440 research outputs found
Medicines and vaccines for the world's poorest: Is there any prospect for public-private cooperation?
This paper reviews the current status of the global pharmaceutical industry and its research and development focus in the context of the health care needs of the developing world. It will consider the attempts to improve access to critical drugs and vaccines, and increase the research effort directed at key public health priorities in the developing world. In particular, it will consider prospects for public-private collaboration. The challenges and opportunities in such public-private partnerships will be discussed briefly along with a look at factors that may be key to success. Much of the focus is on HIV/AIDS where the debate on the optimal balance between intellectual property rights (IPR) and human rights to life and health has been very public and emotive
Has Pakistan's Military Doctrine Transformed?
The importance of military power will remain as long as the nation-state exists. Some prominent military strategists and thinkers like Chanakya, Clausewitz, and Sun Tzu believed that no nation could be secure unless it had a powerful military, which could deter a potential adversary. Military power is the power that not only determines a country's power ranking but, for many states, the development and growth of their military power becomes a catalyst for their rise to great power status. For any military of the world, it is perhaps necessary to have a basic rule/principle or a set of beliefs to serve as its foundation. This is best encapsulated in the form of a doctrine. But the question arises: should the doctrine also reflect the modernisation and transformation which is required to keep the military upgraded and up to date? This would involve a change in the mindset/thought process, review of doctrine, strategy, war-fighting, concept, organisational structures, human resource optimisation, training methodology, and logistics concepts in order to meet the operational challenges of the future. In other words, the transformation would require a profound change in the overall military affairs. In view of this, the article will examine if any changes have taken place in Pakistan's military doctrine. In doing so, the article is divided into three parts: part one traces the etymology of the word doctrine and defines military doctrine; part two, covers the typology of doctrine; and part three, studies the fundamentals of Pakistan's military doctrine in a two-fold perspective: (a) functions of a fundamental military doctrine; (b) roots of a fundamental military doctrine, and analyses the changes in the doctrine
Pakistan: the Balochistan Conundrum: by Tilak Devasher
Publishers: Indian Council of World Affairs and HarperCollins Publishers India (2019)
Location: New Delhi, India. P-ISBN: 978-93-5357-070-5 | E-ISBN: 978-93-5357-071-
CoMeT: An Integrated Interval Thermal Simulation Toolchain for 2D, 2.5 D, and 3D Processor-Memory Systems
Processing cores and the accompanying main memory working in tandem enable
the modern processors. Dissipating heat produced from computation, memory
access remains a significant problem for processors. Therefore, processor
thermal management continues to be an active research topic. Most thermal
management research takes place using simulations, given the challenges of
measuring temperature in real processors. Since core and memory are fabricated
on separate packages in most existing processors, with the memory having lower
power densities, thermal management research in processors has primarily
focused on the cores.
Memory bandwidth limitations associated with 2D processors lead to
high-density 2.5D and 3D packaging technology. 2.5D packaging places cores and
memory on the same package. 3D packaging technology takes it further by
stacking layers of memory on the top of cores themselves. Such packagings
significantly increase the power density, making processors prone to heating.
Therefore, mitigating thermal issues in high-density processors (packaged with
stacked memory) becomes an even more pressing problem. However, given the lack
of thermal modeling for memories in existing interval thermal simulation
toolchains, they are unsuitable for studying thermal management for
high-density processors.
