Measured Response for UAS Integration into the National Airspace System

The measured response (MR) is the response time of aircraft to Air Traffic Controller (ATCo) commands and clearances. The overall MR can be broken up into several components, including the pilot verbal latencies (MR1), the time between the end of an ATCo clearance and the beginning of the pilots read back, and the execution initiation latency (MR2), the time between the end of the ATCos clearance and when the pilot begins to execute a maneuver. The MR is a crucial concern for the integration of Unmanned Aircraft Systems (UAS) into the National Airspace System (NAS) due to potentially greater latencies stemming from remote pilot communication and command execution. As a result, it is important to quantify what latencies in verbal responding and command execution are acceptable for safe and efficient operations in the NAS. The present studies begin to address these issues in a series of four simulations supported by the UAS Integration into the NAS program

Peripherin-2 and Rom-1 have opposing effects on rod outer segment targeting of retinitis pigmentosa-linked peripherin-2 mutants

Mutations in the photoreceptor outer segment (OS) specific peripherin-2 lead to autosomal dominant retinitis pigmentosa (adRP). By contrast, mutations in the peripherin-2 homolog Rom-1 cause digenic RP in combination with certain heterozygous mutations in peripherin-2. The mechanisms underlying the differential role of peripherin-2 and Rom-1 in RP pathophysiology remained elusive so far. Here, focusing on two adRP-linked peripherin-2 mutants, P210L and C214S, we analyzed the binding characteristics, protein assembly, and rod OS targeting of wild type (per(WT)), mutant peripherin-2 (per(MT)), or Rom-1 complexes, which can be formed in patients heterozygous for peripherin-2 mutations. Both mutants are misfolded and lead to decreased binding to per(WT) and Rom-1. Furthermore, both mutants are preferentially forming non-covalent per(MT)-per(MT), per(WT)-per(MT), and Rom-1-per(MT) dimers. However, only per(WT)-per(MT), but not per(MT)-per(MT) or Rom-1-per(MT) complexes could be targeted to murine rod OS. Our study provides first evidence that non-covalent per(WT)-per(MT) dimers can be targeted to rod OS. Finally, our study unravels unexpected opposing roles of per(WT) and Rom-1 in rod OS targeting of adRP-linked peripherin-2 mutants and suggests a new treatment strategy for the affected individuals

The Performance of Alternative Livelihood Initiatives on Local Livelihoods and Forest Conservation Management - A Case Study in Talai Commune, Dong Nai Province, Vietnam

