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The peptide antibiotic albicidin is a DNA topoisomerase inhibitor with low-nanomolar bactericidal activity towards fluoroquinolone-resistant Gram-negative pathogens. However, its mode of action is poorly understood. We determined a 2.6 Å resolution cryoelectron microscopy structure of a ternary complex between Escherichia coli topoisomerase DNA gyrase, a 217 bp double-stranded DNA fragment and albicidin. Albicidin employs a dual binding mechanism where one end of the molecule obstructs the crucial gyrase dimer interface, while the other intercalates between the fragments of cleaved DNA substrate. Thus, albicidin efficiently locks DNA gyrase, preventing it from religating DNA and completing its catalytic cycle. Two additional structures of this trapped state were determined using synthetic albicidin analogues that demonstrate improved solubility, and activity against a range of gyrase variants and E. coli topoisomerase IV. The extraordinary promiscuity of the DNA-intercalating region of albicidins and their excellent performance against fluoroquinolone-resistant bacteria holds great promise for the development of last-resort antibiotics.

Exploiting the transcription regulatory activity of the AlbA resistance protein enables the design of improved albicidin analogs that can overcome the resistance mechanism.

Background The amygdala is a subcortical limbic structure consisting of histologically and functionally distinct subregions. New automated structural magnetic resonance imaging (MRI) segmentation tools facilitate the in vivo study of individual amygdala nuclei in clinical populations such as patients with anorexia nervosa (AN) who show symptoms indicative of limbic dysregulation. This study is the first to investigate amygdala nuclei volumes in AN, their relationships with leptin, a key indicator of AN-related neuroendocrine alterations, and further clinical measures. Methods T1-weighted MRI scans were subsegmented and multi-stage quality controlled using FreeSurfer. Left/right hemispheric amygdala nuclei volumes were cross-sectionally compared between females with AN (n = 168, 12–29 years) and age-matched healthy females (n = 168) applying general linear models. Associations with plasma leptin, body mass index (BMI), illness duration, and psychiatric symptoms were analyzed via robust linear regression. Results Globally, most amygdala nuclei volumes in both hemispheres were reduced in AN v. healthy control participants. Importantly, four specific nuclei (accessory basal, cortical, medial nuclei, corticoamygdaloid transition in the rostral-medial amygdala) showed greater volumetric reduction even relative to reductions of whole amygdala and total subcortical gray matter volumes, whereas basal, lateral, and paralaminar nuclei were less reduced. All rostral-medially clustered nuclei were positively associated with leptin in AN independent of BMI. Amygdala nuclei volumes were not associated with illness duration or psychiatric symptom severity in AN. Conclusions In AN, amygdala nuclei are altered to different degrees. Severe volume loss in rostral-medially clustered nuclei, collectively involved in olfactory/food-related reward processing, may represent a structural correlate of AN-related symptoms. Hypoleptinemia might be linked to rostral-medial amygdala alterations.

Cities are relationally produced social spaces and in constant flux due to the ever-changing everyday spatial practices that produce and condition them. At the same time, they can become concepts abstracted into symbolic, monolithic ideas, pawns in political or historiographic narratives. Consequently, their death or survival in states of exception can become a substitute for the victorious or unsuccessful struggle for certain values or political orders. In this article, I explore how such symbolic connotations of death or survival of a city relate to the concrete experience of losing personal urban spaces and communities and how this interrelation can be represented in literature. In two case studies, Lidija Ginzburg’s Notes from the Blockade (1984) and Miron Białoszewski’s A Memoir of the Warsaw Uprising (1970), I show how literary texts have the potential to turn away from an abstracting view on cities and how they show the complexity of urban life in a state of exception. Consequently, I demonstrate how Ginzburg’s and Białoszewski’s texts narrate the death of a city not as the death of a specific concept, but as an irreversible loss of concrete urban spaces and practices, bringing to the fore the relational aspect of urban space and its decay. Implying such a relational understanding of urban space, these texts constitute apt representations of urbicides – a term which also presupposes the Lefebvrean notion of space being a relational product of building fabric, spatial practice and symbolic spatial attributions. The article thus shows how both Ginzburg’s and Białoszewski’s texts, through their specific perspectivization and narrative structure, subvert the institutional, abstracting memory discourses about the events they address by focusing on the concrete, subjective experience of spatial alienation during the Blockade of Leningrad and the Warsaw Uprising.

