Additional Value of Peer Informants in Psychological Autopsy Studies of Youth Suicides

Qual Health Res. 2021 Jun 24:10497323211022316. doi: 10.1177/10497323211022316. Online ahead of print.


In this study, we examined the feasibility and added value of including peer informants in a psychological autopsy study of youth suicides. Peer semi-structured interview data from 16 cases were analyzed qualitatively and compared to parent data. Results show that peers added information to parents’ narratives in general and particularly on social relationships, bullying, school experiences, social media, and family relations. Peers also provided additional information on the presence of certain issues (such as social media contagion) as well as on the emotional impact from certain adverse events that seemed to have functioned as precipitating factors. We conclude that including peers in psychological autopsy studies of youth suicides is feasible and of added value but that more research is desirable. The results initially can be used in the design of psychological autopsies so that the maximum amount of information about each suicide will be learned.

PMID:34166153 | DOI:10.1177/10497323211022316

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Association Between an Increase in Serum Sodium and In-Hospital Mortality in Critically Ill Patients

Crit Care Med. 2021 Jun 24. doi: 10.1097/CCM.0000000000005173. Online ahead of print.


OBJECTIVES: In critically ill patients, dysnatremia is common, and in these patients, in-hospital mortality is higher. It remains unknown whether changes of serum sodium after ICU admission affect mortality, especially whether normalization of mild hyponatremia improves survival.

DESIGN: Retrospective cohort study.

SETTING: Ten Dutch ICUs between January 2011 and April 2017.

PATIENTS: Adult patients were included if at least one serum sodium measurement within 24 hours of ICU admission and at least one serum sodium measurement 24-48 hours after ICU admission were available.


MEASUREMENTS AND MAIN RESULTS: A logistic regression model adjusted for age, sex, and Acute Physiology and Chronic Health Evaluation-IV-predicted mortality was used to assess the difference between mean of sodium measurements 24-48 hours after ICU admission and first serum sodium measurement at ICU admission (Δ48 hr-[Na]) and in-hospital mortality. In total, 36,660 patients were included for analysis. An increase in serum sodium was independently associated with a higher risk of in-hospital mortality in patients admitted with normonatremia (Δ48 hr-[Na] 5-10 mmol/L odds ratio: 1.61 [1.44-1.79], Δ48 hr-[Na] > 10 mmol/L odds ratio: 4.10 [3.20-5.24]) and hypernatremia (Δ48 hr-[Na] 5-10 mmol/L odds ratio: 1.47 [1.02-2.14], Δ48 hr-[Na] > 10 mmol/L odds ratio: 8.46 [3.31-21.64]). In patients admitted with mild hyponatremia and Δ48 hr-[Na] greater than 5 mmol/L, no significant difference in hospital mortality was found (odds ratio, 1.11 [0.99-1.25]).

CONCLUSIONS: An increase in serum sodium in the first 48 hours of ICU admission was associated with higher in-hospital mortality in patients admitted with normonatremia and in patients admitted with hypernatremia.

PMID:34166287 | DOI:10.1097/CCM.0000000000005173

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Capturing Membrane Phase Separation by Dual Resolution Molecular Dynamics Simulations

J Chem Theory Comput. 2021 Jun 24. doi: 10.1021/acs.jctc.1c00151. Online ahead of print.


Understanding the lateral organization in plasma membranes remains an open problem and is of great interest to many researchers. Model membranes consisting of coexisting domains are commonly used as simplified models of plasma membranes. The coarse-grained (CG) Martini force field has successfully captured spontaneous separation of ternary membranes into a liquid-disordered and a liquid-ordered domain. With all-atom (AA) models, however, phase separation is much harder to achieve due to the slow underlying dynamics. To remedy this problem, here, we apply the virtual site (VS) hybrid method on a ternary membrane composed of saturated lipids, unsaturated lipids, and cholesterol to investigate the phase separation. The VS scheme couples the two membrane leaflets at CG and AA resolution. We found that the rapid phase separation reached by the CG leaflet can accelerate and guide this process in the AA leaflet.

