ΔFosB Regulates Gene Expression and Cognitive Dysfunction in a Mouse Model of Alzheimer\u27s Disease.

Alzheimer\u27s disease (AD) is characterized by cognitive decline and 5- to 10-fold increased seizure incidence. How seizures contribute to cognitive decline in AD or other disorders is unclear. We show that spontaneous seizures increase expression of ΔFosB, a highly stable Fos-family transcription factor, in the hippocampus of an AD mouse model. ΔFosB suppressed expression of the immediate early gene c-Fos, which is critical for plasticity and cognition, by binding its promoter and triggering histone deacetylation. Acute histone deacetylase (HDAC) inhibition or inhibition of ΔFosB activity restored c-Fos induction and improved cognition in AD mice. Administration of seizure-inducing agents to nontransgenic mice also resulted in ΔFosB-mediated suppression of c-Fos, suggesting that this mechanism is not confined to AD mice. These results explain observations that c-Fos expression increases after acute neuronal activity but decreases with chronic activity. Moreover, these results indicate a general mechanism by which seizures contribute to persistent cognitive deficits, even during seizure-free periods

Epigenetic suppression of hippocampal calbindin-D28k by ΔFosB drives seizure-related cognitive deficits.

The calcium-binding protein calbindin-D28k is critical for hippocampal function and cognition, but its expression is markedly decreased in various neurological disorders associated with epileptiform activity and seizures. In Alzheimer\u27s disease (AD) and epilepsy, both of which are accompanied by recurrent seizures, the severity of cognitive deficits reflects the degree of calbindin reduction in the hippocampal dentate gyrus (DG). However, despite the importance of calbindin in both neuronal physiology and pathology, the regulatory mechanisms that control its expression in the hippocampus are poorly understood. Here we report an epigenetic mechanism through which seizures chronically suppress hippocampal calbindin expression and impair cognition. We demonstrate that ΔFosB, a highly stable transcription factor, is induced in the hippocampus in mouse models of AD and seizures, in which it binds and triggers histone deacetylation at the promoter of the calbindin gene (Calb1) and downregulates Calb1 transcription. Notably, increasing DG calbindin levels, either by direct virus-mediated expression or inhibition of ΔFosB signaling, improves spatial memory in a mouse model of AD. Moreover, levels of ΔFosB and calbindin expression are inversely related in the DG of individuals with temporal lobe epilepsy (TLE) or AD and correlate with performance on the Mini-Mental State Examination (MMSE). We propose that chronic suppression of calbindin by ΔFosB is one mechanism through which intermittent seizures drive persistent cognitive deficits in conditions accompanied by recurrent seizures

Medication use, renin-angiotensin system inhibitors, and acute care utilization after hospitalization in patients with chronic kidney disease.

OBJECTIVES: The aims of this secondary analysis were to: (a) characterize medication use following hospital discharge for patients with chronic kidney disease (CKD), and (b) investigate relationships of medication use with the primary composite outcome of acute care utilization 90 days after hospitalization. METHODS: The CKD-Medication Intervention Trial (CKD-MIT) enrolled acutely ill hospitalized patients with CKD stages 3-5 not dialyzed (CKD 3-5 ND). In this post hoc analysis, data for medication use were characterized, and the relationship of medication use with the primary outcome was evaluated using Cox proportional hazards models. RESULTS: Participants were taking a mean of 12.6 (standard deviation=5.1) medications, including medications from a wide variety of medication classes. Nearly half of study participants were taking angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARB). ACE inhibitor/ARB use was associated with decreased risk of the primary outcome (hazard ratio=0.51; 95% confidence interval 0.28-0.95; CONCLUSIONS: A large number, variety, and complexity of medications were used by hospitalized patients with CKD 3-5 ND. ACE inhibitor or ARB use at hospital discharge was associated with a decreased risk of 90-day acute care utilization

Micro-transfer-printing for heterogeneous integration

Micro-transfer-printing is a key enabling technology for the heterogeneous integration of different materials and devices. The technique is particularly applicable to photonics where a typical system requires diverse arrays of components

