Neutrophil-avid nanocarrier uptake by STAT3 dominant-negative hyper-IgE syndrome patient neutrophils.

Recurrent infections are a hallmark of STAT3 dominant-negative hyper-IgE syndrome (STAT3 HIES), a rare immunodeficiency syndrome previously known as Jobs syndrome, along with elevated IgE levels and impaired neutrophil function. We have been developing nanoparticles with neutrophil trophism that home to the sites of infection via these first-responder leukocytes, named neutrophil-avid nanocarriers (NANs). Here, we demonstrate that human neutrophils can phagocytose nanogels (NGs), a type of NAN, with enhanced uptake after particle serum opsonization, comparing neutrophils from healthy individuals to those with STAT3 HIES, where both groups exhibit NG uptake; however, the patient group showed reduced phagocytosis efficiency with serum-opsonized NANs.

Hyperactive mTORC1 in lung mesenchyme induces endothelial cell dysfunction and pulmonary vascular remodeling.

Lymphangioleiomyomatosis (LAM) is a progressive cystic lung disease caused by tuberous sclerosis complex 1/2 (TSC1/2) gene mutations in pulmonary mesenchymal cells, resulting in activation of the mechanistic target of rapamycin complex 1 (mTORC1). A subset of patients with LAM develop pulmonary vascular remodeling and pulmonary hypertension. Little, however, is known regarding how LAM cells communicate with endothelial cells (ECs) to trigger vascular remodeling.

Tracking Regulatory T Cell Development in the Thymus Using Single-Cell RNA Sequencing/TCR Sequencing.

Recent studies have demonstrated that regulatory T cells (T) develop in the thymus via two pathways involving distinct T progenitors (TP): CD25FOXP3 (CD25 TP) and CD25FOXP3 (FOXP3 TP) T progenitors. To examine this process in more detail, we carried out single-cell RNA sequencing (scRNA-Seq) and TCR-Seq on sorted murine CD4CD8 double-positive (DP) thymocytes, CD4 single-positive (CD4SP) thymocytes, CD25FOXP3CD73 TP, CD25FOXP3CD73 TP, newly generated mature CD25FOXP3CD73 T, and FOXP3CD73 recirculating/long-term resident T (RT-T). Sorted populations were individually hashtagged and then combined into one scRNA-Seq/TCR-Seq library before sequencing and subsequent analysis.

Exploiting a strong coupling regime of organic pentamer surface plasmon resonance based on the Otto configuration for creatinine detection.

The sandwiched material-analyte layer in the surface plasmon resonance (SPR)-Otto configuration emulates an optical cavity and, coupled with large optical nonlinearity material, the rate of light escaping from the system is reduced, allowing the formation of a strong coupling regime. Here, we report an organic pentamer SPR sensor using the Otto configuration to induce a strong coupling regime for creatinine detection. Prior to that, the SPR sensor chip was modified with an organic pentamer, 1,4-bis[2-(5-thiophene-2-yl)-1-benzothiopene]-2,5-dioctyloxybenzene (BOBzBT).

Polarization response of planarized optical waveguides to determine the anisotropic complex refractive index of graphene oxide thin films.

The polarization response of graphene oxide (GO)-coated planarized optical waveguides is used to determine the complex refractive index of GO film. GO films with thicknesses between 0.10 and 0.

Functional NMDA receptors are expressed by human pulmonary artery smooth muscle cells.

N-methyl-D-aspartate (NMDA) receptors are widely expressed in the central nervous system. However, their presence and function at extraneuronal sites is less well characterized. In the present study, we examined the expression of NMDA receptor subunit mRNA and protein in human pulmonary artery (HPA) by quantitative polymerase chain reaction (PCR), immunohistochemistry and immunoblotting.

Randomized Controlled Trial of the Gastrin/CCK Receptor Antagonist Netazepide in Patients with Barrett's Esophagus.

Hypergastrinemia has been associated with high-grade dysplasia and adenocarcinoma in patients with Barrett's esophagus, and experimental studies suggest proinflammatory and proneoplastic effects of gastrin on Barrett's esophagus. This is of potential concern, as patients with Barrett's esophagus are treated with medications that suppress gastric acid production, resulting in increased physiologic levels of gastrin. We aimed to determine whether treatment with the novel gastrin/CCK receptor antagonist netazepide reduces expression of markers associated with inflammation and neoplasia in Barrett's esophagus.

Therapeutic Targeting of DGKA-Mediated Macropinocytosis Leads to Phospholipid Reprogramming in Tuberous Sclerosis Complex.

