Incorporation of Multiple ß2-Hydroxy Acids into a Protein In Vivo Using an Orthogonal Aminoacyl-tRNA Synthetase.

The programmed synthesis of sequence-defined biomaterials whose monomer backbones diverge from those of canonical α-amino acids represents the next frontier in protein and biomaterial evolution. Such next-generation molecules provide otherwise nonexistent opportunities to develop improved biologic therapies, bioremediation tools, and biodegradable plastic-like materials. One monomer family of particular interest for biomaterials includes ß-hydroxy acids. Many natural products contain isolated ß-hydroxy acid monomers, and polymers of ß-hydroxy acids (ß-esters) are found in polyhydroxyalkanoate (PHA) polyesters under development as bioplastics and drug encapsulation/delivery systems. Here we report that ß2-hydroxy acids possessing both (R) and (S) absolute configuration are substrates for pyrrolysyl-tRNA synthetase (PylRS) enzymes in vitro and that (S)-ß2-hydroxy acids are substrates in cellulo. Using the orthogonal MaPylRS/MatRNAPyl synthetase/tRNA pair, in conjunction with wild-type E. coli ribosomes and EF-Tu, we report the cellular synthesis of model proteins containing two (S)-ß2-hydroxy acid residues at internal positions. Metadynamics simulations provide a rationale for the observed preference for the (S)-ß2-hydroxy acid and provide mechanistic insights that inform future engineering efforts. As far as we know, this finding represents the first example of an orthogonal synthetase that acylates tRNA with a ß2-hydroxy acid substrate and the first example of a protein hetero-oligomer containing multiple expanded-backbone monomers produced in cellulo.

The prospect of spray pyrolyzed pure, Mn-doped, and Zn-doped nickel oxide thin films as TCO material.

Nickel Oxide films with Manganese (Mn) and Zinc (Zn) doping (NiO, Ni1-xMnxO, and Ni1-xZnxO; where x = 0, 0.02, 0.04, and 0.06) were fabricated using the spray pyrolysis technique on the glass substrates at 400 °C (673K) temperature. The XRD spectra revealed a polycrystalline nature of the films with cubic crystal structure and a favored growth orientation towards the (111) plane. The SEM micrographs revealed a smooth, homogeneous, and uniform surface, while the EDS spectra confirmed the presence of Ni, O, Zn, and Mn elements in the films. Optical analysis using UV-visible absorption spectroscopy demonstrated high transparency of the films in the visible region (400 nm-900 nm), and the transparency increased with higher Zn doping, reaching ∼85 % in Ni0.94Zn0.06O films. Conversely, Ni1-xMnxO films show a slight transmission decline with increasing Mn doping concentrations. The sheet resistance of the films was found to be decreased for low-concentration doping and again began to increase for highly doped Ni0.94Zn0.06O and Ni0.94Mn0.06O films. Among all the films, Ni0.98Zn0.02O exhibited the maximum figure of merit, showing the prospect for optoelectronic applications.

Analysis of the relative frequencies of the multipartite BNYVV genomic RNAs in different plants and tissues.

Multipartite virus genomes are composed of two or more segments, each packaged into an independent viral particle. A potential advantage of multipartitism is the regulation of gene expression through changes in the segment copy number. Soil-borne beet necrotic yellow vein virus (BNYVV) is a typical example of multipartism, given its high number of genomic positive-sense RNAs (up to five). Here we analyse the relative frequencies of the four genomic RNAs of BNYVV type B during infection of different host plants (Chenopodium quinoa, Beta macrocarpa and Spinacia oleracea) and organs (leaves and roots). By successfully validating a two-step reverse-transcriptase digital droplet PCR protocol, we show that RNA1 and -2 genomic segments always replicate at low and comparable relative frequencies. In contrast, RNA3 and -4 accumulate with variable relative frequencies, resulting in distinct RNA1 : RNA2 : RNA3 : RNA4 ratios, depending on the infected host species and organ.

Dynamic extracellular vestibule of human SERT: Unveiling druggable potential with high-affinity allosteric inhibitors.

