt correct lifestyles and to help physicians to monitor patients with chronic diseases. However, a properly validated tool that can evaluate patients' perception of apps is still lacking in many languages. In English, a validated questionnaire, called User Version of the Mobile Application Rating Scale (uMARS), is currently available. We translated the uMARS into Italian and validated our version. METHODS: The uMARS questionnaire was translated from English to Italian by an official translator, and then administered to 100 smartphone users in order to evaluate the same app at times 1 and 2 (after 2 weeks). Paired t-test, Pearson Correlation Coefficient, Intraclass Correlation Coefficient (ICCs) and Cronbach's Alpha were used to evaluate the reliability and validity of the Italian uMARS. RESULTS: We recruited 100 subjects, 52 males (52%) and 48 females (48%), with a mean age of 22.8 (SD: 3.4). All subjects answered all questions both at time 1 and at time 2. Paired t-test showed no statistically significant difference in each answer or group of answers between times 1 and 2 (P > 0.05). Cronbach's alpha was 0.945, as all subjects answered all questions. Each question was further assessed through the Pearson correlation coefficient, which demonstrated high reliability, with significant P (< 0.05) and Pearson Coefficients higher than 0.7. Similarly, ICCs were always higher than 0.750. CONCLUSIONS: Our results validated the Italian version of uMARS, which may become a reliable and useful tool for evaluating health apps.

Use of Kids Helpline by Children and Young People in Australia During the COVID-19 Pandemic.

PURPOSE: The benefits of helplines are particularly valuable during a pandemic when face-to-face services and natural supports are difficult to access. Kids Helpline, Australia's national youth helpline, provides children and young people with free 24/7 information and counseling through telephone, WebChat, and e-mail. We aimed to examine the use of Kids Helpline during the COVID-19 pandemic. METHODS: We analyzed monthly and weekly time trends of demand for and response by the Kids Helpline. The frequency of counseling contacts by common concern types, age, and gender were also examined. We used Joinpoint regression. RESULTS: Analyses of weekly demand for Kids Helpline showed an increase when the pandemic was declared, followed by a gradual decline. A second rise from 12 July 2020 when parts of Australia experienced a second wave of infections, followed by another decline, occurred more recently. Increased demand was almost entirely in the WebChat modality. Most answered counseling contacts were from girls and those aged 13-18 years. The number of contacts about mental health, suicide/self-harm, and family relationships increased, with mental health contacts also increasing as a proportion of total contacts. COVID-19-related concerns were the most common reason for contact in April 2020. CONCLUSIONS: In Australia, the COVID-19 pandemic saw a rapid increase in demand for Kids Helpline, mainly by WebChat, with the virus itself, mental health, suicide/self-harm, and relationships common reasons for contact. Responding to rapid changes in demand for particular modalities is challenging and understanding of the use and effectiveness of different modalities is needed.

Development of the Niggle App for Supporting Young People on Their Dynamic Journey to Well-being: Co-design and Qualitative Research Study.

BACKGROUND: Adolescence is a life stage characterized by intense development and increased vulnerability. Yet, young people rarely seek help for mental health, often due to stigma and embarrassment. Alarmingly, even those who do seek help may not be able to receive it. Interventions focused on well-being offer a protective factor against adversity. Highly effective, innovative, theoretically sound, accessible, and engaging mobile health (mHealth) interventions that can be used to look beyond mental ill-health and toward mental well-being are urgently needed. OBJECTIVE: We aimed to explore how young Australians conceptualize and construct recovery journeys from feeling unwell to being well in order to inform the conceptual design of a youth-led information-, resource-, and support-focused mHealth intervention. METHODS: A sample of young people, grouped by age (12-15 years, 16-19 years, and 20-25 years), took part in 3 in-person participatory design workshops (per group). Young people's understanding and representation of well-being, feeling unwell, and the recovery journey were investigated using visual and linguistic data collection methods: photo elicitation and journey mapping. A social constructionist perspective was used for thematic analysis to produce a conceptual model of the recovery journey. A mobile app was co-designed and all app functions were mapped through iterative development and testing by young people and a team of psychology, research, design and information technology experts. RESULTS: Young people (n=25) described a 6-stage journey with specific barriers and coping strategies. The findings, when situated within the personal recovery framework in mental health, emphasize the cyclic and iterative model of change. Through co-design, the new app-Niggle-was conceptualized as a visual representation of an amorphous problem, which can be addressed through app functions corresponding to the most helpful strategies that young people used to progress through the stages of their recovery journey. CONCLUSIONS: Niggle is available to offer support to young people for a range of problems and provides a hot link to counseling services in Australia. This paper elaborates on the process of in-depth qualitative data collection through visual, linguistic, and co-design methods. The findings of this study give insight into young people's understanding of well-being and recovery. This paper could aid the development of high-quality personalized mHealth interventions and support resources.

Telephone-based motivational interviewing enhanced with individualised personality-specific coping skills training for young people with alcohol-related injuries and illnesses accessing emergency or rest/recovery services: a randomized controlled trial (QuikFix).