Strict eating routines and frequent rigid behavior patterns are commonly observed in patients with anorexia nervosa (AN). A recent theory proposes that while these behaviors may have been reinforced initially, they later become habitual. To date, however, research has been overly focused on eating-disorder (ED)-related habits. Over the course of seven days, we applied an ecological momentary assessment (EMA) to investigate the habit frequency and strength of ED-specific (food intake) and ED-unspecific (hygiene) habits in the daily lives of a sample of n = 57 AN and n = 57 healthy controls (HC). The results of the hierarchical models revealed that habits were significantly more likely in patients compared with HC for both categories, independently. Furthermore, a lower body mass index (BMI) was associated with increased habit frequency in AN. Our study strengthens the habit theory of AN by showing the relevance of habits beyond ED-specific behavioral domains. This also supports the development of innovative therapeutic interventions targeting habitual behavior in EDs.

Antibiotic resistance is a continuously increasing concern for public health care. Understanding resistance mechanisms and their emergence is crucial for the development of new antibiotics and their effective use. Here, we report the discovery of a gene amplification-based mechanism that imparts an up to 1000-fold increase in resistance levels against the antibiotic albicidin. We show that this mechanism protects Salmonella Typhimurium and Escherichia coli by increasing the copy number of the GyrI-like transcription regulator STM3175 (YgiV) which binds albicidin. X-ray crystallography and molecular docking studies reveal a conserved binding motif that can interact with aromatic building blocks of albicidin. Phylogenetic studies suggest that this resistance mechanism is ubiquitous in Gram-negative bacteria and our experiments confirm that STM3175 homologs can convey resistance in pathogens such as Vibrio vulnificus and Pseudomonas aeruginosa.

Albicidin is a potent antibacterial oligoaromatic peptide that is susceptible to the protease AlbD, a resistance factor. This potentially restricts the use of albicidin as a drug. To overcome this obstacle, we synthesized and evaluated six analogues with isosteric replacement of the key amide link. Protease stability was established while maintaining the antibacterial activity, including three analogues with up to eight times higher activity compared with the natural albicidin.

The natural product albicidin is a highly potent inhibitor of bacterial DNA gyrase. Its outstanding activity, particularly against Gram‐negative pathogens, qualifies it as a promising lead structure in the search for new antibacterial drugs. However, as we show here, the N‐terminal cinnamoyl moiety of albicidin is susceptible to photochemical E/Z isomerization. Moreover, the newly formed Z isomer exhibits significantly reduced antibacterial activity, which hampers the development and biological evaluation of albicidin and potent derivatives thereof. Hence, we synthesized 13 different variants of albicidin in which the vulnerable para‐coumaric acid moiety was replaced; this yielded photostable analogues. Biological activity assays revealed that diaryl alkyne analogues exhibited virtually undiminished antibacterial efficacy. This promising scaffold will therefore serve as a blueprint for the design of a potent albicidin‐based drug., Lead optimization: The cinnamoyl residue of the antibiotic albicidin is shown to readily undergo UV‐mediated E/Z isomerization, thereby converting from the highly bioactive E form found in the natural product to the significantly less bioactive Z form. Acetylenic replacement of the susceptible methylacrylamide moiety affords a set of photochemically stable albicidin derivatives with virtually undiminished antibacterial activity.

