Leukocyte CD11b expression is not essential for the development of atherosclerosis in mice

CD11b is an alpha chain of the leukocyte beta(2)-integrin, Mac-1, which mediates binding and extravasation of leukocytes. Because this event is critical in atherosclerosis, we examined the role of CD11b in lesion formation. Atherosclerosis-susceptible, low density lipoprotein receptor-deficient (LDL-R(-/)-) mice were irradiated and repopulated with bone marrow cells from CD11b-deficient (CD11b(-/)-) mice. After 4 weeks, <2% of the peripheral blood leukocytes of the CD11b(-/)- bone marrow-transplanted LDL-R(-/)- mice expressed CD11b, whereas approximately 25% of the CD11b(+/)+ bone marrow-transplanted LDL-R(-/)- mice expressed CD11b. After consuming a high-fat diet for 16 weeks the mean lesion aortic valve area, cholesterol accumulation in the aorta, and the degree of intimal macrophage infiltration were similar in mice reconstituted with either CD11b(+)(/+) or CD11b(-/)- bone marrow cells.The studies confirm that CD11b expression of bone marrow-derived cells does not influence the development of atherosclerosis in hypercholesterolemic LDL-R(-/)- mice.     

The conformation of apolipoprotein A-I in high-density lipoproteins is influenced by core lipid composition and particle size: a surface plasmon resonance study

Plasma high-density lipoproteins (HDL) are a heterogeneous group of particles that vary in size as well as lipid and apoprotein composition. The effect of HDL core lipid composition and particle size on apolipoprotein (apo) A-I structure was studied using surface plasmon resonance (SPR) analysis of the binding of epitope-defined monoclonal antibodies. The association and dissociation rate constants of 12 unique apo A-I-specific monoclonal antibodies for isolated plasma HDL were calculated. In addition, the association rate constants of the antibodies were determined for homogeneous preparations of spherical reconstituted HDL (rHDL) that contained apo A-I as the sole apolipoprotein and differed either in their size or in their core lipid composition. This analysis showed that lipoprotein size affected the conformation of domains dispersed throughout the apo A-I molecule, but the conformation of the central domain between residues 121 and 165 was most consistently modified. In contrast, replacement of core cholesteryl esters with triglyceride in small HDL modified almost the entire molecule, with only two key N-terminal domains of apo A-I being unaffected. This finding suggested that the central and C-terminal domains of apo A-I are in direct contact with rHDL core lipids. This immunochemical analysis has provided valuable insight into how core lipid composition and particle size affect the structure of specific domains of apo A-I on HDL.     

Suppressing Manganese Dissolution from Lithium Manganese Oxide Spinel Cathodes with Single‐Layer Graphene

Spinel‐structured LiMn₂O₄ (LMO) is a desirable cathode material for Li‐ion batteries due to its low cost, abundance, and high power capability. However, LMO suffers from limited cycle life that is triggered by manganese dissolution into the electrolyte during electrochemical cycling. Here, it is shown that single‐layer graphene coatings suppress manganese dissolution, thus enhancing the performance and lifetime of LMO cathodes. Relative to lithium cells with uncoated LMO cathodes, cells with graphene‐coated LMO cathodes provide improved capacity retention with enhanced cycling stability. X‐ray photoelectron spectroscopy reveals that graphene coatings inhibit manganese depletion from the LMO surface. Additionally, transmission electron microscopy demonstrates that a stable solid electrolyte interphase is formed on graphene, which screens the LMO from direct contact with the electrolyte. Density functional theory calculations provide two mechanisms for the role of graphene in the suppression of manganese dissolution. First, common defects in single‐layer graphene are found to allow the transport of lithium while concurrently acting as barriers for manganese diffusion. Second, graphene can chemically interact with Mn³⁺ at the LMO electrode surface, promoting an oxidation state change to Mn⁴⁺, which suppresses dissolution.     

Generation of Influenza Virus from Avian Cells Infected by Salmonella Carrying the Viral Genome

