Biophysical Characteristics of Lipid-Induced Aβ Oligomers Correlate to Distinctive Phenotypes In Transgenic Mice

Alzheimer\u27s disease (AD) is a progressive neurodegenerative disorder that affects cognition and memory. Recent advances have helped identify many clinical sub-types in AD. Mounting evidence point toward structural polymorphism among fibrillar aggregates of amyloid-β (Aβ) to being responsible for the phenotypes and clinical manifestations. In the emerging paradigm of polymorphism and prion-like propagation of aggregates in AD, the role of low molecular weight soluble oligomers, which are long known to be the primary toxic agents, in effecting phenotypes remains inconspicuous. In this study, we present the characterization of three soluble oligomers of Aβ42, namely 14LPOs, 16LPOs, and GM1Os with discreet biophysical and biochemical properties generated using lysophosphatidyl glycerols and GM1 gangliosides. The results indicate that the oligomers share some biophysical similarities but display distinctive differences with GM1Os. Unlike the other two, GM1Os were observed to be complexed with the lipid upon isolation. It also differs mainly in detection by conformation-sensitive dyes and conformation-specific antibodies, temperature and enzymatic stability, and in the ability to propagate morphologically-distinct fibrils. GM1Os also show distinguishable biochemical behavior with pronounced neuronal toxicity. Furthermore, all the oligomers induce cerebral amyloid angiopathy (CAA) and plaque burden in transgenic AD mice, which seems to be a consistent feature among all lipid-derived oligomers, but 16LPOs and GM1Os displayed significantly higher effect than the others. These results establish a correlation between molecular features of Aβ42 oligomers and their distinguishable effects in transgenic AD mice attuned by lipid characteristics, and therefore help bridge the knowledge gap in understanding how oligomer conformers could elicit AD phenotypes

Recommendations for a core outcome set for measuring standing balance in adult populations: a consensus-based approach

Standing balance is imperative for mobility and avoiding falls. Use of an excessive number of standing balance measures has limited the synthesis of balance intervention data and hampered consistent clinical practice.To develop recommendations for a core outcome set (COS) of standing balance measures for research and practice among adults.A combination of scoping reviews, literature appraisal, anonymous voting and face-to-face meetings with fourteen invited experts from a range of disciplines with international recognition in balance measurement and falls prevention. Consensus was sought over three rounds using pre-established criteria.The scoping review identified 56 existing standing balance measures validated in adult populations with evidence of use in the past five years, and these were considered for inclusion in the COS.Fifteen measures were excluded after the first round of scoring and a further 36 after round two. Five measures were considered in round three. Two measures reached consensus for recommendation, and the expert panel recommended that at a minimum, either the Berg Balance Scale or Mini Balance Evaluation Systems Test be used when measuring standing balance in adult populations.Inclusion of two measures in the COS may increase the feasibility of potential uptake, but poses challenges for data synthesis. Adoption of the standing balance COS does not constitute a comprehensive balance assessment for any population, and users should include additional validated measures as appropriate.The absence of a gold standard for measuring standing balance has contributed to the proliferation of outcome measures. These recommendations represent an important first step towards greater standardization in the assessment and measurement of this critical skill and will inform clinical research and practice internationally

'To live and die [for] Dixie': Irish civilians and the Confederate States of America

Around 20,000 Irishmen served in the Confederate army in the Civil War. As a result, they left behind, in various Southern towns and cities, large numbers of friends, family, and community leaders. As with native-born Confederates, Irish civilian support was crucial to Irish participation in the Confederate military effort. Also, Irish civilians served in various supporting roles: in factories and hospitals, on railroads and diplomatic missions, and as boosters for the cause. They also, however, suffered in bombardments, sieges, and the blockade. Usually poorer than their native neighbours, they could not afford to become 'refugees' and move away from the centres of conflict. This essay, based on research from manuscript collections, contemporary newspapers, British Consular records, and Federal military records, will examine the role of Irish civilians in the Confederacy, and assess the role this activity had on their integration into Southern communities. It will also look at Irish civilians in the defeat of the Confederacy, particularly when they came under Union occupation. Initial research shows that Irish civilians were not as upset as other whites in the South about Union victory. They welcomed a return to normalcy, and often 'collaborated' with Union authorities. Also, Irish desertion rates in the Confederate army were particularly high, and I will attempt to gauge whether Irish civilians played a role in this. All of the research in this paper will thus be put in the context of the Drew Gilpin Faust/Gary Gallagher debate on the influence of the Confederate homefront on military performance. By studying the Irish civilian experience one can assess how strong the Confederate national experiment was. Was it a nation without a nationalism

