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1.
Cell ; 164(1-2): 197-207, 2016 Jan 14.
Artículo en Inglés | MEDLINE | ID: mdl-26709045

RESUMEN

Hippocampal neurons show selectivity with respect to visual cues in primates, including humans, but this has never been found in rodents. To address this long-standing discrepancy, we measured hippocampal activity from rodents during real-world random foraging. Surprisingly, ∼ 25% of neurons exhibited significant directional modulation with respect to visual cues. To dissociate the contributions of visual and vestibular cues, we made similar measurements in virtual reality, in which only visual cues were informative. Here, we found significant directional modulation despite the severe loss of vestibular information, challenging prevailing theories of directionality. Changes in the amount of angular information in visual cues induced corresponding changes in head-directional modulation at the neuronal and population levels. Thus, visual cues are sufficient for-and play a predictable, causal role in-generating directionally selective hippocampal responses. These results dissociate hippocampal directional and spatial selectivity and bridge the gap between primate and rodent studies.


Asunto(s)
Conducta Apetitiva , Hipocampo/fisiología , Animales , Electrofisiología/métodos , Movimientos de la Cabeza , Hipocampo/citología , Humanos , Masculino , Neuronas/citología , Ratas , Ratas Long-Evans , Vestíbulo del Laberinto/fisiología
2.
Nature ; 589(7842): 420-425, 2021 01.
Artículo en Inglés | MEDLINE | ID: mdl-33361808

RESUMEN

Everyday tasks in social settings require humans to encode neural representations of not only their own spatial location, but also the location of other individuals within an environment. At present, the vast majority of what is known about neural representations of space for self and others stems from research in rodents and other non-human animals1-3. However, it is largely unknown how the human brain represents the location of others, and how aspects of human cognition may affect these location-encoding mechanisms. To address these questions, we examined individuals with chronically implanted electrodes while they carried out real-world spatial navigation and observation tasks. We report boundary-anchored neural representations in the medial temporal lobe that are modulated by one's own as well as another individual's spatial location. These representations depend on one's momentary cognitive state, and are strengthened when encoding of location is of higher behavioural relevance. Together, these results provide evidence for a common encoding mechanism in the human brain that represents the location of oneself and others in shared environments, and shed new light on the neural mechanisms that underlie spatial navigation and awareness of others in real-world scenarios.


Asunto(s)
Neuronas/fisiología , Percepción Espacial/fisiología , Navegación Espacial/fisiología , Adulto , Concienciación/fisiología , Relojes Biológicos , Cognición/fisiología , Electrodos Implantados , Femenino , Humanos , Masculino , Persona de Mediana Edad , Lóbulo Temporal/fisiología
3.
Nat Rev Genet ; 21(4): 227-242, 2020 04.
Artículo en Inglés | MEDLINE | ID: mdl-31767998

RESUMEN

Bacterial chromosomes are folded to compact DNA and facilitate cellular processes. Studying model bacteria has revealed aspects of chromosome folding that are applicable to many species. Primarily controlled by nucleoid-associated proteins, chromosome folding is hierarchical, from large-scale macrodomains to smaller-scale structures that influence DNA transactions, including replication and transcription. Here we review the environmentally regulated, architectural and regulatory roles of nucleoid-associated proteins and the implications for bacterial cell biology. We also highlight similarities and differences in the chromosome folding mechanisms of bacteria and eukaryotes.


Asunto(s)
Cromosomas Bacterianos , ADN Bacteriano/química , ADN Bacteriano/metabolismo , Proteínas de Unión al ADN/metabolismo , Regulación Bacteriana de la Expresión Génica , Genoma Bacteriano
4.
Bioessays ; 46(11): e2400098, 2024 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-39324242

RESUMEN

The three-dimensional architecture of the bacterial chromosome is intertwined with genome processes such as transcription and replication. Conspicuously so, that the structure of the chromosome permits accurate prediction of active genome processes. Although appreciation of this interplay has developed rapidly in the past two decades, our understanding of this subject is still in its infancy, with research primarily focusing on how the process of transcription regulates and is regulated by chromosome structure. Here, we summarize the latest developments in the field with a focus on the interplay between chromosome structure and transcription in Escherichia coli (E. coli) as mediated by H-NS-a model nucleoid structuring protein. We describe how the organization of chromosomes at the global and local scales is dependent on transcription, and how transcription is regulated by chromosome structure. Finally, we take note of studies that highlight our limited knowledge of structure-function relationships in the chromosome, and we point out research tracks that will improve our insight in the topic.


