67 research outputs found
Pituitary adenylate cyclase-activating peptide induces long-lasting neuroprotection through the induction of activity-dependent signaling via the cyclic AMP response element-binding protein-regulated transcription co-activator 1
Pituitary adenylate cyclase-activating peptide (PACAP) is a neuroprotective peptide which exerts its effects mainly through the cAMP-protein kinase A (PKA) pathway. Here, we show that in cortical neurons, PACAP-induced PKA signaling exerts a major part of its neuroprotective effects indirectly, by triggering action potential (AP) firing. Treatment of cortical neurons with PACAP induces a rapid and sustained PKA-dependent increase in AP firing and associated intracellular Ca(2+) transients, which are essential for the anti-apoptotic actions of PACAP. Transient exposure to PACAP induces long-lasting neuroprotection in the face of apoptotic insults which is reliant on AP firing and the activation of cAMP response element (CRE) binding protein (CREB)-mediated gene expression. Although direct, activity-independent PKA signaling is sufficient to trigger phosphorylation on CREB’s activating serine-133 site, this is insufficient for activation of CREB-mediated gene expression. Full activation is dependent on CREB-regulated transcription co-activator 1 (CRTC1), whose PACAP-induced nuclear import is dependent on firing activity-dependent calcineurin signaling. Over-expression of CRTC1 is sufficient to rescue PACAP-induced CRE-mediated gene expression in the face of activity-blockade, while dominant negative CRTC1 interferes with PACAP-induced, CREB-mediated neuroprotection. Thus, the enhancement of AP firing may play a significant role in the neuroprotective actions of PACAP and other adenylate cyclase-coupled ligands
The Nature of Blue Cores in Spheroids: a Possible Connection with AGN and Star Formation
We investigate the physical nature of blue cores in early-type galaxies
through the first multi-wavelength analysis of a serendipitously discovered
field blue-nucleated spheroid in the background of the deep ACS/WFC griz
multicolor observations of the cluster Abell 1689. The resolved g-r, r-i and
i-z color maps reveal a prominent blue core identifying this galaxy as a
``typical'' case study, exhibiting variations of 0.5-1.0 mag in color between
the center and the outer regions, opposite to the expectations of reddened
metallicity induced gradients in passively evolved ellipticals. From a
Magellan-Clay spectrum we secure the galaxy redshift at . We find a
strong X-ray source coincident with the spheroid galaxy. Spectral features and
a high X-ray luminosity indicate the presence of an AGN in the galaxy. However,
a comparison of the X-ray luminosity to a sample derived from the Chandra Deep
Field South displays Lx to be comparable to Type I/QSO galaxies while the
optical flux is consistent with a normal star-forming galaxy. We conclude that
the galaxy's non-thermal component dominates at high-energy wavelengths while
we associate the spheroid blue light with the stellar spectrum of normal
star-forming galaxies. We argue about a probable association between the
presence of blue cores in spheroids and AGN activity.Comment: Accepted for publication in the Astrophysical Journal. 6 pages, 3
figures. Full resolution images available at
http://acs.pha.jhu.edu/~felipe/e-print
PGC-1α Negatively Regulates Extrasynaptic NMDAR Activity and Excitotoxicity
Underexpression of the transcriptional coactivator PGC-1α is causally linked to certain neurodegenerative disorders, including Huntington's Disease (HD). HD pathoprogression is also associated with aberrant NMDAR activity, in particular an imbalance between synaptic versus extrasynaptic (NMDAR(EX)) activity. Here we show that PGC-1α controls NMDAR(EX) activity in neurons and that its suppression contributes to mutant Huntingtin (mHtt)-induced increases in NMDAR(EX) activity and vulnerability to excitotoxic insults. We found that knock-down of endogenous PGC-1α increased NMDAR(EX) activity and vulnerability to excitotoxic insults in rat cortical neurons. In contrast, exogenous expression of PGC-1α resulted in a neuroprotective reduction of NMDAR(EX) currents without affecting synaptic NMDAR activity. Since HD models are associated with mHtt-mediated suppression of PGC-1α expression, as well as increased NMDAR(EX) activity, we investigated whether these two events were linked. Expression of mHtt (148Q) resulted in a selective increase in NMDAR(EX) activity, compared with wild-type Htt (18Q), and increased vulnerability to NMDA excitotoxicity. Importantly, we observed that the effects of mHtt and PGC-1α knockdown on NMDAR(EX) activity and vulnerability to excitotoxicity were nonadditive and occluded each other, consistent with a common mechanism. Moreover, exogenous expression of PGC-1α reversed mtHtt-mediated increases in NMDAR(EX) activity and protected neurons against excitotoxic cell death. The link between mHtt, PGC-1α, and NMDAR activity was also confirmed in rat striatal neurons. Thus, targeting levels of PGC-1α expression may help reduce aberrant NMDAR(EX) activity in disorders where PGC-1α is underexpressed