PMID:34165988 | DOI:10.1021/acs.jctc.1c00151

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Liposomes and Extracellular Vesicles as Drug Delivery Systems: A Comparison of Composition, Pharmacokinetics, and Functionalization

Adv Healthc Mater. 2021 Jun 24:e2100639. doi: 10.1002/adhm.202100639. Online ahead of print.


Over the past decades, lipid-based nanoparticle drug delivery systems (DDS) have caught the attention of researchers worldwide, encouraging the field to rapidly develop improved ways for effective drug delivery. One of the most prominent examples is liposomes, which are spherical shaped artificial vesicles composed of lipid bilayers and able to encapsulate both hydrophilic and hydrophobic materials. At the same time, biological nanoparticles naturally secreted by cells, called extracellular vesicles (EVs), have emerged as promising more complex biocompatible DDS. In this review paper, the differences and similarities in the composition of both vesicles are evaluated, and critical mediators that affect their pharmacokinetics are elucidate. Different strategies that have been assessed to tweak the pharmacokinetics of both liposomes and EVs are explored, detailing the effects on circulation time, targeting capacity, and cytoplasmic delivery of therapeutic cargo. Finally, whether a hybrid system, consisting of a combination of only the critical constituents of both vesicles, could offer the best of both worlds is discussed. Through these topics, novel leads for further research are provided and, more importantly, gain insight in what the liposome field and the EV field can learn from each other.

PMID:34165909 | DOI:10.1002/adhm.202100639

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The Role of Social Skills in Predicting Treatment-Recovery in Children with a Social Anxiety Disorder

Res Child Adolesc Psychopathol. 2021 Jun 24. doi: 10.1007/s10802-021-00824-x. Online ahead of print.


The current study investigated the role of social skills and its interaction with social anxiety as predictors of treatment outcome in children with an anxiety disorder either with or without a social anxiety disorder (SoAD). In total, 133 children (aged 8 to 13) with an anxiety disorder received a 10-session cognitive behavioral treatment (FRIENDS program). Pre- to post treatment Reliable Change (RC) and Treatment-Recovery (TR) were assessed from a multi-informant perspective, by including diagnostic information (ADIS C/P), child-reported anxiety symptoms (MASC) and parent-reported internalizing symptoms (CBCL-Int). Social skills were assessed with the parent-rated Social Skills Rating System (assertion, self-control, responsibility). Results showed that 1) parents of children with a SoAD reported significantly less favorable use of assertive and responsible social behavior in their children pre-treatment than parents of children without SoAD, 2) children with higher social skills had a better treatment recovery, and 3) children with anxiety and higher responsible behavior pre-treatment and without a SoAD had a better treatment recovery, but this effect did not show for children with SoAD. In conclusion, better use of social behavior increased the likelihood of treatment recovery but not of reliable change. Further studies on the role of social skills in the treatment of childhood (social) anxiety are needed to investigate the mechanisms by which social skills impact treatment outcome.

PMID:34165687 | DOI:10.1007/s10802-021-00824-x

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Correction: Mechanochemical activation of disulfide-based multifunctional polymers for theranostic drug release

Chem Sci. 2021 Mar 9;12(11):4184. doi: 10.1039/d1sc90047a.


[This corrects the article DOI: 10.1039/D0SC06054B.].

PMID:34165449 | PMC:PMC8179529 | DOI:10.1039/d1sc90047a

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The relationship between cognitive functioning and psychopathology in patients with psychiatric disorders: a transdiagnostic network analysis

Psychol Med. 2021 Jun 24:1-10. doi: 10.1017/S0033291721001781. Online ahead of print.


BACKGROUND: Patients with psychiatric disorders often experience cognitive dysfunction, but the precise relationship between cognitive deficits and psychopathology remains unclear. We investigated the relationships between domains of cognitive functioning and psychopathology in a transdiagnostic sample using a data-driven approach.