Asunto(s)
Cromosomas Bacterianos , Proteínas de Unión al ADN , Escherichia coli , Cromosomas Bacterianos/genética , Escherichia coli/genética , Escherichia coli/metabolismo , Proteínas de Unión al ADN/metabolismo , Proteínas de Unión al ADN/genética , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Transcripción Genética , Regulación Bacteriana de la Expresión Génica , Proteínas de Escherichia coli/genética , Proteínas de Escherichia coli/metabolismo
5.
Mol Microbiol ; 120(1): 60-70, 2023 07.
Artículo en Inglés | MEDLINE | ID: mdl-37433047

RESUMEN

Nucleoid-associated proteins (NAPs) are architectural proteins of the bacterial chromosome and transcription factors that dynamically organise the chromosome and regulate gene expression in response to physicochemical environmental signals. While the architectural and regulatory functions of NAPs have been verified independently, the coupling between these functions in vivo has not been conclusively proven. Here we describe a model NAP - histone-like nucleoid structuring protein (H-NS) - as a coupled sensor-effector that directly regulates gene expression by chromatin re-modelling in response to physicochemical environmental signals. We outline how H-NS-binding partners and post-translational modifications modulate the role of H-NS as a transcription factor by influencing its DNA structuring properties. We consolidate our ideas in models of how H-NS may regulate the expression of the proVWX and hlyCABD operons by chromatin re-modelling. The interplay between chromosome structure and gene expression may be a common - but, at present, under-appreciated - concept of transcription regulation in bacteria.


Asunto(s)
Ensamble y Desensamble de Cromatina , Regulación de la Expresión Génica , Factores de Transcripción/genética , Cromosomas Bacterianos/genética , Bacterias/genética , Histonas , Cromatina
6.
Proc Biol Sci ; 291(2023): 20240239, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38808445

RESUMEN

The ocean's midwater is a uniquely challenging yet predictable and simple visual environment. The need to see without being seen in this dim, open habitat has led to extraordinary visual adaptations. To understand these adaptations, we compared the morphological and functional differences between the eyes of three hyperiid amphipods-Hyperia galba, Streetsia challengeri and Phronima sedentaria. Combining micro-CT data with computational modelling, we mapped visual field topography and predicted detection distances for visual targets viewed in different directions through mesopelagic depths. Hyperia's eyes provide a wide visual field optimized for spatial vision over short distances, while Phronima's and Streetsia's eyes have the potential to achieve greater sensitivity and longer detection distances using spatial summation. These improvements come at the cost of smaller visual fields, but this loss is compensated for by a second pair of eyes in Phronima and by behaviour in Streetsia. The need to improve sensitivity while minimizing visible eye size to maintain crypsis has likely driven the evolution of hyperiid eye diversity. Our results provide an integrative look at how these elusive animals have adapted to the unique visual challenges of the mesopelagic.


Asunto(s)
Anfípodos , Animales , Anfípodos/fisiología , Anfípodos/anatomía & histología , Ecosistema , Campos Visuales , Ojo/anatomía & histología , Visión Ocular , Microtomografía por Rayos X
7.
Nucleic Acids Res ; 50(2): e10, 2022 01 25.
Artículo en Inglés | MEDLINE | ID: mdl-34734265

RESUMEN

The interplay between three-dimensional chromosome organisation and genomic processes such as replication and transcription necessitates in vivo studies of chromosome dynamics. Fluorescent organic dyes are often used for chromosome labelling in vivo. The mode of binding of these dyes to DNA cause its distortion, elongation, and partial unwinding. The structural changes induce DNA damage and interfere with the binding dynamics of chromatin-associated proteins, consequently perturbing gene expression, genome replication, and cell cycle progression. We have developed a minimally-perturbing, genetically encoded fluorescent DNA label consisting of a (photo-switchable) fluorescent protein fused to the DNA-binding domain of H-NS - a bacterial nucleoid-associated protein. We show that this DNA label, abbreviated as HI-NESS (H-NS-based indicator for nucleic acid stainings), is minimally-perturbing to genomic processes and labels chromosomes in eukaryotic cells in culture, and in zebrafish embryos with preferential binding to AT-rich chromatin.


