The ability to fabricate sensory systems capable of highly selective operation in complex fluid will undoubtedly underpin key future developments in healthcare. However, the abundance of ...(bio)molecules in these samples can significantly impede performance at the transducing interface where nonspecific adsorption (fouling) can both block specific signal (reducing sensitivity) and greatly reduce assay specificity. Herein, we aim to provide a comprehensive review discussing concepts and recent advances in the construction of antifouling sensors that are, through the use of chemical, physical, or biological engineering, capable of operating in complex sample matrix (e.g., serum). We specifically highlight a range of molecular approaches to the construction of solid sensory interfaces (planar and nanoparticulate) and their characterization and performance in diverse in vitro and in vivo analyte (e.g., proteins, nucleic acids, cells, neuronal transmitters) detection applications via derived selective optical or electrochemical strategies. We specifically highlight those sensors that are capable of detection in complex media or those based on novel architectures/approaches. Finally, we provide perspectives on future developments in this rapidly evolving field.
The coronavirus disease 2019 (COVID-19) pandemic has had significant economic impact on radiology with markedly decreased imaging case volumes. The purpose of this study was to quantify the imaging ...volumes during the COVID-19 pandemic across patient service locations and imaging modality types.
Imaging case volumes in a large health care system were retrospectively studied, analyzing weekly imaging volumes by patient service locations (emergency department, inpatient, outpatient) and modality types (x-ray, mammography, CT, MRI, ultrasound, interventional radiology, nuclear medicine) in years 2020 and 2019. The data set was split to compare pre-COVID-19 (weeks 1-9) and post-COVID-19 (weeks 10-16) periods. Independent-samples t tests compared the mean weekly volumes in 2020 and 2019.
Total imaging volume in 2020 (weeks 1-16) declined by 12.29% (from 522,645 to 458,438) compared with 2019. Post-COVID-19 (weeks 10-16) revealed a greater decrease (28.10%) in imaging volumes across all patient service locations (range 13.60%-56.59%) and modality types (range 14.22%-58.42%). Total mean weekly volume in 2020 post-COVID-19 (24,383 95% confidence interval 19,478-29,288) was statistically reduced (P = .003) compared with 33,913 95% confidence interval 33,429-34,396 in 2019 across all patient service locations and modality types. The greatest decline in 2020 was seen at week 16 specifically for outpatient imaging (88%) affecting all modality types: mammography (94%), nuclear medicine (85%), MRI (74%), ultrasound (64%), interventional (56%), CT (46%), and x-ray (22%).
Because the duration of the COVID-19 pandemic remains uncertain, these results may assist in guiding short- and long-term practice decisions based on the magnitude of imaging volume decline across different patient service locations and specific imaging modality types.
Increased glycolysis in the lung vasculature has been connected to the development of pulmonary hypertension (PH). We therefore investigated whether glycolytic regulator ...6-phosphofructo-2-kinase/fructose-2, 6-bisphosphatase (PFKFB3)-mediated endothelial glycolysis plays a critical role in the development of PH. Heterozygous global deficiency of Pfkfb3 protected mice from developing hypoxia-induced PH, and administration of the PFKFB3 inhibitor 3PO almost completely prevented PH in rats treated with Sugen 5416/hypoxia, indicating a causative role of PFKFB3 in the development of PH. Immunostaining of lung sections and Western blot with isolated lung endothelial cells showed a dramatic increase in PFKFB3 expression and activity in pulmonary endothelial cells of rodents and humans with PH. We generated mice that were constitutively or inducibly deficient in endothelial Pfkfb3 and found that these mice were incapable of developing PH or showed slowed PH progression. Compared with control mice, endothelial Pfkfb3-knockout mice exhibited less severity of vascular smooth muscle cell proliferation, endothelial inflammation, and leukocyte recruitment in the lungs. In the absence of PFKFB3, lung endothelial cells from rodents and humans with PH produced lower levels of growth factors (such as PDGFB and FGF2) and proinflammatory factors (such as CXCL12 and IL1β). This is mechanistically linked to decreased levels of HIF2A in lung ECs following PFKFB3 knockdown. Taken together, these results suggest that targeting PFKFB3 is a promising strategy for the treatment of PH.