Adaptive divergence despite strong genetic drift: genomic analysis of the evolutionary mechanisms causing genetic differentiation in the island fox (\u3ci\u3eUrocyon littoralis\u3c/i\u3e)

The evolutionary mechanisms generating the tremendous biodiversity of islands have long fascinated evolutionary biologists. Genetic drift and divergent selection are pre- dicted to be strong on islands and both could drive population divergence and specia- tion. Alternatively, strong genetic drift may preclude adaptation. We conducted a genomic analysis to test the roles of genetic drift and divergent selection in causing genetic differentiation among populations of the island fox (Urocyon littoralis). This species consists of six subspecies, each of which occupies a different California Chan- nel Island. Analysis of 5293 SNP loci generated using Restriction-site Associated DNA (RAD) sequencing found support for genetic drift as the dominant evolutionary mech- anism driving population divergence among island fox populations. In particular, pop- ulations had exceptionally low genetic variation, small Ne (range = 2.1–89.7; median = 19.4), and significant genetic signatures of bottlenecks. Moreover, islands with the lowest genetic variation (and, by inference, the strongest historical genetic drift) were most genetically differentiated from mainland grey foxes, and vice versa, indicating genetic drift drives genome-wide divergence. Nonetheless, outlier tests identified 3.6–6.6% of loci as high FST outliers, suggesting that despite strong genetic drift, divergent selection contributes to population divergence. Patterns of similarity among populations based on high FST outliers mirrored patterns based on morphology, providing additional evidence that outliers reflect adaptive divergence. Extremely low genetic variation and small Ne in some island fox populations, particularly on San Nicolas Island, suggest that they may be vulnerable to fixation of deleterious alleles, decreased fitness and reduced adaptive potential

Being user-oriented: convergences, divergences, and the potentials for systematic dialogue between disciplines and between researchers, designers, and providers

The challenge this panel addresses is drawn from intersecting literature reviews and critical commentaries focusing on: 1) user studies in multiple fields; and 2) the difficulties of bringing different disciplines and perspectives to bear on user‐oriented research, design, and practice. 1 The challenge is that while we have made some progress in collaborative work, we have some distance to go to become user‐oriented in inter‐disciplinary and inter‐perspective ways. The varieties of our approaches and solutions are, as some observers suggest, an increasing cacophony. One major difficulty is that most discussions are solution‐oriented, offering arguments of this sort ‐‐ if only we addressed users in this way… Each solution becomes yet another addition to the cacophony. This panel implements a central approach documented for its utility by communication researchers and long used by communication mediators and negotiators ‐‐ that of focusing not on communication but rather on meta‐communication: communicating about communication. The intent in the context of this panel is to help us refocus attention from too frequent polarizations between alternative solutions to the possibility of coming to understand what is behind the alternatives and where they point to experientially‐based convergences and divergences, both of which might potentially contribute to synergies. The background project for this panel comes from a series of in‐depth interviews with expert researchers, designers, and providers in three field groupings ‐‐ library and information science; human computer interaction/information technology; and communication and media studies. One set of interviews involved 5‐hour focus groups with directors of academic and public libraries serving 44 colleges and universities in central Ohio; the second involved one‐on‐one interviews averaging 50 minutes with 81 nationally‐internationally known experts in the 3 fields, 25‐27 interviews per field. Using Dervin\u27s Sense‐Making Methodological approach to interviewing, the expert interviews of both kinds asked each interviewee: what he/she considered to be the big unanswered questions about users and what explained why the questions have not been answered; and, what he/she saw as hindering versus helping in attempts to communicate about users across disciplinary and perspective gaps. 2 The panel consists of six teams, two from each field. Prior to the panel presentation at ASIST, each team will have read the set of interviews and completed impressionistic essays of what patterns and themes they saw as emerging. At this stage, team members will purposively not homogenize their differences and most will write solo‐authored essays that will be placed on a web‐site accessible to ASIST members prior to the November meeting. In addition, at least one systematic analysis will be completed and available online. 3 At the ASIST panel, each team\u27s leader will present a brief and intentionally provocative impressionist account of what his/her team came to understand about our struggles communicating across fields and perspectives about users. Again, each team will purposively not homogenize its own differences in viewpoints, but rather highlight them as fodder for discussion. A major purpose will be to invite audience members to join the panel in discussion. At least 20 minutes will be left open for this purpose

