Displaying alphavirus physicochemical consensus antigens on immunogenic liposomes enhances antibody elicitation in mice.

Cobalt-porphyrin phospholipid displays recombinant protein antigens on liposome surfaces via antigen polyhistidine-tag (His-tag), and when combined with monophosphorylated lipid A and QS-21 yields the "CPQ" vaccine adjuvant system. In this proof of principle study, CPQ was used to generate vaccine prototypes that elicited antibodies for two different alphaviruses (AV). Mice were immunized with computationally designed, His-tagged, physicochemical property consensus (PCP) protein antigens representing the variable B-domain of the envelope protein 2 (E2) from the serotype specific Venezuelan Equine Encephalitis Virus (VEEV) or a broad-spectrum AV-antigen termed EVC The CPQ adjuvant enhanced the antigenicity of both proteins without eliciting detectable anti-His-tag antibodies.

PCP consensus protein/peptide alphavirus antigens stimulate broad spectrum neutralizing antibodies.

Vaccines based on proteins and peptides may be safer and if calculated based on many sequences, more broad-spectrum than those designed based on single strains. Physicochemical Property Consensus (PCP) alphavirus (AV) antigens from the B-domain of the E2 envelope protein were designed, synthesized recombinantly and shown to be immunogenic (i.e.

Stiffening of Circumferential F-Actin Bands Correlates With Regenerative Failure and May Act as a Biomechanical Brake in the Mammalian Inner Ear.

The loss of inner ear hair cells causes permanent hearing and balance deficits in humans and other mammals, but non-mammals recover after supporting cells (SCs) divide and replace hair cells. The proliferative capacity of mammalian SCs declines as exceptionally thick circumferential F-actin bands develop at their adherens junctions. We hypothesized that the reinforced junctions were limiting regenerative responses of mammalian SCs by impeding changes in cell shape and epithelial tension.

Skull and vertebral bone marrow are myeloid cell reservoirs for the meninges and CNS parenchyma.

The meninges are a membranous structure enveloping the central nervous system (CNS) that host a rich repertoire of immune cells mediating CNS immune surveillance. Here, we report that the mouse meninges contain a pool of monocytes and neutrophils supplied not from the blood but by adjacent skull and vertebral bone marrow. Under pathological conditions, including spinal cord injury and neuroinflammation, CNS-infiltrating myeloid cells can originate from brain borders and display transcriptional signatures distinct from their blood-derived counterparts.

Aging-associated deficit in CCR7 is linked to worsened glymphatic function, cognition, neuroinflammation, and β-amyloid pathology.

Aging leads to a progressive deterioration of meningeal lymphatics and peripheral immunity, which may accelerate cognitive decline. We hypothesized that an age-related reduction in C-C chemokine receptor type 7 (CCR7)-dependent egress of immune cells through the lymphatic vasculature mediates some aspects of brain aging and potentially exacerbates cognitive decline and Alzheimer's disease-like brain β-amyloid (Aβ) pathology. We report a reduction in CCR7 expression by meningeal T cells in old mice that is linked to increased effector and regulatory T cells.

Meningeal lymphatics affect microglia responses and anti-Aβ immunotherapy.

Alzheimer's disease (AD) is the most prevalent cause of dementia. Although there is no effective treatment for AD, passive immunotherapy with monoclonal antibodies against amyloid beta (Aβ) is a promising therapeutic strategy. Meningeal lymphatic drainage has an important role in the accumulation of Aβ in the brain, but it is not known whether modulation of meningeal lymphatic function can influence the outcome of immunotherapy in AD.

Functional characterization of the dural sinuses as a neuroimmune interface.

Despite the established dogma of central nervous system (CNS) immune privilege, neuroimmune interactions play an active role in diverse neurological disorders. However, the precise mechanisms underlying CNS immune surveillance remain elusive; particularly, the anatomical sites where peripheral adaptive immunity can sample CNS-derived antigens and the cellular and molecular mediators orchestrating this surveillance. Here, we demonstrate that CNS-derived antigens in the cerebrospinal fluid (CSF) accumulate around the dural sinuses, are captured by local antigen-presenting cells, and are presented to patrolling T cells.

Meningeal γδ T cells regulate anxiety-like behavior via IL-17a signaling in neurons.

Interleukin (IL)-17a has been highly conserved during evolution of the vertebrate immune system and widely studied in contexts of infection and autoimmunity. Studies suggest that IL-17a promotes behavioral changes in experimental models of autism and aggregation behavior in worms. Here, through a cellular and molecular characterization of meningeal γδ17 T cells, we defined the nearest central nervous system-associated source of IL-17a under homeostasis.

Producing physicochemical property consensus alphavirus protein antigens for broad spectrum vaccine design.

There is a pressing need for new vaccines against alphaviruses, which can cause fatal encephalitis (Venezuelan equine encephalitis virus (VEEV) and others) and severe arthralgia (e.g. Chikungunya virus, CHIKV).

Publisher Correction: Functional aspects of meningeal lymphatics in ageing and Alzheimer's disease.

Change history: In this Article, Extended Data Fig. 9 was appearing as Fig. 2 in the HTML, and in Fig.

Functional aspects of meningeal lymphatics in ageing and Alzheimer's disease.

Ageing is a major risk factor for many neurological pathologies, but its mechanisms remain unclear. Unlike other tissues, the parenchyma of the central nervous system (CNS) lacks lymphatic vasculature and waste products are removed partly through a paravascular route. (Re)discovery and characterization of meningeal lymphatic vessels has prompted an assessment of their role in waste clearance from the CNS.

Data documenting the performance of the PT/INR line correction method for reconciling INR discrepancies between central laboratory coagulation analyzers using different thromboplastins during the evaluation of a portable Coagulometer.