The serotonin transporter (SERT) tightly regulates synaptic serotonin levels and has been the primary target of antidepressants. Binding of inhibitors to the allosteric site of human SERT (hSERT) impedes the dissociation of antidepressants bound at the central site and may enhance the efficacy of such antidepressants to potentially reduce their dosage and side effects. Here, we report the identification of a series of high-affinity allosteric inhibitors of hSERT in a unique scaffold, with the lead compound, Lu AF88273 (3-(1-(2-(1H-indol-3-yl)ethyl)piperidin-4-yl)-6-chloro-1H-indole), having 2.1 nM allosteric potency in inhibiting imipramine dissociation. In addition, we find that Lu AF88273 also inhibits serotonin transport in a noncompetitive manner. The binding pose of Lu AF88273 in the allosteric site of hSERT is determined with extensive molecular dynamics simulations and rigorous absolute binding free energy perturbation (FEP) calculations, which show that a part of the compound occupies a dynamically formed small cavity. The predicted binding location and pose are validated by site-directed mutagenesis and can explain much of the structure-activity relationship of these inhibitors using the relative binding FEP calculations. Together, our findings provide a promising lead compound and the structural basis for the development of allosteric drugs targeting hSERT. Further, they demonstrate that the divergent allosteric sites of neurotransmitter transporters can be selectively targeted.

Atomistic simulations of the Escherichia coli ribosome provide selection criteria for translationally active substrates.

As genetic code expansion advances beyond L-α-amino acids to backbone modifications and new polymerization chemistries, delineating what substrates the ribosome can accommodate remains a challenge. The Escherichia coli ribosome tolerates non-L-α-amino acids in vitro, but few structural insights that explain how are available, and the boundary conditions for efficient bond formation are so far unknown. Here we determine a high-resolution cryogenic electron microscopy structure of the E. coli ribosome containing α-amino acid monomers and use metadynamics simulations to define energy surface minima and understand incorporation efficiencies. Reactive monomers across diverse structural classes favour a conformational space where the aminoacyl-tRNA nucleophile is <4 Å from the peptidyl-tRNA carbonyl with a Bürgi-Dunitz angle of 76-115°. Monomers with free energy minima that fall outside this conformational space do not react efficiently. This insight should accelerate the in vivo and in vitro ribosomal synthesis of sequence-defined, non-peptide heterooligomers.

Dermoscopy of glomus tumour: a cross-sectional study of 86 cases.

BACKGROUND: Glomus tumours (GTs) are benign cutaneous neoplasms derived from the neuromyoarterial apparatus with a strong predilection for acral sites, especially the subungual space. Current data regarding dermoscopy of these lesions are very limited. OBJECTIVES: To analyse the dermoscopic structures and patterns seen in a large series of subungual (SUGTs) and extraungual glomus tumours (EUGTs) and to determine their diagnostic significance. METHODS: Clinical and dermoscopic images of 86 histopathologically proven cases of GTs (47 SUGTs and 39 EUGTs) collected from 9 hospitals in Spain, France, Italy, and Brazil were evaluated for the presence of dermoscopic structures and patterns. Similarly, 189 and 185 dermoscopic images of other ungual tumours and other extraungual non-pigmented tumours, respectively, were evaluated for the same structures and patterns. Finally, we evaluate diagnostic testing accuracy calculating sensitivity (S), specificity (Sp), and positive and negative predictive values of the different patterns for the diagnosis of GT. RESULTS: Regarding SUGTs, four patterns were built from the combination of different structures. The pattern composed of a structureless purplish/red subungual spot with or without vessels reached the highest S (S1, 78.8%). The combination of a structureless purplish/red subungual spot and longitudinal erythronychia (LE) (S2) is highly specific (96.3%). Patterns S3 (proximal purplish/red subungual spot, LE, and distal notch) and S4 (bed subungual spot and onycholysis) are the most specific and exclusive of matrix and bed tumours, respectively. The most consistent pattern in EUGTs is composed of a structureless purplish-white to reddish-white homogeneous area and linear unfocused vessels (E) (S: 61.5%, Sp: 95.7%). EUGTs did not show lacunae, unlike other vascular tumours. CONCLUSIONS: Dermoscopy is helpful in improving the diagnostic accuracy of GTs, not only in SUGTs but also when these lesions arise out of the ungual apparatus.

