Age-appropriate services for people diagnosed with young onset dementia (YOD): a systematic review.

BACKGROUND: Literature agrees that post-diagnostic services for people living with young onset dementia (YOD) need to be age-appropriate, but there is insufficient evidence of 'what works' to inform service design and delivery. OBJECTIVE: To provide an evidence base of age-appropriate services and to review the perceived effectiveness of current interventions. METHODS: We undertook a systematic review including all types of research relating to interventions for YOD. We searched PubMed, CINHAL Plus, SCOPUS, EBSCO Host EJS, Social Care Online and Google Scholar, hand-searched journals and carried out lateral searches (July-October 2016). Included papers were synthesised qualitatively. Primary studies were critically appraised. RESULTS: Twenty articles (peer-reviewed [n = 10], descriptive accounts [n = 10]) discussing 195 participants (persons diagnosed with YOD [n = 94], caregivers [n = 91] and other [n = 10]) were identified for inclusion. Services enabled people with YOD to remain living at home for longer. However, service continuity was compromised by short-term project-based commissioning and ad-hoc service delivery. CONCLUSION: The evidence on the experience of living with YOD is not matched by research and the innovation needed to mitigate the impact of YOD. The inclusion of people with YOD and their caregivers in service design is critical when planning support in order to delay institutional care

Adipose-derived regenerative cells and fat grafting for treating breast cancer-related lymphedema:Lymphoscintigraphic evaluation with 1 year of follow-up

Background: Breast cancer-related lymphedema (BCRL) is a feared late complication. Treatment options are lacking at present. Recent studies have suggested that mesenchymal stromal cells can alleviate lymphedema. Herein, we report the results from the first human pilot study with adipose-derived regenerative cells (ADRCs) for treating BCRL with 1 year of follow-up. Material and methods: We included 10 patients with BCRL. ADRCs were injected directly into the axillary region together with a scar-releasing fat grafting procedure. Primary endpoint was change in arm volume. Secondary endpoints were change in patient-reported outcomes, changes in lymph flow, and safety. Results: During follow-up, no significant change in volume was noted. Patient-reported outcomes improved significantly with time. Five patients reduced their use of conservative management. Quantitative lymphoscintigraphy did not improve on the lymphedema-affected arms. ADRCs were well tolerated, and only minor transient adverse events related to liposuction were noted. Conclusions: In this pilot study, a single injection of ADRCs improved lymphedema based on patient-reported outcome measures, and there were no serious adverse events during the follow-up period. Lymphoscintigraphic evaluation showed no improvement after ADRC treatment. There was no change in excess arm volume. Results of this trial need to be confirmed in randomized clinical trials.</p

ProteinDBS v2.0: a web server for global and local protein structure search

ProteinDBS v2.0 is a web server designed for efficient and accurate comparisons and searches of structurally similar proteins from a large-scale database. It provides two comparison methods, global-to-global and local-to-local, to facilitate the searches of protein structures or substructures. ProteinDBS v2.0 applies advanced feature extraction algorithms and scalable indexing techniques to achieve a high-running speed while preserving reasonably high precision of structural comparison. The experimental results show that our system is able to return results of global comparisons in seconds from a complete Protein Data Bank (PDB) database of 152 959 protein chains and that it takes much less time to complete local comparisons from a non-redundant database of 3276 proteins than other accurate comparison methods. ProteinDBS v2.0 supports query by PDB protein ID and by new structures uploaded by users. To our knowledge, this is the only search engine that can simultaneously support global and local comparisons. ProteinDBS v2.0 is a useful tool to investigate functional or evolutional relationships among proteins. Moreover, the common substructures identified by local comparison can be potentially used to assist the human curation process in discovering new domains or folds from the ever-growing protein structure databases. The system is hosted at http://ProteinDBS.rnet.missouri.edu