Asunto(s)
Proteínas Bacterianas/metabolismo , Bioensayo/métodos , ADN Bacteriano/metabolismo , Proteínas de Unión al ADN/metabolismo , Coloración y Etiquetado/métodos , Animales , Proteínas Bacterianas/genética , Línea Celular , Clonación Molecular , Replicación del ADN , ADN Bacteriano/química , Proteínas de Unión al ADN/genética , Colorantes Fluorescentes , Expresión Génica , Vectores Genéticos , Microscopía Fluorescente
8.
Psychol Med ; 53(6): 2437-2447, 2023 04.
Artículo en Inglés | MEDLINE | ID: mdl-37310302

RESUMEN

BACKGROUND: Few studies have examined how parenting influences the associations between prenatal maternal stress and children's mental health. The objectives of this study were to examine the sex-specific associations between prenatal maternal stress and child internalizing and externalizing symptoms, and to assess the moderating effects of parenting behaviors on these associations. METHODS: This study is based on 15 963 mother-child dyads from the Norwegian Mother, Father, and Child Cohort Study (MoBa). A broad measure of prenatal maternal stress was constructed using 41 self-reported items measured during pregnancy. Three parenting behaviors (positive parenting, inconsistent discipline, and positive involvement) were assessed by maternal report at child age 5 years. Child symptoms of internalizing and externalizing disorders (depression, anxiety, attention-deficit hyperactivity disorder, conduct disorder, and oppositional-defiant disorder) were assessed by maternal report at age 8. Analyses were conducted using structural equation modeling techniques. RESULTS: Prenatal maternal stress was associated with child internalizing and externalizing symptoms at age 8; associations with externalizing symptoms differed by sex. Associations between prenatal maternal stress and child depression, and conduct disorder and oppositional-defiant disorder in males, became stronger as levels of inconsistent discipline increased. Associations between prenatal maternal stress and symptoms of attention-deficit hyperactivity disorder in females were attenuated as levels of parental involvement increased. CONCLUSIONS: This study confirms associations between prenatal maternal stress and children's mental health outcomes, and demonstrates that these associations may be modified by parenting behaviors. Parenting may represent an important intervention target for improving mental health outcomes in children exposed to prenatal stress.


Asunto(s)
Madres , Responsabilidad Parental , Femenino , Masculino , Embarazo , Humanos , Niño , Preescolar , Estudios de Cohortes , Padres , Padre
9.
Brain Behav Immun ; 114: 165-172, 2023 11.
Artículo en Inglés | MEDLINE | ID: mdl-37607663

RESUMEN

BACKGROUND: Maternal immune activation is a potential mechanism underlying associations between maternal stress during pregnancy and offspring mental health problems. This study examined associations between prenatal maternal stress, maternal inflammation during pregnancy, and children's internalizing and externalizing symptoms from 3 to 10 years of age, and whether maternal inflammation mediated the associations between prenatal maternal stress and children's internalizing and externalizing symptoms. METHODS: This study comprised 4,902 mother-child dyads in the Generation R study. Prenatal maternal stress was assessed using self-reported data collected during pregnancy and analyzed as a latent variable consisting of four stress domains. Maternal inflammation during pregnancy was assessed using serum concentrations of C-reactive protein (CRP) measured at a median of 13.5 weeks' gestation. Child internalizing and externalizing symptoms were assessed using the Child Behavior Checklist (CBCL) by maternal report at ages 3 years, 5 years, and 10 years; paternal-reported CBCL data were also available at 3 years and 10 years. RESULTS: Prenatal maternal stress was associated with maternal-reported internalizing and externalizing symptoms of the child at 3, 5, and 10 years of age, and with paternal-reported internalizing and externalizing symptoms at 3 and 10 years. Prenatal maternal stress was associated with maternal CRP concentrations prior to, but not after, covariate adjustment. Maternal CRP concentrations during pregnancy were associated with paternal-reported internalizing symptoms of offspring at 10 years of age prior to, but not after, covariate adjustment. There was no evidence that CRP concentrations mediated the associations between prenatal maternal stress and children's internalizing or externalizing symptoms. CONCLUSIONS: Maternal stress during pregnancy is associated with higher levels of internalizing and externalizing symptoms in children, but this association is not because of differences in maternal immune activation linked to maternal stress. Replication of these findings in other cohorts is required; examination of other biomarkers or variation in immune activity during pregnancy would also benefit from further exploration.


