Sigma Receptor Ligands Are Potent Antiprion Compounds that Act Independently of Sigma Receptor Binding.

Prion diseases are invariably fatal neurodegenerative diseases of humans and other animals for which there are no effective treatment options. Previous work from our laboratory identified phenethylpiperidines as a novel class of anti-prion compounds. While working to identify the molecular target(s) of these molecules, we unexpectedly discovered ten novel antiprion compounds based on their known ability to bind to the sigma receptors, σ1R and σ2R, which are currently being tested as therapeutic or diagnostic targets for cancer and neuropsychiatric disorders. Surprisingly, however, knockout of the respective genes encoding σ1R and σ2R (Sigmar1 and Tmem97) in prion-infected N2a cells did not alter the antiprion activity of these compounds, demonstrating that these receptors are not the direct targets responsible for the antiprion effects of their ligands. Further investigation of the most potent molecules established that they are efficacious against multiple prion strains and protect against downstream prion-mediated synaptotoxicity. While the precise details of the mechanism of action of these molecules remain to be determined, the present work forms the basis for further investigation of these compounds in preclinical studies. Given the therapeutic utility of several of the tested compounds, including rimcazole and haloperidol for neuropsychiatric conditions, (+)-pentazocine for neuropathic pain, and the ongoing clinical trials of SA 4503 and ANAVEX2-73 for ischemic stroke and Alzheimer's disease, respectively, this work has immediate implications for the treatment of human prion disease.

Plasmonic Diamond Membranes for Ultrafast Silicon Vacancy Emission.

Silicon vacancy centers (SiVs) in diamond have emerged as a promising platform for quantum sciences due to their excellent photostability, minimal spectral diffusion, and substantial zero-phonon line emission. However, enhancing their slow nanosecond excited-state lifetime by coupling to optical cavities remains an outstanding challenge, as current demonstrations are limited to ∼10-fold. Here, we couple negatively charged SiVs to sub-diffraction-limited plasmonic cavities and achieve an instrument-limited ≤8 ps lifetime, corresponding to a 135-fold spontaneous emission rate enhancement and a 19-fold photoluminescence enhancement. Nanoparticles are printed on ultrathin diamond membranes on gold films which create arrays of plasmonic nanogap cavities with ultrasmall volumes. SiVs implanted at 5 and 10 nm depths are examined to elucidate surface effects on their lifetime and brightness. The interplay between cavity, implantation depth, and ultrathin diamond membranes provides insights into generating ultrafast, bright SiV emission for next-generation diamond devices.

Recording γ-secretase activity in living mouse brains.

γ-Secretase plays a pivotal role in the central nervous system. Our recent development of genetically encoded Förster resonance energy transfer (FRET)-based biosensors has enabled the spatiotemporal recording of γ-secretase activity on a cell-by-cell basis in live neurons in culture . Nevertheless, how γ-secretase activity is regulated in vivo remains unclear. Here we employ the near-infrared (NIR) C99 720-670 biosensor and NIR confocal microscopy to quantitatively record γ-secretase activity in individual neurons in living mouse brains. Intriguingly, we uncovered that γ-secretase activity may influence the activity of γ-secretase in neighboring neurons, suggesting a potential "cell non-autonomous" regulation of γ-secretase in mouse brains. Given that γ-secretase plays critical roles in important biological events and various diseases, our new assay in vivo would become a new platform that enables dissecting the essential roles of γ-secretase in normal health and diseases.

Silicon-Lattice-Matched Boron-Doped Gallium Phosphide: A Scalable Acousto-Optic Platform.

The compact size, scalability, and strongly confined fields in integrated photonic devices enable new functionalities in photonic networking and information processing, both classical and quantum. Gallium phosphide (GaP) is a promising material for active integrated photonics due to its high refractive index, wide bandgap, strong nonlinear properties, and large acousto-optic figure of merit. This study demonstrates that silicon-lattice-matched boron-doped GaP (BGaP), grown at the 12-inch wafer scale, provides similar functionalities as GaP. BGaP optical resonators exhibit intrinsic quality factors exceeding 25,000 and 200,000 at visible and telecom wavelengths, respectively. It further demonstrates the electromechanical generation of low-loss acoustic waves and an integrated acousto-optic (AO) modulator. High-resolution spatial and compositional mapping, combined with ab initio calculations, indicate two candidates for the excess optical loss in the visible band: the silicon-GaP interface and boron dimers. These results demonstrate the promise of the BGaP material platform for the development of scalable AO technologies at telecom and provide potential pathways toward higher performance at shorter wavelengths.