Protected forest areas worldwide are located close to forest dependent communities that continue to use forest resources for their livelihoods to varying extents. With these areas designated as protected areas it prevents local people from practising their traditional income-generating or subsistence activities that rely on access to forest areas. Although governments view protected areas as a measure for forest conservation, they pose a number of key challenges to local people's livelihoods. In a number of developing countries, including Vietnam, the use of forest resources in protected areas have presented a threat to forest conservation outcomes. A satisfactory resolution to the tension between livelihoods and biodiversity conservation objectives in protected areas is an ongoing challenge for governments and local people living near protected areas. Cat Tien National Park, a protected area in Dong Nai Province, Vietnam is well-known for its diversity of flora and fauna and offers a noteworthy case study. One of the issues in Cat Tien National Park is the practice of collecting non-timber forest products that is considered widespread, despite it being illegal under the protected status of the Park. Achieving forest conservation goals under these circumstances, even if extraction levels were low, appears to be a challenging task. In order to address livelihood challenges, governmental agencies, and non-governmental organisations have attempted to engage local people in alternative livelihood initiatives. These initiatives commonly seek to provide new income sources as a substitute for earnings from traditional livelihood practices, thereby reducing extraction pressures on the Park. These livelihood initiatives have been active in the last thirteen years. The aim of this thesis is therefore to examine the performance of two alternative livelihood initiatives (the Talai Ecotourism Venture and the Forest Protection Team (FPT)) on local livelihoods for those ethnic groups living in close proximity to the Park and associated effects on forest conservation management goals. The research provided insights into the participation of local people in decisions about the management and conservation of forest resources in their role as FPT members. It also attempts to draw lessons that can be applied to alternative livelihood initiatives elsewhere in Vietnam and other developing countries. A case study approach with a mixed method has been employed in this study. Household surveys (n=150) of three ethnic groups (Chau Ma, Stieng and Kinh) and key informant interviews (n=36) were conducted to collect data on a range of aspects, including: household demographics, forest usage, and local views on the impact of the two alternative livelihood initiatives on their livelihood and perception of forest conservation. The key informants were interviewed at length about their roles, responsibilities, the quality of the local participation, and evaluation of the effectiveness of the two alternative livelihood initiatives on local livelihood and forest conservation. Field research findings were supplemented and triangulated with participant observation activities to gain insight into the physical, social, cultural, and economic aspects of the case context. About one third of Chau Ma and Stieng households had a high reliance on NTFPs, while Kinh households had no reliance on NTFPs for their livelihood. The dependence on NTFPs for Chau Ma and Stieng people was a result of limited opportunities for other livelihood options due to relinquishing agricultural land and low education levels. For Chau Ma and Stieng people struggling to adjust from a subsistence forest-based livelihood to living outside the forest, around 41% continued to visit the forest for cultural reasons, but at low to moderate levels (63%). A significant finding of the study is that the benefits of the alternative livelihood initiatives did not extend to the whole community and were focused largely on those ethnic minorities of Chau Ma and Stieng directly involved in the initiatives. Further, for the two alternative livelihood initiatives, the direct participants gained the greatest benefits either through employment, access to Village Development Fund, or greater access to NTFPs. The study has also found that current livelihood initiatives have not been effective due to limited local participation in decision-making processes, and minimal interaction with local people outside the initiatives. Specifically, the governance of these initiatives was not aligned with communitybased principles. The one-way information sharing, and top-down decision-making led to the ethnic minorities assuming only a passive role in the process for the two alternative livelihood initiatives. In addition, local members of both livelihood initiatives did not receive the training or support they required to effectively carry out their responsibilities. The results of the case studies also showed that there was a lack of responsiveness from key governing authorities such as the Private Company, Talai Forest Station, Park Board to variations in ethnic groups' socio-economic status, and levels of literacy. As a whole, such deficient governance arrangements and processes prevented the initiatives from achieving their goals and engaging with the broader community. In addition, evidence suggests that the Talai Ecotourism Venture and the Forest Protection Team initiatives have not led to a substantial change in local people's awareness of the importance of forest conservation and lessening the pressure on forest resource extraction as expected. These findings demonstrate the need for better governance, which provide stakeholders with the ability to demonstrate their understanding and fulfil their responsibilities independently. A greater level of accountability and transparency in benefit sharing mechanisms such as Village Development Fund (Talai Ecotourism Venture), and Forest Protection Team reporting is also required for ensuring greater community participation and empowerment. Another important implication of improved accountability is for a more effective relationship between government, private enterprise and local people in decision making and empowering them in their roles. Finally, the findings also highlight the significance of capacity building for various stakeholders so that they can develop skills and knowledge required to carry out decision-making responsibilities in ecotourism and forest management. Most importantly, alternative livelihood initiatives need to be designed and implemented with sensitivity to the local cultures otherwise; they can limit potential equality and increase obstacles to local people's participation and decision-making. Thus, it is recommended that Indigenous knowledge should be recognized and incorporated into initiatives for protecting and managing forest resources

Dual roles of the transmembrane protein p23/TMP21 in the modulation of amyloid precursor protein metabolism

BACKGROUND: Alzheimer's disease (AD) is characterized by cerebral deposition of β-amyloid (Aβ) peptides. Aβ is released from ectodomain cleaved amyloid precursor protein (APP) via intramembranous proteolysis by γ-secretase, a complex consisting of presenilin and a few other proteins. p23/TMP21, a member of the p24 family type I transmembrane proteins, was recently identified as a presenilin complex component capable of modulating γ-secretase cleavage. The p24 family proteins form oligomeric complexes and regulate vesicular trafficking in the early secretory pathway, but their role in APP trafficking has not been investigated. RESULTS: Here, we report that siRNA-mediated depletion of p23 in N2a neuroblastoma and HeLa cells produces concomitant knockdown of additional p24 family proteins and increases secretion of sAPP. Furthermore, intact cell and cell-free Aβ production increases following p23 knockdown, similar to data reported earlier using HEK293 cells. However, we find that p23 is not present in mature γ-secretase complexes isolated using an active-site γ-secretase inhibitor. Depletion of p23 and expression of a familial AD-linked PS1 mutant have additive effects on Aβ(42 )production. Knockdown of p23 expression confers biosynthetic stability to nascent APP, allowing its efficient maturation and surface accumulation. Moreover, immunoisolation analyses show decrease in co-residence of APP and the APP adaptor Mint3. Thus, multiple lines of evidence indicate that p23 function influences APP trafficking and sAPP release independent of its reported role in γ-secretase modulation. CONCLUSION: These data assign significance to p24 family proteins in regulating APP trafficking in the continuum of bidirectional transport between the ER and Golgi, and ascribe new relevance to the regulation of early trafficking in AD pathogenesis

East Bay Coalition for the Homeless: Branding Study and Marketing Strategy

There are a number of potential positioning strategies. The two which make the most sense for the EBCH are to “position the EBCH away from others in the category” and to “position the EBCH as unique.” These strategies have the advantage of setting the EBCH apart from the other organizations that address homelessness. Occupying its own “position” in the minds of potential and current donors is not only an effective communications/marketing strategy but also a less costly one because it avoids head-to-head competition and comparisons

