Antisense oligonucleotides restore excitability, GABA signalling and sodium current density in a Dravet syndrome model.

Dravet syndrome is an intractable developmental and epileptic encephalopathy caused by de novo variants in SCN1A resulting in haploinsufficiency of the voltage-gated sodium channel Nav1.1. We showed previously that administration of the antisense oligonucleotide STK-001, also called ASO-22, generated using targeted augmentation of nuclear gene output technology to prevent inclusion of the nonsense-mediated decay, or poison, exon 20N in human SCN1A, increased productive Scn1a transcript and Nav1.1 expression and reduced the incidence of electrographic seizures and sudden unexpected death in epilepsy in a mouse model of Dravet syndrome. Here, we investigated the mechanism of action of ASO-84, a surrogate for ASO-22 that also targets splicing of SCN1A exon 20N, in Scn1a+/- Dravet syndrome mouse brain. Scn1a +/- Dravet syndrome and wild-type mice received a single intracerebroventricular injection of antisense oligonucleotide or vehicle at postnatal Day 2. We examined the electrophysiological properties of cortical pyramidal neurons and parvalbumin-positive fast-spiking interneurons in brain slices at postnatal Days 21-25 and measured sodium currents in parvalbumin-positive interneurons acutely dissociated from postnatal Day 21-25 brain slices. We show that, in untreated Dravet syndrome mice, intrinsic cortical pyramidal neuron excitability was unchanged while cortical parvalbumin-positive interneurons showed biphasic excitability with initial hyperexcitability followed by hypoexcitability and depolarization block. Dravet syndrome parvalbumin-positive interneuron sodium current density was decreased compared to wild-type. GABAergic signalling to cortical pyramidal neurons was reduced in Dravet syndrome mice, suggesting decreased GABA release from interneurons. ASO-84 treatment restored action potential firing, sodium current density and GABAergic signalling in Dravet syndrome parvalbumin-positive interneurons. Our work suggests that interneuron excitability is selectively affected by ASO-84. This new work provides critical insights into the mechanism of action of this antisense oligonucleotide and supports the potential of antisense oligonucleotide-mediated upregulation of Nav1.1 as a successful strategy to treat Dravet syndrome.

Proceed with Caution: Social Acceptability of Forestry Practices in Puerto Rico among Members of Local Environmental Organizations, Academia and Professional Associations.

Social acceptability of forestry practices plays a key role in defining sustainable forestry policies and strategies. In this study an online survey was distributed among members of environmental, non-governmental, professional, and academic organizations to assess the acceptability of forestry practices in Puerto Rico among members of civic society interested in environmental management issues. Participants were asked about their perception of forest uses, their preference of tree harvesting technologies, methods that may apply in small scale wood production settings, and trust in organizations providing forest information. We also inquired about attitudes towards economic activity in forests and the impact of such activity on recreation and biodiversity. The results show that even though participants do not place a high priority on economic development through forestry activities, acceptance of forest management for wood harvesting will be possible by considering adherence to particular forestry technologies and methods to safeguard current recreation activities and biodiversity conservation. Social acceptability information would be worthwhile when seeking consensus among a broader group of local stakeholders. As a next step we suggest the creation of a council constituted by diverse forestry sector stakeholders that would engage in a strategic planning exercise to delineate a clear road map that can guide short and long-term sustainable forest management, including wood industry development.

Persistence, effectiveness, and real-world outcomes in psoriasis patients treated with secukinumab in Portugal.

