Angiogenesis: An update and potential drug approaches

The therapeutic potential of targeting tumor endothelium and vascular supply is now widely recognized to treat different diseases. One such disease is cancer; where endothelial cells are actively proliferating to support the tumor growth. Solid tumors cannot grow beyond the size of a few millimeters without inducing the proliferation of endothelium and formation of new blood vessels. Hence it is crucial to search for new agents that selectively block tumor blood supply. These include anti-angiogenic molecules, vascular disrupting agents or endothelial disrupting agents. The anti-angiogenic molecules such as monoclonal antibodies and tyrosine kinase inhibitors disrupt endothelial cell survival mechanisms and new blood vessel formation, and vascular disrupting agents for instance ligand-directed and small molecules can be used to disrupt the already existing abnormal vasculature that support tumors by targeting their dysmorphic endothelial cells. The recent advances in this area of research have identified a variety of investigational agents which are currently in clinical development at various stages and some of these candidates are already approved in cancer treatment. This report will review some of the recent developments and most significant advances in this field and outline future challenges and directions

A Facile Nanoparticle Immunoassay for Cancer Biomarker Discovery

<p>Abstract</p> <p>Background</p> <p>Gold nanoparticles (AuNPs) scatter light intensely at or near their surface plasmon wavelength region. Using AuNPs coupled with dynamic light scattering (DLS) detection, we developed a facile nanoparticle immunoassay for serum protein biomarker detection and analysis. A serum sample was first mixed with a citrate-protected AuNP solution. Proteins from the serum were adsorbed to the AuNPs to form a protein corona on the nanoparticle surface. An antibody solution was then added to the assay solution to analyze the target proteins of interest that are present in the protein corona. The protein corona formation and the subsequent binding of antibody to the target proteins in the protein corona were detected by DLS.</p> <p>Results</p> <p>Using this simple assay, we discovered multiple molecular aberrations associated with prostate cancer from both mice and human blood serum samples. From the mice serum study, we observed difference in the size of the protein corona and mouse IgG level between different mice groups (i.e., mice with aggressive or less aggressive prostate cancer, and normal healthy controls). Furthermore, it was found from both the mice model and the human serum sample study that the level of vascular endothelial growth factor (VEGF, a protein that is associated with tumor angiogenesis) adsorbed to the AuNPs is decreased in cancer samples compared to non-cancerous or less malignant cancer samples.</p> <p>Conclusion</p> <p>The molecular aberrations observed from this study may become new biomarkers for prostate cancer detection. The nanoparticle immunoassay reported here can be used as a convenient and general tool to screen and analyze serum proteins and to discover new biomarkers associated with cancer and other human diseases.</p

Is it for generation me? A qualitative study exploring marketing and selling plants online to millennial-aged consumers

As online selling of products like living plants increases, it is increasingly important to understand how millennial-aged consumers perceive the purchasing experience. New-media technologies like social media, e-newsletters, and other forms of digital communication are easily adopted by millennial-aged consumers. One of these tools, 360-degree video, offers novel ways to preview products offered online and look inside local brick-and-mortar stores, which can be visited in person. Sales of horticultural goods online have been slow to be developed by industry veterans, creating ample opportunities available to new ventures. This qualitative study used a series of three focus groups to answer the research questions of RQ1: What challenges exist for garden centers attracting millennials? RQ2: What are millennials preferences for purchasing live plants online? RQ3: What aspects of digital online marketing influence millennials to make decisions? RQ4: What are millennials preferences for 360-degree video? Results of this study indicate 360-degree video is not the preferred avenue for marketing plants online to millennials, however, high-quality photos and video with educational content and the use of social media could be effective

