Impaired object-location learning and recognition memory but enhanced sustained attention in M2 muscarinic receptor-deficient mice

© 2018, The Author(s). Rationale: Muscarinic acetylcholine receptors are known to play key roles in mediating cognitive processes, and impaired muscarinic cholinergic neurotransmission is associated with normal ageing processes and Alzheimer’s disease. However, the specific contributions of the individual muscarinic receptor subtypes (M1–M5) to cognition are presently not well understood. Objectives: The aim of this study was to investigate the contribution of M2-type muscarinic receptor signalling to sustained attention, executive control and learning and memory. Methods: M2 receptor-deficient (M2−/−) mice were tested on a touchscreen-operated task battery testing visual discrimination, behavioural flexibility, object-location associative learning, attention and response control. Spontaneous recognition memory for real-world objects was also assessed. Results: We found that M2−/− mice showed an enhancement of attentional performance, but significant deficits on some tests of learning and memory. Executive control and visual discrimination were unaffected by M2-depletion. Conclusions: These findings suggest that M2 activation has heterogeneous effects across cognitive domains, and provide insights into how acetylcholine may support multiple specific cognitive processes through functionally distinct cholinergic receptor subtypes. They also suggest that therapeutics involving M2 receptor-active compounds should be assessed across a broad range of cognitive domains, as they may enhance some cognitive functions, but impair others

Inflation with Non-minimal Gravitational Couplings and Supergravity

We explore in the supergravity context the possibility that a Higgs scalar may drive inflation via a non-minimal coupling to gravity characterised by a large dimensionless coupling constant. We find that this scenario is not compatible with the MSSM, but that adding a singlet field (NMSSM, or a variant thereof) can very naturally give rise to slow-roll inflation. The inflaton is necessarily contained in the doublet Higgs sector and occurs in the D-flat direction of the two Higgs doublets.Comment: 13 pages, 1 figur

Calculating the Prepotential by Localization on the Moduli Space of Instantons

We describe a new technique for calculating instanton effects in supersymmetric gauge theories applicable on the Higgs or Coulomb branches. In these situations the instantons are constrained and a potential is generated on the instanton moduli space. Due to existence of a nilpotent fermionic symmetry the resulting integral over the instanton moduli space localizes on the critical points of the potential. Using this technology we calculate the one- and two-instanton contributions to the prepotential of SU(N) gauge theory with N=2 supersymmetry and show how the localization approach yields the prediction extracted from the Seiberg-Witten curve. The technique appears to extend to arbitrary instanton number in a tractable way.Comment: 24 pages, JHEP.cls, more references and extra discussion on N_F=2N cas

The Moraxella adhesin UspA1 binds to its human CEACAM1 receptor by a deformable trimeric coiled-coil

Moraxella catarrhalis is a ubiquitous human-specific bacterium commonly associated with upper and lower respiratory tract infections, including otitis media, sinusitis and chronic obstructive pulmonary disease. The bacterium uses an autotransporter protein UspA1 to target an important human cellular receptor carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1). Using X-ray crystallography, we show that the CEACAM1 receptor-binding region of UspA1 unusually consists of an extended, rod-like left-handed trimeric coiled-coil. Mutagenesis and binding studies of UspA1 and the N-domain of CEACAM1 have been used to delineate the interacting surfaces between ligand and receptor and guide assembly of the complex. However, solution scattering, molecular modelling and electron microscopy analyses all indicate that significant bending of the UspA1 coiled-coil stalk also occurs. This explains how UspA1 can engage CEACAM1 at a site far distant from its head group, permitting closer proximity of the respective cell surfaces during infection

M1 muscarinic allosteric modulators slow prion neurodegeneration and restore memory loss.

The current frontline symptomatic treatment for Alzheimer's disease (AD) is whole-body upregulation of cholinergic transmission via inhibition of acetylcholinesterase. This approach leads to profound dose-related adverse effects. An alternative strategy is to selectively target muscarinic acetylcholine receptors, particularly the M1 muscarinic acetylcholine receptor (M1 mAChR), which was previously shown to have procognitive activity. However, developing M1 mAChR-selective orthosteric ligands has proven challenging. Here, we have shown that mouse prion disease shows many of the hallmarks of human AD, including progressive terminal neurodegeneration and memory deficits due to a disruption of hippocampal cholinergic innervation. The fact that we also show that muscarinic signaling is maintained in both AD and mouse prion disease points to the latter as an excellent model for testing the efficacy of muscarinic pharmacological entities. The memory deficits we observed in mouse prion disease were completely restored by treatment with benzyl quinolone carboxylic acid (BQCA) and benzoquinazoline-12 (BQZ-12), two highly selective positive allosteric modulators (PAMs) of M1 mAChRs. Furthermore, prolonged exposure to BQCA markedly extended the lifespan of diseased mice. Thus, enhancing hippocampal muscarinic signaling using M1 mAChR PAMs restored memory loss and slowed the progression of mouse prion disease, indicating that this ligand type may have clinical benefit in diseases showing defective cholinergic transmission, such as AD