Sigma receptor ligands are potent anti-prion compounds that act independently of sigma receptor binding.

Prion diseases are invariably fatal neurodegenerative diseases of humans and other animals for which there are no treatment options. Previous work from our laboratory identified phenethyl piperidines as novel class of anti-prion compounds. While working to identify the molecular target(s) of these molecules, we unexpectedly discovered ten novel anti-prion compounds based on their known ability to bind to the sigma receptors, σ 1 R and 2 R, which are currently being tested as therapeutic or diagnostic targets for cancer and neuropsychiatric disorders. Surprisingly, however, knockout of the respective genes encoding σ 1 R and σ 2 R ( Sigmar1 and Tmem97 ), in prion infected N2a cells did not alter the anti-prion activity of these compounds, demonstrating that these receptors are not the direct targets responsible the anti-prion effects of their ligands. Further investigation of the most potent molecules established that they are efficacious against multiple prion strains and protect against downstream prion-mediated synaptotoxicity. While the precise details of the mechanism of action of these molecules remains to be determined, the present work forms the basis for further investigations of these compounds in pre-clinical studies. Given the therapeutic utility of several of the tested compounds, including rimcazole and haloperidol for neuropsychiatric conditions, (+)-pentazocine for neuropathic pain, and the ongoing clinical trials of SA 4503 and ANAVEX2-73 for ischemic stroke and Alzheimer's disease, respectively, this work has immediate implications for the treatment of human prion disease.

Physical activity improves health-related quality of life, 6MWT, and VO2 peak before and during COVID-19 in patients with heart failure: A meta-analysis / La actividad física mejora la calidad de vida relacionada con la salud, el 6MWT y el pico de VO2 antes y durante la COVID-19 en pacientes con insuficiencia cardíaca: un metanálisis

Objective To compare the effects of physical activity on improving health-related quality of life (HRQOL), six minutes walking test (6MWT), and oxygen consumption (VO2) peak before and during Coronavirus disease (COVID-19) in patients with heart failure. Methods Following PRISMA guidelines, we searched for relevant articles from five databases, including Embase, MEDLINE, CINAHL, PEDro, Cochrane, and additional resources. Study quality was assessed using Joanna Briggs Institution (JBI). RevMan 5.3 software was used to perform the meta-analysis. Result Fifteen randomized controlled trial studies met the criteria. Analysis of the subgroup before COVID-19 showed that PA had a significant effect on HRQOL, as measured by MLHFQ (SDM: −0.27, 95% CI: −0.47 to −0.07, n=590), KCCQ (SDM: 2.10, 95% CI: 0.74 to 3.46, n=53), 6MWT (SMD: 1.63, 95% CI: 0.80 to 2.46, n=284), and VO2 peak (SMD: 0.97, 95% CI: 0.00 to 1.93, n=106). Analysis of the subgroup during COVID-19 showed that PA resulted in a significant effect on HRQOL, MLHFQ (SDM: −0.62, 95% CI: −1.32 to 0.09, n=221), KCCQ (SDM: 0.33, 95% CI: 0.15 to 0.50, n=486), 6MWT (SMD: 0.47, 95% CI: 0.22 to 0.73, n=493), and VO2 peak (SMD: 0.35, 95% CI: 0.10 to 0.60, n=325). Conclusion The PA could increase HRQOL, 6MWT, and VO2 peak before and during COVID-19, and therefore should be considered as part of daily activities for patients with HF (AU)