De novo design of immunoglobulin-like domains

Antibodies, and antibody derivatives such as nanobodies, contain immunoglobulin-like (Ig) β-sandwich scaffolds which anchor the hypervariable antigen-binding loops and constitute the largest growing class of drugs. Current engineering strategies for this class of compounds rely on naturally existing Ig frameworks, which can be hard to modify and have limitations in manufacturability, designability and range of action. Here, we develop design rules for the central feature of the Ig fold architecture—the non-local cross-β structure connecting the two β-sheets—and use these to design highly stable Ig domains de novo, confirm their structures through X-ray crystallography, and show they can correctly scaffold functional loops. Our approach opens the door to the design of antibody-like scaffolds with tailored structures and superior biophysical properties.This research was supported by grants from the Spanish Ministry of Science and Innovation (RYC2018-025295-I, EUR2020-112164, and PID2020-120098GA-I00). This study was also supported in part by grants from Spanish and Catalan public and private bodies (grant/fellowship references MCIN/AEI/10.13039/501100011033/PID2019-107725RG-I00, 2017SGR3 and Fundació “La Marató de TV3” 201815). S.R.M. acknowledges grant BES2016-076877 from the Spanish State Agency for Research (MCIN/AEI/10.13039/501100011033) and the European Social Fund “ESF invests in your future”. U.E. was funded by a Beatriu de Pinós post-doctoral fellowship (AGAUR-MSCA COFUND 2018BP00163. J.R.T. was supported by an EMBO postdoctoral fellowship (under grant agreement ALTF 145-2021). J.C.K. was supported by a National Science Foundation Graduate Research Fellowship (grant DGE-1256082). D.B. and T.M.C. acknowledge the Howard Hughes Medical Institute. We thank the Princess Margaret Cancer Centre for funding of the NMR facility. The Structural Genomics Consortium is a registered charity (no: 1097737) that receives funds from Bayer AG, Boehringer Ingelheim, Bristol Myers Squibb, Genentech, Genome Canada through Ontario Genomics Institute [OGI-196], EU/EFPIA/OICR/McGill/KTH/Diamond Innovative Medicines Initiative 2 Joint Undertaking [EUbOPEN grant 875510], Janssen, Merck KGaA (aka EMD in Canada and US), Pfizer and Takeda

Light-driven chloride transport kinetics of halorhodopsin

Despite growing interest in light-driven ion pumps for use in optogenetics, current estimates of their transport rates span two orders of magnitude due to challenges in measuring slow transport processes and determining protein concentration and/or orientation in membranes in vitro. In this study, we report, to our knowledge, the first direct quantitative measurement of light-driven Cl transport rates of the anion pump halorohodopsin from Natronomonas pharaonis (NpHR). We used light-interfaced voltage clamp measurements on NpHR-expressing oocytes to obtain a transport rate of 219 (± 98) Cl /protein/s for a photon flux of 630 photons/protein/s. The measurement is consistent with the literature-reported quantum efficiency of ∼30% for NpHR, i.e., 0.3 isomerizations per photon absorbed. To reconcile our measurements with an earlier-reported 20 ms rate-limiting step, or 35 turnovers/protein/s, we conducted, to our knowledge, novel consecutive single-turnover flash experiments that demonstrate that under continuous illumination, NpHR bypasses this step in the photocycle

Comparative analysis of carboxysome shell proteins

Carboxysomes are metabolic modules for CO2 fixation that are found in all cyanobacteria and some chemoautotrophic bacteria. They comprise a semi-permeable proteinaceous shell that encapsulates ribulose-1,5-bisphosphate carboxylase/oxygenase (RuBisCO) and carbonic anhydrase. Structural studies are revealing the integral role of the shell protein paralogs to carboxysome form and function. The shell proteins are composed of two domain classes: those with the bacterial microcompartment (BMC; Pfam00936) domain, which oligomerize to form (pseudo)hexamers, and those with the CcmL/EutN (Pfam03319) domain which form pentamers in carboxysomes. These two shell protein types are proposed to be the basis for the carboxysome’s icosahedral geometry. The shell proteins are also thought to allow the flux of metabolites across the shell through the presence of the small pore formed by their hexameric/pentameric symmetry axes. In this review, we describe bioinformatic and structural analyses that highlight the important primary, tertiary, and quaternary structural features of these conserved shell subunits. In the future, further understanding of these molecular building blocks may provide the basis for enhancing CO2 fixation in other organisms or creating novel biological nanostructures

