Diabetic retinopathy (DR), a sight-threatening neurovasculopathy, is the leading cause of irreversible blindness in the developed world. DR arises as the result of prolonged hyperglycemia and is ...characterized by leaky retinal vasculature, retinal ischemia, retinal inflammation, angiogenesis, and neovascularization. The number of DR patients is growing with an increase in the elderly population, and therapeutic approaches are limited, therefore, new therapies to prevent retinal injury and enhance repair are a critical unmet need. Besides vascular endothelial growth factor (VEGF)-induced vascular proliferation, several other mechanisms are important in the pathogenesis of diabetic retinopathy, including vascular inflammation. Thus, combining anti-VEGF therapy with other new therapies targeting these pathophysiological pathways of DR may further optimize treatment outcomes. Technological advancements have allowed for high-throughput proteomic studies examining biofluids such as aqueous humor, vitreous humor, tear, and serum. Many DR biomarkers have been identified, especially proteins involved in retinal inflammatory processes. This review attempts to summarize the proteomic biomarkers of DR-associated retinal inflammation identified over the last several years.
This paper uses the task-content-of-occupations framework to analyze trends in employment and wages of female and male workers in the Indian labor market from 1994 to 2017. Workers are classified ...into four main occupational categories: nonroutine cognitive, routine cognitive, nonroutine manual, and routine manual. Decomposing the changes in employment shares into between-industry changes and within-industry changes across occupational categories reveals that within-industry employment changes have increasingly played an important role, suggesting the growing importance of using the task-content framework to analyze labor market trends. The biggest increase in employment shares is for nonroutine cognitive occupations for both female and male workers. The wage analysis reveals that, on average, the gender wage gap has been lowest in routine cognitive occupations for most of the period of analysis. However, the analysis finds no consistent, significant changes in wages based on occupational specialization during the period of analysis.
The severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) pandemic in 2020 highlighted the need for rapid, widespread responses against infectious disease. One such innovation uses ...CRISPR‐Cas13 technology to directly target and cleave viral RNA, thereby inhibiting replication. Due to their programmability, Cas13‐based antiviral therapies can be rapidly deployed to target emerging viruses, in comparison with traditional therapeutic development that takes at least 12–18 months, and often many years. Moreover, similar to the programmability of mRNA vaccines, Cas13 antivirals can be developed to target mutations as the virus evolves.
This Commentary discusses the development and potential clinical translation of the Cas13‐based antiviral therapies.
Interleukin-6 (IL-6) is implicated in various retinal and vascular complications associated with diabetic retinopathy (DR). This cytokine functions through two main modalities: classical signaling, ...in cells expressing the membrane-bound receptor (IL-6Rα); and trans-signaling, possible in most cells through a soluble form of the receptor (sIL-6R). These pathways are considered to be anti-inflammatory and pro-inflammatory, respectively. Our recent studies in retinal endothelial cells and diabetic mice have shown that inhibiting only IL-6 trans-signaling is sufficient to prevent increased vascular leakage, oxidative stress, and inflammation characteristic of DR. Isolating the specific effects of each signaling pathway, however, remains difficult in cells expressing IL-6Rα that are thus capable of both classical and trans-signaling. Müller glial cells (MGCs), the most abundant retinal macroglial cells, span the entire retinal thickness with vital roles in maintaining retinal homeostasis and regulating the blood-retinal barrier through secreted factors. The specific effects of IL-6 trans-signaling in MGCs remain poorly understood given their responsiveness to both IL-6 signaling modalities. In this study, we addressed these concerns by generating an MGC-specific knockout mouse using Cre-loxP deletion of the Il6ra cytokine-binding region. We assessed transcriptional and translational Il6ra expression to confirm the knockout and characterized the effects of knockout on visual functioning in these mice.
Abstract The development of synthetic hydrogels analogs for the extracellular matrix has proven a useful and important tool to study the role of specific signals on biological outcomes in vitro and ...to serve as scaffolds for tissue repair. Although the importance of physical properties (e.g. microstructure and stiffness) in the micro and nano scale on cell fate has been widely reported, bulk modulus measurements are typically used to characterize hydrogels. Thus, the physical properties of hydrogels have not been widely tested for their controlled physical properties in the nano and micron scales. In this report, we show that although fast Michael-type addition crosslinked hydrogels appear uniform by bulk modulus readings and visual inspection, they are non-uniform in the micron scale, with high and low crosslinking regions. Further, we show that these regions of high and low crosslinking result in differences in cellular behavior. Since these regions are random in density and shape, this leads to misleading cellular responses. These inconsistences are most widely observed when the gel forms faster than the material can be mixed. This study slows the gelation rate of thiol-maleimide cross-linked hydrogels in order to overcome the cellular response variability between batches.
