Finding dex-1 Phenotype Suppressing Components

Caenorhabditis elegans is a species of microscopic round worm that has been used as a genetic model for over forty years. When in an adverse environment, C. elegans larvae cease reproductive development and enter the stress-resistant dauer stage. dex-1 mutants of C. elegans are deficient in this protein, resulting in shortened dendrites and a sensitivity to sodium dodecyl sulfate (SDS). SDS will kill any non-dauer C. elegans, but wild type dauers will survive well past the standard concentration of 1% SDS. Thus, treatment with SDS is commonly how labs isolate dauers. By contrast, dex-1 dauers (Fig.3) will die when exposed to 1% SDS, but can potentially survive when exposed to less. The focus of this lab is to characterize the genetic pathways that facilitate morphological changes that occur during the dauer stage by finding potential interactors of dex-1 during dauer when conducting a suppressor screen

The nidogen-domain protein DEX-1 is necessary for the Caenorhabditis elegans dauer morphology and behavior

The ability to modify a given phenotype to adapt to the external environment (i.e. phenotypic plasticity) is a critical component of an organism’s ability to survive unfavorable conditions. The free-living nematode, Caenorhabditis elegans is an excellent example of phenotypic plasticity. When exposed to unfavorable conditions, C. elegans halts reproductive development and enters an alternative developmental stage called dauer. Dauer larvae undergo extensive tissue remodeling, including changes to the outer cuticle, muscle, and nervous system. Although several morphological and behavioral traits of the dauer larvae have been described, the molecular mechanisms underlying dauer-specific tissue remodeling have remained poorly understood. This work provides evidence that the nidogen domain-containing protein DEX-1 facilitates the stage-specific tissue remodeling observed during dauer morphogenesis. DEX-1 was previously shown to function as a secreted extracellular matrix protein that regulates sensory dendrite formation during embryogenesis. However, we found an alternative developmental role for DEX-1. Specifically, we show that DEX-1 is also required for remodeling of the stem-cell like hypodermal seam cells and formation of the cuticular lateral alae. Further, we found that DEX-1 is necessary for proper dauer mobility, and may function as a component of the neuromuscular system to facilitate dauer locomotion behaviors. We show that dex-1 is secreted from the seam cells, but functions locally in a cell-autonomous manner to facilitate dauer morphogenesis. dex-1 expression during dauer is also regulated through DAF-16/FOXO-mediated transcriptional activation. Finally, we show that dex-1 genetically interacts with a family of zona pellucida-domain genes to regulate seam cell remodeling and alae formation. Taken together, this work shows that DEX-1 is an extracellular matrix component that plays a critical role in C. elegans tissue plasticity during dauer formation

The nidogen-domain protein DEX-1 is necessary for the Caenorhabditis elegans dauer morphology and behavior

The ability to modify a given phenotype to adapt to the external environment (i.e. phenotypic plasticity) is a critical component of an organism’s ability to survive unfavorable conditions. The free-living nematode, Caenorhabditis elegans is an excellent example of phenotypic plasticity. When exposed to unfavorable conditions, C. elegans halts reproductive development and enters an alternative developmental stage called dauer. Dauer larvae undergo extensive tissue remodeling, including changes to the outer cuticle, muscle, and nervous system. Although several morphological and behavioral traits of the dauer larvae have been described, the molecular mechanisms underlying dauer-specific tissue remodeling have remained poorly understood. This work provides evidence that the nidogen domain-containing protein DEX-1 facilitates the stage-specific tissue remodeling observed during dauer morphogenesis. DEX-1 was previously shown to function as a secreted extracellular matrix protein that regulates sensory dendrite formation during embryogenesis. However, we found an alternative developmental role for DEX-1. Specifically, we show that DEX-1 is also required for remodeling of the stem-cell like hypodermal seam cells and formation of the cuticular lateral alae. Further, we found that DEX-1 is necessary for proper dauer mobility, and may function as a component of the neuromuscular system to facilitate dauer locomotion behaviors. We show that dex-1 is secreted from the seam cells, but functions locally in a cell-autonomous manner to facilitate dauer morphogenesis. dex-1 expression during dauer is also regulated through DAF-16/FOXO-mediated transcriptional activation. Finally, we show that dex-1 genetically interacts with a family of zona pellucida-domain genes to regulate seam cell remodeling and alae formation. Taken together, this work shows that DEX-1 is an extracellular matrix component that plays a critical role in C. elegans tissue plasticity during dauer formation