To characterize moderate to severe psoriasis (PsO) adult patients treated with secukinumab, estimate drug persistence and assess any reasons for treatment discontinuation. Non-interventional, retrospective, longitudinal record-based study including patients diagnosed with PsO who started secukinumab between January 2018 and January 2020. Baseline characteristics were analyzed by descriptive statistics; drug persistence and predictive factors were assessed through Kaplan-Meier curves and univariate and multivariate analysis, respectively. A total of 302 patients were included in the study: mean age was 48.4 years, 41.7% were female, median time since diagnosis was 12.9 years. 51.3% of patients were bio-naïve while 48.7% had previously been treated with biologics. PsO in difficult-to-treat locations (DTL) was present in 82.1% of patients, with scalp PsO in about half of patients. At 5-years follow-up, 84 patients discontinued secukinumab, 45 of which due to loss of efficacy. At week 104, overall treatment persistence was 71.7%. A higher probability of drug persistence was identified among those patients who initiated secukinumab ≥5 years after diagnosis, were bio-naïve or treated with only one previous biologic, had no PsO on DTL, and had diabetes mellitus. The predictive factors for discontinuation identified in our study were the start of secukinumab <5 years after diagnosis (p = 0.001), the bio-experimented status with ≥2 biologics (p = 0.007), and the presence of PsO on DTL (p = 0.014). A time since diagnosis of ≥5 years, naïve status or previous use of only one biologic are predictors for secukinumab persistence, whereas the presence of PsO on DTL predicts drug discontinuation.

Sodium channel ß1 subunits are post-translationally modified by tyrosine phosphorylation, S-palmitoylation, and regulated intramembrane proteolysis.

Voltage-gated sodium channel (VGSC) ß1 subunits are multifunctional proteins that modulate the biophysical properties and cell-surface localization of VGSC α subunits and participate in cell-cell and cell-matrix adhesion, all with important implications for intracellular signal transduction, cell migration, and differentiation. Human loss-of-function variants in SCN1B, the gene encoding the VGSC ß1 subunits, are linked to severe diseases with high risk for sudden death, including epileptic encephalopathy and cardiac arrhythmia. We showed previously that ß1 subunits are post-translationally modified by tyrosine phosphorylation. We also showed that ß1 subunits undergo regulated intramembrane proteolysis via the activity of ß-secretase 1 and γ-secretase, resulting in the generation of a soluble intracellular domain, ß1-ICD, which modulates transcription. Here, we report that ß1 subunits are phosphorylated by FYN kinase. Moreover, we show that ß1 subunits are S-palmitoylated. Substitution of a single residue in ß1, Cys-162, to alanine prevented palmitoylation, reduced the level of ß1 polypeptides at the plasma membrane, and reduced the extent of ß1-regulated intramembrane proteolysis, suggesting that the plasma membrane is the site of ß1 proteolytic processing. Treatment with the clathrin-mediated endocytosis inhibitor, Dyngo-4a, re-stored the plasma membrane association of ß1-p.C162A to WT levels. Despite these observations, palmitoylation-null ß1-p.C162A modulated sodium current and sorted to detergent-resistant membrane fractions normally. This is the first demonstration of S-palmitoylation of a VGSC ß subunit, establishing precedence for this post-translational modification as a regulatory mechanism in this protein family.

Variant-specific changes in persistent or resurgent sodium current in SCN8A-related epilepsy patient-derived neurons.

Missense variants in the SCN8A voltage-gated sodium channel gene are linked to early-infantile epileptic encephalopathy type 13, also known as SCN8A-related epilepsy. These patients exhibit a wide spectrum of intractable seizure types, severe developmental delay, movement disorders, and elevated risk of sudden unexpected death in epilepsy. The mechanisms by which SCN8A variants lead to epilepsy are poorly understood, although heterologous expression systems and mouse models have demonstrated altered sodium current properties. To investigate these mechanisms using a patient-specific model, we generated induced pluripotent stem cells from three patients with missense variants in SCN8A: p.R1872>L (Patient 1); p.V1592>L (Patient 2); and p.N1759>S (Patient 3). Using small molecule differentiation into excitatory neurons, induced pluripotent stem cell-derived neurons from all three patients displayed altered sodium currents. Patients 1 and 2 had elevated persistent current, while Patient 3 had increased resurgent current compared to controls. Neurons from all three patients displayed shorter axon initial segment lengths compared to controls. Further analyses focused on one of the patients with increased persistent sodium current (Patient 1) and the patient with increased resurgent current (Patient 3). Excitatory cortical neurons from both patients had prolonged action potential repolarization. Using doxycycline-inducible expression of the neuronal transcription factors neurogenin 1 and 2 to synchronize differentiation of induced excitatory cortical-like neurons, we investigated network activity and response to pharmacotherapies. Both small molecule differentiated and induced patient neurons displayed similar abnormalities in action potential repolarization. Patient induced neurons showed increased burstiness that was sensitive to phenytoin, currently a standard treatment for SCN8A-related epilepsy patients, or riluzole, an FDA-approved drug used in amyotrophic lateral sclerosis and known to block persistent and resurgent sodium currents, at pharmacologically relevant concentrations. Patch-clamp recordings showed that riluzole suppressed spontaneous firing and increased the action potential firing threshold of patient-derived neurons to more depolarized potentials. Two of the patients in this study were prescribed riluzole off-label. Patient 1 had a 50% reduction in seizure frequency. Patient 3 experienced an immediate and dramatic seizure reduction with months of seizure freedom. An additional patient with a SCN8A variant in domain IV of Nav1.6 (p.V1757>I) had a dramatic reduction in seizure frequency for several months after starting riluzole treatment, but then seizures recurred. Our results indicate that patient-specific neurons are useful for modelling SCN8A-related epilepsy and demonstrate SCN8A variant-specific mechanisms. Moreover, these findings suggest that patient-specific neuronal disease modelling offers a useful platform for discovering precision epilepsy therapies.