Omanicotyle heterospina n. gen. et n. comb. (Monogenea: Microcotylidae) from the gills of Argyrops spinifer (Forsskal) (Teleostei: Sparidae) from the Sea of Oman

Background: The Sultanate of Oman's aquaculture industry is expanding with an on-going assessment of potential new fish species for culture. The king soldier bream, Argyrops spinifer (Forsskål) (Sparidae), is one such species that is under consideration. During a routine health assessment of specimens caught in the Sea of Oman throughout the period November 2009 to March 2011, a number of gill polyopisthocotylean monogeneans were recovered. Methods: A subsequent study of the monogeneans using a range of morphology-based approaches indicated that these were Bivagina heterospina Mamaev et Parukhin, 1974. In the absence of pre-existing molecular data, an expanded description of this species is provided, including a differential diagnosis with other species and genera belonging to the subfamily Microcotylinae Monticelli, 1892 with the subsequent movement of this species to a new genus to accommodate it. Results: The polyopisthocotyleans collected from the gills of A. spinifer appear to be unique within the family Microcotylidae Taschenberg, 1879 in that, morphologically, they possess a pair of large, muscular vaginae each armed with a full crown of 16-18 robust spines and a unique dorsal region of folded tegument, which permits their discrimination from species of Bivagina Yamaguti, 1963. Sequencing of the SSU rDNA (complete 1968 bp) and LSU rDNA (partial 949 bp) places the specimens collected during this study within the subfamily Microcotylinae, but the LSU rDNA sequence differs from Bivagina and also from other microcotylid genera. Morphological features of B. heterospina sensu Mamaev et Parukhin, 1974 and the specimens collected from the current study are consistent with one another and represent a single species. The vaginal armature of these worms is unique and differs from all other genera within the Microcotylinae, including Bivagina, and its movement to Omanicotyle n. gen. to accommodate this species is proposed. Conclusions: A new genus, Omanicotyle n. gen., is erected to accommodate Omanicotyle [Bivagina] heterospina n. comb. which represents the first monogenean to be described from Omani marine waters. Given the pathogenic potential of microcotylids on captive held fish stocks, a full assessment of Omanicotyle heterospina n. gen. et n. comb. is now required before large-scale production commences

Real-time observation of multiexcitonic states in ultrafast singlet fission using coherent 2D electronic spectroscopy.

Singlet fission is the spin-allowed conversion of a spin-singlet exciton into a pair of spin-triplet excitons residing on neighbouring molecules. To rationalize this phenomenon, a multiexcitonic spin-zero triplet-pair state has been hypothesized as an intermediate in singlet fission. However, the nature of the intermediate states and the underlying mechanism of ultrafast fission have not been elucidated experimentally. Here, we study a series of pentacene derivatives using ultrafast two-dimensional electronic spectroscopy and unravel the origin of the states involved in fission. Our data reveal the crucial role of vibrational degrees of freedom coupled to electronic excitations that facilitate the mixing of multiexcitonic states with singlet excitons. The resulting manifold of vibronic states drives sub-100 fs fission with unity efficiency. Our results provide a framework for understanding singlet fission and show how the formation of vibronic manifolds with a high density of states facilitates fast and efficient electronic processes in molecular systems.This is the author accepted manuscript. The final version is available from NPG via http://dx.doi.org/10.1038/nchem.237

Autoimmunity-Associated LYP-W620 Does Not Impair Thymic Negative Selection of Autoreactive T Cells.