BACKGROUND AND AIMS: Recent meta-analyses of motivational interviewing (MI) for reducing risky alcohol use in young people have reported modest effects. Few studies have targeted individual patient factors to increase MI effectiveness. This study determined if MI enhanced with individualised personality-specific coping skills training (QuikFix) was more efficacious than standard MI or an assessment feedback/information (AF/I) control among young people with alcohol-related injuries or illnesses. DESIGN AND SETTING: Single-centre, single-blind, three-group superiority randomized controlled trial with 1-, 3-, 6- and 12-months follow-ups. Telephone intervention, Brisbane, Australia. PARTICIPANTS: A total of 398 young people (16-25 years; M age = 20.30 years, SD = 2.12; 54% female) with alcohol-related injuries and/or illnesses were recruited from an emergency department (ED) or rest/recovery service (RRS). MEASURES: The primary outcome was total standard (10 g ethanol) drinks in the past month (Timeline Follow back [TLFB]) at 12 months (primary time point). Secondary outcomes were total drinking days and standard drinks per drinking day (TLFB) in the past month and the frequency of alcohol-related problems in the past 3 months (Rutgers Alcohol Problem Index). INTERVENTIONS: Young people were randomized to two sessions of QuikFix enhanced with individualised personality-specific coping skills training (n = 132), two sessions of MI (n = 136) or one session of AF/I (n = 130), all delivered by telehealth. FINDINGS: QuikFix resulted in greater reductions (all P < 0.0017) in the primary outcome of total standard drinks (M = 19.50, CI 99.75% = [11.31, 27.68]) than both MI (M = 32.61, CI 99.75% = [24.82, 40.40]; Cohen's D = 0.40) and AF/I (M = 34.12, CI 99.75% = [26.59, 41.65]; D = 0.45) at 12 months (retention n = 324/398, 81%). QuikFix had greater reductions on drinking days (M = 3.16, CI 99.75% = [2.37, 3.96]) than both MI (M = 4.53, CI 99.75% = [3.57, 5.48];D = 0.38) and AF/I (M = 4.69, CI 99.75% = [3.73, 5.65];D = 0.42) and fewer drinks per drinking day (M = 5.02, CI 99.75% = [3.71, 6.33]) than AF/I (M = 7.15, CI 99.75% = [5.93, 8.38;D = 0.47) at 12 months. CONCLUSIONS: Young people with alcohol-related injuries and/or illnesses who attended ED and rest/recovery services and received an individualised personality-specific coping skills training intervention (QuikFix) had greater reductions in the amount of alcohol consumed at 12 months compared with those who received motivational interviewing or an assessment feedback/information intervention.

Attenuation of the extracellular matrix restores microglial activity during the early stage of amyloidosis.

In the advanced stages of Alzheimer's disease (AD), microglia are transformed to an activated phenotype with thickened and retracted processes, migrate to the site of amyloid-beta (Aß) plaques, and proliferate. In the early stages of AD, it is still poorly understood whether the microglial function is altered and which factors may regulate these changes. Here, we focused on studying microglia in the retrosplenial cortex (RSC) in 3- to 4-month-old 5xFAD mice as a transgenic mouse model of AD. At this age, there are neither Aß plaques, nor activation of microglia, nor dysregulation in the expression of genes encoding major extracellular matrix (ECM) molecules or extracellular proteases in the RSC. Still, histochemical evaluation of the fine structure of neural ECM revealed increased levels of Wisteria floribunda agglutinin labeling in holes of perineuronal nets and changes in the perimeter of ECM barriers around the holes in 5xFAD mice. Two-photon vital microscopy demonstrated normal morphology and resting motility of microglia but strongly diminished number of microglial cells that migrated to the photolesion site in 5xFAD mice. Enzymatic digestion of ECM by chondroitinase ABC (ChABC) ameliorated this defect. Accordingly, the characterization of cell surface markers by flow cytometry demonstrated altered expression of microglial CD45. Moreover, ChABC treatment reduced the invasion of myeloid-derived mononuclear cells into the RSC of 5xFAD mice. Hence, the migration of both microglia and myeloid cells is altered during the early stages of amyloidosis and can be restored at least partially by the attenuation of the ECM.

Light-induced engagement of microglia to focally remodel synapses in the adult brain.

Microglia continuously monitor synapses, but active synaptic remodeling by microglia in mature healthy brains is rarely directly observed. We performed targeted photoablation of single synapses in mature transgenic mice expressing fluorescent labels in neurons and microglia. The photodamage focally increased the duration of microglia-neuron contacts, and dramatically exacerbated both the turnover of dendritic spines and presynaptic boutons as well as the generation of new filopodia originating from spine heads or boutons. The results of microglia depletion confirmed that elevated spine turnover and the generation of presynaptic filopodia are microglia-dependent processes.

A synthetic synaptic organizer protein restores glutamatergic neuronal circuits.

Neuronal synapses undergo structural and functional changes throughout life, which are essential for nervous system physiology. However, these changes may also perturb the excitatory-inhibitory neurotransmission balance and trigger neuropsychiatric and neurological disorders. Molecular tools to restore this balance are highly desirable. Here, we designed and characterized CPTX, a synthetic synaptic organizer combining structural elements from cerebellin-1 and neuronal pentraxin-1. CPTX can interact with presynaptic neurexins and postsynaptic AMPA-type ionotropic glutamate receptors and induced the formation of excitatory synapses both in vitro and in vivo. CPTX restored synaptic functions, motor coordination, spatial and contextual memories, and locomotion in mouse models for cerebellar ataxia, Alzheimer's disease, and spinal cord injury, respectively. Thus, CPTX represents a prototype for structure-guided biologics that can efficiently repair or remodel neuronal circuits.