A Coastal Vulnerability Framework to Guide Natural Infrastructure Funds Allocation in Compressed Time.

Hurricane Maria, a category 4 tropical cyclone, hit the US non-incorporated territory of Puerto Rico on September 20, 2017. Widespread physical and natural infrastructure damage was observed, especially in already vulnerable coastal communities. As public sector funding availability for natural infrastructure (ex. coastal ecosystems) increases, mechanisms for its efficient and equitable allocation are lacking. An accessible and replicable coastal vulnerability indicator framework is presented to assist state and federal policy makers in the allocation of funding for coastal natural infrastructure recovery. To assess funding priorization gaps and test the applicability of the proposed framework, spatial patterns in the estimated funding need identified in state-led post-Hurricane Maria assessments for natural infrastructure rehabilitation efforts were compared to physical and social coastal vulnerability estimations. Three main challenges that emerge during the implementation of a vulnerability indicator framework were considered for its design: (1) the compressed time frame in which decisions are made after an extreme weather event, (2) the availability of data to calculate indicators in a reduced time frame, and (3) the accessibility of results to a broad variety of stakeholders. We propose a vulnerability indicator framework that can become operational in a relatively short period of time, attempts to simplify data gathering efforts, and uses methods that aim to be more transparent and understandable to a broad group of stakeholders.

Enhancing Upland cotton for drought resilience, productivity, and fiber quality: comparative evaluation and genetic dissection.

To provision the world sustainably, modern society must increase overall crop production, while conserving and preserving natural resources. Producing more with diminishing water resources is an especially daunting endeavor. Toward the goal of genetically improving drought resilience of cultivated Upland cotton (Gossypium hirsutum L.), this study addresses the genetics of differential yield components referred to as productivity and fiber quality traits under regular-water versus low-water (LW) field conditions. We used ten traits to assess water stress deficit, which included six productivity and four fiber quality traits on two recombinant inbred line (RIL) populations from reciprocally crossed cultivars, Phytogen 72 and Stoneville 474. To facilitate genetic inferences, we genotyped RILs with the CottonSNP63K array, assembled high-density linkage maps of over 7000 SNPs and then analyzed quantitative trait variations. Analysis of variance revealed significant differences for all traits (p < 0.05) in these RIL populations. Although the LW irrigation regime significantly reduced all traits, except lint percent, the RILs exhibited a broad phenotypic spectrum of heritable differences across the water regimes. Transgressive segregation occurred among the RILs, suggesting the possibility of genetic gain through phenotypic selection for drought resilience and perhaps through marker-based selection. Analyses revealed more than 150 quantitative trait loci (QTLs) associated with productivity and fiber quality traits (p < 0.005) on different genomic regions of the cotton genome. The multiple-QTL models analysis with LOD > 3.0 detected 21 QTLs associated with productivity and 22 QTLs associated with fiber quality. For fiber traits, strong clustering and QTL associations occurred in c08 and its homolog c24 as well as c10, c14, and c21. Using contemporary genome sequence assemblies and bioinformatically related information, the identification of genomic regions associated with responses to plant stress/drought elevates the possibility of using marker-assisted and omics-based selection to enhance breeding for drought resilient cultivars and identifying candidate genes and networks. RILs with different responses to drought indicated that it is possible to maintain high fiber quality under LW conditions or reduce the of LW impact on quality. The heritable variation among elite bi-parental RILs for productivity and quality under field drought conditions, and their association of QTLs, and thus specific genomic regions, indicate opportunities for breeding-based gains in water resource conservation, i.e., enhancing cotton's agricultural sustainability.