Asunto(s)
Inflamación , Niño , Femenino , Embarazo , Humanos
10.
J Exp Biol ; 226(20)2023 10 15.
Artículo en Inglés | MEDLINE | ID: mdl-37732387

RESUMEN

Most animals rely on visual information for a variety of everyday tasks. The information available to a visual system depends in part on its spatial resolving power and contrast sensitivity. Because of their competing demands for physical space within an eye, these traits cannot simultaneously be improved without increasing overall eye size. The contrast sensitivity function is an integrated measure of visual performance that measures both resolution and contrast sensitivity. Its measurement helps us identify how different species have made a trade-off between contrast sensitivity and spatial resolution. It further allows us to identify the evolutionary drivers of sensory processing and visually mediated behaviour. Here, we measured the contrast sensitivity function of the fiddler crab Gelasimus dampieri using its optokinetic responses to wide-field moving sinusoidal intensity gratings of different orientations, spatial frequencies, contrasts and speeds. We further tested whether the behavioural state of the crabs (i.e. whether crabs are actively walking or not) affects their optokinetic gain and contrast sensitivity. Our results from a group of five crabs suggest a minimum perceived contrast of 6% and a horizontal and vertical visual acuity of 0.4 cyc deg-1 and 0.28 cyc deg-1, respectively, in the crabs' region of maximum optomotor sensitivity. Optokinetic gain increased in moving crabs compared with restrained crabs, adding another example of the importance of naturalistic approaches when studying the performance of animals.


Asunto(s)
Braquiuros , Sensibilidad de Contraste , Animales , Braquiuros/fisiología , Agudeza Visual
11.
PLoS Comput Biol ; 18(10): e1010545, 2022 10.
Artículo en Inglés | MEDLINE | ID: mdl-36251706

RESUMEN

Vision in the midwater of the open ocean requires animals to perform visual tasks quite unlike those of any other environment. These tasks consist of detecting small, low contrast objects and point sources against a relatively dim and uniform background. Deep-sea animals have evolved many extraordinary visual adaptations to perform these tasks. Linking eye anatomy to specific selective pressures, however, is challenging, not least because of the many difficulties of studying deep-sea animals. Computational modelling of vision, based on detailed morphological reconstructions of animal eyes, along with underwater optics, offers a chance to understand the specific visual capabilities of individual visual systems. Prior to the work presented here, comprehensive models for apposition compound eyes in the mesopelagic, the dominant eye form of crustaceans, were lacking. We adapted a model developed for single-lens eyes and used it to examine how different parameters affect the model's ability to detect point sources and extended objects. This new model also allowed us to examine spatial summation as a means to improve visual performance. Our results identify a trade-off between increased depth range over which eyes function effectively and increased distance at which extended objects can be detected. This trade-off is driven by the size of the ommatidial acceptance angle. We also show that if neighbouring ommatidia have overlapping receptive fields, spatial summation helps with all detection tasks, including the detection of bioluminescent point sources. By applying our model to the apposition compound eyes of Phronima, a mesopelagic hyperiid amphipod, we show that the specialisations of the large medial eyes of Phronima improve both the detection of point sources and of extended objects. The medial eyes outperformed the lateral eyes at every modelled detection task. We suggest that the small visual field size of Phronima's medial eyes and the strong asymmetry between the medial and lateral eyes reflect Phronima's need for effective vision across a large depth range and its habit of living inside a barrel. The barrel's narrow aperture limits the usefulness of a large visual field and has allowed a strong asymmetry between the medial and lateral eyes. The model provides a useful tool for future investigations into the visual abilities of apposition compound eyes in the deep sea.


