'Let me recommend ': use of digital nudges or recommender systems for overweight and obesity prevention-a scoping review protocol.

INTRODUCTION: Recommender systems, digital tools providing recommendations, and digital nudges increasingly affect our lives. The combination of digital nudges and recommender systems is very attractive for its application in preventing overweight and obesity. However, linking recommender systems with personalised digital nudges has a potential yet to be fully exploited. Therefore, this study aims to conduct a scoping review to identify which digital nudges or recommender systems or their combinations have been used in obesity prevention and to map these systems according to the target population, health behaviour, system classification (eg, mechanisms for developing recommendations, delivery channels, personalisation, interconnection, used combination), and system implementation. METHODS AND ANALYSIS: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews guideline was used to inform protocol development. The eligibility criteria are based on the PCC framework (Population: any human; Concept: recommender systems or digital nudges; Context: obesity prevention). MEDLINE, PsycINFO, Web of Science, CINHAL, Scopus, ACM Digital Library and IEEE Xplore were searched until September 2023. Primary studies with any design published in peer-reviewed academic journals and peer-reviewed conference papers will be included. Data will be extracted into a pre-developed extraction sheet. Results will be synthesised descriptively and narratively. ETHICS AND DISSEMINATION: No ethical approval is required for the scoping review, as data will be obtained from publicly available sources. The results of this scoping review will be published in a peer-reviewed journal, presented at conferences and used to inform the co-creation process and intervention adaptation in the context of a HealthyW8 project (www.healthyw8.eu).

Cyanonaphthalene and cyanonaphthyl radicals: Vibrational structures via computed negative ion photoelectron spectra and thermochemistry of 1- and 2-cyanonaphthalene.

A double harmonic oscillator model is applied to compute the negative ion photoelectron spectra (NIPES) of the 1- and 2-cyanonaphthalene (CNN) radical anions. The computed Franck-Condon factors utilize optimized structures and harmonic vibrational frequencies obtained using density functional theory with the B3LYP 6-311++G (2d,2p) basis set while considering the mode-mixing Duschinsky effects. To test the accuracy of our model, the NIPES of α and ß naphthyl radical anions were computed, and a strong agreement between the slow electron velocity-map ion imaging spectra and the predicted spectra was found. The adiabatic electron affinities (EAs) of the ground singlet states (S0) in 1-CNN and 2-CNN are 0.856 and 0.798 eV, respectively. The origin of the lowest-lying triplet (T1) states in 1-CNN and 2-CNN is found to be 3.226 and 3.266 eV, resulting in singlet-triplet energy splittings (ΔEST) of 2.370 and 2.468 eV, respectively. Both the NIPES for electron detachment to the S0 and T1 states exhibit well-resolved vibrational features, allowing for the assignment of several vibrational fundamental frequencies. Following deprotonation, several isomers are formed, with the most stable deprotonated radical anions in 1-CNN and 2-CNN, corresponding to the removal of the most acidic proton, with EAs of 2.062 and 2.16 eV. The rich spectroscopic and thermochemical data obtained in the current study make the CNN radical anions and their deprotonated species interesting systems for investigation in gas-phase, negative-ion experiments.

Determination of endometrial cancer molecular subtypes using a whole exome-sequencing based single-method approach.

AIM: Endometrial cancer (EC) is heterogeneous with respect to epidemiology, clinical course, histopathology and tumor biology. Recently, The Cancer Genome Atlas (TCGA) network has identified four molecular subtypes with distinct clinical courses by an integrated multi-omics approach. These subtypes are of critical importance in the clinical management of EC. However, determination of TCGA molecular subtypes requires a complex methodological approach that is resource intensive and difficult to implement in diagnostic routine procedures. In this context, Talhouk et al. reported the precise determination of modified subtypes based on molecular surrogates obtained by a two-method approach comprising immunohistochemistry and DNA-sequence analysis (Proactive Molecular Risk Classifier for Endometrial Cancer; ProMisE). In this study, we aimed to identify EC molecular subtypes in analogy to TCGA and ProMisE applying an innovative whole exome-sequencing (WES) based single-method approach. METHODS: WES was performed in a cohort comprising N = 114 EC patients. WES data were analyzed using the oncology treatment decision support software MH Guide (Molecular Health, Heidelberg, Germany) and EC molecular subtypes in analogy to TCGA and ProMisE were determined. Results from both classifications were compared regarding their prognostic values using overall survival and progression-free survival analyses. RESULTS: Applying a single-method WES-approach, EC molecular subtypes analogue to TCGA and ProMisE were identified in the study cohort. The surrogate marker-analogue classification precisely identified high-risk and low-risk EC, whereas the TCGA-analogue classification failed to obtain significant prognostic values in this regard. CONCLUSION: Our data demonstrate that determination of EC molecular subtypes analogue to TCGA and ProMisE is feasible by using a single-method WES approach. Within our EC cohort, prognostic implications were only reliably provided by applying the surrogate marker-analogue approach. Designation of molecular subtypes in EC will be increasingly important in routine clinical practice. Thus, the single-method WES approach provides an important simple tool to tailor therapeutic decisions in EC.