The coronavirus disease 2019 (COVID-19) pandemic has led to accelerated efforts to develop therapeutics and vaccines. A key target of these efforts is the spike (S) protein, which is metastable and ...difficult to produce recombinantly. We characterized 100 structure-guided spike designs and identified 26 individual substitutions that increased protein yields and stability. Testing combinations of beneficial substitutions resulted in the identification of HexaPro, a variant with six beneficial proline substitutions exhibiting higher expression than its parental construct (by a factor of 10) as well as the ability to withstand heat stress, storage at room temperature, and three freeze-thaw cycles. A cryo-electron microscopy structure of HexaPro at a resolution of 3.2 angstroms confirmed that it retains the prefusion spike conformation. High-yield production of a stabilized prefusion spike protein will accelerate the development of vaccines and serological diagnostics for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
Carbon monoxide (CO) poisoning affects 50,000 people a year in the United States. The clinical presentation runs a spectrum, ranging from headache and dizziness to coma and death, with a mortality ...rate ranging from 1 to 3%. A significant number of patients who survive CO poisoning suffer from long-term neurological and affective sequelae. The neurologic deficits do not necessarily correlate with blood CO levels but likely result from the pleiotropic effects of CO on cellular mitochondrial respiration, cellular energy utilization, inflammation, and free radical generation, especially in the brain and heart. Long-term neurocognitive deficits occur in 15-40% of patients, whereas approximately one-third of moderate to severely poisoned patients exhibit cardiac dysfunction, including arrhythmia, left ventricular systolic dysfunction, and myocardial infarction. Imaging studies reveal cerebral white matter hyperintensities, with delayed posthypoxic leukoencephalopathy or diffuse brain atrophy. Management of these patients requires the identification of accompanying drug ingestions, especially in the setting of intentional poisoning, fire-related toxic gas exposures, and inhalational injuries. Conventional therapy is limited to normobaric and hyperbaric oxygen, with no available antidotal therapy. Although hyperbaric oxygen significantly reduces the permanent neurological and affective effects of CO poisoning, a portion of survivors still have substantial morbidity. There has been some early success in therapies targeting the downstream inflammatory and oxidative effects of CO poisoning. New methods to directly target the toxic effect of CO, such as CO scavenging agents, are currently under development.
Tumor-associated macrophages (TAM) in the tumor microenvironment (TME) cooperate with cancer stem cells (CSC) to maintain stemness. We recently identified cluster of differentiation 44 (CD44) as a ...surface marker defining head and neck squamous cell carcinoma (HNSCC) CSC. PI3K-4EBP1-SOX2 activation and signaling regulate CSC properties, yet the upstream molecular control of this pathway and the mechanisms underlying cross-talk between TAM and CSC in HNSCC remain largely unknown. Because CD44 is a molecular mediator in the TME, we propose here that TAM-influenced CD44 signaling could mediate stemness via the PI3K-4EBP1-SOX2 pathway, possibly by modulating availability of hyaluronic acid (HA), the main CD44 ligand. HNSCC IHC was used to identify TAM/CSC relationships, and
coculture spheroid models and
mouse models were used to identify the influence of TAMs on CSC function via CD44. Patient HNSCC-derived TAMs were positively and negatively associated with CSC marker expression at noninvasive and invasive edge regions, respectively. TAMs increased availability of HA and increased cancer cell invasion. HA binding to CD44 increased PI3K-4EBP1-SOX2 signaling and the CSC fraction, whereas CD44-VCAM-1 binding promoted invasive signaling by ezrin/PI3K.
, targeting CD44 decreased PI3K-4EBP1-SOX2 signaling, tumor growth, and CSC. TAM depletion in syngeneic and humanized mouse models also diminished growth and CSC numbers. Finally, a CD44 isoform switch regulated epithelial-to-mesenchymal plasticity as standard form of CD44 and CD44v8-10 determined invasive and tumorigenic phenotypes, respectively. We have established a mechanistic link between TAMs and CSCs in HNSCC that is mediated by CD44 intracellular signaling in response to extracellular signals. SIGNIFICANCE: These findings establish a mechanistic link between tumor cell CD44, TAM, and CSC properties at the tumor-stroma interface that can serve as a vital area of focus for target and drug discovery.
