Universities: The Fallen Angels of Bayh-Dole?

The Bayh-Dole Act of 1980 established a new default rule that allowed nonprofit organizations and small businesses to own, as a routine matter, patents on inventions resulting from research sponsored by the federal government. Although universities helped get the Bayh-Dole Act through Congress, the primary goal, as reflected in the recitals at the beginning of the new statute, was not to benefit universities but to promote the commercial development and utilization of federally funded inventions. In the years since the passage of the Bayh-Dole Act, universities seem to have lost sight of this distinction. Their behavior as patent seekers, patent enforcers, and patent policy stakeholders often seems to work against the commercialization goals of the Bayh-Dole Act and is difficult to explain or justify on any basis other than the pursuit of revenue

The impact of Autism Spectrum Disorder and alexithymia on judgments of moral acceptability

One’s own emotional response toward a hypothetical action can influence judgments of its moral acceptability. Some individuals with autism spectrum disorder (ASD) exhibit atypical emotional processing, and moral judgments. Research suggests, however, that emotional deficits in ASD are due to co-occurring alexithymia, meaning atypical moral judgments in ASD may be due to alexithymia also. Individuals with and without ASD (matched for alexithymia) judged the moral acceptability of emotion-evoking statements and identified the emotion evoked. Moral acceptability judgments were predicted by alexithymia. Crucially, however, this relationship held only for individuals without ASD. While ASD diagnostic status did not directly predict either judgment, those with ASD did not base their moral acceptability judgments on emotional information. Findings are consistent with evidence demonstrating that decision-making is less subject to emotional biases in those with ASD

Epithelial cell-directed efferocytosis in the post-partum mammary gland is necessary for tissue homeostasis and future lactation

<p>Abstract</p> <p>Background</p> <p>Mammary glands harbor a profound burden of apoptotic cells (ACs) during post-lactational involution, but little is known regarding mechanisms by which ACs are cleared from the mammary gland, or consequences if this process is interrupted. We investigated AC clearance, also termed efferocytosis, during post-lactational remodeling, using mice deficient for MerTK, Axl, and Tyro3, three related receptor tyrosine kinases (RTKs) regulating macrophage-mediated efferocytosis in monocytes. MerTK expression, apoptosis and the accumulation of apoptotic debris were examined in histological sections of MerTK-deficient, Axl/Tyro3-deficient, and wild-type mammary glands harvested at specific time points during lactation and synchronized involution. The ability of primary mammary epithelial cells (MECs) to engulf ACs was assessed in culture. Transplant of MerTK-deficient mammary epithelium into cleared WT mammary fat pads was used to assess the contribution of WT mammary macrophages to post-lactational efferocytosis.</p> <p>Results</p> <p>ACs induced MerTK expression in MECs, resulting in elevated MerTK levels at the earliest stages of involution. Loss of MerTK resulted in AC accumulation in post-lactational MerTK-deficient mammary glands, but not in Axl and Tyro3-deficient mammary glands. Increased vascularization, fibrosis, and epithelial hyperproliferation were observed in MerTK-deficient mammary glands through at least 60 days post-weaning, due to failed efferocytosis after lactation, but did not manifest in nulliparous mice. WT host-derived macrophages failed to rescue efferocytosis in transplanted MerTK-deficient mammary epithelium.</p> <p>Conclusion</p> <p>Efferocytosis by MECs through MerTK is crucial for mammary gland homeostasis and function during the post-lactational period. Efferocytosis by MECs thus limits pathologic consequences associated with the apoptotic load following lactation.</p

ErbB4/HER4: Role in Mammary Gland Development, Differentiation and Growth Inhibition

The ErbB receptor tyrosine kinase family has often been associated with increased growth of breast epithelial cells, as well as malignant transformation and progression. In contrast, ErbB4/HER4 exhibits unique attributes from a two step proteolytic cleavage which releases an 80 kilodalton, nuclear localizing, tyrosine kinase to a signal transduction mechanism that slows growth and stimulates differentiation of breast cells. This review provides an overview of ErbB4/HER4 in growth and differentiation of the mammary epithelium, including its physiologic role in development, the contrasting growth inhibition/tumor suppression and growth acceleration of distinct ErbB4/HER4 isoforms and a description of the unique cell cycle regulated pattern of nuclear HER4 ubiquitination and destruction

