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

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)

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

BRCA1 haploinsufficiency for replication stress suppression in primary cells

BRCA1—a breast and ovarian cancer suppressor gene—promotes genome integrity. To study the functionality of BRCA1 in the heterozygous state, we established a collection of primary human BRCA1+/+ and BRCA1mut/+ mammary epithelial cells and fibroblasts. Here we report that all BRCA1mut/+ cells exhibited multiple normal BRCA1 functions, including the support of homologous recombination- type double-strand break repair (HR-DSBR), checkpoint functions, centrosome number control, spindle pole formation, Slug expression and satellite RNA suppression. In contrast, the same cells were defective in stalled replication fork repair and/or suppression of fork collapse, that is, replication stress. These defects were rescued by reconstituting BRCA1mut/+ cells with wt BRCA1. In addition, we observed ‘conditional’ haploinsufficiency for HR-DSBR in BRCA1mut/+ cells in the face of replication stress. Given the importance of replication stress in epithelial cancer development and of an HR defect in breast cancer pathogenesis, both defects are candidate contributors to tumorigenesis in BRCA1-deficient mammary tissue