Asunto(s)
Anfípodos , Animales , Simulación por Computador , Ojo , Visión Ocular , Campos Visuales
12.
Eur Child Adolesc Psychiatry ; 32(9): 1781-1794, 2023 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-35567646

RESUMEN

Positive maternal mental health can improve perceptions of stressful situations and promote the use of adaptive coping strategies. However, few studies have examined how positive maternal mental health affects children's development. The aims of this study were to examine the associations between positive maternal mental health and children's internalizing and externalizing symptoms, and to ascertain whether positive maternal mental health moderated the associations between prenatal stress and children's internalizing and externalizing symptoms. This study is based on the Norwegian Mother, Father, and Child Cohort Study (MoBa), and comprised 36,584 mother-child dyads. Prenatal stress was assessed using 41 self-reported items measured during pregnancy. Positive maternal mental health (self-efficacy, self-esteem, and enjoyment) was assessed by maternal report during pregnancy and postpartum. Child internalizing and externalizing symptoms were assessed by maternal report at age 5. Structural equation modeling was used for analysis. Maternal self-efficacy, self-esteem, and enjoyment were negatively associated with internalizing and externalizing symptoms in males and females. The association between prenatal stress and internalizing symptoms in males was stronger at low than at high levels of maternal self-esteem and enjoyment, whereas for females, the association was stronger at low than at high levels of maternal self-esteem and self-efficacy. This study provides evidence of associations between positive maternal mental health and children's mental health, and suggests that higher positive maternal mental health may buffer against the impacts of prenatal stress. Positive maternal mental health may represent an important intervention target to improve maternal-child well-being and foster intergenerational resilience.


Asunto(s)
Trastornos de la Conducta Infantil , Salud Mental , Femenino , Masculino , Embarazo , Niño , Humanos , Preescolar , Estudios de Cohortes , Trastornos de la Conducta Infantil/psicología , Madres/psicología , Periodo Posparto
13.
Molecules ; 28(2)2023 Jan 11.
Artículo en Inglés | MEDLINE | ID: mdl-36677798

RESUMEN

A novel series of pyrido[2,3-d]pyrimidines; pyrido[3,2-e][1,3,4]triazolo; and tetrazolo[1,5-c]pyrimidines were synthesized via different chemical transformations starting from pyrazolo[3,4-b]pyridin-6-yl)-N,N-dimethylcarbamimidic chloride 3b (prepared from the reaction of o-aminonitrile 1b and phosogen iminiumchloride). The structures of the newly synthesized compounds were elucidated based on spectroscopic data and elemental analyses. Designated compounds are subjected for molecular docking by using Auto Dock Vina software in order to evaluate the antiviral potency for the synthesized compounds against SARS-CoV-2 (2019-nCoV) main protease M pro. The antiviral activity against SARS-CoV-2 showed that tested compounds 7c, 7d, and 7e had the most promising antiviral activity with lower IC50 values compared to Lopinavir, "the commonly used protease inhibitor". Both in silico and in vitro results are in agreement.


Asunto(s)
Antivirales , Pirimidinas , SARS-CoV-2 , Antivirales/farmacología , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Inhibidores de Proteasas/farmacología , Pirimidinas/farmacología , Pirimidinas/química , SARS-CoV-2/efectos de los fármacos
14.
Bioorg Chem ; 127: 105964, 2022 10.
Artículo en Inglés | MEDLINE | ID: mdl-35759881

