Controlled release of human growth hormone fused with a human hybrid Fc fragment through a nanoporous polymer membrane

Nanotechnology has been applied to the development of more effective and compatible drug delivery systems for therapeutic proteins. Human growth hormone (hGH) was fused with a hybrid Fc fragment containing partial Fc domains of human IgD and IgG(4) to produce a long-acting fusion protein. The fusion protein, hGH-hyFc, resulted in the increase of the hydrodynamic diameter (ca. 11 nm) compared with the diameter (ca. 5 nm) of the recombinant hGH. A diblock copolymer membrane with nanopores (average diameter of 14.3 nm) exhibited a constant release rate of hGH-hyFc. The hGH-hyFc protein released in a controlled manner for one month was found to trigger the phosphorylation of Janus kinase 2 (JAK2) in human B lymphocyte and to exhibit an almost identical circular dichroism spectrum to that of the original hGH-hyFc, suggesting that the released fusion protein should maintain the functional and structural integrity of hGH. Thus, the nanoporous release device could be a potential delivery system for the long-term controlled release of therapeutic proteins fused with the hybrid Fc fragment.X111313sciescopu

Hierarchical dynamic causal modeling of resting-state fMRI reveals longitudinal changes in effective connectivity in the motor system after thalamotomy for essential tremor

Thalamotomy at the ventralis intermedius nucleus for essential tremor is known to cause changes in motor circuitry, but how a focal lesion leads to progressive changes in connectivity is not clear. To understand the mechanisms by which thalamotomy exerts enduring effects on motor circuitry, a quantitative analysis of directed or effective connectivity among motor-related areas is required. We characterized changes in effective connectivity of the motor system following thalamotomy using (spectral) dynamic causal modeling (spDCM) for resting-state fMRI. To differentiate long-lasting treatment effects from transient effects, and to identify symptom-related changes in effective connectivity, we subject longitudinal resting-state fMRI data to spDCM, acquired 1 day prior to, and 1 day, 7 days, and 3 months after thalamotomy using a non-cranium-opening MRI-guided focused ultrasound ablation technique. For the group-level (between subject) analysis of longitudinal (between-session) effects, we introduce a multilevel parametric empirical Bayes (PEB) analysis for spDCM. We found remarkably selective and consistent changes in effective connectivity from the ventrolateral nuclei and the supplementary motor area to the contralateral dentate nucleus after thalamotomy, which may be mediated via a polysynaptic thalamic-cortical-cerebellar motor loop. Crucially, changes in effective connectivity predicted changes in clinical motor-symptom scores after thalamotomy. This study speaks to the efficacy of thalamotomy in regulating the dentate nucleus in the context of treating essential tremor. Furthermore, it illustrates the utility of PEB for group-level analysis of dynamic causal modeling in quantifying longitudinal changes in effective connectivity; i.e., measuring long-term plasticity in human subjects non-invasively

Clinical significance of amyloid β positivity in patients with probable cerebral amyloid angiopathy markers

Purpose: We investigated the frequency and clinical significance of amyloid β (Aβ) positivity on PET in patients with cerebral amyloid angiopathy (CAA). / Methods: We recruited 65 patients who met the modified Boston criteria for probable CAA. All underwent amyloid PET, MRI, APOE genotyping and neuropsychological testing, and we obtained information on MRI markers of CAA and ischemic cerebral small-vessel disease (CSVD). We investigated the CAA/ischemic CSVD burden and APOE genotypes in relation to Aβ positivity and investigated the effect of Aβ positivity on longitudinal cognitive decline. / Results: Among the 65 CAA patients, 43 (66.2%) showed Aβ PET positivity (Aβ+). Patients with Aβ+ CAA had more lobar microbleeds (median 9, interquartile range 2–41, vs. 3, 2–8; P = 0.045) and a higher frequency of cortical superficial siderosis (34.9% vs. 9.1%; P = 0.025), while patients with Aβ− CAA had more lacunes (1, 0–2, vs. 0, 0–1; P = 0.029) and a higher frequency of severe white matter hyperintensities (45.5% vs. 20.9%; P = 0.040). The frequency of ε4 carriers was higher in Aβ+ patients (57.1%) than in Aβ− patients (18.2%; P = 0.003), while the frequency of ε2 carriers did not differ between the two groups. Finally, Aβ positivity was associated with faster decline in multiple cognitive domains including language (P < 0.001), visuospatial function (P < 0.001), and verbal memory (P < 0.001) in linear mixed effects models. / Conclusion: Our findings suggest that a significant proportion of patients with probable CAA in a memory clinic are Aβ− on PET. Aβ positivity in CAA patients is associated with a distinct pattern of CSVD biomarker expression, and a worse cognitive trajectory. Aβ positivity has clinical relevance in CAA and might represent either advanced CAA or additional Alzheimer’s disease neuropathological changes

β-catenin activation down-regulates cell-cell junction-related genes and induces epithelial-to-mesenchymal transition in colorectal cancers