This report summarizes the result of a PhD research that was dedicated to investigate and present qualitative indicators for the schooling process of students with Autism Spectrum Disorder (ASD) in the context of Inclusive Education. A set of qualitative indicators structured in six dimensions was established: Pedagogical and Learning Strategies; School management; Family; Environment; Articulated Intersectorial Partnerships; and, Inclusive Organization Structures and Public Policies. These dimensions were structured from references such as Booth and Ainscow (2000), Humphrey and Lewis (2008), Echeita Sarrionandía and Ainscow (2011), UNESCO-OEI (2018) and Silva and Garcez (2019) and were called "schooling of students with ASD in the context of Inclusive Education". The original research consisted of a theoretical-methodological study, with quantitative and qualitative contributions and with the participation of 61 collaborators divided into five groups: teachers, managers, family members, professionals of multidisciplinary care and people with autistic spectrum disorder. The quantitative perspective took place in the first step of the research for the general characterization of the profile of these collaborators. Based on this analysis, a form was sent to employees with more experience and experience in relation to the schooling process, so that they could evaluate the indicators, given their pertinence in each of the proposed dimensions. At the end, an Index for Dimensions is presented as a methodological and evaluation tool for these indicators that can be used in regular schools to strengthen inclusive public policies and practices. Este informe resume el resultado de una investigación de doctorado que se dedicó a investigar y presentar indicadores cualitativos para el proceso de escolarización de estudiantes con Trastorno del Espectro Autista (TEA) en el contexto de la Educación Integrada. Se estableció un conjunto de indicadores cualitativos estructurados en seis dimensiones: Estrategias pedagógicas y de aprendizaje; Gestión escolar; Familia; Medio ambiente; Asociaciones intersectoriales articuladas; y, Estructuras organizativas inclusivas y políticas públicas. Estas dimensiones se estructuraron a partir de referencias como Booth y Ainscow (2000), Humphrey y Lewis (2008), Echeita Sarrionandía y Ainscow (2011), UNESCO-OEI (2018) y Silva y Garcez (2019) y fueron denominadas "escolarización de estudiantes con TEA en el contexto de la Educación Integrada". La investigación original consistió en un estudio teórico-metodológico, con aportes cuantitativos y cualitativos y contó con la participación de 61 colaboradores divididos en cinco grupos: docentes, directivos, familiares, profesionales del cuidado multidisciplinario y personas con trastorno del espectro autista. La perspectiva cuantitativa se dio en el primer paso de la investigación para la caracterización general del perfil de estos colaboradores. Con base en este análisis, se envió un formulario a los colaboradores con mayor trayectoria y experiencia en relación al proceso de escolarización, para que pudieran evaluar los indicadores, dada su pertinencia en cada una de las dimensiones propuestas. Al final, se presenta un Índice por Dimensiones como herramienta metodológica y de evaluación de estos indicadores que puede ser utilizada en las escuelas regulares para fortalecer políticas y prácticas públicas inclusivas. O presente relato sintetiza o resultado de uma pesquisa de doutoramento que se dedicou a investigar e apresentar indicadores qualitativos para o processo de escolarização de estudantes com Transtorno do Espectro Autista (TEA) no contexto da Educação Inclusiva. Foi estabelecido um conjunto de indicadores qualitativos estruturados em seis dimensões: Estratégias Pedagógicas e de Aprendizagem; Gestão Escolar; Família; Ambiente; Parcerias Intersetoriais Articuladas; e, Estruturas de Organização Inclusiva e as Políticas Públicas. Estas dimensões foram estruturadas a partir de referências como Booth e Ainscow (2000), Humphrey e Lewis (2008), Echeita Sarrionandía e Ainscow (2011), UNESCO-OEI (2018) e Silva e Garcez (2019) e foram denominadas como “dimensões da escolarização de estudantes com TEA no contexto da Educação Inclusiva”. A pesquisa original constituiu-se em um estudo teórico-metodológico, com aportes quantitativos e qualitativos e com a participação de 61 colaboradores divididos em cinco grupos: professores, gestores, familiares, profissionais do atendimento multidisciplinar e pessoas com transtorno do espectro autista. A perspectiva quantitativa se deu no primeiro passo da pesquisa para a caracterização geral do perfil destes colaboradores. Partindo desta análise, foi enviado um formulário aos colaboradores com mais experiência e vivência em relação ao processo de escolarização, para que avaliassem os indicadores, tendo em vista a sua pertinência em cada uma das dimensões propostas. Ao final, apresenta-se um Índice para as Dimensões como um instrumento metodológico e de avaliação destes indicadores que podem ser utilizados nas escolas regulares para o fortalecimento de práticas e políticas inclusivas.

O presente relato sintetiza o resultado de uma pesquisa de doutoramento que se dedicou a investigar e apresentar indicadores qualitativos para o processo de escolarização de estudantes com Transtorno do Espectro Autista (TEA) no contexto da Educação Inclusiva. Foi estabelecido um conjunto de indicadores qualitativos estruturados em seis dimensões: Estratégias Pedagógicas e de Aprendizagem; Gestão Escolar; Família; Ambiente; Parcerias Intersetoriais Articuladas; e, Estruturas de Organização Inclusiva e as Políticas Públicas. Estas dimensões foram estruturadas a partir de referências como Booth e Ainscow (2000), Humphrey e Lewis (2008), Echeita Sarrionandía e Ainscow (2011), UNESCO-OEI (2018) e Silva e Garcez (2019) e foram denominadas como “dimensões da escolarização de estudantes com TEA no contexto da Educação Inclusiva”. A pesquisa original constituiu-se em um estudo teórico-metodológico, com aportes quantitativos e qualitativos e com a participação de 61 colaboradores divididos em cinco grupos: professores, gestores, familiares, profissionais do atendimento multidisciplinar e pessoas com transtorno do espectro autista. A perspectiva quantitativa se deu no primeiro passo da pesquisa para a caracterização geral do perfil destes colaboradores. Partindo desta análise, foi enviado um formulário aos colaboradores com mais experiência e vivência em relação ao processo de escolarização, para que avaliassem os indicadores, tendo em vista a sua pertinência em cada uma das dimensões propostas. Ao final, apresenta-se um Índice para as Dimensões como um instrumento metodológico e de avaliação destes indicadores que podem ser utilizados nas escolas regulares para o fortalecimento de práticas e políticas inclusivas.