Discovery of Two Distant Type Ia Supernovae in the Hubble Deep Field North with the Advanced Camera for Surveys
We present observations of the first two supernovae discovered with the
recently installed Advanced Camera for Surveys (ACS) on the Hubble Space
Telescope. The supernovae were found in Wide Field Camera images of the Hubble
Deep Field North taken with the F775W, F850LP, and G800L optical elements as
part of the ACS guaranteed time observation program. Spectra extracted from the
ACS G800L grism exposures confirm that the objects are Type Ia supernovae (SNe
Ia) at redshifts z=0.47 and z=0.95. Follow-up HST observations have been
conducted with ACS in F775W and F850LP and with NICMOS in the near-infrared
F110W bandpass, yielding a total of 9 flux measurements in the 3 bandpasses
over a period of 50 days in the observed frame. We discuss many of the
important issues in doing accurate photometry with the ACS. We analyze the
multi-band light curves using two different fitting methods to calibrate the
supernovae luminosities and place them on the SNe Ia Hubble diagram. The
resulting distances are consistent with the redshift-distance relation of the
accelerating universe model, although evolving intergalactic grey dust remains
as a less likely possibility. The relative ease with which these SNe Ia were
found, confirmed, and monitored demonstrates the potential ACS holds for
revolutionizing the field of high-redshift SNe Ia, and therefore of testing the
accelerating universe cosmology and constraining the "epoch of deceleration".Comment: 11 pages, 8 embedded figures. Accepted for publication in Ap
Minimal information for studies of extracellular vesicles (MISEV2023): From basic to advanced approaches
Extracellular vesicles (EVs), through their complex cargo, can reflect the state of their cell of origin and change the functions and phenotypes of other cells. These features indicate strong biomarker and therapeutic potential and have generated broad interest, as evidenced by the steady year-on-year increase in the numbers of scientific publications about EVs. Important advances have been made in EV metrology and in understanding and applying EV biology. However, hurdles remain to realising the potential of EVs in domains ranging from basic biology to clinical applications due to challenges in EV nomenclature, separation from non-vesicular extracellular particles, characterisation and functional studies. To address the challenges and opportunities in this rapidly evolving field, the International Society for Extracellular Vesicles (ISEV) updates its 'Minimal Information for Studies of Extracellular Vesicles', which was first published in 2014 and then in 2018 as MISEV2014 and MISEV2018, respectively. The goal of the current document, MISEV2023, is to provide researchers with an updated snapshot of available approaches and their advantages and limitations for production, separation and characterisation of EVs from multiple sources, including cell culture, body fluids and solid tissues. In addition to presenting the latest state of the art in basic principles of EV research, this document also covers advanced techniques and approaches that are currently expanding the boundaries of the field. MISEV2023 also includes new sections on EV release and uptake and a brief discussion of in vivo approaches to study EVs. Compiling feedback from ISEV expert task forces and more than 1000 researchers, this document conveys the current state of EV research to facilitate robust scientific discoveries and move the field forward even more rapidly
Synaptic NMDA receptor activity boosts intrinsic antioxidant defenses