Packaging technology for high power blue-green LEDs

High brightness LEDs (HBLEDs) have been fabricated on GaN semiconductor material grown on sapphire substrate. These devices provide an optical output power in excess of 50 mW at a driving current of 1 amp. For this hi-h current application, large size (1.8 mm X 0.6 mm) GaN LEDs are flip-chip mounted onto a heat sink to provide a low thermal resistance path from the junction to the ambient. For the flip-chip mounting, a Au/Sn/Au solder and a Au/Au thermal compression bonding process have been optimized. The bond strength of the Au/Sn solder joints and the Au-Au bonds is measured through shear testing. Good bond strength results of 224 g/f for the Au/Sn/Au solder and 288 g/f for the solid Au bonds have been achieved. The thermal modeling of the assembly is done with a finite element analysis and the optimum design has been adopted for this high current application. At present these assemblies are under lifetime test and so far nearly 6000 hours of continuous operation has been achieved

LED flip-chip assembly with electroplated AuSn alloy

InGaN based high brightness (HB)‐LED chips have been fabricated and bonded to substrates that were coated with electroplated Au/Sn/Au solder. The assemblies yielded a forward voltage of 5.6 V and an optical output power of 42 mW when tested at 1,000 mA bias. The electroluminescence distribution was mapped with a CCD camera to determine the current spreading into the p‐contact region. Computational fluid dynamics (CFD) was used to check the effect of non‐uniform current spreading on the thermal resistance of the assemblies. We show that a good knowledge of the non‐uniform heat generation is required to obtain accurate modelling results. The bond strength of the AuSn solder joints exceeded the norm, when shear tested according to MIL‐STD‐883E (method 2019.5)

State-machine replication for planet-scale systems

Online applications now routinely replicate their data at multiple sites around the world. In this paper we present Atlas, the first state-machine replication protocol tailored for such planet-scale systems. Atlas does not rely on a distinguished leader, so clients enjoy the same quality of service independently of their geographical locations. Furthermore, client-perceived latency improves as we add sites closer to clients. To achieve this, Atlas minimizes the size of its quorums using an observation that concurrent data center failures are rare. It also processes a high percentage of accesses in a single round trip, even when these conflict. We experimentally demonstrate that Atlas consistently outperforms state-of-The-Art protocols in planet-scale scenarios. In particular, Atlas is up to two times faster than Flexible Paxos with identical failure assumptions, and more than doubles the performance of Egalitarian Paxos in the YCSB benchmark.H2020 - Horizon 2020 Framework Programme(825184

Glycan repositioning of influenza hemagglutinin stem facilitates the elicitation of protective cross-group antibody responses.

The conserved hemagglutinin (HA) stem has been a focus of universal influenza vaccine efforts. Influenza A group 1 HA stem-nanoparticles have been demonstrated to confer heterosubtypic protection in animals; however, the protection does not extend to group 2 viruses, due in part to differences in glycosylation between group 1 and 2 stems. Here, we show that introducing the group 2 glycan at Asn38 to a group 1 stem-nanoparticle (gN38 variant) based on A/New Caledonia/20/99 (H1N1) broadens antibody responses to cross-react with group 2 HAs. Immunoglobulins elicited by the gN38 variant provide complete protection against group 2 H7N9 virus infection, while the variant loses protection against a group 1 H5N1 virus. The N38 glycan thus is pivotal in directing antibody responses by controlling access to group-determining stem epitopes. Precise targeting of stem-directed antibody responses to the site of vulnerability by glycan repositioning may be a step towards achieving cross-group influenza protection.We thank D. Scorpio, A. Taylor, H. Bao, C. Chiedi, M. Dillon, L. Gilliam, and G. Sarbador (VRC) for help with animal studies; H. Andersen (Bioqual, Inc.) for mouse challenge studies; C. Case (Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc.) for help with challenge study coordination; A. Kumar (VRC) for producing RSV proteins; and members of Viral Pathogenesis Laboratory and Universal Influenza Vaccine Program (VRC) for helpful discussion. Support for this work was provided by the Intramural Research Program of the Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health. Electron microscopy data collection and analyses were funded by federal funds from the Frederick National Laboratory for Cancer Research, National Institutes of Health, under contract number HHSN261200800001E, and by Leidos Biomedical Research, Inc. (Y.T. and T.S.)