Biomimetic-Membrane-Protected Plasmonic Nanostructures as Dual-Modality Contrast Agents for Correlated Surface-Enhanced Raman Scattering and Photoacoustic Detection of Hidden Tumor Lesions

Optical imaging and spectroscopic modalities are of considerable current interest for in vivo cancer detection and image-guided surgery, but the turbid or scattering nature of biomedical tissues has severely limited their abilities to detect buried or occluded tumor lesions. Here we report the development of a dual-modality plasmonic nanostructure based on colloidal gold nanostars (AuNSs) for simultaneous surface-enhanced Raman scattering (SERS) and photoacoustic (PA) detection of tumor phantoms embedded (hidden) in ex vivo animal tissues. By using red blood cell membranes as a naturally derived biomimetic coating, we show that this class of dual-modality contrast agents can provide both Raman spectroscopic and PA signals for the detection and differentiation of hidden solid tumors with greatly improved depths of tissue penetration. Compared to previous polymer-coated AuNSs, the biomimetic coatings are also able to minimize protein adsorption and cellular uptake when exposed to human plasma without compromising their SERS or PA signals. We further show that tumor-targeting peptides (such as cyclic RGD) can be noncovalently inserted for targeting the ανβ3-integrin receptors expressed on metastatic cancer cells and tracked via both SERS and PA imaging (PAI). Finally, we demonstrate image-guided resections of tumor-mimicking phantoms comprising metastatic tumor cells buried under layers of skin and fat tissues (6 mm in thickness). Specifically, PAI was used to determine the precise tumor location, while SERS spectroscopic signals were used for tumor identification and differentiation. This work opens the possibility of using these biomimetic dual-modality nanoparticles with superior signal and biological stability for intraoperative cancer detection and resection

Plantazolicin Is an Ultranarrow-Spectrum Antibiotic That Targets the Bacillus anthracis Membrane

Plantazolicin (PZN) is a ribosomally synthesized and post-translationally modified natural product from Bacillus methylotrophicus FZB42 and Bacillus pumilus. Extensive tailoring to 12 of the 14 amino acid residues in the mature natural product endows PZN with not only a rigid, polyheterocyclic structure, but also antibacterial activity. Here we report the remarkably discriminatory activity of PZN toward Bacillus anthracis, which rivals a previously described gamma (γ) phage lysis assay in distinguishing <i>B. anthracis</i> from other members of the Bacillus cereus group. We evaluate the underlying cause of this selective activity by measuring the RNA expression profile of PZN-treated <i>B. anthracis</i>, which revealed significant up-regulation of genes within the cell envelope stress response. PZN depolarizes the <i>B. anthracis</i> membrane like other cell envelope-acting compounds but uniquely localizes to distinct foci within the envelope. Selection and whole-genome sequencing of PZN-resistant mutants of <i>B. anthracis</i> implicate a relationship between the action of PZN and cardiolipin (CL) within the membrane. Exogenous CL increases the potency of PZN in wild type <i>B. anthracis</i> and promotes the incorporation of fluorescently tagged PZN in the cell envelope. We propose that PZN localizes to and exacerbates structurally compromised regions of the bacterial membrane, which ultimately results in cell lysis

Cell-Membrane Coated Nanoparticles for Tumor Delineation and Qualitative Estimation of Cancer Biomarkers at Single Wavelength Excitation in Murine and Phantom Models