The generation of molecular chirality in the absence of any molecular chiral inductor is challenging and of fundamental interest for developing a better understanding of homochirality. Here, we show ...the manipulation of molecular chirality through control of the handedness of helical metal nanostructures (referred to as nanohelices) that are produced by glancing angle deposition onto a substrate that rotates in either a clockwise or counterclockwise direction. A prochiral molecule, 2-anthracenecarboxylic acid, is stereoselectively adsorbed on the metal nanohelices as enantiomorphous anti-head-to-head dimers. The dimers show either Si-Si or Re-Re facial stacking depending on the handedness of the nanohelices, which results in a specific enantiopreference during their photoinduced cyclodimerization: a left-handed nanohelix leads to the formation of (+)-cyclodimers, whereas a right-handed one gives (-)-cyclodimers. Density functional theory calculations, in good agreement with the experimental results, point to the enantioselectivity mainly arising from the selective spatial matching of either Si-Si or Re-Re facial stacking at the helical surface; it may also be influenced by chiroplasmonic effects.
Comparing chemical abundances of a planet and the host star reveals the origin and formation pathway of the planet. Stellar abundance is measured with high-resolution spectroscopy. Planet abundance, ...on the other hand, is usually inferred from low-resolution data. For directly imaged exoplanets, the data are available from a slew of high-contrast imaging/spectroscopy instruments. Here, we study the chemical abundance of HR 8799 and its planet c. We measure stellar abundance using LBT/PEPSI (R = 120,000) and archival HARPS data: stellar C/H, O/H, and C/O are 0.11 0.12, 0.12 0.14, and , all consistent with solar values. We conduct atmospheric retrieval using newly obtained Subaru/CHARIS data together with archival Gemini/GPI and Keck/OSIRIS data. We model the planet spectrum with petitRADTRANS and conduct retrieval using PyMultiNest. Retrieved planetary abundance can vary by ∼0.5 dex, from sub-stellar to stellar C and O abundances. The variation depends on whether strong priors are chosen to ensure a reasonable planet mass. Moreover, comparison with previous works also reveals inconsistency in abundance measurements. We discuss potential issues that can cause the inconsistency, e.g., systematics in individual data sets and different assumptions in the physics and chemistry in retrieval. We conclude that no robust retrieval can be obtained unless the issues are fully resolved.
Chronic thromboembolic pulmonary hypertension (CTEPH) is a progressive disease characterized by misguided thrombolysis and remodeling of pulmonary arteries. MicroRNAs are small non-coding RNAs ...involved in multiple cell processes and functions. During CTEPH, circulating microRNA profile endued with characteristics of diseased cells could be identified as a biomarker, and might help in recognition of pathogenesis. Thus, in this study, we compared the differentially expressed microRNAs in plasma of CTEPH patients and healthy controls and investigated their potential functions. Microarray was used to identify microRNA expression profile and qRT-PCR for validation. The targets of differentially expressed microRNAs were identified in silico, and the Gene Ontology database and Kyoto Encyclopedia of Genes and Genomes pathway database were used for functional investigation of target gene profile. Targets of let-7b were validated by fluorescence reporter assay. Protein expression of target genes was determined by ELISA or western blotting. Cell migration was evaluated by wound healing assay. The results showed that 1) thirty five microRNAs were differentially expressed in CTEPH patients, among which, a signature of 17 microRNAs, which was shown to be related to the disease pathogenesis by in silico analysis, gave diagnostic efficacy of both sensitivity and specificity >0.9. 2) Let-7b, one of the down-regulated anti-oncogenic microRNAs in the signature, was validated to decrease to about 0.25 fold in CTEPH patients. 3) ET-1 and TGFBR1 were direct targets of let-7b. Altering let-7b level influenced ET-1 and TGFBR1 expression in pulmonary arterial endothelial cells (PAECs) as well as the migration of PAECs and pulmonary arterial smooth muscle cells (PASMCs). These results suggested that CTEPH patients had aberrant microRNA signature which might provide some clue for pathogenesis study and biomarker screening. Reduced let-7b might be involved in the pathogenesis of CTEPH by affecting ET-1 expression and the function of PAECs and PASMCs.
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