This paper examines the differential effects, based on the size of the plant, of industry-level foreign direct investment (FDI) on plant-level employment and the wages of skilled and unskilled ...workers in India's manufacturing sector. On average, there are strong positive differential effects of increased inward-level FDI for large plants relative to small and average-sized plants in terms of employment and the average wages of both skilled and unskilled workers. Small plants experience negative effects from inward FDI, which can be explained by intra-industry reallocation of output from smaller to larger plants. After conducting a regional analysis, I find positive spillovers to small plants in Indian states that receive large and persistent flows of FDI. This suggests that a critical mass of FDI is necessary for small plants to experience positive spillover effects.
Sensitive methods for risk stratification, monitoring therapeutic efficacy, and early relapse detection may have a major impact on treatment decisions and patient management for stage III colorectal ...cancer patients. Beyond assessing the predictive power of postoperative ctDNA detection, we explored the added benefits of serial analysis: assessing adjuvant chemotherapy (ACT) efficacy, early relapse detection, and ctDNA growth rates.
We recruited 168 patients with stage III colorectal cancer treated with curative intent at Danish and Spanish hospitals between 2014 and 2019. To quantify ctDNA in plasma samples (
= 1,204), 16 patient-specific somatic single-nucleotide variants were profiled using multiplex-PCR, next-generation sequencing.
Detection of ctDNA was a strong recurrence predictor postoperatively HR = 7.0; 95% confidence interval (CI), 3.7-13.5;
< 0.001 and directly after ACT (HR = 50.76; 95% CI, 15.4-167;
< 0.001). The recurrence rate of postoperative ctDNA-positive patients treated with ACT was 80% (16/20). Only patients who cleared ctDNA permanently during ACT did not relapse. Serial ctDNA assessment after the end of treatment was similarly predictive of recurrence (HR = 50.80; 95% CI, 14.9-172;
< 0.001), and revealed two distinct rates of exponential ctDNA growth, slow (25% ctDNA-increase/month) and fast (143% ctDNA-increase/month;
< 0.001). The ctDNA growth rate was prognostic of survival (HR = 2.7; 95% CI, 1.1-6.7;
= 0.039). Serial ctDNA analysis every 3 months detected recurrence with a median lead-time of 9.8 months compared with standard-of-care computed tomography.
Serial postoperative ctDNA analysis has a strong prognostic value and enables tumor growth rate assessment. The novel combination of ctDNA detection and growth rate assessment provides unique opportunities for guiding decision-making.
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Eukaryotes contain inorganic polyphosphate (polyP) and acidocalcisomes, which sequester polyP and store amino acids and divalent cations. Why polyP is sequestered in dedicated organelles is not ...known. We show that polyP produced in the cytosol of yeast becomes toxic. Reconstitution of polyP translocation with purified vacuoles, the acidocalcisomes of yeast, shows that cytosolic polyP cannot be imported, whereas polyP produced by the vacuolar transporter chaperone (VTC) complex, an endogenous vacuolar polyP polymerase, is efficiently imported and does not interfere with growth. PolyP synthesis and import require an electrochemical gradient, probably as a driving force for polyP translocation. VTC exposes its catalytic domain to the cytosol and carries nine vacuolar transmembrane domains. Mutations in the VTC transmembrane regions, which are likely to constitute the translocation channel, block not only polyP translocation but also synthesis. Given that they are far from the cytosolic catalytic domain of VTC, this suggests that the VTC complex obligatorily couples synthesis of polyP to its import in order to avoid toxic intermediates in the cytosol. Sequestration of otherwise toxic polyP might be one reason for the existence of acidocalcisomes in eukaryotes.
MicroRNAs are non-coding RNAs that serve as regulatory molecules in a variety of pathways such as inflammation, metabolism, homeostasis, cell machinery, and development. With the progression of ...sequencing methods and modern bioinformatics tools, novel roles of microRNAs in regulatory mechanisms and pathophysiological states continue to expand. Advances in detection methods have further enabled larger adoption of studies utilizing minimal sample volumes, allowing the analysis of microRNAs in low-volume biofluids, such as the aqueous humor and tear fluid. The reported abundance of extracellular microRNAs in these biofluids has prompted studies to explore their biomarker potential. This review compiles the current literature reporting microRNAs in human tear fluid and their association with ocular diseases including dry eye disease, Sjögren's syndrome, keratitis, vernal keratoconjunctivitis, glaucoma, diabetic macular edema, and diabetic retinopathy, as well as non-ocular diseases, including Alzheimer's and breast cancer. We also summarize the known roles of these microRNAs and shed light on the future progression of this field.
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