METHODS: Cross-sectional network analyses were conducted to investigate the relationships between domains of psychopathology and cognitive functioning and detect clusters in the network. This naturalistic transdiagnostic sample consists of 1016 psychiatric patients who have a variety of psychiatric diagnoses, such as depressive disorders, anxiety disorders, obsessive-compulsive and related disorders, and schizophrenia spectrum and other psychotic disorders. Psychopathology symptoms were assessed using various questionnaires. Core cognitive domains were assessed with a battery of automated tests.

RESULTS: Network analysis detected three clusters that we labelled: general psychopathology, substance use, and cognition. Depressive and anxiety symptoms, verbal memory, and visual attention were the most central nodes in the network. Most associations between cognitive functioning and symptoms were negative, i.e. increased symptom severity was associated with worse cognitive functioning. Cannabis use, (subclinical) psychotic experiences, and anhedonia had the strongest total negative relationships with cognitive variables.

CONCLUSIONS: Cognitive functioning and psychopathology are independent but related dimensions, which interact in a transdiagnostic manner. Depression, anxiety, verbal memory, and visual attention are especially relevant in this network and can be considered independent transdiagnostic targets for research and treatment in psychiatry. Moreover, future research on cognitive functioning in psychopathology should take a transdiagnostic approach, focusing on symptom-specific interactions with cognitive domains rather than investigating cognitive functioning within diagnostic categories.

PMID:34165065 | DOI:10.1017/S0033291721001781

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Development and validation of a prognostic score for long-term transplant-free survival in autoimmune hepatitis type 1

United European Gastroenterol J. 2021 Jun 24. doi: 10.1002/ueg2.12112. Online ahead of print.


BACKGROUND: No prognostic score is currently available for long-term survival in autoimmune hepatitis (AIH) patients.

OBJECTIVE: The aim of this study was to develop and validate such a prognostic score for AIH patients at diagnosis.

METHODS: The prognostic score was developed using uni- & multivariate Cox regression in a 4-center Dutch cohort and validated in an independent 6-center Belgian cohort.

RESULTS: In the derivation cohort of 396 patients 19 liver transplantations (LTs) and 51 deaths occurred (median follow-up 118 months; interquartile range 60-202 months). In multivariate analysis age (hazard ratio [HR] 1.045; p < 0.001), non-caucasian ethnicity (HR 1.897; p = 0.045), cirrhosis (HR 3.266; p < 0.001) and alanine aminotransferase level (HR 0.725; p = 0.003) were significant independent predictors for mortality or LT (C-statistic 0.827; 95% CI 0.790-0.864). In the validation cohort of 408 patients death or LT occurred in 78 patients during a median follow-up of 74 months (interquartile range: 25-142 months). Predicted 5-year event rate did not differ from observed event rate (high risk group 21.5% vs. 15.7% (95% CI: 6.3%-24.2%); moderate risk group 5.8% versus 4.3% (95% CI: 0.0%-9.1%); low risk group 1.9% versus 5.4% (95% CI: 0.0%-11.4%); C-statistic 0.744 [95% CI 0.644-0.844]).

CONCLUSIONS: A Dutch-Belgian prognostic score for long-term transplant-free survival in AIH patients at diagnosis was developed and validated.

PMID:34165262 | DOI:10.1002/ueg2.12112

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Publisher Correction: Elongation factor ELOF1 drives transcription-coupled repair and prevents genome instability

Nat Cell Biol. 2021 Jun 23. doi: 10.1038/s41556-021-00720-y. Online ahead of print.


PMID:34163038 | DOI:10.1038/s41556-021-00720-y

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A Cross-Sectional Survey on Medication Management Practices for Noncommunicable Diseases in Europe During the Second Wave of the COVID-19 Pandemic

Front Pharmacol. 2021 Jun 7;12:685696. doi: 10.3389/fphar.2021.685696. eCollection 2021.


