Detection of Bronchiolitis Obliterans Syndrome Following Pediatric Hematopoietic Stem Cell Transplantation. An Official American Thoracic Society Clinical Practice Guideline.

BACKGROUND: Many children undergo allogeneic Hematopoietic Stem Cell Transplantation (HSCT) for the treatment of malignant and non-malignant conditions. Unfortunately, pulmonary complications occur frequently post-HSCT, with bronchiolitis obliterans syndrome (BOS) being the most common non-infectious pulmonary complication. Current international guidelines contain conflicting recommendations regarding post-HSCT surveillance for BOS, and a recent National Institutes of Health workshop highlighted the need for a standardized approach to post-HSCT monitoring. As such, this guideline provides an evidence-based approach to detection of post-HSCT BOS in children. METHODS: A multinational, multidisciplinary panel of experts identified six questions regarding surveillance for, and evaluation of post-HSCT BOS in children. Systematic review of the literature was undertaken to answer each question. The Grading of Recommendations, Assessment, Development, and Evaluation approach was used to rate the quality of evidence and the strength of recommendations. RESULTS: The panel members considered the strength of each recommendation and evaluated the benefits and risks of applying the intervention. In formulating the recommendations, the panel considered patient and caregiver values, the cost of care, and feasibility. Recommendations addressing the role of screening pulmonary function testing and diagnostic tests in children with suspected post-HSCT BOS were made. Following a Delphi process, new diagnostic criteria for pediatric post-HSCT BOS were also proposed. CONCLUSIONS: This document provides an evidence-based approach to detection of post-HSCT BOS in children, while also highlighting considerations for implementation of each recommendation. Further, the document describes important areas for future research.

Diagnosis of Post-Hematopoietic Stem Cell Transplantation Bronchiolitis Obliterans Syndrome in Children: Time for a Rethink?

Hematopoietic stem cell transplantation (HSCT) is undertaken in children with the aim of curing a range of malignant and nonmalignant conditions. Unfortunately, pulmonary complications, especially bronchiolitis obliterans syndrome (BOS), are significant sources of morbidity and mortality post-HSCT. Currently, criteria developed by a National Institutes of Health (NIH) working group are used to diagnose BOS in children post-HSCT. Unfortunately, during the development of a recent American Thoracic Society (ATS) Clinical Practice Guideline on this topic, it became apparent that the NIH criteria have significant limitations in the pediatric population, leading to late diagnosis of BOS. Specific limitations include use of an outdated pulmonary function testing reference equation, a reliance on spirometry, use of a fixed forced expiratory volume in 1 second (FEV1) threshold, focus on obstructive defects defined by FEV1/vital capacity, and failure to acknowledge that BOS and infection can coexist. In this review, we summarize the evidence regarding the limitations of the current criteria. We also suggest potential evidence-based ideas for improving these criteria. Finally, we highlight a new proposed criteria for post-HSCT BOS in children that were developed by the authors of the recently published ATS clinical practice guideline, along with a pathway forward for improving timely diagnosis of BOS in children post-HSCT.

Protective Application of Chinese Herbal Compounds and Formulae in Intestinal Inflammation in Humans and Animals.

Intestinal inflammation is a chronic gastrointestinal disorder with uncertain pathophysiology and causation that has significantly impacted both the physical and mental health of both people and animals. An increasing body of research has demonstrated the critical role of cellular signaling pathways in initiating and managing intestinal inflammation. This review focuses on the interactions of three cellular signaling pathways (TLR4/NF-κB, PI3K-AKT, MAPKs) with immunity and gut microbiota to explain the possible pathogenesis of intestinal inflammation. Traditional medicinal drugs frequently have drawbacks and negative side effects. This paper also summarizes the pharmacological mechanism and application of Chinese herbal compounds (Berberine, Sanguinarine, Astragalus polysaccharide, Curcumin, and Cannabinoids) and formulae (Wumei Wan, Gegen-Qinlian decoction, Banxia xiexin decoction) against intestinal inflammation. We show that the herbal compounds and formulae may influence the interactions among cell signaling pathways, immune function, and gut microbiota in humans and animals, exerting their immunomodulatory capacity and anti-inflammatory and antimicrobial effects. This demonstrates their strong potential to improve gut inflammation. We aim to promote herbal medicine and apply it to multispecies animals to achieve better health.

Visible-Light-Promoted α-Benzylation of N-Phenyl α-Amino Acids to α-Amino Phenylpropanoids.

A new method for the synthesis of α-amino phenylpropanoids under blue light-emitting diode irradiation has been developed through α-C-H benzylation of readily available N-phenyl glycine ester with benzyl oxalates as a coupling partner under mild conditions. A range of N-phenyl glycine esters were successfully converted to α-amino phenylpropanoid products in moderate to good yields. The utility of this methodology is underlined by its application to the late-state modification of natural products.