Variable-temperature, variable-field magnetic circular dichroism spectroscopic study of NifEN-bound precursor and “FeMoco”

NifEN plays a key role in the biosynthesis of the iron–molybdenum cofactor (FeMoco) of nitrogenase. A scaffold protein that hosts the conversion of a FeMoco precursor to a mature cofactor, NifEN can assume three conformations during the process of FeMoco maturation. One, designated ΔnifB NifEN, contains only two permanent [Fe4S4]-like clusters. The second, designated NifENPrecursor, contains the permanent clusters and a precursor form of FeMoco. The third, designated NifEN“FeMoco”, contains the permanent [Fe4S4]-like clusters and a fully complemented, “FeMoco”-like structure. Here, we report a variable-temperature, variable-field magnetic circular dichroism spectroscopic investigation of the electronic structure of the metal clusters in the three forms of dithionite-reduced NifEN. Our data indicate that the permanent [Fe4S4]-like clusters are structurally and electronically conserved in all three NifEN species and exhibit spectral features of classic [Fe4S4]+ clusters; however, they are present in a mixed spin state with a small contribution from the S > ½ spin state. Our results also suggest that both the precursor and “FeMoco” have a conserved Fe/S electronic structure that is similar to the electronic structure of FeMoco in the MoFe protein, and that the “FeMoco” in NifEN“FeMoco” exists, predominantly, in an S = 3/2 spin state with spectral parameters identical to those of FeMoco in the MoFe protein. These observations provide strong support to the outcome of our previous EPR and X-ray absorption spectroscopy/extended X-ray absorption fine structure analysis of the three NifEN species while providing significant new insights into the unique electronic properties of the precursor and “FeMoco” in NifEN

Tumor-induced STAT3 activation in monocytic myeloid-derived suppressor cells enhances stemness and mesenchymal properties in human pancreatic cancer

Pancreatic cancer (PC) mobilizes myeloid cells from the bone marrow to the tumor where they promote tumor growth and proliferation. Cancer stem cells (CSCs) are a population of tumor cells that are responsible for tumor initiation. Aldehyde dehydrogenase-1 activity in PC identifies CSCs, and its activity has been correlated with poor overall prognosis in human PC. Myeloid cells have been shown to impact tumor stemness, but the impact of immunosuppressive tumor-infiltrating granulocytic and monocytic myeloid-derived suppressor cells (Mo-MDSC) on ALDH1(Bright) CSCs and epithelial to mesenchymal transition is not well understood. In this study, we demonstrate that Mo-MDSC (CD11b(+)/Gr1(+)/Ly6G(−)/Ly6C(hi)) significantly increase the frequency of ALDH1(Bright) CSCs in a mouse model of PC. Additionally, there was significant upregulation of genes associated with epithelial to mesenchymal transition. We also found that human PC converts CD14(+) peripheral blood monocytes into Mo-MDSC (CD14(+)/HLA-DR(low/−)) in vitro, and this transformation is dependent on the activation of the STAT3 pathway. In turn, these Mo-MDSC increase the frequency of ALDH1(Bright) CSCs and promote mesenchymal features of tumor cells. Finally, blockade of STAT3 activation reversed the increase in ALDH1(Bright) CSCs. These data suggest that the PC tumor microenvironment transforms monocytes to Mo-MDSC by STAT3 activation, and these cells increase the frequency of ALDH1(Bright) CSCs. Therefore, targeting STAT3 activation may be an effective therapeutic strategy in targeting CSCs in PC. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00262-014-1527-x) contains supplementary material, which is available to authorized users