Maintaining healthcare for noncommunicable diseases (NCDs) is particularly important during the COVID-19 pandemic; however, diversion of resources to acute care, and physical distancing restrictions markedly affected management of NCDs. We aimed to assess the medication management practices in place for NCDs during the second wave of the COVID-19 pandemic across European countries. In December 2020, the European Network to Advance Best practices & technoLogy on medication adherencE (ENABLE) conducted a cross-sectional, web-based survey in 38 European and one non-European countries. Besides descriptive statistics of responses, nonparametric tests and generalized linear models were used to evaluate the impact on available NCD services of the number of COVID-19 cases and deaths per 100,000 inhabitants, and gross domestic product (GDP) per capita. Fifty-three collaborators from 39 countries completed the survey. In 35 (90%) countries face-to-face primary-care, and out-patient consultations were reduced during the COVID-19 pandemic. The mean ± SD number of available forms of teleconsultation services in the public healthcare system was 3 ± 1.3. Electronic prescriptions were available in 36 (92%) countries. Online ordering and home delivery of prescription medication (avoiding pharmacy visits) were available in 18 (46%) and 26 (67%) countries, respectively. In 20 (51%) countries our respondents were unaware of any national guidelines regarding maintaining medication availability for NCDs, nor advice for patients on how to ensure access to medication and adherence during the pandemic. Our results point to an urgent need for a paradigm shift in NCD-related healthcare services to assure the maintenance of chronic pharmacological treatments during COVID-19 outbreaks, as well as possible future disasters.

PMID:34163364 | PMC:PMC8216671 | DOI:10.3389/fphar.2021.685696

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Impact of mitral regurgitation in patients with worsening heart failure: Insights from BIOSTAT-CHF

Eur J Heart Fail. 2021 Jun 23. doi: 10.1002/ejhf.2276. Online ahead of print.


BACKGROUND: Few data regarding the prevalence and prognostic impact of mitral regurgitation (MR) in patients with worsening chronic or new-onset acute heart failure (HF) are available. We investigated the role of MR in the BIOlogy Study to TAilored Treatment in Chronic Heart Failure (BIOSTAT-CHF).

METHODS AND RESULTS: We performed a retrospective post-hoc analysis including patients from both the index and validation BIOSTAT-CHF cohorts with data regarding MR status. The primary endpoint was a composite of all-cause death or HF hospitalization. Among 4023 patients included, 1653 patients (41.1%) had moderate-severe MR. Compared to others, patients with moderate-severe MR were more likely to have atrial fibrillation and chronic kidney disease and had larger left ventricular (LV) dimensions, lower left ventricular ejection fraction (LVEF), worse QoL, and higher plasma concentrations of NT-proBNP. A primary outcome event occurred in 697 patients with, compared to 836 patients without, moderate-severe MR (Kaplan-Meier 2-year estimate: 42.2% vs. 35.3%; hazard ratio [HR], 1.28; 95% confidence interval [CI], 1.16-1.41; log-rank p < 0.0001). The association between MR and the primary endpoint remained significant after adjusting for baseline variables and the previously validated BIOSTAT-CHF risk score (adjusted HR, 1.11; 95% CI, 1.00-1.23; p = 0.041). Subgroup analyses showed a numerically larger impact of MR on primary endpoint in patients with lower LVEF, larger LV end-diastolic diameter, and higher plasma NT-proBNP.

CONCLUSIONS: Moderate-severe MR is common in patients with worsening chronic or new-onset acute HF and is strongly associated with outcome, independently of other features related to HF severity. This article is protected by copyright. All rights reserved.

PMID:34164895 | DOI:10.1002/ejhf.2276

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The role of seasonality in reproduction of multiannual delayed gametophytes of Saccharina latissima

J Phycol. 2021 Jun 23. doi: 10.1111/jpy.13191. Online ahead of print.