To address this issue, we present CoMeT, the first integrated Core and Memory
interval Thermal simulation toolchain. CoMeT comprehensively supports thermal
simulation of high- and low-density processors corresponding to four different
core-memory configurations - off-chip DDR memory, off-chip 3D memory, 2.5D, and
3D. CoMeT supports several novel features that facilitate overlying system
research. Compared to an equivalent state-of-the-art core-only toolchain, CoMeT
adds only a ~5% simulation-time overhead. The source code of CoMeT has been
made open for public use under the MIT license.Comment: https://github.com/marg-tools/CoMe
Performance, Power and Cooling Trade-Offs with NCFET-based Many-Cores
Negative Capacitance Field-Effect Transistor (NCFET) is an emerging technology that incorporates a ferroelectric layer within the transistor gate stack to overcome the fundamental limit of sub-threshold swing in transistors. Even though physics-based NCFET models have been recently proposed, system-level NCFET models do not exist and research is still in its infancy. In this work, we are the first to investigate the impact of NCFET on performance, energy and cooling costs in many-core processors. Our proposed methodology starts from accurate physics models all the way up to the system level, where the performance and power of a many-core are widely affected. Our new methodology and system-level models allow, for the first time, the exploration of the novel trade-offs between performance gains and power losses that NCFET now offers to system-level designers. We demonstrate that an optimal ferroelectric thickness does exist. In addition, we reveal that current state-of-the-art power management techniques fail when NCFET (with a thick ferroelectric layer) comes into play
DISC1-dependent Regulation of Mitochondrial Dynamics Controls the Morphogenesis of Complex Neuronal Dendrites
The DISC1 protein is implicated in major mental illnesses including schizophrenia, depression, bipolar disorder, and autism. Aberrant mitochondrial dynamics are also associated with major mental illness. DISC1 plays a role in mitochondrial transport in neuronal axons, but its effects in dendrites have yet to be studied. Further, the mechanisms of this regulation and its role in neuronal development and brain function are poorly understood. Here we have demonstrated that DISC1 couples to the mitochondrial transport and fusion machinery via interaction with the outer mitochondrial membrane GTPase proteins Miro1 and Miro2, the TRAK1 and TRAK2 mitochondrial trafficking adaptors, and the mitochondrial fusion proteins (mitofusins). Using live cell imaging, we show that disruption of the DISC1-Miro-TRAK complex inhibits mitochondrial transport in neurons. We also show that the fusion protein generated from the originally described DISC1 translocation (DISC1-Boymaw) localizes to the mitochondria, where it similarly disrupts mitochondrial dynamics. We also show by super resolution microscopy that DISC1 is localized to endoplasmic reticulum contact sites and that the DISC1-Boymaw fusion protein decreases the endoplasmic reticulum-mitochondria contact area. Moreover, disruption of mitochondrial dynamics by targeting the DISC1-Miro-TRAK complex or upon expression of the DISC1-Boymaw fusion protein impairs the correct development of neuronal dendrites. Thus, DISC1 acts as an important regulator of mitochondrial dynamics in both axons and dendrites to mediate the transport, fusion, and cross-talk of these organelles, and pathological DISC1 isoforms disrupt this critical function leading to abnormal neuronal development
Multi-omic Profiling Reveals Dynamics of the Phased Progression of Pluripotency
Pluripotency is highly dynamic and progresses through a continuum of pluripotent stem cell states. The two states that bookend the pluripotency continuum, naive and primed, are well characterized, but our understanding of the intermediate states and transitions between them remains incomplete. Here, we dissect the dynamics of pluripotent state transitions underlying pre- to post-implantation epiblast differentiation. Through comprehensive mapping of the proteome, phosphoproteome, transcriptome, and epigenome of embryonic stem cells transitioning from naive to primed pluripotency, we find that rapid, acute, and widespread changes to the phosphoproteome precede ordered changes to the epigenome, transcriptome, and proteome. Reconstruction of the kinase-substrate networks reveals signaling cascades, dynamics, and crosstalk. Distinct waves of global proteomic changes mark discrete phases of pluripotency, with cell-state-specific surface markers tracking pluripotent state transitions. Our data provide new insights into multi-layered control of the phased progression of pluripotency and a foundation for modeling mechanisms regulating pluripotent state transitions (www.steamcellatlas.org)
Climate change effects on pest spectrum and incidence in grain legumes
Global warming and climate change will influence activity, diversity, distribution and population dynamics of insect pests including the grain legumes. Several insect pests damage grain legume crops, of which the pod borer, Helicoverpa armigera; spotted pod borer, Maruca vitrata; spiny pod borer, Etiella zinckenella; pod fly, Melanagromyza obtusa; aphid, Aphis craccivora; defoliators, Spodoptera litura and S. exigua; thrips, Megaleurothrips usitatus and Caliothrips indicus and the bruchid, Callasobruchus chinensis cause extensive losses in grain legumes. The incidence and extent of losses due to these pests varies across seasons, locations, and cropping systems. The pest spectrum on grain legumes will change considerably due to impending global warming and climate change. The geographical distribution of some of the pests might extend to temperate regions in Europe and America, while the outbreaks of some other pests will become more frequent. Several outbreaks of pod borer, H. armigera and spotted pod borer, M. vitrata have been recorded on grain legumes in India, which at times have resulted in complete crop loss. The scale insect, Ceroplastodes cajani in pigeonpea and beet armyworm, Spodoptera exigua, mealy bug, Ferrisia virgata, and white fly, Bemisia tabaci in chickpea have emerged as new pests; while leaf miner, Porphyrosela neodoxa, mealy bugs, Drepanococcus cajani, and Coccidohystrix insolita are some of the emerging pest problems in pigeonpea in India. In addition, there will be greater genotype x environment interactions for expression of resistance to insect pests, and this warrants a greater effort for identification of diverse sources of resistance and need for integrated pest management packages that will be effective under global warming and climate change
The autism and schizophrenia associated gene CYFIP1 is critical for the maintenance of dendritic complexity and the stabilization of mature spines.