Learning pair-wise gene functional similarity by multiplex gene expression maps

Abstract Background The relationships between the gene functional similarity and gene expression profile, and between gene function annotation and gene sequence have been studied extensively. However, not much work has considered the connection between gene functions and location of a gene's expression in the mammalian tissues. On the other hand, although unsupervised learning methods have been commonly used in functional genomics, supervised learning cannot be directly applied to a set of normal genes without having a target (class) attribute. Results Here, we propose a supervised learning methodology to predict pair-wise gene functional similarity from multiplex gene expression maps that provide information about the location of gene expression. The features are extracted from expression maps and the labels denote the functional similarities of pairs of genes. We make use of wavelet features, original expression values, difference and average values of neighboring voxels and other features to perform boosting analysis. The experimental results show that with increasing similarities of gene expression maps, the functional similarities are increased too. The model predicts the functional similarities between genes to a certain degree. The weights of the features in the model indicate the features that are more significant for this prediction. Conclusions By considering pairs of genes, we propose a supervised learning methodology to predict pair-wise gene functional similarity from multiplex gene expression maps. We also explore the relationship between similarities of gene maps and gene functions. By using AdaBoost coupled with our proposed weak classifier we analyze a large-scale gene expression dataset and predict gene functional similarities. We also detect the most significant single voxels and pairs of neighboring voxels and visualize them in the expression map image of a mouse brain. This work is very important for predicting functions of unknown genes. It also has broader applicability since the methodology can be applied to analyze any large-scale dataset without a target attribute and is not restricted to gene expressions

MFAP4 Deficiency Attenuates Angiotensin II-Induced Abdominal Aortic Aneurysm Formation Through Regulation of Macrophage Infiltration and Activity

Objective: Abdominal aortic aneurysm (AAA) is a common age-related vascular disease characterized by progressive weakening and dilatation of the aortic wall. Microfibrillar-associated protein 4 (MFAP4) is an extracellular matrix (ECM) protein involved in the induction of vascular remodeling. This study aimed to investigate if MFAP4 facilitates the development of AAA and characterize the underlying MFAP4-mediated mechanisms. Approach and Results: Double apolipoprotein E- and Mfap4-deficient (ApoE -/- Mfap4 -/-) and control apolipoprotein E-deficient (ApoE -/-) mice were infused subcutaneously with angiotensin II (Ang II) for 28 days. Mfap4 expression was localized within the adventitial and medial layers and was upregulated after Ang II treatment. While Ang II-induced blood pressure increase was independent of Mfap4 genotype, ApoE -/- Mfap4 -/- mice exhibited significantly lower AAA incidence and reduced maximal aortic diameter compared to ApoE -/- littermates. The ApoE -/- Mfap4 -/- AAAs were further characterized by reduced macrophage infiltration, matrix metalloproteinase (MMP)-2 and MMP-9 activity, proliferative activity, collagen content, and elastic membrane disruption. MFAP4 deficiency also attenuated activation of integrin- and TGF-β-related signaling within the adventitial layer of AAA tissues. Finally, MFAP4 stimulation promoted human monocyte migration and significantly upregulated MMP-9 activity in macrophage-like THP-1 cells. Conclusion: This study demonstrates that MFAP4 induces macrophage-rich inflammation, MMP activity, and maladaptive remodeling of the ECM within the vessel wall, leading to an acceleration of AAA development and progression. Collectively, our findings suggest that MFAP4 is an essential aggravator of AAA pathology that acts through regulation of monocyte influx and MMP production.</p

Cardiac injury of the newborn mammalian heart accelerates cardiomyocyte terminal differentiation

After birth cardiomyocytes undergo terminal differentiation, characterized by binucleation and centrosome disassembly, rendering the heart unable to regenerate. Yet, it has been suggested that newborn mammals regenerate their hearts after apical resection by cardiomyocyte proliferation. Thus, we tested the hypothesis that apical resection either inhibits, delays, or reverses cardiomyocyte centrosome disassembly and binucleation. Our data show that apical resection rather transiently accelerates centrosome disassembly as well as the rate of binucleation. Consistent with the nearly 2-fold increased rate of binucleation there was a nearly 2-fold increase in the number of cardiomyocytes in mitosis indicating that the majority of injury-induced cardiomyocyte cell cycle activity results in binucleation, not proliferation. Concurrently, cardiomyocytes undergoing cytokinesis from embryonic hearts exhibited midbody formation consistent with successful abscission, whereas those from 3 day-old cardiomyocytes after apical resection exhibited midbody formation consistent with abscission failure. Lastly, injured hearts failed to fully regenerate as evidenced by persistent scarring and reduced wall motion. Collectively, these data suggest that should a regenerative program exist in the newborn mammalian heart, it is quickly curtailed by developmental mechanisms that render cardiomyocytes post-mitotic