RESUMEN

Multitargeting kinase inhibitors recently proved to be a profitable approach for conquering cancer proliferation. The current study represents the design and synthesis of new thiophene, thienopyridine, and thiazoline-based derivatives 4-14a,b. All the target compounds were examined in vitro against three cancer cell lines; the liver (HepG-2), breast (MCF-7), and colon (HCT-116) where the thiophene-based compounds 5a-c, demonstrated the most potent activity. Furthermore, the latter derivatives revealed a safety profile against WI-38 normal cell line of selectivity indices ranging from 4.43 to 17.44. In vitro enzyme assay of 5a-c revealed that the carbohydrazide analog 5c has the most promising multitargeting inhibiting activity against Pim-1, VEGFR-2, and EGFRWT enzymes of IC50 values; 0.037 ± 0.02, 0.95 ± 0.24, and 0.16 ± 0.05 µM, respectively. As it was the most potent analog, 5c was further subjected to cell cycle and apoptosis analysis. The results indicated that it induced preG1 arrest and an apoptotic effect in the early and late stages. Moreover, further apoptosis studies were carried out for 5c to evaluate its proapoptotic potential. Interestingly, 5c enhanced the levels of Bax/Bcl-2 ratio, p53, and active caspase 3 by 18, 6.4, and 24 folds, respectively compared to the untreated cells. The antimicrobial evaluation showed that only compounds 3 and 5a produced broad-spectrum potency, while 5b and 5c exhibited outstanding antifungal effects. Finally, a molecular docking study was carried out to discover the probable interactions of compound 5c with the active sites of Pim-1, VEGFR-2, and EGFRWT kinases.


Asunto(s)
Antineoplásicos , Receptor 2 de Factores de Crecimiento Endotelial Vascular , Antineoplásicos/química , Línea Celular Tumoral , Proliferación Celular , Ensayos de Selección de Medicamentos Antitumorales , Receptores ErbB/metabolismo , Simulación del Acoplamiento Molecular , Estructura Molecular , Inhibidores de Proteínas Quinasas , Relación Estructura-Actividad , Tienopiridinas/farmacología , Tiofenos/química
15.
Molecules ; 27(6)2022 Mar 19.
Artículo en Inglés | MEDLINE | ID: mdl-35335354

RESUMEN

The impact of the charge transfer complex on the dielectric relaxation processes in free poly(methyl methacrylate) (PMMA) polymer sheets was investigated. The frequency dependence of dielectric properties was obtained over the frequency range 0.1 Hz-1 MHz at temperatures ranging between 303 K and 373 K for perylene dye and acceptors (picric acid (PA) and chloranilic acid (CLA)) in an in situ PMMA polymer. The TG/dTG technique was used to investigate the thermal degradation of the synthesized polymeric sheets. Additionally, the kinetic parameters have been assessed using the Coats-Redfern relation. The dielectric relaxation spectroscopy of the synthesized polymeric sheets was analyzed in terms of complex dielectric constant, dielectric loss, electrical modulus, electrical conductivity, and Cole-Cole impedance spectroscopy. α- and ß-relaxation processes were detected and discussed. The σ(ω) dispersion curves of the synthesized polymeric sheets show two distinct regions with increasing frequency. The impedance data of the synthesized polymeric sheets can be represented by the equivalent circuit (parallel RC).

16.
Inorg Chem ; 60(18): 14475-14487, 2021 Sep 20.
Artículo en Inglés | MEDLINE | ID: mdl-34494829

RESUMEN

The ability to identify promising candidate switchable molecules computationally, prior to synthesis, represents a considerable advance in the development of switchable molecular materials. Even more useful would be the possibility of predicting the switching temperature. Cobalt-dioxolene complexes can exhibit thermally induced valence tautomeric switching between low-spin CoIII-catecholate and high-spin CoII-semiquinonate forms, where the half-temperature (T1/2) is the temperature at which there are equal amounts of the two tautomers. We report the first simple computational strategy for accurately predicting T1/2 values for valence tautomeric complexes. Dispersion-corrected density functional theory (DFT) methods have been applied to the [Co(dbdiox)(dbsq)(N2L)] (dbdiox/dbsq•- = 3,5-di-tert-butyldioxolene/semiquinonate; N2L = diimine) family of valence tautomeric complexes, including the newly reported [Co(dbdiox)(dbsq)(MeO-bpy)] (1) (MeO-bpy = 4,4'-dimethoxy-2,2'-bipyridine). The DFT strategy has been thoroughly benchmarked to experimental data, affording highly accurate spin-distributions and an excellent energy match between experimental and calculated spin-states. Detailed orbital analysis of the [Co(dbdiox)(dbsq)(N2L)] complexes has revealed that the diimine ligand tunes the T1/2 value primarily through π-acceptance. We have established an excellent correlation between experimental T1/2(toluene) values for [Co(dbdiox)(dbsq)(N2L)] complexes and the calculated lowest unoccupied molecular orbital energy of the corresponding diimine ligand. The model affords accurate T1/2(toluene) values for [Co(dbdiox)(dbsq)(N2L)] complexes, with an average error of only 3.7%. This quantitative and simple DFT strategy allows experimentalists to not only rapidly identify proposed VT complexes but also predict the transition temperature. This study lays the groundwork for future in silico screening of candidate switchable molecules prior to experimental investigation, with associated time, cost, and environmental benefits.