This article presents the results of a research whose objective was to analyze the publications of the Mathematics and its technologies section of the Revista Prática Docente. The research addressed the state of knowledge regarding the scientific production of this journal, from its institution in 2016 to the last issue of 2021. A mapping of scientific production related to teaching practice in mathematics is developed, involving both teaching methods and the initial or continuing teacher training, whether in teaching practices, experience reports or public policies. The IRaMuTeQ program was used to aid the analysis, which among its functions provides different types of analysis of textual data, based on the lexicography of words. According to the results, it can be seen that all Similitude Analyzes carried out from the textual bodies composed of abstracts, objectives, methods and results indicated in the articles relate mathematics to teacher training and student teaching or learning., Este artículo presenta los resultados de una investigación cuyo objetivo fue analizar las publicaciones de la sección Matemáticas y sus tecnologías de la Revista Prática Docente. La investigación abordó el estado del conocimiento respecto a la producción científica de esta revista, desde su institución en 2016 hasta el último número de 2021. Se desarrolla un mapeo de la producción científica relacionada con la práctica docente en matemáticas, involucrando tanto los métodos de enseñanza como la formación inicial o continua. la formación docente, ya sea en prácticas docentes, relatos de experiencia o políticas públicas. Para auxiliar el análisis se utilizó el programa IRaMuTeQ, que entre sus funciones brinda diferentes tipos de análisis de datos textuales, basados en la lexicografía de palabras. De acuerdo con los resultados, se puede apreciar que todos los Análisis de Similitud realizados a partir de los cuerpos textuales compuestos por abstractos, objetivos, métodos y resultados señalados en los artículos relacionan las matemáticas con la formación docente y la enseñanza o aprendizaje de los estudiantes., Esse artigo apresenta os resultados de uma pesquisa cujo objetivo foi analisar as publicações da seção de Matemática e suas tecnologias da Revista Prática Docente. A pesquisa abordou o estado do conhecimento em relação à produção científica desse periódico, desde sua instituição em 2016 até o último número de 2021. Desenvolve-se um mapeamento da produção científica relacionada à prática docente em matemática, envolvendo tanto os métodos de ensino quando a formação inicial ou continuada de professores, sejam em práticas de ensino, relatos de experiência ou políticas públicas. Para o auxílio das análises, utilizou-se o programa IRaMuTeQ, que dentre suas funções fornece diversos tipos de análises de dados textuais, baseado na lexicografia das palavras. De acordo com os resultados, pode ser percebido que todas as Análises de Similitude realizadas a partir dos corpos textuais composto pelos resumos, objetivos, métodos e resultados indicados nos artigos relacionam a matemática com a formação de professores e com o ensino ou aprendizagem do estudante.

Background: There is sound evidence that the hypothalamic-pituitary-thyroid axis plays a role in mood regulation. Alterations in this axis, particularly low triiodothyronine syndrome, are a common neuroendocrine adaptation to semi-starvation in patients with anorexia nervosa (AN), who also frequently suffer from co-existing depressive symptoms. We therefore aimed to investigate the associations between pituitary-thyroid function and psychopathology, in particular depressive symptoms, at different stages of AN using a combined cross-sectional and longitudinal study design. Methods: Pituitary-thyroid status (FT3, free triiodothyronine; FT4, free thyroxine; conversion ratio FT3/FT4; TSH, thyroid-stimulating hormone) was assessed in 77 young acutely underweight females with AN (acAN) and in 55 long-term weight-recovered individuals with former AN (recAN) in a cross-sectional comparison to 122 healthy controls (HC). Further, pituitary-thyroid status of 48 acAN was reassessed after short-term weight-restoration. We performed correlation analyses of pituitary-thyroid parameters with self-reported measures of psychopathology. Results: AcAN showed significantly lower FT3, FT4, FT3/FT4 ratio, and TSH levels compared to HC. Pituitary-thyroid alterations were partly reversed after short-term weight-restoration. RecAN still had lower FT3 concentrations than HC. Lower FT3 concentrations and FT3/FT4 ratios were associated with more severe depressive symptoms in acAN, occurring prominently in cases of manifest low triiodothyronine syndrome. Longitudinally increasing FT3/FT4 ratios (change scores) were inversely correlated with depressive and general psychiatric symptoms after short-term weight-restoration. Conclusions: Our results suggest a potential modulation of the severity of depressive symptoms by temporarily decreased FT3 concentrations and inhibited thyroid hormone conversion (FT3/FT4 ratios) in acutely underweight AN. Associations between conversion ratios FT3/FT4 and psychopathology seem to persist across short-term weight-restoration. The findings of our study might have relevant clinical implications, ranging from thyroid monitoring to experimental low-dose thyroid hormone supplementation in certain patients with AN showing severe psychiatric impairment and overt thyroid hormone alterations.