Objetivo Comparar los efectos de la actividad física en la mejora de la calidad de vida relacionada con la salud (CVRS), el 6MWT y el pico de VO2 antes y durante la COVID-19 en pacientes con insuficiencia cardíaca. Métodos Siguiendo las pautas PRISMA, buscamos artículos relevantes en 5 bases de datos, incluidas Embase, MEDLINE, CINAHL, PEDro y Cochrane, así como recursos adicionales. Para evaluar la calidad del estudio se utilizó el Instituto Joanna Briggs, y el software RevMan 5.3 para realizar el metanálisis. Resultado Quince artículos de ensayos controlados aleatorizados cumplieron con los criterios. El análisis del subgrupo antes de la COVID-19 mostró que la actividad física tuvo un efecto significativo en la CVRS, según lo medido por el MLHFQ (DE: −0,27, IC 95%: −0,47 a −0,07, n=590), el KCCQ (DE: 2,10, IC 95%: 0,74 a 3,46, n=53), el 6MWT (DE: 1,63, IC 95%: 0,80 a 2,46, n=284) y el pico de VO2 (DE: 0,97, IC 95%: 0,00 a 1,93, n=106). El análisis del subgrupo durante la COVID-19 mostró que la actividad física tuvo un efecto significativo en la CVRS, el MLHFQ (DE: −0,66, IC 95%: −1,32 a 0,09, n=221), el KCCQ (DE: 0,33, IC 95%: 0,15 a 0,50, n=486), el 6MWT (DE: 0,47, IC 95%: 0,22 a 0,73, n=493) y el pico de VO2 (DE: 0,35, IC 95%: 0,10 a 0,60, n=325). Conclusión La actividad física podría aumentar la CVRS, el 6MWT y el pico de VO2 antes y durante la COVID-19, por lo que debe ser considerada como parte de las actividades diarias de los pacientes con insuficiencia cardíaca (AU)

PS1/gamma-secretase acts as rogue chaperone of glutamate transporter EAAT2/GLT-1 in Alzheimer's disease.

The recently discovered interaction between presenilin 1 (PS1), a catalytic subunit of γ-secretase responsible for the generation of amyloid-ß(Aß) peptides, and GLT-1, the major glutamate transporter in the brain (EAAT2 in the human) may provide a mechanistic link between two important pathological aspects of Alzheimer's disease (AD): abnormal Aßoccurrence and neuronal network hyperactivity. In the current study, we employed a FRET-based approach, fluorescence lifetime imaging microscopy (FLIM), to characterize the PS1/GLT-1 interaction in its native environment in the brain tissue of sporadic AD (sAD) patients. There was significantly less interaction between PS1 and GLT-1 in sAD brains, compared to tissue from patients with frontotemporal lobar degeneration (FTLD), or non-demented age-matched controls. Since PS1 has been shown to adopt pathogenic "closed" conformation in sAD but not in FTLD, we assessed the impact of changes in PS1 conformation on the interaction. Familial AD (fAD) PS1 mutations which induce a "closed" PS1 conformation similar to that in sAD brain and gamma-secretase modulators (GSMs) which induce a "relaxed" conformation, reduced and increased the interaction, respectively. This indicates that PS1 conformation seems to have a direct effect on the interaction with GLT-1. Furthermore, using biotinylation/streptavidin pull-down, western blotting, and cycloheximide chase assays, we determined that the presence of PS1 increased GLT-1 cell surface expression and GLT-1 homomultimer formation, but did not impact GLT-1 protein stability. Together, the current findings suggest that the newly described PS1/GLT-1 interaction endows PS1 with chaperone activity, modulating GLT-1 transport to the cell surface and stabilizing the dimeric-trimeric states of the protein. The diminished PS1/GLT-1 interaction suggests that these functions of the interaction may not work properly in AD.

The psychometric properties test of the Malay version of the endometriosis health profile-30.

OBJECTIVES: To validate and determine the psychometric properties of the Malay version of the endometriosis health profile-30 (EHP-30) by confirmatory factor analysis. METHODS: A cross-sectional study was carried out in the main city of Malaysia at a tertiary teaching hospital between January to April 2021. A total of 218 women diagnosed with endometriosis symptoms were recruited using the universal sampling method to answer the questionnaire. RESULTS: The revised Malay version of the EHP-30 with 28 items demonstrated that the factor loading of the 28 items had an acceptable value range between 0.60-0.90. The model fit was acceptable after the inclusion of 28 items correlated errors of the root mean square of error approximation: 0.072, 90% confidence interval: [0.065-0.080], comparative fit index (0.939), Tucker-Lewis index (0.932), and Chi-square/degrees of Freedom (2.135). The Cronbach's alpha ranged from 0.89-0.97. Concurrent validity for the composite reliability was between 0.88-0.96, while the average variance extracted was between 0.65-0.74. CONCLUSION: This revised Malay version of the EHP-30 is a reliable and valid tool that can be used for the next study.

