5,988 research outputs found
Transcriptional down-regulation of suppressor of cytokine signaling (SOCS)-3 in chronic obstructive pulmonary disease
Background: Tobacco is a leading environmental factor in the initiation of respiratory diseases and causes chronic obstructive pulmonary disease (COPD). Suppressor of cytokine signaling (SOCS) family members are involved in the pathogenesis of many inflammatory diseases and SOCS-3 has been shown to play an important role in the regulation, onset and maintenance of airway allergic inflammation indicating that SOCS-3 displays a potential therapeutic target for anti-inflammatory respiratory drugs development. Since chronic obstructive pulmonary disease (COPD) is also characterized by inflammatory changes and airflow limitation, the present study assessed the transcriptional expression of SOCS-3 in COPD.
Methods: Real-time PCR was performed to assess quantitative changes in bronchial biopsies of COPD patients in comparison to unaffected controls.
Results: SOCS-3 was significantly down-regulated in COPD at the transcriptional level while SOCS-4 and SOCS-5 displayed no change.
Conclusions: It can be concluded that the presently observed inhibition of SOCS-3 mRNA expression may be related to the dysbalance of cytokine signaling observed in COPD
Recommended from our members
Insights into Activation Mechanisms of Store-Operated TRPC1 Channels in Vascular Smooth Muscle.
In vascular smooth muscle cells (VMSCs), the stimulation of store-operated channels (SOCs) mediate Ca2+ influx pathways which regulate important cellular functions including contraction, proliferation, migration, and growth that are associated with the development of vascular diseases. It is therefore important that we understand the biophysical, molecular composition, activation pathways, and physiological significance of SOCs in VSMCs as these maybe future therapeutic targets for conditions such as hypertension and atherosclerosis. Archetypal SOCs called calcium release-activated channels (CRACs) are composed of Orai1 proteins and are stimulated by the endo/sarcoplasmic reticulum Ca2+ sensor stromal interaction molecule 1 (STIM1) following store depletion. In contrast, this review focuses on proposals that canonical transient receptor potential (TRPC) channels composed of a heteromeric TRPC1/C5 molecular template, with TRPC1 conferring activation by store depletion, mediate SOCs in native contractile VSMCs. In particular, it summarizes our recent findings which describe a novel activation pathway of these TRPC1-based SOCs, in which protein kinase C (PKC)-dependent TRPC1 phosphorylation and phosphatidylinositol 4,5-bisphosphate (PIP2) are obligatory for channel opening. This PKC- and PIP2-mediated gating mechanism is regulated by the PIP2-binding protein myristoylated alanine-rich C kinase (MARCKS) and is coupled to store depletion by TRPC1-STIM1 interactions which induce Gq/PLCΞ²1 activity. Interestingly, the biophysical properties and activation mechanisms of TRPC1-based SOCs in native contractile VSMCs are unlikely to involve Orai1
How Resilient Are Our Societies? Analyses, Models, and Preliminary Results
Traditional social organizations such as those for the management of
healthcare and civil defence are the result of designs and realizations that
matched well with an operational context considerably different from the one we
are experiencing today: A simpler world, characterized by a greater amount of
resources to match less users producing lower peaks of requests. The new
context reveals all the fragility of our societies: unmanageability is just
around the corner unless we do not complement the "old recipes" with smarter
forms of social organization. Here we analyze this problem and propose a
refinement to our fractal social organizations as a model for resilient
cyber-physical societies. Evidence to our claims is provided by simulating our
model in terms of multi-agent systems.Comment: Paper submitted for publication in the Proc. of SERENE 2015
(http://serene.disim.univaq.it/2015/
Immune gene expression profiling of Proliferative Kidney Disease in rainbow trout Oncorhynchus mykiss reveals a dominance of anti-inflammatory, antibody and T helper cell-like activities
Peer reviewedPublisher PD
SQUASH: Simple QoS-Aware High-Performance Memory Scheduler for Heterogeneous Systems with Hardware Accelerators
Modern SoCs integrate multiple CPU cores and Hardware Accelerators (HWAs)
that share the same main memory system, causing interference among memory
requests from different agents. The result of this interference, if not
controlled well, is missed deadlines for HWAs and low CPU performance.
State-of-the-art mechanisms designed for CPU-GPU systems strive to meet a
target frame rate for GPUs by prioritizing the GPU close to the time when it
has to complete a frame. We observe two major problems when such an approach is
adapted to a heterogeneous CPU-HWA system. First, HWAs miss deadlines because
they are prioritized only close to their deadlines. Second, such an approach
does not consider the diverse memory access characteristics of different
applications running on CPUs and HWAs, leading to low performance for
latency-sensitive CPU applications and deadline misses for some HWAs, including
GPUs.
In this paper, we propose a Simple Quality of service Aware memory Scheduler
for Heterogeneous systems (SQUASH), that overcomes these problems using three
key ideas, with the goal of meeting deadlines of HWAs while providing high CPU
performance. First, SQUASH prioritizes a HWA when it is not on track to meet
its deadline any time during a deadline period. Second, SQUASH prioritizes HWAs
over memory-intensive CPU applications based on the observation that the
performance of memory-intensive applications is not sensitive to memory
latency. Third, SQUASH treats short-deadline HWAs differently as they are more
likely to miss their deadlines and schedules their requests based on worst-case
memory access time estimates.