RAF inhibitors activate the integrated stress response by direct activation of GCN2

Paradoxical RAF activation by chemical RAF inhibitors (RAFi) is a well-understood on-target biological and clinical response. In this study, we show that a range of RAFi drive ERK1/2-independent activation of the Unfolded Protein Response (UPR), including expression of ATF4 and CHOP, that required the translation initiation factor eIF2-alpha. RAFi-induced ATF4 and CHOP expression was not reversed by inhibition of PERK, a known upstream activator of the eIF2-alpha-dependent Integrated Stress Response (ISR). Rather, we found that RAFi exposure activated GCN2, an alternate eIF2-alpha kinase, leading to eIF2-alpha-dependent (and ERK1/2-independent) ATF4 and CHOP expression. The GCN2 kinase inhibitor A-92, GCN2 RNAi, GCN2 knock-out or ISRIB (an eIF2-alpha antagonist) all reversed RAFi-induced expression of ATF4 and CHOP indicating that RAFi require GCN2 to activate the ISR. RAFi also activated full-length recombinant GCN2 in vitro and in cells, generating a characteristic bell-shaped concentration-response curve, reminiscent of RAFi-driven paradoxical activation of WT RAF dimers. Activation of the ISR by RAFi was abolished by GCN2 kinase dead mutations and M802A or M802G gatekeeper mutations, suggesting that RAFi bind directly to the GCN2 kinase domain; this was supported by mechanistic structural models of RAFi interaction with GCN2. Since the ISR is a critical pathway for determining cell survival or death, our observations may be relevant to the clinical use of RAFi, where paradoxical GCN2 activation may be a previously unappreciated off-target effect that may modulate tumour cell responses

Sustainable management of groundwater extraction: An Australian perspective on current challenges

Study focus: Our incomplete knowledge of groundwater systems and processes imposes barriers in attempting to manage groundwater sustainably. Challenges also arise through complex institutional arrangements and decision-making processes, and the difficulty in involving stakeholders. In some areas, these difficulties have led to water table decline and impacts on groundwater users and groundwater-dependent ecosystems. However, there is potential to improve the sustainable use of groundwater resources through improvements in management practices. We discuss some of the challenges, and present survey results of research, government, and industry professionals across the groundwater sector in Australia. New hydrological insights for the region: The highest-ranked challenge identified in the survey was the difficulty in determining regional-scale volumetric water extraction limits. This is surprising given the criticism in the international literature of volumetric based approaches for groundwater management, and the decreased reliance on this approach in Australia and elsewhere in recent years. Other major challenges are the difficulty in determining and implementing maximum drawdown criteria for groundwater levels, determining water needs of ecosystems, and managing groundwater impacts on surface water. Notwithstanding these gaps in technical understanding and tools and a lack of resources for groundwater studies, improvements in stakeholder communication should enable more effective decision-making and improve compliance with regulations designed to protect groundwater and dependent ecosystems

Ack1 Mediated AKT/PKB Tyrosine 176 Phosphorylation Regulates Its Activation

The AKT/PKB kinase is a key signaling component of one of the most frequently activated pathways in cancer and is a major target of cancer drug development. Most studies have focused on its activation by Receptor Tyrosine Kinase (RTK) mediated Phosphatidylinositol-3-OH kinase (PI3K) activation or loss of Phosphatase and Tensin homolog (PTEN). We have uncovered that growth factors binding to RTKs lead to activation of a non-receptor tyrosine kinase, Ack1 (also known as ACK or TNK2), which directly phosphorylates AKT at an evolutionarily conserved tyrosine 176 in the kinase domain. Tyr176-phosphorylated AKT localizes to the plasma membrane and promotes Thr308/Ser473-phosphorylation leading to AKT activation. Mice expressing activated Ack1 specifically in the prostate exhibit AKT Tyr176-phosphorylation and develop murine prostatic intraepithelial neoplasia (mPINs). Further, expression levels of Tyr176-phosphorylated-AKT and Tyr284-phosphorylated-Ack1 were positively correlated with the severity of disease progression, and inversely correlated with the survival of breast cancer patients. Thus, RTK/Ack1/AKT pathway provides a novel target for drug discovery