Domestic poultry serve as intermediates for transmission of influenza A virus from the wild aquatic bird reservoir to humans, resulting in influenza outbreaks in poultry and potential epidemics/pandemics among human beings. To combat emerging avian influenza virus, an inexpensive, heat-stable, and orally administered influenza vaccine would be useful to vaccinate large commercial poultry flocks and even migratory birds. Our hypothesized vaccine is a recombinant attenuated bacterial strain able to mediate production of attenuated influenza virus in vivo to induce protective immunity against influenza. Here we report the feasibility and technical limitations toward such an ideal vaccine based on our exploratory study. Five 8-unit plasmids carrying a chloramphenicol resistance gene or free of an antibiotic resistance marker were constructed. Influenza virus was successfully generated in avian cells transfected by each of the plasmids. The Salmonella carrier was engineered to allow stable maintenance and conditional release of the 8-unit plasmid into the avian cells for recovery of influenza virus. Influenza A virus up to 10⁷ 50% tissue culture infective doses (TCID₅₀)/ml were recovered from 11 out of 26 co-cultures of chicken embryonic fibroblasts (CEF) and Madin-Darby canine kidney (MDCK) cells upon infection by the recombinant Salmonella carrying the 8-unit plasmid. Our data prove that a bacterial carrier can mediate generation of influenza virus by delivering its DNA cargoes into permissive host cells. Although we have made progress in developing this Salmonella influenza virus vaccine delivery system, further improvements are necessary to achieve efficient virus production, especially in vivo.     

Characterization of Remitting and Relapsing Hyperglycemia in Post-Renal-Transplant Recipients

Background

Hyperglycemia following solid organ transplant is common among patients without pre-existing diabetes mellitus (DM). Post-transplant hyperglycemia can occur once or multiple times, which if continued, causes new-onset diabetes after transplantation (NODAT).

Objective

To study if the first and recurrent incidence of hyperglycemia are affected differently by immunosuppressive regimens, demographic and medical-related risk factors, and inpatient hyperglycemic conditions (i.e., an emphasis on the time course of post-transplant complications).

Methods

We conducted a retrospective analysis of 407 patients who underwent kidney transplantation at Mayo Clinic Arizona. Among these, there were 292 patients with no signs of DM prior to transplant. For this category of patients, we evaluated the impact of (1) immunosuppressive drugs (e.g., tacrolimus, sirolimus, and steroid), (2) demographic and medical-related risk factors, and (3) inpatient hyperglycemic conditions on the first and recurrent incidence of hyperglycemia in one year post-transplant. We employed two versions of Cox regression analyses: (1) a time-dependent model to analyze the recurrent cases of hyperglycemia and (2) a time-independent model to analyze the first incidence of hyperglycemia.

Results

Age (P = 0.018), HDL cholesterol (P = 0.010), and the average trough level of tacrolimus (P<0.0001) are significant risk factors associated with the first incidence of hyperglycemia, while age (P<0.0001), non-White race (P = 0.002), BMI (P = 0.002), HDL cholesterol (P = 0.003), uric acid (P = 0.012), and using steroid (P = 0.007) are the significant risk factors for the recurrent cases of hyperglycemia.

Discussion

This study draws attention to the importance of analyzing the risk factors associated with a disease (specially a chronic one) with respect to both its first and recurrent incidence, as well as carefully differentiating these two perspectives: a fact that is currently overlooked in the literature.     

Efficient cargo sorting by ESCRT-I and the subsequent release of ESCRT-I from multivesicular bodies requires the subunit Mvb12

The endosomal sorting complex required for transport (ESCRT)-I protein complex functions in recognition and sorting of ubiquitinated transmembrane proteins into multivesicular body (MVB) vesicles. It has been shown that ESCRT-I contains the vacuolar protein sorting (Vps) proteins Vps23, Vps28, and Vps37. We identified an additional subunit of yeast ESCRT-I called Mvb12, which seems to associate with ESCRT-I by binding to Vps37. Transient recruitment of ESCRT-I to MVBs results in the rapid degradation of Mvb12. In contrast to mutations in other ESCRT-I subunits, which result in strong defects in MVB cargo sorting, deletion of MVB12 resulted in only a partial sorting phenotype. This trafficking defect was fully suppressed by overexpression of the ESCRT-II complex. Mutations in MVB12 did not affect recruitment of ESCRT-I to MVBs, but they did result in delivery of ESCRT-I to the vacuolar lumen via the MVB pathway. Together, these observations suggest that Mvb12 may function in regulating the interactions of ESCRT-I with cargo and other proteins of the ESCRT machinery to efficiently coordinate cargo sorting and release of ESCRT-I from the MVB.     

Dietary boron: progress in establishing essential roles in human physiology

This review summarizes the progress made in establishing essential roles for boron in human physiology and assesses that progress in view of criteria for essentiality of elements. The evidence to date suggests that humans and at least some higher animals may use boron to support normal biological functions. These include roles in calcium metabolism, bone growth and maintenance, insulin metabolism, and completion of the life cycle. The biochemical mechanisms responsible for these effects are poorly understood but the nature of boron biochemistry suggests further characterization of the cell signaling molecules capable of complexing with boron. Such characterization may provide insights into the biochemical function(s) of boron in humans.