Glutamate-Evoked Ca2+ Responses in the Rat Suprachiasmatic Nucleus: Involvement of Na+/K+-ATPase and Na+/Ca2+-Exchanger.

Glutamate mediates photic entrainment of the central clock in the suprachiasmatic nucleus (SCN) by evoking intracellular Ca2+ signaling mechanisms. However, the detailed mechanisms of glutamate-evoked Ca2+ signals are not entirely clear. Here, we used a ratiometric Ca2+ and Na+ imaging technique to investigate glutamate-evoked Ca2+ responses. The comparison of Ca2+ responses to glutamate (100 µM) and high (20 mM) K+ solution indicated slower Ca2+ clearance, along with rebound Ca2+ suppression for glutamate-evoked Ca2+ transients. Increasing the length of exposure time in glutamate, but not in 20 mM K+, slowed Ca2+ clearance and increased rebound Ca2+ suppression, a result correlated with glutamate-induced Na+ loads. The rebound Ca2+ suppression was abolished by ouabain, monensin, Na+-free solution, or nimodipine, suggesting an origin of activated Na+/K+-ATPase (NKA) by glutamate-induced Na+ loads. Ouabain or Na+-free solution also slowed Ca2+ clearance, apparently by retarding Na+/Ca2+-exchanger (NCX)-mediated Ca2+ extrusion. Together, our results indicated the involvement of glutamate-induced Na+ loads, NKA, and NCX in shaping the Ca2+ response to glutamate. Nevertheless, in the absence of external Na+ (NMDG substituted), Ca2+ clearance was still slower for the Ca2+ response to glutamate than for 20 mM K+, suggesting participation of additional Ca2+ handlers to the slower Ca2+ clearance under this condition.

Primary graft dysfunction grade 3 following pediatric lung transplantation is associated with chronic lung allograft dysfunction.

BACKGROUND: Severe primary graft dysfunction (PGD) is associated with the development of bronchiolitis obliterans syndrome (BOS), the most common form of chronic lung allograft dysfunction (CLAD), in adults. However, PGD associations with long-term outcomes following pediatric lung transplantation are unknown. We hypothesized that PGD grade 3 (PGD 3) at 48- or 72-hours would be associated with shorter CLAD-free survival following pediatric lung transplantation. METHODS: This was a single center retrospective cohort study of patients ≤ 21 years of age who underwent bilateral lung transplantation between 2005 and 2019 with ≥ 1 year of follow-up. PGD and CLAD were defined by published criteria. We evaluated the association of PGD 3 at 48- or 72-hours with CLAD-free survival by using time-to-event analyses. RESULTS: Fifty-one patients were included (median age 12.7 years; 51% female). The most common transplant indications were cystic fibrosis (29%) and pulmonary hypertension (20%). Seventeen patients (33%) had PGD 3 at either 48- or 72-hours. In unadjusted analysis, PGD 3 was associated with an increased risk of CLAD or mortality (HR 2.10, 95% CI 1.01-4.37, p=0.047). This association remained when adjusting individually for multiple potential confounders. There was evidence of effect modification by sex (interaction p = 0.055) with the association of PGD 3 and shorter CLAD-free survival driven predominantly by males (HR 4.73, 95% CI 1.44-15.6) rather than females (HR 1.23, 95% CI 0.47-3.20). CONCLUSIONS: PGD 3 at 48- or 72-hours following pediatric lung transplantation was associated with shorter CLAD-free survival. Sex may be a modifier of this association.

Photoredox catalysed reductive aminomethylation of quaternary benzophenanthridine alkaloids.

Reduction of C = N double bond is the most important phase I metabolism process of quaternary benzophenanthridine alkaloids (QBAs). Inspired by the NADPH mediated reduction in QBAs, a visible-light promoted reductive aminomethylation of QBAs for synthesis of 6-substituted benzophenanthridines was reported using QBAs and N,N-dimethylaniline as coupling partners in this study. An α-amino radical that derived from QBAs was supposed to be the key intermediate in this visible-light promoted reductive aminomethylation reaction.

Early weaning leads to the remodeling of lipid profile in piglet jejunal crypt cells during post-weaning days.