Perspectives on climate action and the changing burden of infectious diseases among young Italian doctors and students: a national survey.

Background: The eco-climatic crisis has been defined by the World Health Organization as the "single biggest health threat facing humanity," influencing both the emergence of zoonoses and the spread of vector-borne and water-borne diseases. The aim of this survey was to explore knowledge, eco-anxiety and attitudes toward the ecological and climate crisis among young Italian doctors and medical students. Methods: A cross-sectional, multicenter survey was conducted from November 2022 to June 2023, by administering an anonymous questionnaire to Italian doctors and students of medicine. Endpoint of the study was a Knowledge, Attitudes and Practices (KAP) score on ecological and climate crisis (0-20 points). Association between variables and KAP score was assessed by Kruskal-Wallis' or Spearman's test, as appropriate, and significant variables were included into ordinal regression model and reported as adjusted odds ratio (aOR) with their 95% confidence intervals (CI). Results: Both KAP and eco-anxiety scores showed acceptable levels of consistency with Cronbach's alpha. A total of 605 medical doctors and students living in 19 Italian regions were included in the study. Median age [Q1-Q3] was 27.6 [24.1-31.3] and females were 352 (58.2%). Despite showing good attitudes toward climate action, knowledge gap were found, with 42.5% (n = 257) of the respondents not knowing the temperature limits set by the Paris Agreements and 45.5% (n = 275) believing that climate change is caused by sunspots. Fears suggestive for eco-anxiety were common. At multivariable ordinal regression, high levels of eco-anxiety (aOR 1.29, p = 0.001) and low trust in government action (aOR 1.96, p = 0.003) were associated with a higher KAP score. Only one Italian medical school offered an educational module on climate change. Conclusion: Young Italian doctors and medical students are concerned about the climate crisis but show poor knowledge of these topics. The Italian academic system should urgently respond to this need.

Exploring the potential of omics technologies in medicinal plant research: a review in Colombia / Explorando el potencial de las tecnologías ómicas en la investigación de plantas medicinales: una revisión en Colombia

This review presents advances in the implementation of high - throughput se quencing and its application to the knowledge of medicinal plants. We conducted a bibliographic search of papers published in PubMed, Science Direct, Google Scholar, Scopus, and Web of Science databases and analyzed the obtained data using VOSviewer (versi on 1.6.19). Given that medicinal plants are a source of specialized metabolites with immense therapeutic values and important pharmacological properties, plant researchers around the world have turned their attention toward them and have begun to examine t hem widely. Recent advances in sequencing technologies have reduced cost and time demands and accelerated medicinal plant research. Such research leverages full genome sequencing, as well as RNA (ribonucleic acid) sequencing and the analysis of the transcr iptome, to identify molecular markers of species and functional genes that control key biological traits, as well as to understand the biosynthetic pathways of bioactive metabolites and regulatory mechanisms of environmental responses. As such, the omics ( e.g., transcriptomics, metabolomics, proteomics, and genomics, among others) have been widely applied within the study of medicinal plants, although their usage in Colombia is still few and, in some areas, scarce. (185)