Charla para sensibilizar a adolescentes durante la pandemia, y explicar el uso correcto y tipos de mascarillas. "Por una Navidad responsable" / Talk to raise awareness among adolescents during the pandemic, and explain the correct use and types of masks. "For a responsible Christmas

JUSTIFICACIÓN: en noviembre del 2020, enfrentando ya la tercera ola de la pandemia por COVID-19, y observando la gran importancia de los jóvenes en la propagación, por sus hábitos sociales y desinformación, surgió la necesidad, como farmacia comunitaria, de llegar a esos jóvenes usando lenguaje adaptado a su edad, y dando información correcta. Se eligieron 2 centros educativos de Don Benito, para abarcar el máximo número de alumnos.OBJETIVOS: 1) Informar correctamente a los adolescentes, de la realidad de la COVID, y ayudar a su prevención. 2) Aclarar tipos de mascarillas, uso y características.3) Presentar al farmacéutico comunitario como educador durante la pandemia, aportando información clara y científica. Material y Métodos: Material: Pendrive, ordenador, pantalla y equipo informático en aulas.MÉTODOS :1) En el primer centro (Colegio Claret), se optó por dar charlas de 20 minutos, presenciales a 454 asistentes en 20 aulas (Eso, bachillerato y grados). 2) En el segundo centro (I.E.S. Donoso Cortés), se realizó una exposición en red a 786 asistentes en 36 aulas (ESO, Bachillerato y grados). Desarrollo:1)Se elaboraron diapositivas con tipos de mascarillas y sus normas ISO; se buscaron y eligieron dos videos sobre mascarillas para adolescentes y se pidió colaboración a paciente COVID joven, para compartir su testimonio.2)Se telefoneó a los centros (uno contacto anterior, por proyecto “Conóceme”).3)Entrevista personal (segundo centro), presentando material y eligiendo la opción charla en red.4)Coordinar días y horas, sin perjudicar la organización de ambos centros.5)Impartir charlas presenciales en horarios y días elegidos.RESULTADOS: -Se informó y educó en prevención, a dos de seis centros de la localidad, llegando a 1.240 alumnos, y a sus familias. -Se publica la intervención en revistas locales y regionales, así como en anuarios de cada centro, en la radio de un centro, páginas web y redes sociales. (AU)

Dermoscopy in Basal Cell Carcinoma: An Updated Review. / Dermatoscopia del carcinoma basocelular: revisión actualizada.

Dermoscopy is a noninvasive technique that has been demonstrated to improve diagnostic accuracy in basal cell carcinoma (BCC). The first dermoscopic model for the diagnosis of BCC, based mainly on the identification of pigmented structures, was described by Menzies et al., and since then dermoscopy has generated an abundance of literature useful to routine clinical practice. From a practical perspective, dermoscopic structures associated with BCC can be classified as pigmented, vascular, or nonpigmented/nonvascular. One of the most recent applications of dermoscopy in BCC is as an aid to predicting histologic subtype and essentially differentiating between superficial and nonsuperficial BCC. It can also, however, help raise suspicion of more aggressive variants with a higher risk of recurrence. A thorough dermoscopic examination during follow-up of patients with actinic damage or a history of multiple BCCs can facilitate the detection of very incipient lesions and significantly impact treatment and prognosis.

Associations of Non-Alcoholic Beverages with Major Depressive Disorder History and Depressive Symptoms Clusters in a Sample of Overweight Adults.

BACKGROUND: Meta-analysis of observational studies concluded that soft drinks may increase the risk of depression, while high consumption of coffee and tea may reduce the risk. Objectives were to explore the associations between the consumption of soft drinks, coffee or tea and: (1) a history of major depressive disorder (MDD) and (2) the severity of depressive symptoms clusters (mood, cognitive and somatic/vegetative symptoms). METHODS: Cross-sectional and longitudinal analysis based on baseline and 12-month-follow-up data collected from four countries participating in the European MooDFOOD prevention trial. In total, 941 overweight adults with subsyndromal depressive symptoms aged 18 to 75 years were analyzed. History of MDD, depressive symptoms and beverages intake were assessed. RESULTS: Sugar-sweetened soft drinks were positively related to MDD history rates whereas soft drinks with non-nutritive sweeteners were inversely related for the high vs. low categories of intake. Longitudinal analysis showed no significant associations between beverages and mood, cognitive and somatic/vegetative clusters. CONCLUSION: Our findings point toward a relationship between soft drinks and past MDD diagnoses depending on how they are sweetened while we found no association with coffee and tea. No significant effects were found between any studied beverages and the depressive symptoms clusters in a sample of overweight adults.

