The Antimicrobial Peptide Histatin-5 Causes a Spatially Restricted Disruption on the Candida albicans Surface, Allowing Rapid Entry of the Peptide into the Cytoplasm

Antimicrobial peptides play an important role in host defense against microbial pathogens. Their high cationic charge and strong amphipathic structure allow them to bind to the anionic microbial cell membrane and disrupt the membrane bilayer by forming pores or channels. In contrast to the classical pore-forming peptides, studies on histatin-5 (Hst-5) have suggested that the peptide is transported into the cytoplasm of Candida albicans in a non-lytic manner, and cytoplasmic Hst-5 exerts its candicidal activities on various intracellular targets, consistent with its weak amphipathic structure. To understand how Hst-5 is internalized, we investigated the localization of FITC-conjugated Hst-5. We find that Hst-5 is internalized into the vacuole through receptor-mediated endocytosis at low extracellular Hst-5 concentrations, whereas under higher physiological concentrations, Hst-5 is translocated into the cytoplasm through a mechanism that requires a high cationic charge on Hst-5. At intermediate concentrations, two cell populations with distinct Hst-5 localizations were observed. By cell sorting, we show that cells with vacuolar localization of Hst-5 survived, while none of the cells with cytoplasmic Hst-5 formed colonies. Surprisingly, extracellular Hst-5, upon cell surface binding, induces a perturbation on the cell surface, as visualized by an immediate and rapid internalization of Hst-5 and propidium iodide or rhodamine B into the cytoplasm from the site using time-lapse microscopy, and a concurrent rapid expansion of the vacuole. Thus, the formation of a spatially restricted site in the plasma membrane causes the initial injury to C. albicans and offers a mechanism for its internalization into the cytoplasm. Our study suggests that, unlike classical channel-forming antimicrobial peptides, action of Hst-5 requires an energized membrane and causes localized disruptions on the plasma membrane of the yeast. This mechanism of cell membrane disruption may provide species-specific killing with minimal damage to microflora and the host and may be used by many other antimicrobial peptides

Effect of protocatechuic acid on insulin responsiveness and inflammation in visceral adipose tissue from obese individuals: possible role for PTP1B

n/

Molecular and behavioral consequences of Ube3a gene overdosage in mice

Chromosome 15q11.2-q13.1 duplication syndrome (Dup15q syndrome) is a severe neurodevelopmental disorder characterized by intellectual disability, impaired motor coordination, and autism spectrum disorder. Chromosomal multiplication of the UBE3A gene is presumed to be the primary driver of Dup15q pathophysiology, given that UBE3A exhibits maternal monoallelic expression in neurons and that maternal duplications typically yield far more severe neurodevelopmental outcomes than paternal duplications. However, studies into the pathogenic effects of UBE3A overexpression in mice have yielded conflicting results. Here, we investigated the neurodevelopmental impact of Ube3a gene overdosage using bacterial artificial chromosome-based transgenic mouse models (Ube3aOE) that recapitulate the increases in Ube3a copy number most often observed in Dup15q. In contrast to previously published Ube3a overexpression models, Ube3aOE mice were indistinguishable from wild-type controls on a number of molecular and behavioral measures, despite suffering increased mortality when challenged with seizures, a phenotype reminiscent of sudden unexpected death in epilepsy. Collectively, our data support a model wherein pathogenic synergy between UBE3A and other overexpressed 15q11.2-q13.1 genes is required for full penetrance of Dup15q syndrome phenotypes

Measurement of the charge and current of magnetic monopoles in spin ice

The transport of electrically charged quasiparticles (based on electrons or ions) plays a pivotal role in modern technology as well as in determining the essential functions of biological organisms. In contrast, the transport of magnetic charges has barely been explored experimentally, mainly because magnetic charges, in contrast to electric ones, are generally considered at best to be convenient macroscopic parameters, rather than well-defined quasiparticles. However, it was recently proposed that magnetic charges can exist in certain materials in the form of emergent excitations that manifest like point charges, or magnetic monopoles. Here we address the question of whether such magnetic charges and their associated currents-'magnetricity'-can be measured directly in experiment, without recourse to any material-specific theory. By mapping the problem onto Onsager's theory of electrolytes, we show that this is indeed possible, and devise an appropriate method for the measurement of magnetic charges and their dynamics. Using muon spin rotation as a suitable local probe, we apply the method to a real material, the 'spin ice' Dy(2)Ti(2)O(7) (refs 5-8). Our experimental measurements prove that magnetic charges exist in this material, interact via a Coulomb potential, and have measurable currents. We further characterize deviations from Ohm's law, and determine the elementary unit of magnetic charge to be 5 mu(B) A(-1), which is equal to that recently predicted using the microscopic theory of spin ice. Our measurement of magnetic charge and magnetic current establishes an instance of a perfect symmetry between electricity and magnetism