Physical activity improves health-related quality of life, 6MWT, and VO2 peak before and during COVID-19 in patients with heart failure: A meta-analysis.

OBJECTIVE: To compare the effects of physical activity on improving health-related quality of life (HRQOL), six minutes walking test (6MWT), and oxygen consumption (VO2) peak before and during Coronavirus disease (COVID-19) in patients with heart failure. METHODS: Following PRISMA guidelines, we searched for relevant articles from five databases, including Embase, MEDLINE, CINAHL, PEDro, Cochrane, and additional resources. Study quality was assessed using Joanna Briggs Institution (JBI). RevMan 5.3 software was used to perform the meta-analysis. RESULT: Fifteen randomized controlled trial studies met the criteria. Analysis of the subgroup before COVID-19 showed that PA had a significant effect on HRQOL, as measured by MLHFQ (SDM: -0.27, 95% CI: -0.47 to -0.07, n=590), KCCQ (SDM: 2.10, 95% CI: 0.74 to 3.46, n=53), 6MWT (SMD: 1.63, 95% CI: 0.80 to 2.46, n=284), and VO2 peak (SMD: 0.97, 95% CI: 0.00 to 1.93, n=106). Analysis of the subgroup during COVID-19 showed that PA resulted in a significant effect on HRQOL, MLHFQ (SDM: -0.62, 95% CI: -1.32 to 0.09, n=221), KCCQ (SDM: 0.33, 95% CI: 0.15 to 0.50, n=486), 6MWT (SMD: 0.47, 95% CI: 0.22 to 0.73, n=493), and VO2 peak (SMD: 0.35, 95% CI: 0.10 to 0.60, n=325). CONCLUSION: The PA could increase HRQOL, 6MWT, and VO2 peak before and during COVID-19, and therefore should be considered as part of daily activities for patients with HF.

Hybrid Integration of GaP Photonic Crystal Cavities with Silicon-Vacancy Centers in Diamond by Stamp-Transfer.

Optically addressable solid-state defects are emerging as some of the most promising qubit platforms for quantum networks. Maximizing photon-defect interaction by nanophotonic cavity coupling is key to network efficiency. We demonstrate fabrication of gallium phosphide 1-D photonic crystal waveguide cavities on a silicon oxide carrier and subsequent integration with implanted silicon-vacancy (SiV) centers in diamond using a stamp-transfer technique. The stamping process avoids diamond etching and allows fine-tuning of the cavities prior to integration. After transfer to diamond, we measure cavity quality factors (Q) of up to 8900 and perform resonant excitation of single SiV centers coupled to these cavities. For a cavity with a Q of 4100, we observe a 3-fold lifetime reduction on-resonance, corresponding to a maximum potential cooperativity of C = 2. These results indicate promise for high photon-defect interaction in a platform which avoids fabrication of the quantum defect host crystal.

Endosome and Lysosome Membrane Properties Functionally Link to γ-Secretase in Live/Intact Cells.

Our unique multiplexed imaging assays employing FRET biosensors have previously detected that γ-secretase processes APP C99 primarily in late endosomes and lysosomes in live/intact neurons. Moreover we have shown that Aß peptides are enriched in the same subcellular loci. Given that γ-secretase is integrated into the membrane bilayer and functionally links to lipid membrane properties in vitro, it is presumable that γ-secretase function correlates with endosome and lysosome membrane properties in live/intact cells. In the present study, we show using unique live-cell imaging and biochemical assays that the endo-lysosomal membrane in primary neurons is more disordered and, as a result, more permeable than in CHO cells. Interestingly, γ-secretase processivity is decreased in primary neurons, resulting in the predominant production of long Aß42 instead of short Aß38. In contrast, CHO cells favor Aß38 over the Aß42 generation. Our findings are consistent with the previous in vitro studies, demonstrating the functional interaction between lipid membrane properties and γ-secretase and provide further evidence that γ-secretase acts in late endosomes and lysosomes in live/intact cells.

Triply-resonant sum frequency conversion with gallium phosphide ring resonators.