Real-time guidance through fluorescence imaging improves the surgical outcomes of tumor resections, reducing the chances of leaving positive margins behind. As tumors are heterogeneous, it is imperative to interrogate multiple overexpressed cancer biomarkers with high sensitivity and specificity to improve surgical outcomes. However, for accurate tumor delineation and ratiometric detection of tumor biomarkers, current methods require multiple excitation wavelengths to image multiple biomarkers, which is impractical in a clinical setting. Here, we have developed a biomimetic platform comprising near-infrared fluorescent semiconducting polymer nanoparticles (SPNs) with red blood cell membrane (RBC) coating, capable of targeting two representative cell-surface biomarkers (folate, αυβ3 integrins) using a single excitation wavelength for tumor delineation during surgical interventions. We evaluate our single excitation ratiometric nanoparticles in in vitro tumor cells, ex vivo tumor-mimicking phantoms, and in vivo mouse xenograft tumor models. Favorable biological properties (improved biocompatibility, prolonged blood circulation, reduced liver uptake) are complemented by superior spectral features: (i) specific fluorescence enhancement in tumor regions with high tumor-to-normal tissue (T/NT) ratios in ex vivo samples and (ii) estimation of cell-surface tumor biomarkers with single wavelength excitation providing insights about cancer progression (metastases). Our single excitation, dual output approach has the potential to differentiate between the tumor and healthy regions and simultaneously provide a qualitative indicator of cancer progression, thereby guiding surgeons in the operating room with the resection process

The structural and social determinants of Alzheimer\u27s disease related dementias

INTRODUCTION: The projected growth of Alzheimer\u27s disease (AD) and AD-related dementia (ADRD) cases by midcentury has expanded the research field and impelled new lines of inquiry into structural and social determinants of health (S/SDOH) as fundamental drivers of disparities in AD/ADRD. METHODS: In this review, we employ Bronfenbrenner\u27s ecological systems theory as a framework to posit how S/SDOH impact AD/ADRD risk and outcomes. RESULTS: Bronfenbrenner defined the macrosystem as the realm of power (structural) systems that drive S/SDOH and that are the root cause of health disparities. These root causes have been discussed little to date in relation to AD/ADRD, and thus, macrosystem influences, such as racism, classism, sexism, and homophobia, are the emphasis in this paper. DISCUSSION: Under Bronfenbrenner\u27s macrosystem framework, we highlight key quantitative and qualitative studies linking S/SDOH with AD/ADRD, identify scientific gaps in the literature, and propose guidance for future research. HIGHLIGHTS: Ecological systems theory links structural/social determinants to AD/ADRD. Structural/social determinants accrue and interact over the life course to impact AD/ADRD. Macrosystem is made up of societal norms, beliefs, values, and practices (e.g., laws). Most macro-level determinants have been understudied in the AD/ADRD literature

Prospective observational cohort study on grading the severity of postoperative complications in global surgery research

Background The Clavien–Dindo classification is perhaps the most widely used approach for reporting postoperative complications in clinical trials. This system classifies complication severity by the treatment provided. However, it is unclear whether the Clavien–Dindo system can be used internationally in studies across differing healthcare systems in high- (HICs) and low- and middle-income countries (LMICs). Methods This was a secondary analysis of the International Surgical Outcomes Study (ISOS), a prospective observational cohort study of elective surgery in adults. Data collection occurred over a 7-day period. Severity of complications was graded using Clavien–Dindo and the simpler ISOS grading (mild, moderate or severe, based on guided investigator judgement). Severity grading was compared using the intraclass correlation coefficient (ICC). Data are presented as frequencies and ICC values (with 95 per cent c.i.). The analysis was stratified by income status of the country, comparing HICs with LMICs. Results A total of 44 814 patients were recruited from 474 hospitals in 27 countries (19 HICs and 8 LMICs). Some 7508 patients (16·8 per cent) experienced at least one postoperative complication, equivalent to 11 664 complications in total. Using the ISOS classification, 5504 of 11 664 complications (47·2 per cent) were graded as mild, 4244 (36·4 per cent) as moderate and 1916 (16·4 per cent) as severe. Using Clavien–Dindo, 6781 of 11 664 complications (58·1 per cent) were graded as I or II, 1740 (14·9 per cent) as III, 2408 (20·6 per cent) as IV and 735 (6·3 per cent) as V. Agreement between classification systems was poor overall (ICC 0·41, 95 per cent c.i. 0·20 to 0·55), and in LMICs (ICC 0·23, 0·05 to 0·38) and HICs (ICC 0·46, 0·25 to 0·59). Conclusion Caution is recommended when using a treatment approach to grade complications in global surgery studies, as this may introduce bias unintentionally