Feasibility of using NF1-GRD and AAV for gene replacement therapy in NF1-associated tumors

Neurofibromatosis type 1, including the highly aggressive malignant peripheral nerve sheath tumors (MPNSTs), is featured by the loss of functional neurofibromin 1 (NF1) protein resulting from genetic alterations. A major function of NF1 is suppressing Ras activities, which is conveyed by an intrinsic GTPase-activating protein-related domain (GRD). In this study, we explored the feasibility of restoring Ras GTPase via exogenous expression of various GRD constructs, via gene delivery using a panel of adeno-associated virus (AAV) vectors in MPNST and human Schwann cells (HSCs). We demonstrated that several AAV serotypes achieved favorable transduction efficacies in those cells and a membrane-targeting GRD fused with an H-Ras C-terminal motif (C10) dramatically inhibited the Ras pathway and MPNST cells in a NF1-specific manner. Our results opened up a venue of gene replacement therapy in NF1-related tumors

On the Nature of the X-ray Emission from the Ultraluminous X-ray Source, M33 X-8: New Constraints from NuSTAR and XMM-Newton

We present nearly simultaneous NuSTAR and XMM-Newton observations of the nearby (832 kpc) ultraluminous X-ray source (ULX) M33 X-8. M33 X-8 has a 0.3-10 keV luminosity of LX ~ 1.4 x 10^39 erg/s, near the boundary of the "ultraluminous" classification, making it an important source for understanding the link between typical Galactic X-ray binaries and ULXs. Past studies have shown that the 0.3-10 keV spectrum of X-8 can be characterized using an advection-dominated accretion disk model. We find that when fitting to our NuSTAR and XMM-Newton observations, an additional high-energy (>10 keV) Comptonization component is required, which allows us to rule out single advection-dominated disk and classical sub-Eddington models. With our new constraints, we analyze XMM-Newton data taken over the last 17 years to show that small (~30%) variations in the 0.3-10 keV flux of M33 X-8 result in spectral changes similar to those observed for other ULXs. The two most likely phenomenological scenarios suggested by the data are degenerate in terms of constraining the nature of the accreting compact object (i.e., black hole versus neutron star). We further present a search for pulsations using our suite of data; however, no clear pulsations are detected. Future observations designed to observe M33 X-8 at different flux levels across the full 0.3-30 keV range would significantly improve our constraints on the nature of this important source.Comment: Accepted for publication in ApJ (15 pages, 4 tables, 6 figures

Potential Risks to International Joint Ventures In Developing Economies: The Ghanaian Construction Industry Experience

International construction companies are increasingly entering into joint ventures with local companies in developing countries to explore perceived profitable opportunities overseas. Joint ventures generally offer a number of benefits but they can become very difficult to manage as a result of many complexities introduced by the association of two or more companies from different countries, with differing political, cultural and legal frameworks, technical and managerial capabilities, and national economic environments. This theoretical study assesses the risks associated with International Construction Joint Ventures in developing economies with particular reference to Ghana. The nature, strengths, weaknesses, opportunities and threats within the Ghanaian construction industry were reviewed. The economy, governance, business environment, infrastructure, resources, etc. of Ghana were also assessed. The main risks factors to International Joint Ventures (IJVs) identified in Ghana can be categorised into two: major risk factors including the microeconomic and financial risk factors and joint venture partner problems. The client’s ability to finance the projects and poor technical, financial and managerial capacities of Ghanaian construction firms were the main factors in this group. The minor risks factors include the availability and high cost of construction materials, issues of bribery and corruption, power supply problems and security

Uncovering Red and Dusty Ultraluminous X-Ray Sources with Spitzer

We present a mid-infrared (IR) sample study of nearby ultraluminous X-ray sources (ULXs) using multiepoch observations with the Infrared Array Camera (IRAC) on the Spitzer Space Telescope. Spitzer/IRAC observations taken after 2014 were obtained as part of the Spitzer Infrared Intensive Transients Survey. Our sample includes 96 ULXs located within 10 Mpc. Of the 96 ULXs, 12 have candidate counterparts consistent with absolute mid-IR magnitudes of supergiants, and 16 counterparts exceeded the mid-IR brightness of single supergiants and are thus more consistent with star clusters or non-ULX background active galactic nuclei. The supergiant candidate counterparts exhibit a bimodal color distribution in a Spitzer/IRAC color–magnitude diagram, where "red" and "'blue" ULXs fall in IRAC colors [3.6] – [4.5] ~ 0.7 and [3.6] – [4.5] ~ 0.0, respectively. The mid-IR colors and absolute magnitudes of four "red" and five "blue" ULXs are consistent with those of supergiant B[e] (sgB[e]) and red supergiant (RSG) stars, respectively. Although "blue," RSG-like mid-IR ULX counterparts likely host RSG mass donors; we propose that "red" counterparts are ULXs exhibiting the "B[e] phenomenon" rather than hosts of sgB[e] mass donors. We show that the mid-IR excess from the "red" ULXs is likely due to thermal emission from circumstellar or circumbinary dust. Using dust as a probe for total mass, we estimate mass-loss rates of Ṁ ~ 1 x 10^(-4) M_⊙ yr^(−1) in dust-forming outflows of red ULXs. Based on the transient mid-IR behavior and its relatively flat spectral index, α = −0.19 ± 0.1, we suggest that the mid-IR emission from Holmberg IX X-1 originates from a variable jet

Genome-wide association study identifies 30 loci associated with bipolar disorder.