Delayed gametophytes are able to grow vegetatively for prolonged periods of time. As such, they are potentially very valuable for kelp aquaculture given their great promise in opening up novel opportunities for kelp breeding and farming. However, large-scale application would require more in-depth understanding of how to control reproduction in delayed gametophytes. For newly formed gametophytes, many environmental factors for reproduction have been identified, with key drivers being light intensity, temperature, and the initial gametophyte density. However, the question of whether delayed gametophytes react similarly to these life cycle controls remains open for exploration. In this study, we performed a full factorial experiment on the influences of light intensity, temperature, and density on the reproduction of multiannual delayed gametophytes of Saccharina latissima, during which the number of sporophytes formed were counted. We demonstrate that delayed gametophytes of S. latissima can reliably reproduce sexually after more than a year of vegetative growth, depending on the effects between light intensity and temperature. Under higher light intensities (≥29 µmol photons · m-2 · s-1 ), optimal reproduction was observed at lower temperatures (10.2°C), while at lower light intensities (≤15 µmol photons · m-2 · s-1 ), optimal reproduction was observed at higher temperatures (≥12.6°C). Given the seasonal lag between solar radiation and sea surface temperature in natural systems, these conditions resemble those found during spring (i.e., increasing light intensity with low temperatures) and autumn (i.e., decreasing light intensity with higher temperatures). Seasonality that can be used as an aquaculture tool to better control the reproduction of delayed gametophytes.

PMID:34164815 | DOI:10.1111/jpy.13191

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Comparison of genome-wide gene expression profiling by RNA Sequencing <em>versus</em> microarray in bronchial biopsies of COPD patients before and after inhaled corticosteroid treatment: does it provide new insights?

ERJ Open Res. 2021 Jun 21;7(2):00104-2021. doi: 10.1183/23120541.00104-2021. eCollection 2021 Apr.


More DEGs are detected by RNA-Seq than microarrays in COPD lung biopsies and are associated with immunological pathways. Performing bulk tissue cell-type deconvolution in microarray lung samples, using the SVR method, reflects RNA-Seq results.

PMID:34164552 | PMC:PMC8215328 | DOI:10.1183/23120541.00104-2021

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Mechanochemical activation of disulfide-based multifunctional polymers for theranostic drug release

Chem Sci. 2020 Dec 15;12(5):1668-1674. doi: 10.1039/d0sc06054b.


Drug delivery systems responsive to physicochemical stimuli allow spatiotemporal control over drug activity to overcome limitations of systemic drug administration. Alongside, the non-invasive real-time tracking of drug release and uptake remains challenging as pharmacophore and reporter function are rarely unified within one molecule. Here, we present an ultrasound-responsive release system based on the mechanochemically induced 5-exo-trig cyclization upon scission of disulfides bearing cargo molecules attached via β-carbonate linker within the center of a water soluble polymer. In this bifunctional theranostic approach, we release one reporter molecule per drug molecule to quantitatively track drug release and distribution within the cell in real-time. We use N-butyl-4-hydroxy-1,8-naphthalimide and umbelliferone as fluorescent reporter molecules to accompany the release of camptothecin and gemcitabine as clinically employed anticancer agents. The generality of this approach paves the way for the theranostic release of a variety of probes and drugs by ultrasound.

PMID:34163927 | PMC:PMC8179261 | DOI:10.1039/d0sc06054b

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Photochemical control of bacterial gene expression based on <em>trans</em> encoded genetic switches

Chem Sci. 2021 Jan 12;12(7):2646-2654. doi: 10.1039/d0sc05479h.


Controlling gene expression by light with fine spatiotemporal resolution not only allows understanding and manipulating fundamental biological processes but also fuels the development of novel therapeutic strategies. In complement to exploiting optogenetic tools, photochemical strategies mostly rely on the incorporation of photo-responsive small molecules into the corresponding biomacromolecular scaffolds. Therefore, generally large synthetic effort is required and the switching of gene expression in both directions within a single system remains a challenge. Here, we report a trans encoded ribo-switch, which consists of an engineered tRNA mimicking structure (TMS), under control of small photo-switchable signalling molecules. The signalling molecules consist of two amino glycoside molecules that are connected via an azobenzene unit. The light responsiveness of our system originates from the photo-switchable noncovalent interactions between the signalling molecule and the TMS switch, leading to the demonstration of photochemically controlled expression of two different genes. We believe that this modular design will provide a powerful platform for controlling the expression of other functional proteins with high spatiotemporal resolution employing light as a stimulus.

