Context Alterations in serum lipid values have been widely reported among persons infected with human immunodeficiency virus (HIV) type 1 treated with highly active antiretroviral therapy (HAART), but no data have yet been reported on changes from preseroconversion lipid values.Objective To describe changes in serum cholesterol levels associated with HIV infection and antiretroviral medication exposure, and 1-time assessment of triglyceride levels post-HAART initiation. Design, Setting, and ParticipantsThe Multicenter AIDS Cohort Study, a prospective study in which homosexual and bisexual men were enrolled and from which 50 of 517 HIV seroconverters were drawn for the analysis herein, who later initiated HAART, involving measurements of stored serum samples obtained between 1984 and 2002. Main Outcome MeasuresChanges in levels of total cholesterol (TC), highdensity lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) at 6 time points during an average of 12 years; 1-time assessment of triglyceride levels from the third post-HAART clinic visit. Results Among the 50 men, notable declines in mean serum TC (-30 mg/dL [−0.78 mmol/L]), HDL-C (-12 mg/dL [−0.31 mmol/L]), and LDL-C values (-22 mg/dL [−0.57 mmol/L]) were observed after HIV infection. Following HAART initiation, there were large increases in mean TC and LDL-C values (50 and 21 mg/dL [1.30 and 0.54 mmol/ L], respectively); however, the mean changes from the preseroconversion values were 20 mg/dL (0.52 mmol/L) (95% confidence interval [CI], -1 to 41) and -1 mg/dL (−0.03 mmol/L) (95% CI, -25 to 22), respectively. Mean HDL-C remained below baseline levels throughout follow-up. The median value (interquartile range) of triglycerides was 225 mg/dL (2.54 mmol/L) (147-331 mg/dL).Conclusions Before treatment, HIV infection results in substantial decreases in serum TC, HDL-C, and LDL-C levels. Subsequent HAART initiation is associated with increases in TC and LDL-C but little change in HDL-C. Increases in TC and LDL-C observed after about 3 years of HAART possibly represent a return to preinfection serum lipid levels after accounting for expected age-related changes.

A number of functional magnetic resonance imaging (fMRI) studies reported the existence of default mode network (DMN) and its disruption due to the presence of a disease such as Alzheimer’s disease (AD). In this current investigation, firstly, we used the independent component analysis (ICA) technique to confirm the DMN difference between patients with AD and normal control (NC) reported in previous studies. Consistent with previous studies, the decreased resting-state functional connectivity of DMN in AD was identified in posterior cingulated cortex (PCC), medial prefrontal cortex (MPFC), inferior parietal cortex (IPC), inferior temporal cortex (ITC) and hippocampus (HC). Moreover, we introduced Bayesian Network (BN) to study the effective connectivity of DMN and the difference between AD and NC. Compared the DMN effective connectivity in AD to the one in NC using a non-parametric random permutation test, we found that connections from left HC to left IPC, left ITC to right HC, right HC to left IPC, to MPFC and to PCC were all lost. In addition, in AD group, the connection directions between right HC and left HC, between left HC and left ITC, and between right IPC and right ITC were opposite to those in NC group. The connections of right HC to other regions, except left HC, within the BN were all statistically in-distinguishable from 0, suggesting an increased right hippocampal pathological and functional burden in AD. The altered effective connectivity in patients with AD may reveal more characteristics of the disease and may serve as a potential biomarker.

In response to cell activation signals, integrins switch from a low to a high affinity state. Physiologic ligands bind to integrins through a von Willebrand Factor Atype domain. Crystallographic studies revealed two conformations of this domain, "closed" and "open." The latter crystallizes in complex with a pseudoligand or ligand, suggesting that it represents the high affinity state; data linking structure and activity are lacking however. In this communication, we expressed stable low and high affinity forms of integrin CD11b A-domain and determined their binding isotherms and crystal structures. The low affinity form, generated by deleting an N-terminal extension extrinsic to the domain, did not bind to physiologic ligands, and crystallized in the closed conformation. The high affinity form was generated by either deleting or substituting an invariable C-terminal Ile 316 , wedged into a hydrophobic socket in the closed form, but displaced from it in the open structure. Both mutants crystallized in the open conformation, and the Ile 316 3 Gly-modified integrin displayed high affinity. Structural differences between the low and high affinity forms were detected in solution. These data establish the structure-function correlates for the CD11b A-domain, and define a ligand-independent isoleucine-based allosteric switch intrinsic to this domain that controls its conformation and affinity.Integrins are heterodimeric receptors that mediate vital cellcell and cell-matrix adhesive interactions (1). Integrins bind to physiologic ligands in a divalent cation-dependent manner and require a solvent-exposed acidic residue in their respective ligands for binding. Integrin interactions with physiologic ligands are dependent on inside-out signals, which switch integrins from a "low" to a high affinity state (2). This functional up-regulation is associated with conformational changes in the extracellular regions of integrins (2) that involve two major ligand binding sites, a von Willebrand Factor (vWF) 1 A-type domain (named A-or I-domain) present in the ␣ subunits of nine integrins, and an A-like domain embedded in all eight integrin ␤ subunits (3, 4).The integrin A-domain assumes a dinucleotide-binding fold (3,(5)(6)(7)(8), with a metal ion-dependent adhesion site (MIDAS) on one end (defined as the top of the domain) and is connected through the adjacent N and C termini on the opposite end (bottom) to the body of the integrin. MIDAS and its surrounding surface-exposed side chains form the binding site for several physiologic ligands (4, 6, 9 -12) and for the antagonist, neutrophil inhibitory factor, NIF (13,14). The A-domain has been crystallized in two conformations, "open" and "closed". In the open conformation, three noncharged residues in the protein directly coordinate the metal ion in MIDAS; a pseudoligand or ligand glutamate residue (3, 6, 15) completes metal coordination. In the closed form, the amphipathic C-terminal ␣7 helix is shifted upwards by 10 Å. This large shift is associated with a change in metal coordinat...

Viral capsids are dynamic macromolecular machines which self-assemble and undergo concerted conformational changes during their life cycle. We have taken advantage of the inherent structural flexibility of viral capsids and generated two morphologically different types of viral nanoplatforms from the bacteriophage P22 capsids. Their interior surfaces were genetically manipulated for site-specific attachment of a biotin linker. The extent of internal modifications in each capsid form was characterized by high-resolution mass spectrometry and the analyses revealed that the reactivity of the genetically introduced residues located on the internal surface changes according to the structural transformation of the capsid. Internally modified capsids having 10 nm diameter pores at the 12 icosahedral vertices, so-called wiffle-balls (WB), exhibited the capability to entrap the large tetrameric protein complex streptavidin via the biotin linker anchored onto the interior surface of the WB.