This article shares an educational action based on the STEAM approach, which articulates Science, Technology, Engineering, Arts and Mathematics from the perspective of the melody of the bird Pitangus sulphuratus, the popular bem-te-vi. The setting and learning environment is the Parque Mãe Bonifácia, in Cuiabá (MT). The objective is to develop proposals for activities based on the STEAM approach. The issue was characterized in how to elaborate the STEAM from a local natural guest of the park, bem-te-vi. Lined up with this idea, supported by a Scientific Education perspective, five areas are intertwined in two structuring concepts: Bioacoustics and Biomimicry. Thus, it is presented the articulation of concepts immersed in this set of ideas for the contribution of processes that enhance, in students, skills, aiming at a critical and conscious participation in relation to knowledge, from the natural guest of the Park, the good -I saw you., Este artículo comparte una acción educativa basada en el enfoque STEAM, que articula Ciencia, Tecnología, Ingeniería, Artes y Matemáticas desde la perspectiva de la melodía del pájaro Pitangus sulphuratus, el popular bem-te-vi. El escenario y entorno de aprendizaje es el Parque Mãe Bonifácia, en Cuiabá (MT). El objetivo es desarrollar propuestas de actividades basadas el enfoque STEAM. El problema se caracterizó en cómo desarrollar el enfoque STEAM a partir de un huésped natural del parque, el papamoscas. Alineándose con esta idea, apoyada en una perspectiva de Educación Científica, se entrelazan cinco áreas en dos conceptos estructurantes: Bioacústica y Biomimética. Así, la articulación de conceptos inmersos en este conjunto de ideas se presenta para la contribución de procesos que potencien, en los estudiantes, las habilidades, apuntando a una participación crítica y consciente en relación al conocimiento, a partir del huésped natural del Parque, el papamoscas., Este artigo compartilha uma ação educativa fundamentada na abordagem STEAM, a qual articula Ciências, Tecnologia, Engenharia, Artes e Matemática sob a perspectiva da melodia do pássaro Pitangus sulphuratus, o popular bem-te-vi. O cenário e ambiente de aprendizagem é o Parque Mãe Bonifácia, em Cuiabá (MT). O objetivo consiste em desenvolver propostas de atividades a partir da abordagem STEAM. A problemática caracterizou-se em como elaborar a abordagem STEAM a partir de um hóspede natural local do parque, o bem-te-vi. Alinhando se com essa ideia, com respaldo em uma perspectiva de Educação Científica, entrelaçam-se cinco áreas em dois conceitos estruturantes: a Bioacústica e o Biomimetismo. Assim, apresenta-se a articulação de conceitos imersos nesse conjunto de ideias para a contribuição de processos que potencializem, nos estudantes, as habilidades, visando a uma participação crítica e consciente em relação ao conhecimento, a partir do hóspede natural do Parque, o bem-te-vi.

Lantibiotics are a promising class of natural antimicrobial peptides. Lichenicidin is a two-peptide lantibiotic in which two mature peptides act synergistically to exhibit full bioactivity. Considering the two-peptide lantibiotics described so far, only cytolysin has been deeply characterized in terms of toxicity towards eukaryotic cells and it was found to be hemolytic and cytotoxic. This work aimed to improve the production of lichenicidin in vivo and characterize its antibacterial activity and toxicity against human cells. Peptides were purified and minimal inhibitory concentration (MIC) was determined against several strains; a time-kill assay was performed with Staphylococcus aureus. The hemolytic effect of lichenicidin was evaluated on blood samples from healthy donors and its toxicity towards human fibroblasts. The quantity of purified peptides was 1 mg/l Bliα and 0.4 mg/l Bliβ. MIC for methicillin-sensitive and resistant S. aureus (MSSA and MRSA) strains were 16-32 µg/ml and 64-128 µg/ml, respectively. At the MIC, lichenicidin took less than 3 h to eliminate MSSA, indicating a strong bactericidal effect. It induces cell lysis at the highest concentration, an effect that might be potentiated by Bliβ. Lichenicidin was not cytotoxic to human erythrocytes and fibroblasts. In this work, we evaluated the therapeutic potential of lichenicidin as a possible antimicrobial alternative.