El extracto de cloroformo (CE) y las fracciones obtenidas de las raíces de Aldama arenaria se evaluaron para determinar su actividad antiproliferativa in vitro contra 10 líneas ce lulares tumorales humanas [leucemia (K - 562), mama (MCF - 7), ovario que expresa un fenotipo resistente a múltiples fármacos (NCI/ADR - RES), melanoma (UACC - 62), pulmón (NCI - H460), próstata (PC - 3), colon (HT29), ovario (OVCAR - 3), glioma (U251) y riñón (786 - 0)]. CE presentó actividad antiproliferativa débil a moderada (log GI 50 medio 1.07), mientras que las fracciones 3 y 4, enriquecidas con diterpenos de tipo pimarane [ent - pimara - 8 (14), ácido 15 - dien - 19 - oico y ent - 8(14),15 - pimaradien - 3 ß - ol], presentaron activid ad moderada a potente para la mayoría de las líneas celulares, con un log GI 50 medio de 0.62 y 0.59, respectivamente. Los resultados mostraron una acción antiproliferativa in vitro prometedora de las muestras obtenidas de A. arenaria , con los mejores resul tados para NCI/ADR - RES, HT29 y OVCAR - 3, y valores de TGI que van desde 5.95 a 28.71 µg.mL - 1, demostrando que los compuestos de esta clase pueden ser prototipos potenciales para el descubrimiento de nuevos agentes terapéuticos

Haemodynamic effect of a leg compression bandage on the distal posterior tibial artery using 4D flow magnetic resonance imaging: A quantitative study.

The uncertainty concerning the physiological effects of compression bandaging on the peripheral blood flow is a challenge for healthcare professionals. The main objective was to determine the haemodynamic impact on the distal posterior tibial artery after the application of a high-compression leg multicomponent bandaging system using 4D flow magnetic resonance imaging. Leg dominance disparities of the posterior tibial artery before and after the application of the compressive bandage were also analysed. Twenty-eight healthy female volunteers were recruited (mean: 25.71, standard deviation: 4.74 years old) through a non-probability convenience sampling. The 4D flow magnetic resonance imaging of the distal tibial posterior artery was performed in all participants, first under standard resting conditions and after the application of a compression bandage in the leg. When the strong compressive bandage was applied, the area of the assessed artery decreased by 14.2%, whilst the average speed increased by 19.6% and the flow rate increased by 184.8%. There were differences between the haemodynamic parameters of both legs according to dominance, being statistically significantly lower in the dominant leg. The application of strong compressive bandaging significantly increases the arterial flow and mean velocity in the distal segment of the posterior tibial artery, in healthy volunteers by 4D flow magnetic resonance imaging. In this study, leg dominance influenced some of the haemodynamic parameters. According to the results, leg compression bandages cannot be contraindicated in vascular ulcers with arterial compromise.

Epistasis mediates the evolution of the receptor binding mode in recent human H3N2 hemagglutinin.

The receptor-binding site of influenza A virus hemagglutinin partially overlaps with major antigenic sites and constantly evolves. In this study, we observe that mutations G186D and D190N in the hemagglutinin receptor-binding site have coevolved in two recent human H3N2 clades. X-ray crystallography results show that these mutations coordinately drive the evolution of the hemagglutinin receptor binding mode. Epistasis between G186D and D190N is further demonstrated by glycan binding and thermostability analyses. Immunization and neutralization experiments using mouse and human samples indicate that the evolution of receptor binding mode is accompanied by a change in antigenicity. Besides, combinatorial mutagenesis reveals that G186D and D190N, along with other natural mutations in recent H3N2 strains, alter the compatibility with a common egg-adaptive mutation in seasonal influenza vaccines. Overall, our findings elucidate the role of epistasis in shaping the recent evolution of human H3N2 hemagglutinin and substantiate the high evolvability of its receptor-binding mode.

PRDX6 contributes to selenocysteine metabolism and ferroptosis resistance.

Selenocysteine (Sec) metabolism is crucial for cellular function and ferroptosis prevention and has traditionally been thought to begin with the uptake of the Sec carrier selenoprotein P (SELENOP). Following uptake, Sec released from SELENOP undergoes metabolisation via selenocysteine lyase (SCLY), producing selenide, a substrate used by selenophosphate synthetase 2 (SEPHS2), which provides the essential selenium donor - selenophosphate - for the biosynthesis of the selenocysteine tRNA. Here, we report the discovery of an alternative pathway mediating Sec metabolisation that is independent of SCLY and mediated by peroxiredoxin 6 (PRDX6). Mechanistically, we demonstrate that PRDX6 can readily react with selenide and interact with SEPHS2, potentially acting as a selenium delivery system. Moreover, we demonstrate the presence and functional significance of this alternative route in cancer cells where we reveal a notable association between elevated expression of PRDX6 with a highly aggressive neuroblastoma subtype. Altogether, our study sheds light on a previously unrecognized aspect of Sec metabolism and its implications in ferroptosis, offering new avenues for therapeutic exploitation.