The HER4 Cytoplasmic Domain, But Not Its C Terminus, Inhibits Mammary Cell Proliferation

Unlike the proliferative action of other EGF receptor family members, HER4/ErbB4 is often associated with growth inhibitory and differentiation signaling. These actions may involve HER4 two-step proteolytic processing by intra-membraneous γ-secretase, releasing the soluble, intracellular 80kDa HER4 cytoplasmic domain, s80HER4. We demonstrate that pharmacologic inhibition of either γ-secretase activity or HER4 tyrosine kinase activity blocked heregulin-dependent growth inhibition of SUM44 breast cancer cells. We next generated breast cell lines stably expressing GFP-s80HER4 (GFP fused to the N-terminus of the HER4 cytoplasmic domain, residues 676–1308), GFP-CTHER4 (GFP fused to N-terminus of the HER4 C-terminus distal to the tyrosine kinase domain, residues 989–1308) or GFP alone. Both GFP-s80HER4 and GFP-CTHER4 were found in the nucleus, but GFP-s80HER4 accumulated to a greater extent and sustained its nuclear localization. s80HER4 was constitutively tyrosine phosphorylated and treatment of cells with a specific HER family tyrosine kinase inhibitor i) blocked tyrosine phosphorylation; ii) markedly diminished GFP-s80HER4 nuclear localization, and iii) reduced STAT5A tyrosine phosphorylation and nuclear localization as well as GFP-s80HER4:STAT5A interaction. Multiple normal mammary and breast cancer cell lines, stably expressing GFP-s80HER4 (SUM44, MDA-MB-453, MCF10A, SUM102, and HC11) were growth inhibited compared to the same cell line expressing GFP-CTHER4, or GFP alone. The s80HER4-induced cell number reduction was due to slower growth, as rates of apoptosis were equivalent in GFP, GFP-CTHER4, and GFP-s80HER4 expressing cells. Lastly, GFP-s80HER4 enhanced differentiation signaling as indicated by increased basal and prolactin-dependent β–casein expression. These results indicate that surface HER4 tyrosine phosphorylation and ligand-dependent release of s80HER4 are necessary, and s80HER4 signaling is sufficient for HER4-dependent growth inhibition

Environmental change: prospects for conservation and agriculture in a southwest Australia biodiversity hotspot

Accelerating environmental change is perhaps the greatest challenge for natural resource management; successful strategies need to be effective for decades to come. Our objective is to identify opportunities that new environmental conditions may provide for conservation, restoration, and resource use in a globally recognized biodiversity hotspot in southwestern Australia. We describe a variety of changes to key taxonomic groups and system-scale characteristics as a consequence of environmental change (climate and land use), and outline strategies for conserving and restoring important ecological and agricultural characteristics. Opportunities for conservation and economic adaptation are substantial because of gradients in rainfall, temperature, and land use, extensive areas of remnant native vegetation, the ability to reduce and ameliorate areas affected by secondary salinization, and the existence of large national parks and an extensive network of nature reserves. Opportunities presented by the predicted environmental changes encompass agricultural as well as natural ecosystems. These may include expansion of aquaculture, transformation of agricultural systems to adapt to drier autumns and winters, and potential increases in spring and summer rain, carbon-offset plantings, and improving the network of conservation reserves. A central management dilemma is whether restoration/preservation efforts should have a commercial or biodiversity focus, and how they could be integrated. Although the grand challenge is conserving, protecting, restoring, and managing for a future environment, one that balances economic, social, and environmental values, the ultimate goal is to establish a regional culture that values the unique regional environment and balances the utilization of natural resources against protecting remaining natural ecosystems