Enhanced Metallophilicity in Metal-Carbene Systems: Stronger Character of Aurophilic Interactions in Solution.

Metallophilicity is an essential concept that builds upon the attraction between closed shell metal ions. We report on the [M2 (bisNHC)2 ]2+ (M=AuI , AgI ; NHC=N-heterocyclic carbene) systems, which display almost identical features in the solid state. However, in solution the Au2 cation exhibits a significantly higher degree of rigidity owed to the stronger character of the aurophilic interactions. Both Au2 and Ag2 cationic constructs are able to accommodate Ag+ ions via M-M interactions, despite their inherent Coulombic repulsion. When electrostatic repulsion between host and guest is partially diminished, M-M distances are substantially shortened. Quantum chemical calculations estimate intermetallic bond orders up to 0.2. Although at the limit of (or beyond) the van der Waals radii, metallophilic interactions are responsible for their behavior in solution.

Hypersensitivity to antibiotics in drug reaction with eosinophilia and systemic symptoms (DRESS) from other culprits.

BACKGROUND: Antibiotics have been implicated in the reactivation of exanthema and systemic involvement in drug reaction with eosinophilia and systemic symptoms (DRESS); however, it is not clear whether these patients become sensitized to the antibiotic. OBJECTIVE: To evaluate if, after DRESS, patients become sensitized to antibiotics. METHODS: We retrospectively reviewed the patch test (PT) data and clinical files of DRESS patients who were administered antibiotics during DRESS from other culprits. RESULTS: Nine patients out of 17 (53%) were positive to antibiotics in PT: six to the penicillin group and three to cephalosporins (including one patient with additional positivity to vancomycin). Considering the eight patients who were negative to antibiotics in PT, seven were exposed to a fluoroquinolone. Four cases were patch tested again and three remained positive to antibiotics 2 to 5 years thereafter. Two patients with positive PT results had an accidental re-exposure to antibiotics and developed a maculopapular exanthema without systemic symptoms. CONCLUSION: Exposure to antibiotics during DRESS or its prodromal phase could enhance sensitization to antibiotics, as confirmed by a positive PT. Reproducibility of positive PTs to antibiotics after several years and reactivation after re-exposure support that T-cell-mediated hypersensitivity to antibiotics in the setting of DRESS is a specific reaction.

Neuronal hyperexcitability in a mouse model of SCN8A epileptic encephalopathy.

Patients with early infantile epileptic encephalopathy (EIEE) experience severe seizures and cognitive impairment and are at increased risk for sudden unexpected death in epilepsy (SUDEP). EIEE13 [Online Mendelian Inheritance in Man (OMIM) # 614558] is caused by de novo missense mutations in the voltage-gated sodium channel gene SCN8A Here, we investigated the neuronal phenotype of a mouse model expressing the gain-of-function SCN8A patient mutation, p.Asn1768Asp (Nav1.6-N1768D). Our results revealed regional and neuronal subtype specificity in the effects of the N1768D mutation. Acutely dissociated hippocampal neurons from Scn8aN1768D/+ mice showed increases in persistent sodium current (INa) density in CA1 pyramidal but not bipolar neurons. In CA3, INa,P was increased in both bipolar and pyramidal neurons. Measurement of action potential (AP) firing in Scn8aN1768D/+ pyramidal neurons in brain slices revealed early afterdepolarization (EAD)-like AP waveforms in CA1 but not in CA3 hippocampal or layer II/III neocortical neurons. The maximum spike frequency evoked by depolarizing current injections in Scn8aN1768D/+ CA1, but not CA3 or neocortical, pyramidal cells was significantly reduced compared with WT. Spontaneous firing was observed in subsets of neurons in CA1 and CA3, but not in the neocortex. The EAD-like waveforms of Scn8aN1768D/+ CA1 hippocampal neurons were blocked by tetrodotoxin, riluzole, and SN-6, implicating elevated persistent INa and reverse mode Na/Ca exchange in the mechanism of hyperexcitability. Our results demonstrate that Scn8a plays a vital role in neuronal excitability and provide insight into the mechanism and future treatment of epileptogenesis in EIEE13.