We demonstrate quasi-phase matched, triply-resonant sum frequency conversion in 10.6-µm-diameter integrated gallium phosphide ring resonators. A small-signal, waveguide-to-waveguide power conversion efficiency of 8 ± 1.1%/mW; is measured for conversion from telecom (1536 nm) and near infrared (1117 nm) to visible (647 nm) wavelengths with an absolute power conversion efficiency of 6.3 ± 0.6%; measured at saturation pump power. For the complementary difference frequency generation process, a single photon conversion efficiency of 7.2%/mW from visible to telecom is projected for resonators with optimized coupling. Efficient conversion from visible to telecom will facilitate long-distance transmission of spin-entangled photons from solid-state emitters such as the diamond NV center, allowing long-distance entanglement for quantum networks.

[Recombinant Schistosoma japonicum egg ribonuclease SjCP1412 inhibits the activation of LX-2 hepatic stellate cells in vitro].

OBJECTIVE: To investigate the effect of recombinant Schistosoma japonicum egg ribonuclease SjCP1412 (rSjCP1412) on proliferation, cell cycle, apoptosis and activation of human hepatic stellate cells LX-2 in vitro, and explore the underlying mechanisms. METHODS: The rSjCP1412 protein was expressed in Escherichia coli BL21 by prokaryotic expression, and the highly purified soluble rSjCP1412 protein was prepared by Ni NTA affinity chromatography and urea gradient refolding dialysis. Yeast RNA was digested using 12.5, 25.0, 50.0 µg rSjCP1412 proteins at 37 °C for 2, 3, 4 h, and the enzymatic products were electrophoresed on 1.5% agarose gel to observe the RNAase activity of rSjCP1412 protein. The proliferation of LX-2 cells stimulated by different doses of rSjCP1412 protein for 48 hours was measured using CCK-8 assay, and the apoptosis of LX-2 cells stimulated by different doses of rSjCP1412 protein for 48 hours was detected using the Annexin V-FITC/PI double staining, while the percentage of LX-2 cells at G0/G1, S and G2/M phases of cell cycle following stimulation with different doses of rSjCP1412 protein for 48 h was detected by DAPI staining. The type I collagen, type III collagen and α-smooth muscle actin (α-SMA) mRNA expression was quantified using quantitative florescent real-time PCR (qPCR) assay and Western blotting at transcriptional and translational levels in LX-2 cells following stimulation with different doses of rSjCP1412 protein for 48 h, while soluble egg antigen (SEA) served a positive control and PBS without rSjCP1412 protein as a normal control in the above experiments. The expression of collagen I, α-SMA and Smad4 protein was determined using Western blotting in LX-2 cells following stimulation with rSjCP1412 protein, transforming growth factor-ß1 (TGF-ß1) alone or in combination, to examine the signaling for the effect of rSjCP1412 protein on LX-2 cells. RESULTS: The rSjCP1412 protein was successfully expressed and the highly purified soluble rSjCP1412 protein was prepared, which had a RNase activity. Compared with the normal group, the survival rates of LX-2 cells significantly decreased post-treatment with 12.5, 25.0, 50.0 µg/mL rSjCP1412 protein and SEA for 48 h (F = 22.417 and 20.448, both P values < 0.05). The apoptotic rates of LX-2 cells significantly increased post-treatment with 12.5, 25.0, 50.0 µg/mL rSjCP1412 protein for 48 h (F = 11.350, P < 0.05), and treatment with 12.5, 25.0, 50.0 µg/mL rSjCP1412 protein for 48 h resulted in arrest of LX-2 cells in G0/G1 phase (F = 20.710, P < 0.05). Treatment with 12.5, 25.0, 50.0 µg/mL rSjCP1412 protein for 48 h caused a significant reduction in relative expression levels of collagen I (F = 11.340, P < 0.05), collagen III (F = 456.600, P < 0.05) and α-SMA mRNA (F = 23.100, P < 0.05) in LX-2 cells, and both rSjCP1412 protein and SEA treatment caused a significant reduction in collagen I (F = 1 302.000, P < 0.05), α-SMA (F = 49.750, P < 0.05) and Smad4 protein expression (F = 52.420, P < 0.05) in LX-2 cells. In addition, rSjCP1412 protein treatment inhibited collagen I (F = 66.290, P < 0.05), α-SMA (F = 31.300, P < 0.05) and Smad4 protein expression (F = 27.010, P < 0.05) in LX-2 cells activated by TGF-ß1. CONCLUSIONS: rSjCP1412 protein may induce apoptosis of LX-2 cells and inhibit proliferation, cell cycle and activation of LX-2 cells through down-regulating Smad4 signaling molecules.