Intrinsic antioxidant defenses are important for neuronal longevity. We found that in rat neurons, synaptic activity, acting via NMDA receptor (NMDAR) signaling, boosted antioxidant defenses by making changes to the thioredoxin-peroxiredoxin (Prx) system. Synaptic activity enhanced thioredoxin activity, facilitated the reduction of overoxidized Prxs and promoted resistance to oxidative stress. Resistance was mediated by coordinated transcriptional changes; synaptic NMDAR activity inactivated a previously unknown Forkhead box O target gene, the thioredoxin inhibitor Txnip. Conversely, NMDAR blockade upregulated Txnip in vivo and in vitro, where it bound thioredoxin and promoted vulnerability to oxidative damage. Synaptic activity also upregulated the Prx reactivating genes Sesn2 (sestrin 2) and Srxn1 (sulfiredoxin), via C/EBPβ and AP-1, respectively. Mimicking these expression changes was sufficient to strengthen antioxidant defenses. Trans-synaptic stimulation of synaptic NMDARs was crucial for boosting antioxidant defenses; chronic bath activation of all (synaptic and extrasynaptic) NMDARs induced no antioxidative effects. Thus, synaptic NMDAR activity may influence the progression of pathological processes associated with oxidative damage
Recommended from our members
Research and Design of a Routing Protocol in Large-Scale Wireless Sensor Networks
无线传感器网络,作为全球未来十大技术之一,集成了传感器技术、嵌入式计算技术、分布式信息处理和自组织网技术,可实时感知、采集、处理、传输网络分布区域内的各种信息数据,在军事国防、生物医疗、环境监测、抢险救灾、防恐反恐、危险区域远程控制等领域具有十分广阔的应用前景。 本文研究分析了无线传感器网络的已有路由协议,并针对大规模的无线传感器网络设计了一种树状路由协议,它根据节点地址信息来形成路由,从而简化了复杂繁冗的路由表查找和维护,节省了不必要的开销,提高了路由效率,实现了快速有效的数据传输。 为支持此路由协议本文提出了一种自适应动态地址分配算——ADAR(AdaptiveDynamicAddre...As one of the ten high technologies in the future, wireless sensor network, which is the integration of micro-sensors, embedded computing, modern network and Ad Hoc technologies, can apperceive, collect, process and transmit various information data within the region. It can be used in military defense, biomedical, environmental monitoring, disaster relief, counter-terrorism, remote control of haz...学位:工学硕士院系专业:信息科学与技术学院通信工程系_通信与信息系统学号:2332007115216
ChAcNLS, a Novel Modification to Antibody-Conjugates Permitting Target Cell-Specific Endosomal Escape, Localization to the Nucleus, and Enhanced Total Intracellular Accumulation
The
design of antibody-conjugates (ACs) for delivering molecules
for targeted applications in humans has sufficiently progressed to
demonstrate clinical efficacy in certain malignancies and reduced
systemic toxicity that occurs with standard nontargeted therapies.
One area that can advance clinical success for ACs will be to increase
their intracellular accumulation. However, entrapment and degradation
in the endosomal-lysosomal pathway, on which ACs are reliant for the
depositing of their molecular payload inside target cells, leads to
reduced intracellular accumulation. Innovative approaches that can
manipulate this pathway may provide a strategy for increasing accumulation.
We hypothesized that escape from entrapment inside the endosomal-lysosomal
pathway and redirected trafficking to the nucleus could be an effective
approach to increase intracellular AC accumulation in target cells.
Cholic acid (ChAc) was coupled to the peptide CGYGPKKKRKVGG containing
the nuclear localization sequence (NLS) from SV-40 large T-antigen,
which is termed ChAcNLS. ChAcNLS was conjugated to the mAb 7G3 (7G3-ChAcNLS),
which has nanomolar affinity for the cell-surface leukemic antigen
interleukin-3 receptor-α (IL-3Rα). Our aim was to determine
whether 7G3-ChAcNLS increased intracellular accumulation while retaining
nanomolar affinity and IL-3Rα-positive cell selectivity. Competition
ELISA and cell treatment assays were performed. Cell fractionation,
confocal microscopy, flow cytometry, and Western blot techniques were
used to determine the level of antibody accumulation inside cells
and in corresponding nuclei. In addition, the radioisotope copper-64
(<sup>64</sup>Cu) was also utilized as a surrogate molecular cargo
to evaluate nuclear and intracellular accumulation by radioactivity
counting. 7G3-ChAcNLS effectively escaped endosome entrapment and
degradation resulting in a unique intracellular distribution pattern.
mAb modification with ChAcNLS maintained 7G3 nM affinity and produced
high selectivity for IL-3Rα-positive cells. In contrast, 7G3
ACs with the ability to either escape endosome entrapment or traffic
to the nucleus was not superior to 7G3-ChAcNLS for increasing intracellular
accumulation. Transportation of <sup>64</sup>Cu when complexed to
7G3-ChAcNLS also resulted in increased nuclear and intracellular radioactivity
accumulation. Thus, ChAcNLS is a novel mAb functionalizing technology
that demonstrates its ability to increase AC intracellular accumulation
in target cells through escaping endosome entrapment coupled to nuclear
trafficking
- …