A C1858T (R620W) variation in the PTPN22 gene encoding the tyrosine phosphatase LYP is a major risk factor for human autoimmunity. LYP is a known negative regulator of signaling through the T cell receptor (TCR), and murine Ptpn22 plays a role in thymic selection. However, the mechanism of action of the R620W variant in autoimmunity remains unclear. One model holds that LYP-W620 is a gain-of-function phosphatase that causes alterations in thymic negative selection and/or thymic output of regulatory T cells (Treg) through inhibition of thymic TCR signaling. To test this model, we generated mice in which the human LYP-W620 variant or its phosphatase-inactive mutant are expressed in developing thymocytes under control of the proximal Lck promoter. We found that LYP-W620 expression results in diminished thymocyte TCR signaling, thus modeling a "gain-of-function" of LYP at the signaling level. However, LYP-W620 transgenic mice display no alterations of thymic negative selection and no anomalies in thymic output of CD4(+)Foxp3(+) Treg were detected in these mice. Lck promoter-directed expression of the human transgene also causes no alteration in thymic repertoire or increase in disease severity in a model of rheumatoid arthritis, which depends on skewed thymic selection of CD4(+) T cells. Our data suggest that a gain-of-function of LYP is unlikely to increase risk of autoimmunity through alterations of thymic selection and that LYP likely acts in the periphery perhaps selectively in regulatory T cells or in another cell type to increase risk of autoimmunity

Age-Dependent Maturation of Toll-Like Receptor-Mediated Cytokine Responses in Gambian Infants

The global burden of neonatal and infant mortality due to infection is staggering, particularly in resource-poor settings. Early childhood vaccination is one of the major interventions that can reduce this burden, but there are specific limitations to inducing effective immunity in early life, including impaired neonatal leukocyte production of Th1-polarizing cytokines to many stimuli. Characterizing the ontogeny of Toll-like receptor (TLR)-mediated innate immune responses in infants may shed light on susceptibility to infection in this vulnerable age group, and provide insights into TLR agonists as candidate adjuvants for improved neonatal vaccines. As little is known about the leukocyte responses of infants in resource-poor settings, we characterized production of Th1-, Th2-, and anti-inflammatory- cytokines in response to agonists of TLRs 1-9 in whole blood from 120 Gambian infants ranging from newborns (cord blood) to 12 months of age. Most of the TLR agonists induced TNFα, IL-1β, IL-6, and IL-10 in cord blood. The greatest TNFα responses were observed for TLR4, -5, and -8 agonists, the highest being the thiazoloquinoline CLO75 (TLR7/8) that also uniquely induced cord blood IFNγ production. For most agonists, TLR-mediated TNFα and IFNγ responses increased from birth to 1 month of age. TLR8 agonists also induced the greatest production of the Th1-polarizing cytokines TNFα and IFNγ throughout the first year of life, although the relative responses to the single TLR8 agonist and the combined TLR7/8 agonist changed with age. In contrast, IL-1β, IL-6, and IL-10 responses to most agonists were robust at birth and remained stable through 12 months of age. These observations provide fresh insights into the ontogeny of innate immunity in African children, and may inform development of age-specific adjuvanted vaccine formulations important for global health

A Systematically Improved High Quality Genome and Transcriptome of the Human Blood Fluke Schistosoma mansoni

Schistosomiasis is one of the most prevalent parasitic diseases, affecting millions of people in developing countries. Amongst the human-infective species, Schistosoma mansoni is also the most commonly used in the laboratory and here we present the systematic improvement of its draft genome. We used Sanger capillary and deep-coverage Illumina sequencing from clonal worms to upgrade the highly fragmented draft 380 Mb genome to one with only 885 scaffolds and more than 81% of the bases organised into chromosomes. We have also used transcriptome sequencing (RNA-seq) from four time points in the parasite's life cycle to refine gene predictions and profile their expression. More than 45% of predicted genes have been extensively modified and the total number has been reduced from 11,807 to 10,852. Using the new version of the genome, we identified trans-splicing events occurring in at least 11% of genes and identified clear cases where it is used to resolve polycistronic transcripts. We have produced a high-resolution map of temporal changes in expression for 9,535 genes, covering an unprecedented dynamic range for this organism. All of these data have been consolidated into a searchable format within the GeneDB (www.genedb.org) and SchistoDB (www.schistodb.net) databases. With further transcriptional profiling and genome sequencing increasingly accessible, the upgraded genome will form a fundamental dataset to underpin further advances in schistosome research