Flow analysis from multiparticle azimuthal correlations

We present a new method for analyzing directed and elliptic flow in heavy ion collisions. Unlike standard methods, it separates the contribution of flow to azimuthal correlations from contributions due to other effects. The separation relies on a cumulant expansion of multiparticle azimuthal correlations, and includes corrections for detector inefficiencies. This new method allows the measurement of the flow of identified particles in narrow phase-space regions, and can be used in every regime, from intermediate to ultrarelativistic energies.Comment: 31 pages, revtex. Published version (references added

In Vivo Analysis of Disease-Associated Point Mutations Unveils Profound Differences in mRNA Splicing of Peripherin-2 in Rod and Cone Photoreceptors

Point mutations in peripherin-2 (PRPH2) are associated with severe retinal degenerative disorders affecting rod and/or cone photoreceptors. Various disease-causing mutations have been identified, but the exact contribution of a given mutation to the clinical phenotype remains unclear. Exonic point mutations are usually assumed to alter single amino acids, thereby influencing specific protein characteristics;however, they can also affect mRNA splicing. To examine the effects of distinct PRPH2 point mutations on mRNA splicing and protein expression in vivo, we designed PRPH2 minigenes containing the three coding exons and relevant intronic regions of human PRPH2. Minigenes carrying wild type PRPH2 or PRPH2 exon 2 mutations associated with rod or cone disorders were expressed in murine photoreceptors using recombinant adeno-associated virus (rAAV) vectors. We detect three PRPH2 splice isoforms in rods and cones: correctly spliced, intron 1 retention, and unspliced. In addition, we show that only the correctly spliced isoform results in detectable protein expression. Surprisingly, compared to rods, differential splicing leads to lower expression of correctly spliced and higher expression of unspliced PRPH2 in cones. These results were confirmed in qRT-PCR experiments from FAC-sorted murine rods and cones. Strikingly, three out of five cone disease-causing PRPH2 mutations profoundly enhanced correct splicing of PRPH2, which correlated with strong upregulation of mutant PRPH2 protein expression in cones. By contrast, four out of six PRPH2 mutants associated with rod disorders gave rise to a reduced PRPH2 protein expression via different mechanisms. These mechanisms include aberrant mRNA splicing, protein mislocalization, and protein degradation. Our data suggest that upregulation of PRPH2 levels in combination with defects in the PRPH2 function caused by the mutation might be an important mechanism leading to cone degeneration. By contrast, the pathology of rod-specific PRPH2 mutations is rather characterized by PRPH2 downregulation and impaired protein localization

Novel Small Molecules Targeting the Intrinsically Disordered Structural Ensemble of a-Synuclein Protect Against Diverse a-Synuclein Mediated Dysfunctions

The over-expression and aggregation of α-synuclein (αSyn) are linked to the onset and pathology of Parkinson’s disease. Native monomeric αSyn exists in an intrinsically disordered ensemble of interconverting conformations, which has made its therapeutic targeting by small molecules highly challenging. Nonetheless, here we successfully target the monomeric structural ensemble of αSyn and thereby identify novel drug-like small molecules that impact multiple pathogenic processes. Using a surface plasmon resonance high-throughput screen, in which monomeric αSyn is incubated with microchips arrayed with tethered compounds, we identified novel αSyn interacting drug-like compounds. Because these small molecules could impact a variety of αSyn forms present in the ensemble, we tested representative hits for impact on multiple αSyn malfunctions in vitro and in cells including aggregation and perturbation of vesicular dynamics. We thereby identified a compound that inhibits αSyn misfolding and is neuroprotective, multiple compounds that restore phagocytosis impaired by αSyn overexpression, and a compound blocking cellular transmission of αSyn. Our studies demonstrate that drug-like small molecules that interact with native αSyn can impact a variety of its pathological processes. Thus, targeting the intrinsically disordered ensemble of αSyn offers a unique approach to the development of small molecule research tools and therapeutics for Parkinson’s disease

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts

Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas

Although theMYConcogene has been implicated incancer, a systematic assessment of alterations ofMYC, related transcription factors, and co-regulatoryproteins, forming the proximal MYC network (PMN),across human cancers is lacking. Using computa-tional approaches, we define genomic and proteo-mic features associated with MYC and the PMNacross the 33 cancers of The Cancer Genome Atlas.Pan-cancer, 28% of all samples had at least one ofthe MYC paralogs amplified. In contrast, the MYCantagonists MGA and MNT were the most frequentlymutated or deleted members, proposing a roleas tumor suppressors.MYCalterations were mutu-ally exclusive withPIK3CA,PTEN,APC,orBRAFalterations, suggesting that MYC is a distinct onco-genic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such asimmune response and growth factor signaling; chro-matin, translation, and DNA replication/repair wereconserved pan-cancer. This analysis reveals insightsinto MYC biology and is a reference for biomarkersand therapeutics for cancers with alterations ofMYC or the PMN