Interpretation problems with the BASC-3 SRP-A F Index for patients with depressive disorders: An initial analysis and proposal for future research.

The Behavioral Assessment System for Children, 3rd edition (BASC-3) is a commonly used clinical assessment to evaluate a variety of behavioral and emotional concerns in children and adolescents. The focus of the current study is on the problematic interpretation of the F Index of the BASC-3 self-report measure for adolescents (SRP-A) suffering from depressive disorders. In this study, we used data from 214 patients in an adolescent partial hospitalization program within a psychiatric facility, all of whom were administered the BASC-3 SRP-A upon intake. Results suggest that the BASC-3 SRP-A F Index may confound an invalid response style of intentional overreporting with significant psychopathology in this specific psychiatric population. Our findings raise the question of similar confounding across psychiatric diagnoses and similar interpretation problems. We encourage further studies with independent samples of adolescents with a broad spectrum of diagnoses to address this question and offer a proposal if indeed there is evidence of a more generalized problem with the SRP-A F Index. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Efficacy of Three Low-Intensity, Internet-Based Psychological Interventions for the Treatment of Depression in Primary Care: Randomized Controlled Trial.

BACKGROUND: Primary care is a major access point for the initial treatment of depression, but the management of these patients is far from optimal. The lack of time in primary care is one of the major difficulties for the delivery of evidence-based psychotherapy. During the last decade, research has focused on the development of brief psychotherapy and cost-effective internet-based interventions mostly based on cognitive behavioral therapy (CBT). Very little research has focused on alternative methods of treatment for depression using CBT. Thus, there is a need for research into other therapeutic approaches. OBJECTIVE: This study aimed to assess the effectiveness of 3 low-intensity, internet-based psychological interventions (healthy lifestyle psychoeducational program [HLP], focused program on positive affect promotion [PAPP], and brief intervention based on mindfulness [MP]) compared with a control condition (improved treatment as usual [iTAU]). METHODS: A multicenter, 4-arm, parallel randomized controlled trial was conducted between March 2015 and March 2016, with a follow-up of 12 months. In total, 221 adults with mild or moderate major depression were recruited in primary care settings from 3 Spanish regions. Patients were randomly distributed to iTAU (n=57), HLP (n=54), PAPP (n=56), and MP (n=54). All patients received iTAU from their general practitioners. The main outcome was the Spanish version of the Patient Health Questionnaire-9 (PHQ-9) from pretreatment (time 1) to posttreatment (time 2) and up to 6 (time 3) and 12 (time 4) months' follow-up. Secondary outcomes included the visual analog scale of the EuroQol, the Short-Form Health Survey (SF-12), the Positive and Negative Affect Schedule (PANAS), and the Pemberton Happiness Index (PHI). We conducted regression models to estimate outcome differences along study stages. RESULTS: A moderate decrease was detected in PHQ-9 scores from HLP (ß=-3.05; P=.01) and MP (ß=-3.00; P=.01) compared with iTAU at posttreatment. There were significant differences between all intervention groups and iTAU in physical SF-12 scores at 6 months after treatment. Regarding well-being, MP and PAPP reported better PHI results than iTAU at 6 months post treatment. PAPP intervention significantly decreased PANAS negative affect scores compared with iTAU 12 months after treatment. CONCLUSIONS: The low-intensity, internet-based psychological interventions (HLP and MP) for the treatment of depression in primary care are more effective than iTAU at posttreatment. Moreover, all low-intensity psychological interventions are also effective in improving medium- and long-term quality of life. PAPP is effective for improving health-related quality of life, negative affect, and well-being in patients with depression. Nevertheless, it is important to examine possible reasons that could be implicated for PAPP not being effective in reducing depressive symptomatology; in addition, more research is still needed to assess the cost-effectiveness analysis of these interventions. TRIAL REGISTRATION: ISRCTN Registry ISRCTN82388279; http://www.isrctn.com/ISRCTN82388279. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.1186/s12888-015-0475-0.

The mechanism of a high-affinity allosteric inhibitor of the serotonin transporter.