Protozoal populations drive system-wide variation in the rumen microbiome

While rapid progress has been made to characterize the bacterial and archaeal populations of the rumen microbiome, insight into how they interact with keystone protozoal species remains elusive. Here, we reveal two distinct system-wide rumen community types (RCT-A and RCT-B) that are not strongly associated with host phenotype nor genotype but instead linked to protozoal community patterns. We leveraged a series of multi-omic datasets to show that the dominant Epidinium spp. in animals with RCT-B employ a plethora of fiber-degrading enzymes that present enriched Prevotella spp. a favorable carbon landscape to forage upon. Conversely, animals with RCT-A, dominated by genera Isotricha and Entodinium, harbor a more even distribution of fiber, protein, and amino acid metabolizers, reflected by higher detection of metabolites from both protozoal and bacterial activity. Our results indicate that microbiome variation across key protozoal and bacterial populations is interlinked, which should act as an important consideration for future development of microbiome-based technologies

The biological function of some human transcription factor binding motifs varies with position relative to the transcription start site

A number of previous studies have predicted transcription factor binding sites (TFBSs) by exploiting the position of genomic landmarks like the transcriptional start site (TSS). The studies’ methods are generally too computationally intensive for genome-scale investigation, so the full potential of ‘positional regulomics’ to discover TFBSs and determine their function remains unknown. Because databases often annotate the genomic landmarks in DNA sequences, the methodical exploitation of positional regulomics has become increasingly urgent. Accordingly, we examined a set of 7914 human putative promoter regions (PPRs) with a known TSS. Our methods identified 1226 eight-letter DNA words with significant positional preferences with respect to the TSS, of which only 608 of the 1226 words matched known TFBSs. Many groups of genes whose PPRs contained a common word displayed similar expression profiles and related biological functions, however. Most interestingly, our results included 78 words, each of which clustered significantly in two or three different positions relative to the TSS. Often, the gene groups corresponding to different positional clusters of the same word corresponded to diverse functions, e.g. activation or repression in different tissues. Thus, different clusters of the same word likely reflect the phenomenon of ‘positional regulation’, i.e. a word's regulatory function can vary with its position relative to a genomic landmark, a conclusion inaccessible to methods based purely on sequence. Further integrative analysis of words co-occurring in PPRs also yielded 24 different groups of genes, likely identifying cis-regulatory modules de novo. Whereas comparative genomics requires precise sequence alignments, positional regulomics exploits genomic landmarks to provide a ‘poor man's alignment’. By exploiting the phenomenon of positional regulation, it uses position to differentiate the biological functions of subsets of TFBSs sharing a common sequence motif

The C1C2: A framework for simultaneous model selection and assessment

BACKGROUND: There has been recent concern regarding the inability of predictive modeling approaches to generalize to new data. Some of the problems can be attributed to improper methods for model selection and assessment. Here, we have addressed this issue by introducing a novel and general framework, the C1C2, for simultaneous model selection and assessment. The framework relies on a partitioning of the data in order to separate model choice from model assessment in terms of used data. Since the number of conceivable models in general is vast, it was also of interest to investigate the employment of two automatic search methods, a genetic algorithm and a brute-force method, for model choice. As a demonstration, the C1C2 was applied to simulated and real-world datasets. A penalized linear model was assumed to reasonably approximate the true relation between the dependent and independent variables, thus reducing the model choice problem to a matter of variable selection and choice of penalizing parameter. We also studied the impact of assuming prior knowledge about the number of relevant variables on model choice and generalization error estimates. The results obtained with the C1C2 were compared to those obtained by employing repeated K-fold cross-validation for choosing and assessing a model. RESULTS: The C1C2 framework performed well at finding the true model in terms of choosing the correct variable subset and producing reasonable choices for the penalizing parameter, even in situations when the independent variables were highly correlated and when the number of observations was less than the number of variables. The C1C2 framework was also found to give accurate estimates of the generalization error. Prior information about the number of important independent variables improved the variable subset choice but reduced the accuracy of generalization error estimates. Using the genetic algorithm worsened the model choice but not the generalization error estimates, compared to using the brute-force method. The results obtained with repeated K-fold cross-validation were similar to those produced by the C1C2 in terms of model choice, however a lower accuracy of the generalization error estimates was observed. CONCLUSION: The C1C2 framework was demonstrated to work well for finding the true model within a penalized linear model class and accurately assess its generalization error, even for datasets with many highly correlated independent variables, a low observation-to-variable ratio, and model assumption deviations. A complete separation of the model choice and the model assessment in terms of data used for each task improves the estimates of the generalization error.</p