Objective Functional magnetic resonance imaging (fMRI) studies have repeatedly shown alterations in patients with anorexia nervosa (AN). These alterations might be driven by baseline signal characteristics such as the (fractional) amplitude of low frequency fluctuations (fALFF/ALFF), as well as regional signal consistency (ie, regional homogeneity [ReHo]) within circumscribed brain regions. Previous studies have also demonstrated gray matter (pseudo-) atrophy in underweight individuals with AN. Here we study fALFF/ALFF and ReHo in predominantly adolescent patients with AN, while taking gray matter changes into consideration. Method Resting state fMRI data were acquired from a sample of 148 female volunteers: 74 underweight patients with AN and 74 age-matched female healthy controls (HC). Results Group differences for fALFF and ReHo measures were found in several AN-relevant brain regions, including networks related to cognitive control, habit formation, and the ventral visual stream. Furthermore, the magnitude of correlation between gray matter volume/thickness and fALFF and ReHo were reduced in AN compared to HC. Conclusion Abnormal local resting state characteristics in AN-related brain-networks as well as reduced structure−function relationships may help to explain previously reported task-related and classical resting state neural alterations in underweight AN. Patients with AN may serve as a valuable population for investigating dynamic changes in the relationships between brain structure and function.

A total of 314 individuals representing the three major ethno-linguistic groups (ethnic Macedonians, Albanians and Turks) in the Republic of North Macedonia were analyzed for Y-SNPs and Y-STRs using minisequencing and fragment analysis. The haplogroup composition differed remarkably between the three groups with dominance of haplogroup I2 in ethnic Macedonians (28.1%), E1b in Albanians (35.3%) and J2a (34.9%) in Turks, respectively. The haplotype analysis using the YFilerPlus kit disclosed a significant reduction in diversity values (DC, GD) for the Turkish subgroup compared to the Macedonian and Albanian speaking populations. The Y-STR based population analysis revealed a similarity of ethnic Macedonians with neighboring Serbians and Bulgarians. The same holds true for the Albanian speakers from Macedonia and Albania, whereas the Turkish minority in North Macedonia stands apart from the population in Turkey.

Previous studies have proposed that altered reward processing and elevated cognitive control underlie the etiology of anorexia nervosa (AN). A newly debated notion suggests altered habit learning and an overreliance on habits may contribute to the persistence of AN. In weight-recovered AN patients, we previously found neuroimaging-based evidence for unaltered reward processing, but elevated cognitive control. In order to differentiate between state versus trait factors, we here contrast the aforementioned hypotheses in a sample of acutely underweight AN (acAN) patients. 37 acAN patients and 37 closely matched healthy controls (HC) underwent a functional MRI while performing an established instrumental motivation task. We found no group differences with respect to neural responses during the anticipation or receipt of reward. However, the behavioral response data showed a bimodal distribution, indicative for a goal-directed (gAN) and a habit-driven (hAN) patient subgroup. Additional analyses revealed decreased mOFC activation during reward anticipation in hAN, which would be in line with a habit-driven response. These findings provide a new perspective on the debate regarding the notion of increased goal-directed versus habitual behavior in AN. If replicable, the observed dissociation between gAN and hAN might help to tailor therapeutic approaches to individual patient characteristics.

The worrisome development and spread of multidrug-resistant bacteria demands new antibacterial agents with strong bioactivities particularly against Gram-negative bacteria. Albicidins were recently structurally characterized as highly active antibacterial natural products from the bacterium Xanthomonas albilineans. Albicidin, which effectively targets the bacterial DNA-gyrase, is a lipophilic hexapeptide mostly consisting of para amino benzoic acid units and only one α-amino acid. In this study, we report on the design and synthesis of new albicidins, containing N-atoms on each of the 5 different phenyl rings. We systematically introduced N-atoms into the aromatic backbone to monitor intramolecular H-bonds and for one derivative correlated them with a significant enhancement of the antibacterial activity and activity spectrum, particularly also towards Gram-positive bacteria. In parallel we conducted DFT calculations to find the most stable conformation of each derivative. A drastic angle-change was observed for the lead compound and shows a preferred planarity through H-bonding with the introduced N-atom at the D-fragment of albicidin. Finally, we went to the next level and conducted the first in vivo experiments with an albicidin analogue. Our lead compound was evaluated in two different mouse experiments: In the first we show a promising PK profile and the absence of toxicity and in the second very good efficiency and reduction of the bacterial titre in an E. coli infection model with FQ-resistant clinically relevant strains. These results qualify albicidins as active antibacterial substances with the potential to be developed as a drug for treatment of infections caused by Gram-negative and Gram-positive bacteria., A systematic pyridine-scan of the albicidin molecule provides a new lead structure with improved antimicrobial properties.