Collagen fibrillar structure and hierarchies

Collagen is most commonly found in animals as long, slender generally cylindrical fibrillar structures with tapered ends that are most easily recognized by a 65-67 nm axial periodicity. Collagen fibrils are substantial constituents of skin, tendon, bone, ligament, cornea, and cartilage, where the fundamental tensile properties of the fibril are finely tuned to serve bespoke biomechanical, and less well understood structural signaling roles. Many of these properties derive from the structural organization within a fibril, where the axial and lateral organization and topology of the collagen molecules ensure strong intermolecular interactions and cross-linkage. The presence of different collagen types within a single fibril is a structural prerequisite in many tissues. However, the necessity for heterotypic fibrillar structures may point to fine tuning of the structural properties in a composite, such as fibril size regulation, dispersion of crystallinity, and interfibrillar communication. Furthermore the specific properties of an individual tissue also rely on the suprafibrillar architecture at the mesoscopic level. The chapter will discuss current information about fibrillar structure from both homo-and heterotypic fibrils from a structural and biochemical viewpoint. Fibrils rich in collagen I, II and III will be considered as will the contribution of minor fibrillar and FACIT collagens. The molecular organization in both axial and lateral senses will be reviewed for both helicoidal and quasi crystalline fibrillar structures. Current models that account for the dynamic behavior of collagen segments within the fibril will be reviewed and the basis for order and disorder within the fibril discussed. The discrete size and polydispersity of fibrils will be discussed in terms of tissue properties and characteristics. The surface features of fibrils will be considered which conveniently leads to the possible features of interfibrillar interactions. The overall properties and morphology of a fibril are as important as its internal organization. For example, the fibril surface is a complex area that contains collagen molecules and a variety of proteoglycans. These dictate the interaction between fibrils and specify the environment of partner macromolecules. They are also important in restricting fibril growth and permitting fusion to occur. The defined diameter (or distribution of fibril diameters) and overall slender tapering of collagen fibrils has significance in determining the macroscopic mechanical properties of the tissues. The variety of local suprafibrillar and resultant architectures such as bundles, felt work, lamellae and fibers that are evidenced in tissues will be discussed. © 2008 Springer Science+Business Media, LLC

Use of attenuated total reflection-Fourier transform infrared spectroscopy to measure collagen degradation in historical parchments

Developing a noninvasive method to assess the degraded state of historical parchments is essential to providing the best possible care for these documents. The conformational changes observed when collagen molecules, the primary constituent of parchment, unfold have been analyzed using attenuated total reflection-Fourier transform infrared (ATR-FT-IR) spectroscopy and the nanoscopic structural changes have been analyzed using X-ray diffraction (XRD). The relationship between the results obtained from these techniques was studied using principal component analysis, where correlation was found. The extent of gelatinization of historical parchments has been assessed using ATR-FT-IR and XRD and the frequency shifts observed as collagen degrades into gelatin have been reported. These results indicate that collagen degradation can be measured noninvasively in parchment and demonstrate the utility of ATR-FT-IR spectroscopy as a method to investigate historical documents

Changes in the molecular packing of fibrillin microfibrils during extension indicate intrafibrillar and interfibrillar reorganization in elastic response

Fibrillin-rich microfibrils are the major structural components of the extracellular matrix that provide elasticity in a majority of connective tissues. The basis of elastic properties lies in the organization of fibrillin molecules, which, unfortunately, is still poorly understood. An X-ray diffraction study of hydrated fibrillin-rich microfibrils from zonular filaments has been conducted to give an insight into the molecular structure of microfibrils in intact tissue. A series of measurements was taken during controlled tissue extension to observe alterations in the lateral packing of microfibrils. Computer-generated simulated patterns were used to fit the experimental X-ray scattering data and to obtain the fibril diameter and lateral distance between the fibrils. The results suggest a nonlinear correlation between external strain and decrease in fibril diameter and lateral spacing. This was accompanied by a nonlinear increase in axial periodicity and a structure with a 160-nm periodicity, which is reported here for the first time using X-ray diffraction. These changes may reflect the unraveling of fibrillin from the complex folded arrangement into a linear structure. This finding supports a pleating model where fibrillin molecules are highly folded within the microfibrils; more importantly, the connection is made between the interaction of individual microfibrils and the change in their suprafibrillar coherent organization during extension. We suggest that the intermediate states observed in our study reflect sequential unfolding of fibrillin and can explain the process of its reversible unraveling