Spin-defect qubits in two-dimensional transition metal dichalcogenides operating at telecom wavelengths.

Solid state quantum defects are promising candidates for scalable quantum information systems which can be seamlessly integrated with the conventional semiconductor electronic devices within the 3D monolithically integrated hybrid classical-quantum devices. Diamond nitrogen-vacancy (NV) center defects are the representative examples, but the controlled positioning of an NV center within bulk diamond is an outstanding challenge. Furthermore, quantum defect properties may not be easily tuned for bulk crystalline quantum defects. In comparison, 2D semiconductors, such as transition metal dichalcogenides (TMDs), are promising solid platform to host a quantum defect with tunable properties and a possibility of position control. Here, we computationally discover a promising defect family for spin qubit realization in 2D TMDs. The defects consist of transition metal atoms substituted at chalcogen sites with desirable spin-triplet ground state, zero-field splitting in the tens of GHz, and strong zero-phonon coupling to optical transitions in the highly desirable telecom band.

[Bioinformatics analysis of core differentially expressed genes in hepatitis B virus-related hepatocellular carcinoma].

OBJECTIVE: To identify the core genes associated with the development and progression of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC), so as to provide insights into the elucidation of pathogenesis of HBV-related HCC. METHODS: GSE55092 and GSE121248 datasets were downloaded from the Gene Expression Omnibus (GEO) database. The differentially expressed genes (DEGs) between HCC and peri-cancer tissues were screened using the R package, and the volcano map of DEGs were plotted. The DEGs were subjected to Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses, and a protein-protein interaction (PPI) network was created. The hub DEGs were screened using Molecular Complex Detection (MCODE) and cytoHubba plugins in the open-access platform Cytoscape 3.9.0. Then, the screened hub DEGs were validated for differential expression and survival analysis using clinical sample data captured from the UALCAN and Kaplan Meier-plotter databases. RESULTS: A total of 1 148 and 686 DEGs were screened between HCC and peri-cancer tissues in GSE55092 and GSE121248 datasets, including 703 and 477 down-regulated genes and 445 and 209 up-regulated genes, respectively. A total of 557 common DEGs were screened between GSE55092 and GSE121248 datasets, including 384 down-regulated genes and 173 up-regulated genes. GO enrichment analysis showed that these DEGs were significantly enriched in biological processes of cell division, cell proliferation, redox process, immune response and proteolysis, cellular components of cell nucleus, cytoplasm, extracellular vesicle and endoplasmic reticulum membrane, and molecular functions of binding to calcium ion, protein kinase, DNA and heme. KEGG pathway analysis revealed that these DEGs were significantly enriched in pathways of cell cycle, oocyte meiosis, metabolic pathway, antibiotic biosynthesis and p53 signaling. PPI network analysis identified 10 DEGs, including CDK1, CCNB1, CCNA2, TOP2A, AURKA, CCNB2, KIF11, CDC20, KIF20A and BUB1B, and CDK1, KIF11 and KIF20A were found to be differentially expressed and correlate with poor prognosis among HBV-related HCC patients following clinical sample data validation. CONCLUSIONS: CDK1, KIF11 and KIF20A may play a critical role in the development and progression of HBV-related HCC, which may be potential diagnostic biomarkers and therapeutic targets of HBV-related HCC.

In-Depth Characterization of Endo-Lysosomal Aß in Intact Neurons.