17.
Bioorg Chem ; 114: 105078, 2021 09.
Artículo en Inglés | MEDLINE | ID: mdl-34161878

RESUMEN

This study was focused on the synthesis of new pyrimidines 4a,b, 5a,b and pyrazoles 6a, b as ATP mimicking tyrosine kinase inhibitors of the epidermal growth factor receptor (EGFR). The new compounds were assessed as cytotoxic candidates against human breast cancer cells (MCF-7) and hepatocellular carcinoma cells (HepG-2). All the new compounds appeared as more potent cytotoxic agents than erlotinib, while only compound 4a exhibited more potency than 5-flourouracil and 4b analogue was equipotent to it. Accordingly, the kinase suppression effect of 4a and 4b was further evaluated against EGFRWT, EGFRL858R and EGFRT790M. Both pyrimidine analogues 4a and 4b displayed outstanding inhibitory activity against EGFRWT and its two mutated isoforms EGFRL858R and EGFRT790M in comparing to erlotinib and osimertinib as reference drugs. Additionally, all the new analogues were subjected to antimicrobial assay. Interestingly, both 4a and 4b represented the most promising activity of wide spectrum antimicrobial effect against the examined microbes in comparison to gentamycin and ketoconazole as standard drugs. Moreover, docking results proved the good binding interactions of the compounds 4a and 4b with EGFRWT and EGFRT790M which were in accordance with the results of the in vitro enzyme assay. Additional in silico ADMET studies were performed for the new derivatives which represented their good oral absorption, good drug-likeness properties and low toxicity risks in human.


Asunto(s)
Antibacterianos/farmacología , Antifúngicos/farmacología , Antineoplásicos/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Pirazoles/farmacología , Pirimidinas/farmacología , Antibacterianos/síntesis química , Antibacterianos/química , Antifúngicos/síntesis química , Antifúngicos/química , Antineoplásicos/síntesis química , Antineoplásicos/química , Aspergillus fumigatus/efectos de los fármacos , Línea Celular Tumoral , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/metabolismo , Humanos , Pruebas de Sensibilidad Microbiana , Modelos Moleculares , Estructura Molecular , Mucorales/efectos de los fármacos , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Proteus vulgaris/efectos de los fármacos , Pirazoles/síntesis química , Pirazoles/química , Pirimidinas/síntesis química , Pirimidinas/química , Streptococcus/efectos de los fármacos , Relación Estructura-Actividad
18.
Soc Psychiatry Psychiatr Epidemiol ; 56(4): 619-638, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-32892249

RESUMEN

PURPOSE: Parenting practices represent important and modifiable factors for health and wellbeing in children and adolescents; however, strength and quality of studies examining relationships between parenting practices in childhood and risk of depression and anxiety in adolescence are unclear. The objective of this systematic review was to synthesize the longitudinal literature that describes these associations. METHODS: Six electronic databases were searched for articles published through March 2018. Eligible articles were published in the English language, peer-reviewed, and had prospective cohort study designs. Articles eligible for inclusion examined positive and negative parenting practices of parents and/or guardians when study subjects were between 0 and 9 years of age, and symptoms of depression, anxiety, and internalizing symptoms when subjects were between 10 and 19 years of age. Heterogeneity of included articles precluded meta-analysis: findings were reported narratively. RESULTS: 4558 references were screened for inclusion, and 19 articles met eligibility criteria and were included for review. Ten articles examined positive parenting practices, and four demonstrated statistically significant associations between positive parenting practices and lower risk of adolescent depression, anxiety, and/or internalizing symptoms. Fifteen articles examined negative parenting practices, and five demonstrated significant associations between negative parenting practices and higher risk of adolescent depression, anxiety, and/or internalizing symptoms. CONCLUSION: This review demonstrates that the evidence base supporting longitudinal associations between parenting practices in childhood and adolescent symptoms of depression, anxiety, and internalizing problems is inconsistent. Findings from this review highlight limitations of the existing literature and identify understudied parenting dimensions that require further investigation.