Reportedly, proteins involved in lipid metabolism change significantly in the jejunal crypt cells of early-weaned piglets, but the exact lipid profile change remains uncertain. In the present study, 32 piglets weaned at 21 d of age were randomly divided into 4 groups with 8 replicates. The jejunal crypt cells of a group of piglets on the post-weaning day (PWD) 1, 3, 7, and 14 were isolated per time point. Crypt cell lipid profiles were analyzed using ultra-high-performance liquid chromatography coupled with hybrid quadrupole time-of-flight mass spectrometry. This study showed that piglets suffered the greatest weaning stress on PWD 3 in terms of the lowest relative weight of the small intestine, the highest relative weight of the spleen, and the highest levels of malondialdehyde, cholesterol, and low-density lipoprotein cholesterol. The lipid profile of jejunal crypt cells including carnitine, sulfatide, sphingomyelin, hexosylceramide, and ceramide greatly changed after weaning, especially between PWD 3 and 14 (P < 0.05). The differential lipid species between these 2 d were mainly involved in the glycerophospholipid metabolism pathway. In addition, potential lipid biomarkers for weaning stress in crypt cells such as phosphatidylcholine (PC) (9:0/26:1), PC (17:0/18:2), carnitine (24:0), carnitine (22:0), sphingomyelin (d14:1/22:0), PC (P-18:0/18:4), phosphatidylethanolamine (P-16:0/20:4), phosphatidylinositol (15:1/24:4), and dihexosylceramide (d14:1/26:1) were identified. The changes in lipid profile might be related to the inflammation caused by early weaning. These findings might provide new therapeutical targets for intestinal dysfunctions caused by weaning stress.

In situ tunable circular dichroism of flexible chiral metasurfaces composed of plasmonic nanorod trimers.

The circularly polarized light source is one of the keys to chiral photonic circuits and systems. However, it is difficult to integrate conventional light-emitting devices with circular polarization converters directly into compact chip-scale photonic systems partly because of their bulky structures. In this study, in situ optical chirality tunable nanorod trimer metasurfaces consisting of two types of nanorod dimers are demonstrated and integrated with a flexible polydimethylsiloxane (PDMS) substrate. The optical chirality variations originating from the tunable asymmetricity of nanorod trimers under different stretching scenarios are evaluated. Through the processes, the gap distances between nanorods are varied, and the degree of circular polarization of the transmitted wave is controlled through the manipulation of localized surface plasmon resonance (LSPR) coupling. The results reveal the circular dichroism tunability and durability of fabricated chiral metasurfaces which can be important elements for chip-scale flexible optoelectronic integrated circuits for sensing, display and communication applications.

Visible-light-promoted and chlorophyll-catalyzed aerobic desulfurization of thioamides to amides.

A novel method for the metal-free synthesis of amides from thioamides based on visible-light photoredox catalysis and in an air atmosphere is reported. Natural pigment chlorophyll is used as a photosensitizer to generate singlet molecular oxygen 1O2, which is involved in the aerobic desulfurization of thioamides. The protocol provides amides in good yields at room temperature under mild conditions. On the basis of experimental results, a plausible photoredox mechanism is proposed.

Biomimetic synthesis of 6-substituted dihydrobenzophenanthridine alkaloids based on visible-light promoted radical addition reaction.

Oxidative C-H functionalization of dihydrobenzophenanthridines catalyzed by dihydrobenzophenanthridine oxidase (DBOX) is believed to be the key step involved in the biosynthetic pathway of some novel 6-substituted benzophenanthridine alkaloids. In this study, a visible-light promoted biomimetic synthesis of 6-substituted benzophenanthridines was reported under photoredox-neutral conditions. α-Amino radical that derived from dihydrobenzophenanthridines was supposed to be the key intermediate in this visible-light promoted radical-type Michael addition reaction.

Visible-Light-Promoted Biomimetic Reductive Functionalization of Quaternary Benzophenanthridine Alkaloids.

Reduction of an iminium C═N double bond is the most important phase I metabolism process associated with the cytotoxic property of quaternary benzophenanthridine alkaloids (QBAs). Inspired by the light-mediated reduction of QBAs with nicotinamide adenine dinucleotide, a visible-light-promoted reductive functionalization reaction of QBAs is reported in this study. C4-Alkyl-1,4-dihydropyridines (DHPs) enable the direct reductive alkylation of QBA independently, serving as both single-electron-transfer reductant reagents under irradiation with 455 nm blue light in the absence of photocatalysts and additional additives. Our protocol can be further applied to the semisynthesis of natural 6-substituted dihydrobenzophenanthridine derivatives such as O-acetyl maclekarpine E.

An integrated strategy toward comprehensive characterization and quantification of multiple components from herbal medicine: An application study in Gelsemium elegans.