The serotonin transporter (SERT) terminates serotonin signaling by rapid presynaptic reuptake. SERT activity is modulated by antidepressants, e.g., S-citalopram and imipramine, to alleviate symptoms of depression and anxiety. SERT crystal structures reveal two S-citalopram binding pockets in the central binding (S1) site and the extracellular vestibule (S2 site). In this study, our combined in vitro and in silico analysis indicates that the bound S-citalopram or imipramine in S1 is allosterically coupled to the ligand binding to S2 through altering protein conformations. Remarkably, SERT inhibitor Lu AF60097, the first high-affinity S2-ligand reported and characterized here, allosterically couples the ligand binding to S1 through a similar mechanism. The SERT inhibition by Lu AF60097 is demonstrated by the potentiated imipramine binding and increased hippocampal serotonin level in rats. Together, we reveal a S1-S2 coupling mechanism that will facilitate rational design of high-affinity SERT allosteric inhibitors.

Estudio Delphi para el uso de apremilast en la psoriasis / The Use of Apremilast in Psoriasis: A Delphi Study

ANTECEDENTES: El manejo de apremilast en la práctica clínica complementa la información procedente de los ensayos clínicos pivotales. MATERIAL Y MÉTODO: Tras una revisión de la literatura se consideraron, por parte de un panel de dermatólogos expertos en el manejo de la psoriasis, 5 áreas donde la evidencia sobre el uso de apremilast en la psoriasis moderada era insuficiente o controvertida, que fueron evaluadas a través de un cuestionario diseñado según la metodología Delphi. RESULTADOS: Se alcanzó consenso en 96 de los 143 ítems planteados (67%) (85 en el acuerdo y 11 en el desacuerdo). El objetivo terapéutico con apremilast debería ponderarse entre la respuesta clínica, la sintomatología asociada, la calidad de vida y la satisfacción del paciente. El perfil en el que el uso de apremilast se considera con mayores posibilidades de éxito sería el de un paciente con psoriasis moderada estable. La mayoría de los clínicos consideraron que apremilast es adecuado para pacientes en los que hayan fracasado o estén contraindicados los tratamientos convencionales, preferentemente de forma previa a la indicación de terapia biológica. Hubo consenso en reconocer apremilast como una opción terapéutica adecuada para el tratamiento en localizaciones difíciles, como la psoriasis palmoplantar y del cuero cabelludo. La necesidad de cribado, así como de su monitorización durante el seguimiento, se consideró menor que la de otros tratamientos sistémicos, convencionales y biológicos. CONCLUSIONES: Apremilast podría representar una opción terapéutica en un perfil de pacientes distinto al presentado en los ensayos clínicos. La ausencia de un consenso sobre la definición de psoriasis moderada, la escasa evidencia acerca del fármaco en la vida real, así como algunos aspectos relacionados con la tolerabilidad representan limitaciones a estas propuestas

BACKGROUND: Experience in the use of apremilast in clinical practice complements the information available from pivotal clinical trials. MATERIAL AND METHOD: Following a review of the literature, a panel of dermatologists with expertise in the management of psoriasis considered 5 scenarios in which the evidence supporting the use of apremilast to treat moderate psoriasis is insufficient or controversial. These scenarios were then assessed using a Delphi questionnaire. RESULTS: Consensus was reached on 96 (67%) of the 143 items (positive in 85 and negative in 11). The therapeutic goal for apremilast should be based on 4 outcomes: clinical response, symptoms, quality of life, and patient satisfaction. The scenario in which the use of apremilast was considered to have the greatest possibility of success was in patients with stable moderate psoriasis. Most of the clinicians considered apremilast to be an appropriate treatment when conventional therapies fail or are contraindicated, preferably before the prescription of biologic therapy. Consensus was reached that apremilast is an appropriate treatment for psoriasis in difficult locations, such as the scalp or the palms and soles. It was also agreed that apremilast requires less prescreening and monitoring than other conventional and biologic systemic therapies. CONCLUSIONS: Apremilast could be a treatment option for patients with a different profile to that of clinical trial participants. The limitations of this proposal are the absence of consensus on the definition of moderate psoriasis, the lack of real-world evidence on the use of apremilast, and certain aspects related to tolerability

The Glu102 mutation disrupts higher-order oligomerization of the sigma 1 receptor.