PMID:34164033 | PMC:PMC8179269 | DOI:10.1039/d0sc05479h

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Effect of charge-transfer enhancement on the efficiency and rotary mechanism of an oxindole-based molecular motor

Chem Sci. 2021 Apr 29;12(21):7486-7497. doi: 10.1039/d1sc01105g.


Harvesting energy and converting it into mechanical motion forms the basis for both natural and artificial molecular motors. Overcrowded alkene-based light-driven rotary motors are powered through sequential photochemical and thermal steps. The thermal helix inversion steps are well characterised and can be manipulated through adjustment of the chemical structure, however, the insights into the photochemical isomerisation steps still remain elusive. Here we report a novel oxindole-based molecular motor featuring pronounced electronic push-pull character and a four-fold increase of the photoisomerization quantum yield in comparison to previous motors of its class. A multidisciplinary approach including synthesis, steady-state and transient absorption spectroscopies, and electronic structure modelling was implemented to elucidate the excited state dynamics and rotary mechanism. We conclude that the charge-transfer character of the excited state diminishes the degree of pyramidalisation at the alkene bond during isomerisation, such that the rotational properties of this oxindole-based motor stand in between the precessional motion of fluorene-based molecular motors and the axial motion of biomimetic photoswitches.

PMID:34163839 | PMC:PMC8171491 | DOI:10.1039/d1sc01105g

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A β-hairpin epitope as novel structural requirement for protein arginine rhamnosylation

Chem Sci. 2020 Dec 7;12(4):1560-1567. doi: 10.1039/d0sc05823h.


For canonical asparagine glycosylation, the primary amino acid sequence that directs glycosylation at specific asparagine residues is well-established. Here we reveal that a recently discovered bacterial enzyme EarP, that transfers rhamnose to a specific arginine residue in its acceptor protein EF-P, specifically recognizes a β-hairpin loop. Notably, while the in vitro rhamnosyltransferase activity of EarP is abolished when presented with linear substrate peptide sequences derived from EF-P, the enzyme readily glycosylates the same sequence in a cyclized β-hairpin mimic. Additional studies with other substrate-mimicking cyclic peptides revealed that EarP activity is sensitive to the method used to induce cyclization and in some cases is tolerant to amino acid sequence variation. Using detailed NMR approaches, we established that the active peptide substrates all share some degree of β-hairpin formation, and therefore conclude that the β-hairpin epitope is the major determinant of arginine-rhamnosylation by EarP. Our findings add a novel recognition motif to the existing knowledge on substrate specificity of protein glycosylation, and are expected to guide future identifications of rhamnosylation sites in other protein substrates.

PMID:34163919 | PMC:PMC8179230 | DOI:10.1039/d0sc05823h

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The electronic structure and deexcitation pathways of an isolated metalloporphyrin ion resolved by metal L-edge spectroscopy

Chem Sci. 2021 Feb 3;12(11):3966-3976. doi: 10.1039/d0sc06591a.


The local electronic structure of the metal-active site and the deexcitation pathways of metalloporphyrins are crucial for numerous applications but difficult to access by commonly employed techniques. Here, we applied near-edge X-ray absorption mass spectrometry and quantum-mechanical restricted active space calculations to investigate the electronic structure of the metal-active site of the isolated cobalt(iii) protoporphyrin IX cation (CoPPIX+) and its deexcitation pathways upon resonant absorption at the cobalt L-edge. The experiments were carried out in the gas phase, thus allowing for control over the chemical state and molecular environment of the metalloporphyrin. The obtained mass spectra reveal that resonant excitations of CoPPIX+ at the cobalt L3-edge lead predominantly to the formation of the intact radical dication and doubly charged fragments through losses of charged and neutral side chains from the macrocycle. The comparison between experiment and theory shows that CoPPIX+ is in a 3A2g triplet ground state and that competing excitations to metal-centred non-bonding and antibonding σ* molecular orbitals lead to distinct deexcitation pathways.