Copy number variation (CNV) at the 15q11.2 region has been identified as a significant risk locus for neurological and neuropsychiatric conditions such as schizophrenia (SCZ) and autism spectrum disorder (ASD). However, the individual roles for genes at this locus in nervous system development, function and connectivity remain poorly understood. Haploinsufficiency of one gene in this region, Cyfip1, may provide a model for 15q11.2 CNV-associated neuropsychiatric phenotypes. Here we show that altering CYFIP1 expression levels in neurons both in vitro and in vivo influences dendritic complexity, spine morphology, spine actin dynamics and synaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor lateral diffusion. CYFIP1 is highly enriched at synapses and its overexpression in vitro leads to increased dendritic complexity. Neurons derived from Cyfip1 heterozygous animals on the other hand, possess reduced dendritic complexity, increased mobile F-actin and enhanced GluA2-containing AMPA receptor mobility at synapses. Interestingly, Cyfip1 overexpression or haploinsufficiency increased immature spine number, whereas activity-dependent changes in spine volume were occluded in Cyfip1 haploinsufficient neurons. In vivo, Cyfip1 heterozygous animals exhibited deficits in dendritic complexity as well as an altered ratio of immature-to-mature spines in hippocampal CA1 neurons. In summary, we provide evidence that dysregulation of CYFIP1 expression levels leads to pathological changes in CNS maturation and neuronal connectivity, both of which may contribute to the development of the neurological symptoms seen in ASD and SCZ
Overexpression of BLM promotes DNA damage and increased sensitivity to platinum salts in triple negative breast and serous ovarian cancers
Background: Platinum based therapy is an effective treatment for a subset of triple negative breast cancer and ovarian cancer patients. In order to increase response rate and decrease unnecessary use, robust biomarkers that predict response to therapy are needed. Patients and methods: We performed an integrated genomic approach combining differential analysis of gene expression and DNA copy number in sensitive compared to resistant triple negative breast cancers in two independent neoadjuvant cisplatin treated cohorts. Functional relevance of significant hits was investigated in vitro by overexpression, knockdown and targeted inhibitor treatment. Results: We identified two genes, the Bloom helicase (BLM) and Fanconi anemia complementation group I (FANCI), that have both increased DNA copy number and gene expression in the platinum sensitive cases. Increased level of expression of these two genes was also associated with platinum but not with taxane response in ovarian cancer. As a functional validation, we found that overexpression of BLM promotes DNA damage and induces sensitivity to cisplatin, but has no effect on paclitaxel sensitivity. Conclusions: A biomarker based on the expression levels of the BLM and FANCI genes is a potential predictor of platinum sensitivity in triple negative breast cancer and ovarian cancer. Short description: Through integrated analysis of gene expression and copy number data from two independent clinical trials in triple negative breast cancer, we identify two genes, BLM and FANCI, involved in double-strand DNA repair where increased expression is related to sensitivity to platinum induced DNA damage. Further functional validation reveals that overexpression of BLM alone promotes DNA damage
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