Pain habituation is associated with a decrease of activation in brain areas related to pain perception. However, little is known about the specificity of these decreases to pain, as habituation has also been described for other responses like spinal reflexes and other sensory responses. Thus, it might be hypothesized that previously reported reductions in activation are not specifically related to pain habituation. For this reason, we performed a 3T fMRI study using either painful or non-painful electrical stimulation via an electrode attached to the back of the left hand. Contrasting painful vs. non-painful stimulation revealed significant activation clusters in regions well-known to be related to pain processing, such as bilateral anterior and posterior insula, primary/secondary sensory cortices (S1/S2) and anterior midcingulate cortex (aMCC). Importantly, our results show distinct habituation patterns for painful (in aMCC) and non-painful (contralateral claustrum) stimulation, while similar habituation for both types of stimulation was identified in bilateral inferior frontal gyrus (IFG) and contralateral S2. Our findings thus distinguish a general habituation in somatosensory processing (S2) and reduced attention (IFG) from specific pain and non-pain related habituation effects where pain-specific habituation effects within the aMCC highlight a change in affective pain perception.

Anorexia nervosa (AN) is a severe psychiatric condition associated with high mortality and chronicity. The hunt for state, trait, subtyping, and prognostic biomarkers is ongoing and the orexigenic hormone ghrelin and its different forms, acyl ghrelin and desacyl ghrelin, have been proposed to be increased in AN, especially in the restrictive subtype. A systematic literature search was performed using established databases up to 30 November 2020. Forty-nine studies met inclusion criteria for cross-sectional and longitudinal meta-analyses on total ghrelin, acyl ghrelin, and desacyl ghrelin. All forms of ghrelin were increased in the acute stage of anorexia nervosa during fasting compared to healthy controls. Previous notions on differences in ghrelin levels between AN subtypes were not supported by current data. In addition, a significant decrease in total ghrelin was observed pre-treatment to follow-up. However, total ghrelin levels at follow-up were still marginally elevated compared to healthy controls, whereas for acyl ghrelin, no overall effect of treatment was observed. Due to heterogeneity in follow-up designs and only few data on long-term recovered patients, longitudinal results should be interpreted with caution. While the first steps towards a biomarker in acute AN have been completed, the value of ghrelin as a potential indicator of treatment success or recovery status or its use in subtype differentiation are yet to be established.

Objective Refeeding is the cornerstone of anorexia nervosa (AN) treatment, but little is known regarding the optimal pace and dietary composition or possible adverse effects of current clinical practices. Plasma lipids may be a moderating factor underlying unfavorable refeeding effects in AN, such as an abnormal central body fat distribution. The objective of this study was to analyze the plasma lipidome in the acutely underweight state of AN before and after refeeding. Method Using high-throughput quantitative mass spectrometry−based shotgun lipidomics, we measured 13 lipid classes and 204 lipid species or subspecies in the plasma of young female patients with acute AN, before (n = 39) and after (n = 23) short-term weight restoration during an intensive inpatient refeeding program (median body mass index [BMI] increase = 26.4%), in comparison to those in healthy control participants (n = 37). Results Before inpatient treatment, patients with AN exhibited increased concentrations of cholesterol and several other lipid classes. After refeeding, multiple lipid classes including cholesterol and ceramides, as well as certain ceramide species previously associated with obesity or overfeeding, showed increased concentrations, and a pattern of shorter and more saturated triacylgycerides emerged. A machine learning model trained to predict BMI based on the lipidomic profiles revealed a sizable overprediction in patients with AN after weight restoration. Conclusion The results point toward a profound lipid dysregulation with similarities to obesity and other features of the metabolic syndrome after short-term weight restoration. Thus, this study provides evidence for possible short-term adverse effects of current refeeding practices on the metabolic state and should inspire more research on nutritional interventions in AN.

Ecuador is a multiethnic and pluricultural country with a complex history defined by migration and admixture processes. The present study aims to increase our knowledge on the Ecuadorian Native Amerindian groups and the unique South American Y-chromosome haplogroup C3-MPB373 through the analysis of up to 23 Y-chromosome STRs (Y-STRs) and several Y-SNPs in a sample of 527 Ecuadorians from 7 distinct populations and geographic areas, including Kichwa and non-Kichwa Native Amerindians, Mestizos and Afro-Ecuadorians. Our results reveal the presence of C3-MPB373 both in the Amazonian lowland Kichwa with frequencies up to 28 % and, for the first time, in notable proportions in Kichwa populations from the Ecuadorian highlands. The substantially higher frequencies of C3-MPB373 in the Amazonian lowlands found in Kichwa and Waorani individuals suggest a founder effect in that area. Notably, estimates for the time to the most recent common ancestor (TMRCA) in the range of 7.2-9.0 kya point to an ancient origin of the haplogroup and suggest an early Holocene expansion of C3-MPB373 into South America. Finally, the pairwise genetic distances (RST) separate the Kichwa Salasaka from all the other Native Amerindian and Ecuadorian groups, indicating a so far hidden diversity among the Kichwa-speaking populations and suggesting a more southern origin of this population. In sum, our study provides a more in-depth knowledge of the male genetic structure of the multiethnic Ecuadorian population, as well as a valuable reference dataset for forensic use.