Amyloid-beta (Aß) peptides are produced within neurons. Some peptides are released into the brain parenchyma, while others are retained inside the neurons. However, the detection of intracellular Aß remains a challenge since antibodies against Aß capture Aß and its precursor proteins (i.e., APP and C99). To overcome this drawback, we recently developed 1) the C99 720-670 biosensor for recording γ-secretase activity and 2) a unique multiplexed immunostaining platform that enables the selective detection of intracellular Aß with subcellular resolution. Using these new assays, we showed that C99 is predominantly processed by γ-secretase in late endosomes and lysosomes, and intracellular Aß is enriched in the same subcellular loci in intact neurons. However, the detailed properties of Aß in the acidic compartments remain unclear. Here, we report using fluorescent lifetime imaging microscopy (FLIM) that intracellular Aß includes both long Aß intermediates bound to γ-secretase and short peptides dissociated from the protease complex. Surprisingly, our results also suggest that the dissociated Aß is bound to the glycoproteins on the inner membrane of lysosomes. Furthermore, we show striking cell-to-cell heterogeneity in intracellular Aß levels in primary neurons and APP transgenic mouse brains. These findings provide a basis for the further investigation of the role(s) of intracellular Aß and its relevance to Alzheimer's disease (AD).

Roles of isometric contraction training in promoting neuroprotection and angiogenesis after stroke in adult rats.

100 rats were randomly divided into a sham-operated group and middle cerebral artery occlusion (MCAO) modeling groups. The sham group after surgery was observed for 14 days. After MCAO, some rats received isometric contraction training (ICT) which was as follows: an atraumatic tourniquet was placed around left or right hind limb to achieve hind limb ischemia for 5 min, followed by 5 min of reperfusion, 4 cycles for one time, once a day, and five days per week. The MCAO modeling groups included the following four groups: i) a group only received MCAO, and was observed for seven days (MCAO-7d), ii) a group only received MCAO, and was observed for 14 days (MCAO-14d), iii) a group, after MCAO, received ICT for seven days (ICT-7d), and iv) a group, after MCAO, received ICT for 14 days (ICT-14d). Brain infarct area, behavioral outcomes, the number of neurons, apoptosis, cerebral edema and cerebral water content were assessed, respectively. The mRNA expression of vascular endothelial growth factor (VEGF) was assayed with RT-PCR, and protein expression of VEGF was quantified with western blot. compared with MCAO controls, cerebral infarction, neurological deficits and neuronal apoptosis were reduced significantly in the ICT groups, while the number of neurons was increased. Moreover, the mRNA expression of VEGF and protein expression of VEGF were enhanced after 1 and 2 weeks of ICT. ICT may promote angiogenesis and neuroprotection after ischemic stroke and this new remodeling method provide a novel strategy for rehabilitation of stroke patients.

Rectifying cow infertility under heat stress by immunization against inhibin and supplementation of progesterone.

This study was undertaken for the development of novel techniques that are based on immunoneutralization of inhibin bioactivity to improve Holstein cow fertility. A series of 4 experiments were carried out on 2 farms that were located in subtropical or temperate regions, to test the effects of immunization against inhibin alpha subunit on cow fertility under varying degrees of heat stress conditions. Though immunization against inhibin alone improved conception rate (CR) after TAI moderately in cows under mild heat stress conditions, the treatment plus progesterone supplementation substantially enhanced CR in the range of 25 to 35 percentages from severe heat stress to comfortable weather conditions. There existed an additive effect between immunization against inhibin and progesterone supplementation that maximally enhanced CR. Further, immunization against inhibin increased both FSH and activin A concentrations in blood during both follicular and luteal phases. It also significantly increased blood concentrations of E2 in the follicular phase but decreased P4 concentrations during the early pregnancy. However, interferon-tau concentrations in blood around the time of pregnancy recognition were doubled in the inhibin immunized cows. In conclusion, immunization against inhibin plus P4 treatment enhances ovarian follicle and the subsequent early embryo developments that help to greatly improve the fertility of Holstein dairy cows.

Precise electron beam-based target-wavelength trimming for frequency conversion in integrated photonic resonators.

We demonstrate post-fabrication target-wavelength trimming with a gallium phosphide on a silicon nitride integrated photonic platform using controlled electron-beam exposure of hydrogen silsesquioxane cladding. A linear relationship between the electron-beam exposure dose and resonant wavelength red-shift enables deterministic, individual trimming of multiple devices on the same chip to within 30 pm of a single target wavelength. Second harmonic generation from telecom to near infrared at a target wavelength is shown in multiple devices with quality factors on the order of 104. Post-fabrication tuning is an essential tool for targeted wavelength applications including quantum frequency conversion.