The clinical spectrum of dermatomyositis and the new autoantibodies - with regard to two clinical cases with distinct associations.

Dermatomyositis is a rare idiopathic inflammatory myopathy associated with different autoantibodies (anti-MDA5, anti-TIF1-γ) which are linked with typical and distinct phenotypes of dermatomyositis. We describe two cases that illustrate these diverse cutaneous and systemic manifestations.

Induced Gamma-Band Activity during Actual and Imaginary Movements: EEG Analysis.

The purpose of this paper is to record and analyze induced gamma-band activity (GBA) (30-60 Hz) in cerebral motor areas during imaginary movement and to compare it quantitatively with activity recorded in the same areas during actual movement using a simplified electroencephalogram (EEG). Brain activity (basal activity, imaginary motor task and actual motor task) is obtained from 12 healthy volunteer subjects using an EEG (Cz channel). GBA is analyzed using the mean power spectral density (PSD) value. Event-related synchronization (ERS) is calculated from the PSD values of the basal GBA (GBAb), the GBA of the imaginary movement (GBAim) and the GBA of the actual movement (GBAac). The mean GBAim and GBAac values for the right and left hands are significantly higher than the GBAb value (p = 0.007). No significant difference is detected between mean GBA values during the imaginary and actual movement (p = 0.242). The mean ERS values for the imaginary movement (ERSimM (%) = 23.52) and for the actual movement (ERSacM = 27.47) do not present any significant difference (p = 0.117). We demonstrated that ERS could provide a useful way of indirectly checking the function of neuronal motor circuits activated by voluntary movement, both imaginary and actual. These results, as a proof of concept, could be applied to physiology studies, brain-computer interfaces, and diagnosis of cognitive or motor pathologies.

Cardiac arrhythmia in a mouse model of sodium channel SCN8A epileptic encephalopathy.

Patients with early infantile epileptic encephalopathy (EIEE) are at increased risk for sudden unexpected death in epilepsy (SUDEP). De novo mutations of the sodium channel gene SCN8A, encoding the sodium channel Nav1.6, result in EIEE13 (OMIM 614558), which has a 10% risk of SUDEP. Here, we investigated the cardiac phenotype of a mouse model expressing the gain of function EIEE13 patient mutation p.Asn1768Asp in Scn8a (Nav1.6-N1768D). We tested Scn8aN1768D/+ mice for alterations in cardiac excitability. We observed prolongation of the early stages of action potential (AP) repolarization in mutant myocytes vs. controls. Scn8aN1768D/+ myocytes were hyperexcitable, with a lowered threshold for AP firing, increased incidence of delayed afterdepolarizations, increased calcium transient duration, increased incidence of diastolic calcium release, and ectopic contractility. Calcium transient duration and diastolic calcium release in the mutant myocytes were tetrodotoxin-sensitive. A selective inhibitor of reverse mode Na/Ca exchange blocked the increased incidence of diastolic calcium release in mutant cells. Scn8aN1768D/+ mice exhibited bradycardia compared with controls. This difference in heart rate dissipated after administration of norepinephrine, and there were no differences in heart rate in denervated ex vivo hearts, implicating parasympathetic hyperexcitability in the Scn8aN1768D/+ animals. When challenged with norepinephrine and caffeine to simulate a catecholaminergic surge, Scn8aN1768D/+ mice showed ventricular arrhythmias. Two of three mutant mice under continuous ECG telemetry recording experienced death, with severe bradycardia preceding asystole. Thus, in addition to central neuron hyperexcitability, Scn8aN1768D/+ mice have cardiac myoycte and parasympathetic neuron hyperexcitability. Simultaneous dysfunction in these systems may contribute to SUDEP associated with mutations of Scn8a.

Empirical Mode Decomposition-Based Filter Applied to Multifocal Electroretinograms in Multiple Sclerosis Diagnosis.