Extensive evaluations across a wide variety of different workloads and
systems show that SQUASH achieves significantly better CPU performance than the
best previous scheduler while always meeting the deadlines for all HWAs,
including GPUs, thereby largely improving frame rates
Sequence learning in Associative Neuronal-Astrocytic Network
The neuronal paradigm of studying the brain has left us with limitations in
both our understanding of how neurons process information to achieve biological
intelligence and how such knowledge may be translated into artificial
intelligence and its most brain-derived branch, neuromorphic computing.
Overturning our fundamental assumptions of how the brain works, the recent
exploration of astrocytes is revealing that these long-neglected brain cells
dynamically regulate learning by interacting with neuronal activity at the
synaptic level. Following recent experimental evidence, we designed an
associative, Hopfield-type, neuronal-astrocytic network and analyzed the
dynamics of the interaction between neurons and astrocytes. We show that
astrocytes were sufficient to trigger transitions between learned memories in
the neuronal component of the network. Further, we mathematically derived the
timing of the transitions that was governed by the dynamics of the
calcium-dependent slow-currents in the astrocytic processes. Overall, we
provide a brain-morphic mechanism for sequence learning that is inspired by,
and aligns with, recent experimental findings. To evaluate our model, we
emulated astrocytic atrophy and showed that memory recall becomes significantly
impaired after a critical point of affected astrocytes was reached. This
brain-inspired and brain-validated approach supports our ongoing efforts to
incorporate non-neuronal computing elements in neuromorphic information
processing.Comment: 8 pages, 5 figure
The potential of programmable logic in the middle: cache bleaching
Consolidating hard real-time systems onto modern multi-core Systems-on-Chip (SoC) is an open challenge. The extensive sharing of hardware resources at the memory hierarchy raises important unpredictability concerns. The problem is exacerbated as more computationally demanding workload is expected to be handled with real-time guarantees in next-generation Cyber-Physical Systems (CPS). A large body of works has approached the problem by proposing novel hardware re-designs, and by proposing software-only solutions to mitigate performance interference. Strong from the observation that unpredictability arises from a lack of fine-grained control over the behavior of shared hardware components, we outline a promising new resource management approach. We demonstrate that it is possible to introduce Programmable Logic In-the-Middle (PLIM) between a traditional multi-core processor and main memory. This provides the unique capability of manipulating individual memory transactions. We propose a proof-of-concept system implementation of PLIM modules on a commercial multi-core SoC. The PLIM approach is then leveraged to solve long-standing issues with cache coloring. Thanks to PLIM, colored sparse addresses can be re-compacted in main memory. This is the base principle behind the technique we call Cache Bleaching. We evaluate our design on real applications and propose hypervisor-level adaptations to showcase the potential of the PLIM approach.Accepted manuscrip
Functional Diversity and Structural Disorder in the Human Ubiquitination Pathway
The ubiquitin-proteasome system plays a central role in cellular regulation and protein quality control (PQC). The system is built as a pyramid of increasing complexity, with two E1 (ubiquitin activating), few dozen E2 (ubiquitin conjugating) and several hundred E3 (ubiquitin ligase) enzymes. By collecting and analyzing E3 sequences from the KEGG BRITE database and literature, we assembled a coherent dataset of 563 human E3s and analyzed their various physical features. We found an increase in structural disorder of the system with multiple disorder predictors (IUPred - E1: 5.97%, E2: 17.74%, E3: 20.03%). E3s that can bind E2 and substrate simultaneously (single subunit E3, ssE3) have significantly higher disorder (22.98%) than E3s in which E2 binding (multi RING-finger, mRF, 0.62%), scaffolding (6.01%) and substrate binding (adaptor/substrate recognition subunits, 17.33%) functions are separated. In ssE3s, the disorder was localized in the substrate/adaptor binding domains, whereas the E2-binding RING/HECT-domains were structured. To demonstrate the involvement of disorder in E3 function, we applied normal modes and molecular dynamics analyses to show how a disordered and highly flexible linker in human CBL (an E3 that acts as a regulator of several tyrosine kinase-mediated signalling pathways) facilitates long-range conformational changes bringing substrate and E2-binding domains towards each other and thus assisting in ubiquitin transfer. E3s with multiple interaction partners (as evidenced by data in STRING) also possess elevated levels of disorder (hubs, 22.90% vs. non-hubs, 18.36%). Furthermore, a search in PDB uncovered 21 distinct human E3 interactions, in 7 of which the disordered region of E3s undergoes induced folding (or mutual induced folding) in the presence of the partner. In conclusion, our data highlights the primary role of structural disorder in the functions of E3 ligases that manifests itself in the substrate/adaptor binding functions as well as the mechanism of ubiquitin transfer by long-range conformational transitions. Β© 2013 Bhowmick et al
- β¦