It is a widely held view that humans have control over their food choices and consumption. However, research also suggests that eating behavior is often triggered by contextual cues and guided by automaticities and habits. Interestingly, the dichotomy between automatic and controlled processing has recently been challenged, suggesting that they may be intertwined. In a large female sample (n = 567), we investigated the hypothesis that task-based and self-reported measures of automatic and controlled processing would interact and impact self-reported eating behavior. Results analyzed via structural equation modeling suggest that automatic, but not controlled processing, during a modified flanker task, including a context-specific proportion congruent (CSPC) manipulation, was inversely associated with self-reported self-control. The influence of self-control on unhealthy eating behavior (i.e., uncontrolled and emotional eating, heightened consumption of fat and sugar) was only indirect via habitual behavior, which itself had a strong direct impact. Unhealthy eating was further associated with real-life outcomes (e.g., body mass index (BMI)). Our findings suggest that eating behavior may indeed be guided primarily by automaticities and habits, whereas self-control might facilitate this association. Having self-control over eating might therefore be most effective by avoiding contextual cues eliciting undesired automatic behavior and establishing habits that serve long-term goals.

Background Patients with anorexia nervosa forgo eating despite emaciation and severe health consequences. Such dysfunctional decision-making might be explained by an excessive level of self-control, alterations in homeostatic and hedonic regulation, or an interplay between these processes. We aimed to understand value-based decision-making in anorexia nervosa and its association with the gut hormone ghrelin. Besides its homeostatic function, ghrelin has been implicated in the hedonic regulation of appetite and reward via the modulation of phasic dopamine signalling. Methods In a cross-sectional design, we studied acutely underweight (n = 94) and recovered (n = 37) patients with anorexia nervosa of the restrictive subtype, as well as healthy control participants (n = 119). We assessed plasma concentrations of desacyl ghrelin and parameters of delay discounting, probability discounting for gains and losses, and loss aversion. Results Recovered patients displayed higher risk aversion for gains, but we observed no group differences for the remaining decision-making parameters. Desacyl ghrelin was higher in acutely underweight and recovered participants with anorexia nervosa relative to healthy controls. Moreover, we found a significant group × desacyl ghrelin interaction in delay discounting, indicating that in contrast to healthy controls, acutely underweight patients with anorexia nervosa who had high desacyl ghrelin concentrations preferably chose the delayed reward option. Limitations We probed decision-making using monetary rewards, but patients with anorexia nervosa may react differently to disorder-relevant stimuli. Furthermore, in contrast to acyl ghrelin, the functions of desacyl ghrelin are unclear. Therefore, the interpretation of the results is preliminary. Conclusion The propensity for risk aversion as found in recovered patients with anorexia nervosa could help them successfully complete therapy, or it could reflect sequelae of the disorder. Conversely, ghrelin findings might be related to a mechanism contributing to disease maintenance; that is, in acutely underweight anorexia nervosa, a hungry state may facilitate the ability to forgo an immediate reward to achieve a (dysfunctional) long-term goal.

Rumination about body weight/figure as well as food is common in patients with Anorexia Nervosa (AN) and may be a maintenance factor of the disorder. While rumination can generally be considered as a cognitive-affective process, food-related rumination may be driven primarily by a physiological response to undernutrition. In the current longitudinal study, we integrate ecological momentary assessment of rumination and affect and, as a biological marker of undernutrition, plasma leptin levels collected from 33 AN patients. At the very acute stage and again after short-term weight-restoration patients answered short questionnaires six times per day over two weeks. Analyses via hierarchical linear modelling confirmed that rumination is closely linked to affect in AN before and after weight-restoration. Rumination about food decreased during weight-restoration and was correlated with leptin levels. In contrast, rumination about body weight/figure was not linked to leptin, persisted after weight gain, and showed stronger connections with affect. This suggests that rumination about body weight/figure seems to be a cognitive-affective aspect of the disorder, but food-related rumination may need to be considered from a physiological perspective. It is possible that food-related ruminative thoughts reflect a physiological symptom induced by undernutrition, similar to well-described leptin-associated changes in physical activity.