Bipolar disorder is a highly heritable psychiatric disorder. We performed a genome-wide association study (GWAS) including 20,352 cases and 31,358 controls of European descent, with follow-up analysis of 822 variants with P < 1 × 10-4 in an additional 9,412 cases and 137,760 controls. Eight of the 19 variants that were genome-wide significant (P < 5 × 10-8) in the discovery GWAS were not genome-wide significant in the combined analysis, consistent with small effect sizes and limited power but also with genetic heterogeneity. In the combined analysis, 30 loci were genome-wide significant, including 20 newly identified loci. The significant loci contain genes encoding ion channels, neurotransmitter transporters and synaptic components. Pathway analysis revealed nine significantly enriched gene sets, including regulation of insulin secretion and endocannabinoid signaling. Bipolar I disorder is strongly genetically correlated with schizophrenia, driven by psychosis, whereas bipolar II disorder is more strongly correlated with major depressive disorder. These findings address key clinical questions and provide potential biological mechanisms for bipolar disorder

High density lipoprotein mediates anti-inflammatory transcriptional reprogramming of macrophages via the transcriptional repressor ATF3

High Density Lipoprotein (HDL) mediates reverse cholesterol transport and it is known to be protective against atherosclerosis. In addition, HDL has potent anti-inflammatory properties that may be critical for protection against other inflammatory diseases. The molecular mechanisms of how HDL can modulate inflammation, particularly in immune cells such as macrophages, remain poorly understood. Here we identify the transcriptional repressor ATF3, as an HDL-inducible target gene in macrophages that down-regulates the expression of Toll-like receptor (TLR)-induced pro-inflammatory cytokines. The protective effects of HDL against TLR-induced inflammation were fully dependent on ATF3 in vitro and in vivo. Our findings may explain the broad anti-inflammatory and metabolic actions of HDL and provide the basis for predicting the success of novel HDL-based therapies

Uncovering Red and Dusty Ultraluminous X-Ray Sources with Spitzer

We present a mid-infrared (IR) sample study of nearby ultraluminous X-ray sources (ULXs) using multiepoch observations with the Infrared Array Camera (IRAC) on the Spitzer Space Telescope. Spitzer/IRAC observations taken after 2014 were obtained as part of the Spitzer Infrared Intensive Transients Survey. Our sample includes 96 ULXs located within 10 Mpc. Of the 96 ULXs, 12 have candidate counterparts consistent with absolute mid-IR magnitudes of supergiants, and 16 counterparts exceeded the mid-IR brightness of single supergiants and are thus more consistent with star clusters or non-ULX background active galactic nuclei. The supergiant candidate counterparts exhibit a bimodal color distribution in a Spitzer/IRAC color–magnitude diagram, where "red" and "'blue" ULXs fall in IRAC colors [3.6] – [4.5] ~ 0.7 and [3.6] – [4.5] ~ 0.0, respectively. The mid-IR colors and absolute magnitudes of four "red" and five "blue" ULXs are consistent with those of supergiant B[e] (sgB[e]) and red supergiant (RSG) stars, respectively. Although "blue," RSG-like mid-IR ULX counterparts likely host RSG mass donors; we propose that "red" counterparts are ULXs exhibiting the "B[e] phenomenon" rather than hosts of sgB[e] mass donors. We show that the mid-IR excess from the "red" ULXs is likely due to thermal emission from circumstellar or circumbinary dust. Using dust as a probe for total mass, we estimate mass-loss rates of Ṁ ~ 1 x 10^(-4) M_⊙ yr^(−1) in dust-forming outflows of red ULXs. Based on the transient mid-IR behavior and its relatively flat spectral index, α = −0.19 ± 0.1, we suggest that the mid-IR emission from Holmberg IX X-1 originates from a variable jet

Applying genetic technologies to combat infectious diseases in aquaculture

Disease and parasitism cause major welfare, environmental and economic concerns for global aquaculture. In this review, we examine the status and potential of technologies that exploit genetic variation in host resistance to tackle this problem. We argue that there is an urgent need to improve understanding of the genetic mechanisms involved, leading to the development of tools that can be applied to boost host resistance and reduce the disease burden. We draw on two pressing global disease problems as case studies—sea lice infestations in salmonids and white spot syndrome in shrimp. We review how the latest genetic technologies can be capitalised upon to determine the mechanisms underlying inter- and intra-species variation in pathogen/ parasite resistance, and how the derived knowledge could be applied to boost disease resistance using selective breeding, gene editing and/or with targeted feed treatments and vaccines. Gene editing brings novel opportunities, but also implementation and dissemination challenges, and necessitates new protocols to integrate the technology into aquaculture breeding programmes. There is also an ongoing need to minimise risks of disease agents evolving to overcome genetic improvements to host resistance, and insights from epidemiological and evolutionary models of pathogen infestation in wild and cultured host populations are explored. Ethical issues around the different approaches for achieving genetic resistance are discussed. Application of genetic technologies and approaches has potential to improve fundamental knowledge of mechanisms affecting genetic resistance and provide effective pathways for implementation that could lead to more resistant aquaculture stocks, transforming global aquaculture.publishedVersio