As multiple sclerosis (MS) usually affects the visual pathway, visual electrophysiological tests can be used to diagnose it. The objective of this paper is to research methods for processing multifocal electroretinogram (mfERG) recordings to improve the capacity to diagnose MS. MfERG recordings from 15 early-stage MS patients without a history of optic neuritis and from 6 control subjects were examined. A normative database was built from the control subject signals. The mfERG recordings were filtered using empirical mode decomposition (EMD). The correlation with the signals in a normative database was used as the classification feature. Using EMD-based filtering and performance correlation, the mean area under the curve (AUC) value was 0.90. The greatest discriminant capacity was obtained in ring 4 and in the inferior nasal quadrant (AUC values of 0.96 and 0.94, respectively). Our results suggest that the combination of filtering mfERG recordings using EMD and calculating the correlation with a normative database would make mfERG waveform analysis applicable to assessment of multiple sclerosis in early-stage patients.

Understanding G Protein Selectivity of Muscarinic Acetylcholine Receptors Using Computational Methods.

The neurotransmitter molecule acetylcholine is capable of activating five muscarinic acetylcholine receptors, M1 through M5, which belong to the superfamily of G-protein-coupled receptors (GPCRs). These five receptors share high sequence and structure homology; however, the M1, M3, and M5 receptor subtypes signal preferentially through the Gαq/11 subset of G proteins, whereas the M2 and M4 receptor subtypes signal through the Gαi/o subset of G proteins, resulting in very different intracellular signaling cascades and physiological effects. The structural basis for this innate ability of the M1/M3/M5 set of receptors and the highly homologous M2/M4 set of receptors to couple to different G proteins is poorly understood. In this study, we used molecular dynamics (MD) simulations coupled with thermodynamic analyses of M1 and M2 receptors coupled to both Gαi and Gαq to understand the structural basis of the M1 receptor's preference for the Gαq protein and the M2 receptor's preference for the Gαi protein. The MD studies showed that the M1 and M2 receptors can couple to both Gα proteins such that the M1 receptor engages with the two Gα proteins in slightly different orientations and the M2 receptor engages with the two Gα proteins in the same orientation. Thermodynamic studies of the free energy of binding of the receptors to the Gα proteins showed that the M1 and M2 receptors bind more strongly to their cognate Gα proteins compared to their non-cognate ones, which is in line with previous experimental studies on the M3 receptor. A detailed analysis of receptor-G protein interactions showed some cognate-complex-specific interactions for the M2:Gαi complex; however, G protein selectivity determinants are spread over a large overlapping subset of residues. Conserved interaction between transmembrane helices 5 and 6 far away from the G-protein-binding receptor interface was found only in the two cognate complexes and not in the non-cognate complexes. An analysis of residues implicated previously in G protein selectivity, in light of the cognate and non-cognate structures, shaded a more nuanced role of those residues in affecting G protein selectivity. The simulation of both cognate and non-cognate receptor-G protein complexes fills a structural gap due to difficulties in determining non-cognate complex structures and provides an enhanced framework to probe the mechanisms of G protein selectivity exhibited by most GPCRs.

Drastic Effect of the Peptide Sequence on the Copper-Binding Properties of Tripeptides and the Electrochemical Behaviour of Their Copper(II) Complexes.

The binding and electrochemical properties of the complexes CuII -HAH, CuII -HWH, CuII -Ac-HWH, CuII -HHW, and CuII -WHH have been studied by using NMR and UV/Vis spectroscopies, CV, and density functional calculations. The results obtained highlight the importance of the peptidic sequence on the coordination properties and, consequently, on the redox properties of their CuII complexes. For CuII -HAH and CuII -HWH, no cathodic processes are observed up to -1.2 V; that is, the complexes exhibit very high stability towards copper reduction. This behaviour is associated with the formation of very stable square-planar (5,5,6)-membered chelate rings (ATCUN motif), which enclose two deprotonated amides. In contrast, for non-ATCUN CuII -Ac-HWH, CuII -HHW complexes, simulations seem to indicate that only one deprotonated amide is enclosed in the coordination sphere. In these cases, the main electrochemical feature is a reductive irreversible one electron-transfer process from CuII to CuI , accompanied with structural changes of the metal coordination sphere and reprotonation of the amide. Finally, for CuII -WHH, two major species have been detected: one at low pH (<5), with no deprotonated amides, and another one at high pH (>10) with an ATCUN motif, both species coexisting at intermediate pH. The present study shows that the use of CV, using glassy carbon as a working electrode, is an ideal and rapid tool for the determination of the redox properties of CuII metallopeptides.