Impacts of urbanisation on the native avifauna of Perth, Western Australia

Urban development either eliminates, or severely fragments, native vegetation, and therefore alters the distribution and abundance of species that depend on it for habitat. We assessed the impact of urban development on bird communities at 121 sites in and around Perth, Western Australia. Based on data from community surveys, at least 83 % of 65 landbirds were found to be dependent, in some way, on the presence of native vegetation. For three groups of species defined by specific patterns of habitat use (bushland birds), there were sufficient data to show that species occurrences declined as the landscape changed from variegated to fragmented to relictual, according to the percentage of vegetation cover remaining. For three other groups (urban birds) species occurrences were either unrelated to the amount of vegetation cover, or increased as vegetation cover declined. In order to maximise the chances of retaining avian diversity when planning for broad-scale changes in land-use (i.e. clearing native vegetation for housing or industrial development), land planners should aim for a mosaic of variegated urban landscapes (\u3e60 % vegetation retention) set amongst the fragmented and relictual urban landscapes (% vegetation retention) that are characteristic of most cities and their suburbs. Management actions for conserving remnant biota within fragmented urban landscapes should concentrate on maintaining the integrity and quality of remnant native vegetation, and aim at building awareness among the general public of the conservation value of remnant native vegetation

Consequences of various landscape-scale ecosystem management strategies and fire cycles on age-class structure and harvest in boreal forests

At the landscape scale, one of the key indicators of sustainable forest management is the age-class distribution of stands, since it provides a coarse synopsis of habitat potential, structural complexity, and stand volume, and it is directly modified by timber extraction and wildfire. To explore the consequences of several landscape-scale boreal forest management strategies on age-class structure in the Mauricie region of Quebec, we used spatially explicit simulation modelling. Our study investigated three different harvesting strategies (the one currently practiced and two different strategies to maintain late seral stands) and interactions between fire and harvesting on stand age-class distribution. We found that the legacy of initial forested age structure and its spatial configuration can pose short- (<50 years) to medium-term (150-300 years) challenges to balancing wood supply and ecological objectives. Also, ongoing disturbance by fire, even at relatively long cycles in relation to historic levels, can further constrain the achievement of both timber and biodiversity goals. For example, when fire was combined with management, harvest shortfalls occurred in all scenarios with a fire cycle of 100 years and most scenarios with a fire cycle of 150 years. Even a fire cycle of 500 years led to a reduction in older forest when its maintenance was not a primary constraint. Our results highlight the need to consider the broad-scale effects of natural disturbance when developing ecosystem management policies and the importance of prioritizing objectives when planning for multiple resource use

Mutations in the SPG7 gene cause chronic progressive external ophthalmoplegia through disordered mitochondrial DNA maintenance.

Despite being a canonical presenting feature of mitochondrial disease, the genetic basis of progressive external ophthalmoplegia remains unknown in a large proportion of patients. Here we show that mutations in SPG7 are a novel cause of progressive external ophthalmoplegia associated with multiple mitochondrial DNA deletions. After excluding known causes, whole exome sequencing, targeted Sanger sequencing and multiplex ligation-dependent probe amplification analysis were used to study 68 adult patients with progressive external ophthalmoplegia either with or without multiple mitochondrial DNA deletions in skeletal muscle. Nine patients (eight probands) were found to carry compound heterozygous SPG7 mutations, including three novel mutations: two missense mutations c.2221G>A; p.(Glu741Lys), c.2224G>A; p.(Asp742Asn), a truncating mutation c.861dupT; p.Asn288*, and seven previously reported mutations. We identified a further six patients with single heterozygous mutations in SPG7, including two further novel mutations: c.184-3C>T (predicted to remove a splice site before exon 2) and c.1067C>T; p.(Thr356Met). The clinical phenotype typically developed in mid-adult life with either progressive external ophthalmoplegia/ptosis and spastic ataxia, or a progressive ataxic disorder. Dysphagia and proximal myopathy were common, but urinary symptoms were rare, despite the spasticity. Functional studies included transcript analysis, proteomics, mitochondrial network analysis, single fibre mitochondrial DNA analysis and deep re-sequencing of mitochondrial DNA. SPG7 mutations caused increased mitochondrial biogenesis in patient muscle, and mitochondrial fusion in patient fibroblasts associated with the clonal expansion of mitochondrial DNA mutations. In conclusion, the SPG7 gene should be screened in patients in whom a disorder of mitochondrial DNA maintenance is suspected when spastic ataxia is prominent. The complex neurological phenotype is likely a result of the clonal expansion of secondary mitochondrial DNA mutations modulating the phenotype, driven by compensatory mitochondrial biogenesis