The sigma 1 receptor (σ1R) is a unique endoplasmic reticulum membrane protein. Its ligands have been shown to possess therapeutic potential for neurological and substance use disorders among others. The E102Q mutation of σ1R has been found to elicit familial cases of amyotrophic lateral sclerosis (ALS). Despite reports of its downstream signaling consequences, the mechanistic details of the functional impact of E102Q at molecular level are not clear. Here, we investigate the molecular mechanism of the E102Q mutation with a spectrum of biochemical, biophysical, and pharmacological approaches. Our analysis of the interaction network of σ1R indicates that a set of residues near E102 is critical for the integrity of C-terminal ligand-binding domain. However, this integrity is not affected by the E102Q and E102A mutations, which is confirmed by the radioligand binding results. Instead, the E102 mutations disrupt the connection between the C-terminal domain and the N-terminal transmembrane helix (NT-helix). Results from bioluminescence resonance energy transfer and western blot assays demonstrate that these mutations destabilize higher-order σ1R oligomers, while our molecular dynamics simulations based on a σ1R crystal structure reveal a potential mechanism by which the mutations perturb the NT-helix dynamics. Thus, we propose that E102 is at a critical position in propagating the effects of ligand binding from the C-terminal domain to the NT-helix, while the latter may be involved in forming alternative oligomer interfaces, separate from the previously reported trimer interface. Together, these results provide the first account of the molecular mechanism of σ1R dysfunction caused by E102Q.

Distinct inactive conformations of the dopamine D2 and D3 receptors correspond to different extents of inverse agonism.

By analyzing and simulating inactive conformations of the highly homologous dopamine D2 and D3 receptors (D2R and D3R), we find that eticlopride binds D2R in a pose very similar to that in the D3R/eticlopride structure but incompatible with the D2R/risperidone structure. In addition, risperidone occupies a sub-pocket near the Na+ binding site, whereas eticlopride does not. Based on these findings and our experimental results, we propose that the divergent receptor conformations stabilized by Na+-sensitive eticlopride and Na+-insensitive risperidone correspond to different degrees of inverse agonism. Moreover, our simulations reveal that the extracellular loops are highly dynamic, with spontaneous transitions of extracellular loop 2 from the helical conformation in the D2R/risperidone structure to an extended conformation similar to that in the D3R/eticlopride structure. Our results reveal previously unappreciated diversity and dynamics in the inactive conformations of D2R. These findings are critical for rational drug discovery, as limiting a virtual screen to a single conformation will miss relevant ligands.

Almost a third of prescribed drugs work by acting on a group of proteins known as GPCRs (short for G-protein coupled receptors), which help to transmit messages across the cell's outer barrier. The neurotransmitter dopamine, for instance, can act in the brain and body by attaching to dopamine receptors, a sub-family of GPCRs. The binding process changes the three-dimensional structure (or conformation) of the receptor from an inactive to active state, triggering a series of molecular events in the cell. However, GPCRs do not have a single 'on' or 'off' state; they can adopt different active shapes depending on the activating molecule they bind to, and this influences the type of molecular cascade that will take place in the cell. Some evidence also shows that classes of GPCRs can have different inactive structures; whether this is also the case for the dopamine D₂ and D₃ receptors remained unclear. Mapping out inactive conformations of receptors is important for drug discovery, as compounds called antagonists can bind to inactive receptors and interfere with their activation. Lane et al. proposed that different types of antagonists could prefer specific types of inactive conformations of the dopamine D₂ and D₃ receptors. Based on the structures of these two receptors, the conformations of D₂ bound with the drugs risperidone and eticlopride (two dopamine antagonists) were simulated and compared. The results show that the inactive conformations of D₂ were very different when it was bound to eticlopride as opposed to risperidone. In addition D₂ and D₃ showed a very similar conformation when attached to eticlopride. The two drugs also bound to the inactive receptors in overlapping but different locations. These computational findings, together with experimental validations, suggest that D₂ and D₃ exist in several inactive states that only allow the binding of specific drugs; these states could also reflect different degrees of inactivation. Overall, the work by Lane et al. contributes to a more refined understanding of the complex conformations of GPCRs, which could be helpful to screen and develop better drugs.

The Use of Apremilast in Psoriasis: A Delphi Study. / Estudio Delphi para el uso de apremilast en la psoriasis.