Lymphangioleiomyomatosis is a rare destructive lung disease affecting primarily women and is the primary lung manifestation of tuberous sclerosis complex (TSC). In lymphangioleiomyomatosis, biallelic loss of TSC1/2 leads to hyperactivation of mTORC1 and inhibition of autophagy. To determine how the metabolic vulnerabilities of TSC2-deficient cells can be targeted, we performed a high-throughput screen utilizing the "Repurposing" library at the Broad Institute of MIT and Harvard (Cambridge, MA), with or without the autophagy inhibitor chloroquine.

mTORC1 activation in lung mesenchyme drives sex- and age-dependent pulmonary structure and function decline.

Lymphangioleiomyomatosis (LAM) is a rare fatal cystic lung disease due to bi-allelic inactivating mutations in tuberous sclerosis complex (TSC1/TSC2) genes coding for suppressors of the mechanistic target of rapamycin complex 1 (mTORC1). The origin of LAM cells is still unknown. Here, we profile a LAM lung compared to an age- and sex-matched healthy control lung as a hypothesis-generating approach to identify cell subtypes that are specific to LAM.

Genomic copy number predicts esophageal cancer years before transformation.

Recent studies show that aneuploidy and driver gene mutations precede cancer diagnosis by many years. We assess whether these genomic signals can be used for early detection and pre-emptive cancer treatment using the neoplastic precursor lesion Barrett's esophagus as an exemplar. Shallow whole-genome sequencing of 777 biopsies, sampled from 88 patients in Barrett's esophagus surveillance over a period of up to 15 years, shows that genomic signals can distinguish progressive from stable disease even 10 years before histopathological transformation.

Inhibition of Growth of TSC2-Null Cells by a PI3K/mTOR Inhibitor but Not by a Selective MNK1/2 Inhibitor.

Lymphangioleiomyomatosis (LAM) is a rare metastatic cystic lung disease due to a mutation in a TSC tumor suppressor, resulting in hyperactive mTOR growth pathways. Sirolimus (rapamycin), an allosteric mTORC1 inhibitor, is a therapeutic option for women with LAM but it only maintains lung volume during treatment and does not provide benefit for all LAM patients. The two major mTORC1 protein synthesis pathways are via S6K/S6 or 4E-BP/eIF4E activation.

Mitochondrial dysfunction is a key determinant of the rare disease lymphangioleiomyomatosis and provides a novel therapeutic target.

Lymphangioleiomyomatosis (LAM) is a rare and progressive systemic disease affecting mainly young women of childbearing age. A deterioration in lung function is driven by neoplastic growth of atypical smooth muscle-like LAM cells in the pulmonary interstitial space that leads to cystic lung destruction and spontaneous pneumothoraces. Therapeutic options for preventing disease progression are limited and often end with lung transplantation temporarily delaying an inevitable decline.

Immune Checkpoint Ligand PD-L1 Is Upregulated in Pulmonary Lymphangioleiomyomatosis.

Pulmonary lymphangioleiomyomatosis (LAM) is a slow-progressing metastatic disease that is driven by mutations in the tumor suppressor tuberous sclerosis complex 1/2 (TSC1/2). Rapamycin inhibits LAM cell proliferation and is the only approved treatment, but it cannot cause the regression of existing lesions and can only stabilize the disease. However, in other cancers, immunotherapies such as checkpoint blockade against PD-1 and its ligand PD-L1 have shown promise in causing tumor regression and even curing some patients.

Rapamycin-independent IGF2 expression in Tsc2-null mouse embryo fibroblasts and human lymphangioleiomyomatosis cells.

Lymphangioleiomyomatosis (LAM) is a rare, almost exclusively female lung disease linked to inactivating mutations in tuberous sclerosis complex 2 (TSC2), a tumor suppressor gene that controls cell metabolic state and growth via regulation of the mechanistic target of rapamycin (mTORC1) signaling. mTORC1 is frequently activated in human cancers and, although the mTORC1 inhibitor rapamycin has a cytostatic effect, it is, in general, unable to elicit a robust curative effect or tumor regression. Using RNA-Seq, we identified (1) Insulin-like Growth Factor (IGF2) as one of the genes with the highest fold-change difference between human TSC2-null and TSC2-expressing angiomyolipoma cells from a patient with LAM, and (2) the mouse IGF2 homolog Igf2, as a top-ranking gene according to fold change between Tsc2-/- and Tsc2+/+ mouse embryo fibroblasts (MEFs).

Asymmetric split H-shape nanoantennas for molecular sensing.

In this paper we report on a very sensitive biosensor based on gold asymmetric nanoantennas that are capable of enhancing the molecular resonances of C-H bonds. The nanoantennas are arranged as arrays of asymmetric-split H-shape (ASH) structures, tuned to produce plasmonic resonances with reflectance double peaks within the mid-infrared vibrational resonances of C-H bonds for the assay of deposited films of the molecule 17β-estradiol (E2), used as an analyte. Measurements and numerical simulations of the reflectance spectra have enabled an estimated enhancement factor on the order of 10 to be obtained for a thin film of E2 on the ASH array.