WNT signaling activation in colorectal cancers (CRCs) occurs through APC inactivation or β-catenin mutations. Both processes promote β-catenin nuclear accumulation, which up-regulates epithelial-to-mesenchymal transition (EMT). We investigated β-catenin localization, transcriptome, and phenotypic differences of HCT116 cells containing a wild-type (HCT116-WT) or mutant β-catenin allele (HCT116-MT), or parental cells with both WT and mutant alleles (HCT116-P). We then analyzed β-catenin expression and associated phenotypes in CRC tissues. Wild-type β-catenin showed membranous localization, whereas mutant showed nuclear localization; both nuclear and non-nuclear localization were observed in HCT116-P. Microarray analysis revealed down-regulation of Claudin-7 and E-cadherin in HCT116-MT vs. HCT116-WT. Claudin-7 was also down-regulated in HCT116-P vs. HCT116-WT without E-cadherin dysregulation. We found that ZEB1 is a critical EMT factor for mutant β-catenin-mediated loss of E-cadherin and Claudin-7 in HCT116-P and HCT116-MT cells. We also demonstrated that E-cadherin binds to both WT and mutant β-catenin, and loss of E-cadherin releases β-catenin from the cell membrane and leads to its degradation. Alteration of Claudin-7, as well as both Claudin-7 and E-cadherin respectively caused tight junction (TJ) impairment in HCT116-P, and dual loss of TJs and adherens junctions (AJs) in HCT116-MT. TJ loss increased cell motility, and subsequent AJ loss further up-regulated that. Immunohistochemistry analysis of 101 CRCs revealed high (14.9%), low (52.5%), and undetectable (32.6%) β-catenin nuclear expression, and high β-catenin nuclear expression was significantly correlated with overall survival of CRC patients (P = 0.009). Our findings suggest that β-catenin activation induces EMT progression by modifying cell-cell junctions, and thereby contributes to CRC aggressiveness

Intrinsic and Extrinsic Performance Limits of Graphene Devices on SiO2

The linear dispersion relation in graphene[1,2] gives rise to a surprising prediction: the resistivity due to isotropic scatterers (e.g. white-noise disorder[3] or phonons[4-8]) is independent of carrier density n. Here we show that acoustic phonon scattering[4-6] is indeed independent of n, and places an intrinsic limit on the resistivity in graphene of only 30 Ohm at room temperature (RT). At a technologically-relevant carrier density of 10^12 cm^-2, the mean free path for electron-acoustic phonon scattering is >2 microns, and the intrinsic mobility limit is 2x10^5 cm^2/Vs, exceeding the highest known inorganic semiconductor (InSb, ~7.7x10^4 cm^2/Vs[9]) and semiconducting carbon nanotubes (~1x10^5 cm^2/Vs[10]). We also show that extrinsic scattering by surface phonons of the SiO2 substrate[11,12] adds a strong temperature dependent resistivity above ~200 K[8], limiting the RT mobility to ~4x10^4 cm^2/Vs, pointing out the importance of substrate choice for graphene devices[13].Comment: 16 pages, 3 figure

Noninvasive imaging of radiolabeled exosome-mimetic nanovesicle using Tc-99m-HMPAO

Exosomes known as nano-sized extracellular vesicles attracted recent interests due to their potential usefulness in drug delivery. Amid remarkable advances in biomedical applications of exosomes, it is crucial to understand in vivo distribution and behavior of exosomes. Here, we developed a simple method for radiolabeling of macrophage-derived exosome-mimetic nanovesicles (ENVs) with Tc-99m-HMPAO under physiologic conditions and monitored in vivo distribution of Tc-99m-HMPAO-ENVs using SPECT/CT in living mice. ENVs were produced from the mouse RAW264.7 macrophage cell line and labeled with Tc-99m-HMPAO for 1 hr incubation, followed by removal of free Tc-99m-HMPAO. SPECT/CT images were serially acquired after intravenous injection to BALB/c mouse. When ENVs were labeled with Tc-99m-HMPAO, the radiochemical purity of Tc-99m-HMPAO-ENVs was higher than 90% and the expression of exosome specific protein (CD63) did not change in Tc-99m-HMPAO-ENVs. Tc-99m-HMPAOENVs showed high serum stability (90%) which was similar to that in phosphate buffered saline until 5 hr. SPECT/CT images of the mice injected with Tc-99m-HMPAO-ENVs exhibited higher uptake in liver and no uptake in brain, whereas mice injected with Tc-99m-HMPAO showed high brain uptake until 5 hr. Our noninvasive imaging of radiolabeled-ENVs promises better understanding of the in vivo behavior of exosomes for upcoming biomedical application.114327Ysciescopu

Three-Dimensional Graphene Nano-Networks with High Quality and Mass Production Capability via Precursor-Assisted Chemical Vapor Deposition

We report a novel approach to synthesize chemical vapor deposition-grown three-dimensional graphene nano-networks (3D-GNs) that can be mass produced with large-area coverage. Annealing of a PVA/iron precursor under a hydrogen environment, infiltrated into 3D-assembled-colloidal silicas reduces iron ions and generates few-layer graphene by precipitation of carbon on the iron surface. The 3D-GN can be grown on any electronic device-compatible substrate, such as Al2O3, Si, GaN, or Quartz. The conductivity and surface area of a 3D-GN are 52 S/cm and 1,025 m(2)/g, respectively, which are much better than the previously reported values. Furthermore, electrochemical double-layer capacitors based on the 3D-GN have superior supercapacitor performance with a specific capacitance of 245 F/g and 96.5% retention after 6,000 cycles due to the outstanding conductivity and large surface area. The excellent performance of the 3D-GN as an electrode for supercapacitors suggests the great potential of interconnected graphene networks in nano-electronic devices and energy-related materials.open15

Acute presentation of a solitary caecal diverticulum: a case report

which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Introduction: Solitary caecal diverticulitis is a rare cause of abdominal pain in Caucasian patients. The condition is often misdiagnosed and only correctly identified on exploration for suspected acute appendicitis. Our aim is to improve awareness of this condition amongst surgical trainees to ensure that its first encounter is not in the operating theatre. We review the role of pre-operative radiological imaging in this condition and the wide and controversial management options are als