PMID:34163667 | PMC:PMC8179464 | DOI:10.1039/d0sc06591a

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Tailoring the optical and dynamic properties of iminothioindoxyl photoswitches through acidochromism

Chem Sci. 2021 Feb 9;12(12):4588-4598. doi: 10.1039/d0sc07000a.


Multi-responsive functional molecules are key for obtaining user-defined control of the properties and functions of chemical and biological systems. In this respect, pH-responsive photochromes, whose switching can be directed with light and acid-base equilibria, have emerged as highly attractive molecular units. The challenge in their design comes from the need to accommodate application-defined boundary conditions for both light- and protonation-responsivity. Here we combine time-resolved spectroscopic studies, on time scales ranging from femtoseconds to seconds, with density functional theory (DFT) calculations to elucidate and apply the acidochromism of a recently designed iminothioindoxyl (ITI) photoswitch. We show that protonation of the thermally stable Z isomer leads to a strong batochromically-shifted absorption band, allowing for fast isomerization to the metastable E isomer with light in the 500-600 nm region. Theoretical studies of the reaction mechanism reveal the crucial role of the acid-base equilibrium which controls the populations of the protonated and neutral forms of the E isomer. Since the former is thermally stable, while the latter re-isomerizes on a millisecond time scale, we are able to modulate the half-life of ITIs over three orders of magnitude by shifting this equilibrium. Finally, stable bidirectional switching of protonated ITI with green and red light is demonstrated with a half-life in the range of tens of seconds. Altogether, we designed a new type of multi-responsive molecular switch in which protonation red-shifts the activation wavelength by over 100 nm and enables efficient tuning of the half-life in the millisecond-second range.

PMID:34163724 | PMC:PMC8179557 | DOI:10.1039/d0sc07000a

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A Protective Role of FAM13A in Human Airway Epithelial Cells Upon Exposure to Cigarette Smoke Extract

Front Physiol. 2021 Jun 7;12:690936. doi: 10.3389/fphys.2021.690936. eCollection 2021.


BACKGROUND: Chronic Obstructive Pulmonary Disease (COPD) is a progressive lung disease characterized by chronic inflammation upon inhalation of noxious particles, e.g., cigarette smoke. FAM13A is one of the genes often found to be associated with COPD, however its function in the pathophysiology of COPD is incompletely understood. We studied its role in airway epithelial barrier integrity and cigarette smoke-induced epithelial responses.

MATERIALS AND METHODS: Protein level and localization of FAM13A was assessed with immunohistochemistry in lung tissue from COPD patients and non-COPD controls. In vitro, FAM13A expression was determined in the absence or presence of cigarette smoke extract (CSE) in primary airway epithelial cells (AECs) from COPD patients and controls by western blotting. FAM13A was overexpressed in cell line 16HBE14o- and its effect on barrier function was monitored real-time by electrical resistance. Expression of junctional protein E-cadherin and β-catenin was assessed by western blotting. The secretion of neutrophil attractant CXCL8 upon CSE exposure was measured by ELISA.

RESULTS: FAM13A was strongly expressed in airway epithelium, but significantly weaker in airways of COPD patients compared to non-COPD controls. In COPD-derived AECs, but not those of controls, FAM13A was significantly downregulated by CSE. 16HBE14o- cells overexpressing FAM13A built up epithelial resistance significantly more rapidly, which was accompanied by higher E-cadherin expression and reduced CSE-induced CXCL8 levels.

CONCLUSION: Our data indicate that the expression of FAM13A is lower in airway epithelium of COPD patients compared to non-COPD controls. In addition, cigarette smoking selectively downregulates airway epithelial expression of FAM13A in COPD patients. This may have important consequences for the pathophysiology of COPD, as the more rapid build-up of epithelial resistance upon FAM13A overexpression suggests improved (re)constitution of barrier function. The reduced epithelial secretion of CXCL8 upon CSE-induced damage suggests that lower FAM13A expression upon cigarette smoking may facilitate epithelial-driven neutrophilia.

PMID:34163376 | PMC:PMC8215130 | DOI:10.3389/fphys.2021.690936

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