Intramolecular Photocycloaddition of 2(5 H)-Furanones to Temporarily Tethered Terminal Alkenes as a Stereoselective Source of Enantiomerically Pure Polyfunctionalyzed Cyclobutanes.

Allyloxymethyloxymethyl and 4-pentenoyloxymethyl substituents have been used as tethering groups to study the intramolecular [2 + 2] photocycloaddition of chiral 5-substituted 2(5 H)-furanones. The photoreactions proceed in good yield and provide the expected regio- and diastereoselective tricyclic compounds with complementary regioselectivity, which depends on whether the vinyl chain is attached to the furanone by an acetal or an ester linkage. Computational simulations agree with experimental observations and indicate that the origin of the different observed regioselectivity in the intramolecular photochemical reaction of lactones 5 and 6 arises from the relative stability of the initial conformers. The synthetic potential of the enantiomerically pure photoadducts is illustrated by preparing an all- cis 1,2,3-trisubstituted cyclobutane bearing fully orthogonally protected hydroxyl groups.

Allergic contact dermatitis caused by dexpanthenol-Probably a frequent allergen.

BACKGROUND: Panthenol (synonym: dexpanthenol), the alcohol analogue of panthothenic acid, is frequently included in moisturizers, wound-healing agents, and other cosmetics, and has been shown to be responsible for allergic contact dermatitis (ACD). OBJECTIVES: To evaluate the frequency of ACD caused by dexpanthenol, and to characterize reactive patients. METHODS: We retrospectively reviewed the files of patients patch tested between 2009 and 2017 in the Department of Dermatology of the Coimbra's University Hospital and describe patients who reacted to dexpanthenol 5% pet., tested initially in a cosmetic/vehicle series and in the last 3 years in consecutive patients. RESULTS: Among 2171 patients, 26 (1.2%) had positive patch test reactions to dexpanthenol, mostly patients tested for chronic eczema (88.5%, n = 23), either widespread (5), or localized to the hands (5), face (4), or legs (7). Relevance could be traced in 20 patients (76.9%), related to the use of Bepanthene cream (15), moisturizers (3), topical medications (1), and a shampoo (1). Twenty-five of 26 patients (96.2%) reacted to several other allergens, mostly ingredients of cosmetic or pharmaceutical products. CONCLUSIONS: Although ACD caused by dexpanthenol is considered to be rare, it may be frequently overlooked. As we found a relatively high frequency of relevant cases, in agreement with a previous study, the inclusion of dexpanthenol in patch test series, at least in cosmetic and topical drug series, is encouraged.

Photochemical Relaxation Pathways in Dinitropyrene Isomer Pollutants.

Dinitropyrenes are polycyclic aromatic pollutants prevalent in the environment. While their transformations by sunlight in the environment have been documented, the effect that the nitro-group substitution pattern has on the relaxation pathways has not been extensively studied. In this contribution, the steady-state and femtosecond-to-microsecond excited-state dynamics of 1,3-dinitropyrene and 1,8-dinitropyrene isomers are investigated upon visible light excitation at 425 nm and compared with those recently reported for the 1,6-dinitropyrene isomer. The experimental results are complemented with ground- and excited-state density functional calculations. It is shown that excitation at 425 nm results in the ultrafast branching of the excited-state population in the S1 state to populate the triplet state in ca. 90% yield and to form a nitropyrenoxy radical in less than 10% yield. In addition, the position of the NO2 group does not affect significantly the excited-state relaxation mechanism, while it does influence the absorption and fluorescence spectra, the fluorescence, triplet, singlet oxygen, and photodegradation yields, as well as the relative yield of radical formation. Radical formation is implicated in the photodegradation of these pollutants, while in the presence of hydrogen donors, direct reactions from the triplet state are also observed.