Asunto(s)
Depresión , Responsabilidad Parental , Adolescente , Adulto , Ansiedad/epidemiología , Trastornos de Ansiedad , Niño , Depresión/epidemiología , Humanos , Estudios Prospectivos , Adulto Joven
19.
J Exp Biol ; 223(Pt 21)2020 11 09.
Artículo en Inglés | MEDLINE | ID: mdl-33168543

RESUMEN

Selective attention is of fundamental relevance to animals for performing a diversity of tasks such as mating, feeding, predation and avoiding predators. Within natural environments, prey animals are often exposed to multiple, simultaneous threats, which significantly complicates the decision-making process. However, selective attention is rarely studied in complex, natural environments or in the context of escape responses. We therefore asked how relatively simple animals integrate the information from multiple, concurrent threatening events. Do they identify and respond only to what they perceive as the most dangerous threat, or do they respond to multiple stimuli at the same time? Do simultaneous threats evoke an earlier or stronger response than single threats? We investigated these questions by conducting field experiments and compared escape responses of the fiddler crab Gelasimus dampieri when faced with either a single or two simultaneously approaching dummy predators. We used the dummies' approach trajectories to manipulate the threat level; a directly approaching dummy indicated higher risk while a tangentially approaching dummy that passed the crabs at a distance represented a lower risk. The crabs responded later, but on average more often, when approached more directly. However, when confronted with the two dummies simultaneously, the crabs responded as if approached only by the directly approaching dummy. This suggests that the crabs are able to predict how close the dummy's trajectory is to a collision course and selectively suppress their normally earlier response to the less dangerous dummy. We thus provide evidence of predictive selective attention within a natural environment.


Asunto(s)
Braquiuros , Animales , Atención , Ambiente , Conducta Predatoria
20.
J Exp Biol ; 223(Pt 23)2020 12 02.
Artículo en Inglés | MEDLINE | ID: mdl-33097568

RESUMEN

Colour signals, and the ability to detect them, are important for many animals and can be vital to their survival and fitness. Fiddler crabs use colour information to detect and recognise conspecifics, but their colour vision capabilities remain unclear. Many studies have attempted to measure their spectral sensitivity and identify contributing retinular cells, but the existing evidence is inconclusive. We used electroretinogram (ERG) measurements and intracellular recordings from retinular cells to estimate the spectral sensitivity of Gelasimus dampieri and to track diurnal changes in spectral sensitivity. G. dampieri has a broad spectral sensitivity and is most sensitive to wavelengths between 420 and 460 nm. Selective adaptation experiments uncovered an ultraviolet (UV) retinular cell with a peak sensitivity shorter than 360 nm. The species' spectral sensitivity above 400 nm is too broad to be fitted by a single visual pigment and using optical modelling, we provide evidence that at least two medium-wavelength sensitive (MWS) visual pigments are contained within a second blue-green sensitive retinular cell. We also found a ∼25 nm diurnal shift in spectral sensitivity towards longer wavelengths in the evening in both ERG and intracellular recordings. Whether the shift is caused by screening pigment migration or changes in opsin expression remains unclear, but the observation shows the diel dynamism of colour vision in this species. Together, these findings support the notion that G. dampieri possesses the minimum requirement for colour vision, with UV and blue/green receptors, and help to explain some of the inconsistent results of previous research.


Asunto(s)
Braquiuros , Visión de Colores , Animales , Electrorretinografía , Células Fotorreceptoras Retinianas Conos , Pigmentos Retinianos
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