The data presented here was produced as part of an evaluation of the performance of the CoaguChek XS point-of-care coagulation analyzer, which is discussed in the research article "POCT PT INR - Is it adequate for Patient Care? A Comparison of the Roche Coaguchek XS vs. Stago Star vs. Siemens BCS in Patients Routinely Seen in an Anticoagulation Clinic" (Baker et al.

POCT PT INR - Is it adequate for patient care? A comparison of the Roche Coaguchek XS vs. Stago Star vs. Siemens BCS in patients routinely seen in an anticoagulation clinic.

Background: In this study we examined the difference in patient INR values as measured by the POCT CoaguChek XS device and central laboratory Stago Evolution and Siemens BCS XP analyzers.

Methods: This study composed of 100 warfarin therapy patients and 20 coagulation normal subjects, showed that the difference between the POCT and clinical laboratory values increased with increasing INR and was exacerbated by the use of different thromboplastin reagents by the POCT and central lab.

Results: The CoaguChek XS and on-site Stago analyzers which used human recombinant (ISI=1.

Current and future therapies for addressing the effects of inflammation on HDL cholesterol metabolism.

Unlabelled: Cardiovascular disease (CVD) is a major cause of morbidity and mortality worldwide. Inflammatory processes arising from metabolic abnormalities are known to precipitate the development of CVD. Several metabolic and inflammatory markers have been proposed for predicting the progression of CVD, including high density lipoprotein cholesterol (HDL-C).

Unexpected role of interferon-γ in regulating neuronal connectivity and social behaviour.

Immune dysfunction is commonly associated with several neurological and mental disorders. Although the mechanisms by which peripheral immunity may influence neuronal function are largely unknown, recent findings implicate meningeal immunity influencing behaviour, such as spatial learning and memory. Here we show that meningeal immunity is also critical for social behaviour; mice deficient in adaptive immunity exhibit social deficits and hyper-connectivity of fronto-cortical brain regions.

Methyl-CpG Binding Protein 2 Regulates Microglia and Macrophage Gene Expression in Response to Inflammatory Stimuli.

Mutations in MECP2, encoding the epigenetic regulator methyl-CpG-binding protein 2, are the predominant cause of Rett syndrome, a disease characterized by both neurological symptoms and systemic abnormalities. Microglial dysfunction is thought to contribute to disease pathogenesis, and here we found microglia become activated and subsequently lost with disease progression in Mecp2-null mice. Mecp2 was found to be expressed in peripheral macrophage and monocyte populations, several of which also became depleted in Mecp2-null mice.

Health workers' views of a program to facilitate physical health care in mental health settings: implications for implementation and training.

Objective: Physical comorbidities shorten the lifespan of people with severe mental illness therefore mental health clinicians need to support service users in risk factor-related behaviour change. We investigated mental health care workers' views of a physical health self-management support program in order to identify implementation requirements.

Method: Qualitative interviews were conducted with workers who had differing levels of experience with a self-management support program.

Over half the hair cells in the mouse utricle first appear after birth, with significant numbers originating from early postnatal mitotic production in peripheral and striolar growth zones.

Many non-mammalian vertebrates produce hair cells throughout life and recover from hearing and balance deficits through regeneration. In contrast, embryonic production of hair cells declines sharply in mammals where deficits from hair cell losses are typically permanent. Hair cell density estimates recently suggested that the vestibular organs of mice continue to add hair cells after birth, so we undertook comprehensive counting in murine utricles at different ages.

The postnatal accumulation of junctional E-cadherin is inversely correlated with the capacity for supporting cells to convert directly into sensory hair cells in mammalian balance organs.

Mammals experience permanent impairments from hair cell (HC) losses, but birds and other non-mammals quickly recover hearing and balance senses after supporting cells (SCs) give rise to replacement HCs. Avian HC epithelia express little or no E-cadherin, and differences in the thickness of F-actin belts at SC junctions strongly correlate with different species' capacities for HC replacement, so we investigated junctional cadherins in human and murine ears. We found strong E-cadherin expression at SC-SC junctions that increases more than sixfold postnatally in mice.

Child-adult differences in second-language phonological learning: the role of cross-language similarity.

This study evaluated whether age effects on second language (L2) speech learning derive from changes in how the native language (L1) and L2 sound systems interact. According to the "interaction hypothesis" (IH), the older the L2 learner, the less likely the learner is able to establish new vowel categories needed for accurate L2 vowel production and perception because, with age, L1 vowel categories become more likely to perceptually encompass neighboring L2 vowels. These IH predictions were evaluated in two experiments involving 64 native Korean- and English-speaking children and adults.

EMBL Nucleotide Sequence Database: developments in 2005.

The EMBL Nucleotide Sequence Database (www.ebi.ac.

Interaction of native- and second-language vowel system(s) in early and late bilinguals.

The objective of this study was to determine how bilinguals' age at the time of language acquisition influenced the organization of their phonetic system(s). The productions of six English and five Korean vowels by English and Korean monolinguals were compared to the productions of the same vowels by early and late Korean-English bilinguals varying in amount of exposure to their second language. Results indicated that bilinguals' age profoundly influenced both the degree and the direction of the interaction between the phonetic systems of their native (L1) and second (L2) languages.

The EMBL Nucleotide Sequence Database.

The EMBL Nucleotide Sequence Database (http://www.ebi.ac.

The EMBL Nucleotide Sequence Database.

The EMBL Nucleotide Sequence Database (http://www.ebi.ac.

The EMBL Nucleotide Sequence Database: major new developments.

The EMBL Nucleotide Sequence Database (http://www.ebi.ac.