BACKGROUND: Experience in the use of apremilast in clinical practice complements the information available from pivotal clinical trials. MATERIAL AND METHOD: Following a review of the literature, a panel of dermatologists with expertise in the management of psoriasis considered 5 scenarios in which the evidence supporting the use of apremilast to treat moderate psoriasis is insufficient or controversial. These scenarios were then assessed using a Delphi questionnaire. RESULTS: Consensus was reached on 96 (67%) of the 143 items (positive in 85 and negative in 11). The therapeutic goal for apremilast should be based on 4 outcomes: clinical response, symptoms, quality of life, and patient satisfaction. The scenario in which the use of apremilast was considered to have the greatest possibility of success was in patients with stable moderate psoriasis. Most of the clinicians considered apremilast to be an appropriate treatment when conventional therapies fail or are contraindicated, preferably before the prescription of biologic therapy. Consensus was reached that apremilast is an appropriate treatment for psoriasis in difficult locations, such as the scalp or the palms and soles. It was also agreed that apremilast requires less prescreening and monitoring than other conventional and biologic systemic therapies. CONCLUSIONS: Apremilast could be a treatment option for patients with a different profile to that of clinical trial participants. The limitations of this proposal are the absence of consensus on the definition of moderate psoriasis, the lack of real-world evidence on the use of apremilast, and certain aspects related to tolerability.

High-potency ligands for DREADD imaging and activation in rodents and monkeys.

Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) are a popular chemogenetic technology for manipulation of neuronal activity in uninstrumented awake animals with potential for human applications as well. The prototypical DREADD agonist clozapine N-oxide (CNO) lacks brain entry and converts to clozapine, making it difficult to apply in basic and translational applications. Here we report the development of two novel DREADD agonists, JHU37152 and JHU37160, and the first dedicated 18F positron emission tomography (PET) DREADD radiotracer, [18F]JHU37107. We show that JHU37152 and JHU37160 exhibit high in vivo DREADD potency. [18F]JHU37107 combined with PET allows for DREADD detection in locally-targeted neurons, and at their long-range projections, enabling noninvasive and longitudinal neuronal projection mapping.

A Novel Bromine-Containing Paroxetine Analogue Provides Mechanistic Clues for Binding Ambiguity at the Central Primary Binding Site of the Serotonin Transporter.

The serotonin transporter (SERT) is the primary target for the selective serotonin reuptake inhibitors (SSRIs). However, the structural basis for the extraordinarily high binding affinity of the widely prescribed SSRI, paroxetine, to human SERT (hSERT) has not yet been fully elucidated. Our previous findings unveiled a plausible ambiguity in paroxetine's binding orientations that may constitute an integral component of this SSRI's high affinity for hSERT. Herein, we investigate factors contributing to paroxetine's high affinity by modifying both the ligand and the protein. We generated a series of bromine (Br)-containing derivatives and found that the one in which the 4-F of paroxetine had been replaced with the chemically similar but more electron-rich Br atom (13) had the highest affinity. By comparatively characterizing the binding of paroxetine and 13 to both wild type (WT) and a construct harboring a paroxetine-sensitive mutation in the binding cavity, we identified a mechanistic determinant responsible for the pose ambiguity of paroxetine, which can guide future drug design.

Interferometric optical testing to discriminate benign and malignant brain tumors.

When normal cells suffer from the malignant disease, changes occur in cellular size and structure, and their constituents. These changes can affect the biological response of cells and tissues. Conventional hematoxylin and eosin staining, which is the gold standard of tumor diagnosis provide a very detailed view of the tissue by staining cell structures to diagnose a disease based on the deformation of the cells. However, this study shows changes in cells and tissues structure due to malignant diseases can also affect the optical properties. The purpose of this research was to assess and compare these effects to identify benign and malignant brain tissues from each other. Various samples of adult human brain tissues were studied using Mach-Zehnder interferometer as an optical method and using the Fourier transform method as an analytical process. The formed interference patterns of benign and malignant brain tumors were investigated to obtain the phase distribution of tumors. The obtained information demonstrated that the phase distribution of malignant brain tissues was different from benign brain tissues. The phase distribution approximately ranged from 10 to 120 rad for benign samples and from 10 to 160 rad for malignant samples. Moreover, the average of unwrapped phase distribution was 63.79 and 85.69 rad in benign and malignant samples, respectively. This results indicated that the proposed laser-based technique, Mach-Zehnder interferometer method, can be used as an auxiliary procedure along with histological techniques to identify benign and malignant brain tumors from each other. It is suggested that the unwrapped phase distribution of tissues be considered as an optical property for differentiating various brain tumors.