Photo-induced reduction of graphene oxide coating on optical waveguide and consequent optical intermodulation.

Increased absorption of transverse-magnetic (TM)-polarised light by a graphene-oxide (GO) coated polymer waveguide has been observed in the presence of transverse-electric (TE)-polarised light. The GO-coated waveguide exhibits very strong photo-absorption of TE-polarised light--and acts as a TM-pass waveguide polariser. The absorbed TE-polarised light causes a significant temperature increase in the GO film and induces thermal reduction of the GO, resulting in an increase in optical-frequency conductivity and consequently increased optical propagation loss.

Pharmacological targeting of VEGFR signaling with axitinib inhibits Tsc2-null lesion growth in the mouse model of lymphangioleiomyomatosis.

Pulmonary lymphangioleiomyomatosis (LAM), a rare progressive lung disease associated with mutations of the tuberous sclerosis complex 2 (Tsc2) tumor suppressor gene, manifests by neoplastic growth of LAM cells, induction of cystic lung destruction, and respiratory failure. LAM severity correlates with upregulation in serum of the prolymphangiogenic vascular endothelial growth factor D (VEGF-D) that distinguishes LAM from other cystic diseases. The goals of our study was to determine whether Tsc2 deficiency upregulates VEGF-D, and whether axitinib, the Food and Drug Administration-approved small-molecule inhibitor of VEGF receptor (VEGFR) signaling, will reduce Tsc2-null lung lesion growth in a mouse model of LAM.

Graphene oxide-based waveguide polariser: from thin film to quasi-bulk.

We have demonstrated a broadband waveguide polariser with high extinction ratio on a polymer optical waveguide coated with graphene oxide via the drop-casting method. The highest extinction ratio of nearly 40 dB is measured at 1590 nm, with a variation of 4.5 dB across a wavelength range from 1530 nm to 1630 nm, a ratio that is (to our knowledge) the highest reported for graphene-based waveguide polarisers to date.

Enhanced Fano resonance of organic material films deposited on arrays of asymmetric split-ring resonators (A-SRRs).

Depositing very thin organic films on the surface of arrays of asymmetric split-ring resonators (A-SRRs) produces a shift in their resonance spectra that can be utilized for sensitive analyte detection. Here we show that when poly-methyl-methacrylate (PMMA) is used as an organic probe (analyte) on top of the A-SRR array, the phase and amplitude of a characteristic molecular Fano resonance associated with a carbonyl bond changes according to the spectral positions of the trapped mode resonance of the A-SRRs and their plasmonic reflection peaks. Furthermore, we localize blocks of PMMA at different locations on the A-SRR array to determine the effectiveness of detection of very small amounts of non-uniformly distributed analyte.

Direct airborne acoustic wave modulation of Fabry-Perot fiber laser (FPFL) over 100 kHz of operating bandwidth.

The idea of applying a simple Fabry-Perot fiber laser (FPFL) set-up in a free-running condition as an acoustic sensing medium is proposed. Conventional optical microphone requires a stringently aligned diaphragm to mediate the acoustic impedance mismatch between air and silica fiber. Motivated by the difficulty of optical sensing of airborne acoustic waves, a new sensing method is proposed to sense acoustic waves without the assistance of a diaphragm as transducer.

Modulational instability in a silicon-on-insulator directional coupler: role of the coupling-induced group velocity dispersion.

We report frequency conversion experiments in silicon-on-insulator (SOI) directional couplers. We demonstrate that the evanescent coupling between two subwavelength SOI waveguides is strongly dispersive and significantly modifies modulational instability (MI) spectra through the coupling induced group velocity dispersion (GVD). As the separation between two 380-nm-wide silicon photonic wires decreases, the increasing dispersion of the coupling makes the GVD in the symmetric supermode more normal and suppresses the bandwidth of the MI gain observed for larger separations.

Charge state switching of deep levels for low-power optical modulation in silicon waveguides.

We demonstrate a method for the efficient modulation of optical wavelengths around 1550 nm in silicon waveguides. The amplitude of a propagating signal is mediated via control of the charge state of indium centers, rather than using free-carriers alone as in the plasma-dispersion effect. A 1×1 switch formed of an integrated p-i-n junction in an indium-doped silicon on insulator (SOI) waveguide provides 'normally-off' silicon absorption of greater than 7 dB at zero bias.

Emission characteristics of photonic crystal light-emitting diodes.

Experimentally measured optical properties of photonic crystal LEDs are reported here. Photonic crystal and photonic quasi-crystal structures were fabricated on GaN epilayer LED wafer material using both direct-write electron beam lithography and nanoimprint lithography. Some of these structures were processed to make finished LEDs.