Objective: To develop a powerful integrated strategy based on liquid chromatography coupled with mass spectrometry (LC-MS) systems for the comprehensive characterization and quantification of multiple components of herbal medicines. Methods: Firstly, different mobile phase additives, analysis time, and MS acquisition modes were orthogonally tested with liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (LC-QTOF/MS) in order to detect as many components of Gelsemium elegans as possible with high peak intensity. Secondly, several data mining strategies, including database searching, diagnostic ion filtering and neutral loss filtering, were utilized to perform chemical profiling. Subsequently, this study focused on the quantification and validation of the performance of a liquid chromatography-triple mass spectrometry (LC-QqQ/MS) assay based on derivative multiple reaction monitoring (DeMRM). Results: A total of 147 components from G. elegans were characterized, among them 116 nontarget components were reported for the first time. A sensitive and reproducible LC-QqQ/MS method was successfully developed and validated for the simultaneous relative quantification of 41 components of G. elegans. This LC-QqQ/MS method was then applied to compare the contents of components in the roots, stems and leaves. Conclusion: The present integrated strategy would significantly contribute to chemical studies on herbal medicine, and its utility could be extended to other research fields, such as metabolomics, quality control, and pharmacokinetics.

High Circular Polarized Nanolaser with Chiral Gammadion Metal Cavity.

We demonstrate a circularly polarized laser with the metal-gallium-nitride gammadion nanocavities. The ultraviolet lasing signal was observed with the high circular dichroism at room temperature under pulsed optical pump conditions. Without external magnetism which breaks the time-reversal symmetry to favor optical transitions of a chosen handedness, the coherent outputs of these chiral nanolasers show a dissymmetry factor as high as 1.1. The small footprint of these lasers are advantageous for applications related to circularly polarized photons in future integrated systems, in contrast to the bulky setup of linearly-polarized lasers and quarter-wave plates.

Markers of malignant prostate cancer cells: Golgi localization of α-mannosidase 1A at GM130-GRASP65 site and appearance of high mannose N-glycans on cell surface.

The ability to distinguish malignant from indolent prostate cancer cells is critically important for identification of clinically significant prostate cancer to minimize unnecessary overtreatment and sufferings endured by patients who have indolent cancer. Recently, we discovered that loss of giantin function as the primary Golgi targeting site for endoplasmic reticulum-derived transport vesicles in aggressive prostate cancer cells caused a shift of the Golgi localization site of α-mannosidase 1A to 130 KDa Golgi matrix protein (GM130)-65 KDa Golgi reassembly-stacking protein (GRASP65) site resulting in emergence of high mannose N-glycans on trans-Golgi enzymes and cell surface glycoproteins. To extend this observation, we isolated two cell clones (Clone 1 and Clone 2) from high passage LNCaP cells, which exhibited androgen refractory property missing in low passage LNCaP cells, and characterized their malignant property. We have found that comparing to Clone 2, which does not have cell surface high mannose N-glycans and exhibits localization of α-mannosidase 1A at giantin site, Clone 1 displays cell surface high mannose N-glycans, exhibits localization of α-mannosidase 1A at GM130-GRASP65 site, and shows a faster rate of closing the wound in a wound healing assay. The results indicate that Golgi localization of α-mannosidase 1A at GM130-GRASP65 site and appearance of cell surface high mannose N-glycans may serve as markers of malignant prostate cancer cells.

Full-Spectrum Analysis of Perovskite-Based Surface Plasmon Nanolasers.

We systematically studied the characteristics of hybrid perovskite-based surface plasmon nanolasers. If one changes the anion composition of perovskites, the emission wavelength can be easily tuned. We conducted in full-spectrum modeling that featured hybrid perovskite nanowires placed on different SiO2-coated metallic (Au, Ag, and Al) plates. The proposed nanocavities that supported plasmonic gap modes exhibited distinguished properties of nanolasers, such as low-transparency threshold-gain and low lasing threshold. The corresponding experimental results for the MAPbBr3 nanolaser on Ag revealed the low-threshold operation. These superior features were attributed to enhanced light-matter interaction with strong coupling. Therefore, the proposed scheme, integrated with hybrid perovskite as gain material, provides an excellent platform for nanoscale plasmon lasing in the visible to near-infrared spectra.

Chiral Second-Harmonic Generation from Monolayer WS2/Aluminum Plasmonic Vortex Metalens.

Two-dimensional spiral plasmonic structures have emerged as a versatile approach to generate near-field vortex fields with tunable topological charges. We demonstrate here a far-field approach to observe the chiral second-harmonic generation (SHG) at designated visible wavelengths from a single plasmonic vortex metalens. This metalens comprises an Archimedean spiral slit fabricated on atomically flat aluminum epitaxial film, which allows for precise tuning of plasmonic resonances and subsequent transfer of two-dimensional materials on top of the spiral slit. The nonlinear optical measurements show a giant SHG circular dichroism. Furthermore, we have achieved an enhanced chiral SHG conversion efficiency (about an order of magnitude greater than the bare aluminum lens) from monolayer tungsten disulfide (WS2)/aluminum metalens, which is designed at the C-exciton resonance of WS2. Since the C-exciton is not a valley exciton, the enhanced chiral SHG in this hybrid system originates from the plasmonic vortex field-enhanced SHG under the optical spin-orbit interaction.