Anterior enterocele after cystectomy: case report and review of the literature.

PURPOSE: Anterior enterocele is a rare but potentially serious complication after cystectomy with heterogeneous treatment options. METHODS: Here we report on the management of a 71-year-old patient with recurrence of anterior enterocele after cystectomy and provide a systematic review of the literature using the PubMed/MEDLINE database. RESULTS: The 71-year-old patient with recurrence of anterior enterocele after cystectomy was successfully treated with colpocleisis and anterior colporrhaphy at the Department of Gynecology and Gynecological Oncology, University Hospital Bonn. The use of a synthetic mesh was not needed. At 16-month follow-up postoperatively, the patient was asymptomatic and had no signs of recurrence. n = 14 publications including n = 39 patients were identified for the systematic review including case reports and reviews. The median duration of developing an anterior enterocele after cystectomy was 9 months (range 3 months to 8 years). Patients had a median age of 71 years (range 44-84). In all cases, a surgical approach was described using a wide variety of surgical procedures. In total, 36% of all patients developed a recurrence with an average time period of 7 months after primary surgery. A rare complication represents a vaginal evisceration with the need of urgent surgery. Furthermore, the occurrence of a fistula is a possible long-term complication. CONCLUSION: Anterior enterocele after cystectomy is a rare complication requiring an individual and interdisciplinary treatment.

Establishment of a Biorepository for Down Syndrome: Experience of the Inter-Institutional Multidisciplinary BioBank - BioBIM.

BACKGROUND: Down syndrome, or Trisomy 21, is the leading genetic cause of cognitive disability in children and is associated with a high risk of several comorbidities, particularly congenital heart defects, early onset Alzheimer's disease, leukaemia, and autoimmune disorders. OBJECTIVE: This study describes the design, methods, and operational procedures employed to establish a biobank dedicated to Down syndrome that can support research projects investigating the effects of various genetic and environmental factors on this complex disease. METHODS: Blood was collected from all recruited subjects, processed, aliquoted and immediately frozen at -80 °C in the Interinstitutional Multidisciplinary BioBank (BioBIM) facilities. A small aliquot of the sample was used to perform blood tests for which analysis would not be feasible at a later date, such as blood cell counts. Each biological sample was coded, assigned a Standard PREanalytical Code, and registered in the oloBIOBANK software connected to a medical card containing all the donor's anamnestic data. All samples were stored under continuous real-time temperature recording using a freezer connected to a T-GUARD alarm system. In addition, a radiofrequency identification tracking system strictly monitored each cryopreservation operation performed throughout the sample lifecycle. RESULTS: Biological samples were collected from 454 individuals with Down syndrome from 2007 to 2023. A total of 2233 biological samples were available for research purposes, including whole blood in different anticoagulants, serum, plasma, and frozen peripheral blood mononuclear cells. The quality of the nucleic acids obtained through specific standard operating procedures demonstrated that these samples were appropriate for clinical and basic research. CONCLUSION: By establishing this biobank, we have gathered a significant number of biological samples and clinical data from individuals with Down syndrome, thereby fostering collaboration between different research groups in an open and transparent manner. Sharing expertise and resources among scientists will ultimately facilitate the transfer of knowledge to clinical practice, leading to the development of more effective therapeutic treatments to improve the outcomes and quality of life of patients with Down syndrome.

Nanoemulsion with wine lees: a green approach.

Bioactive substances can be found in wine lees, a waste from the winemaking industry. This work developed two formulations, a nanoemulsion with coconut oil (NE-OC) and a nanoemulsion with coconut oil and 0.5% of wine lees extract (NE-OC-Ext), to investigate their effect on untreated, bleached, and bleached-colored hair. The oil-in-water (O/W) nanoemulsions were prepared with coconut oil, TweenTM 80, SpanTM 80, AristoflexTM AVC, Conserve NovaMit MFTM, wine lees extract, and deionized water. The hydration measurements were carried out using a Corneometer® CM 825 with the capacitance method. Scanning electron microscopy (SEM) was used to characterize the effect of formulations on hair fibers. Differential Thermal Analysis (DTA) was to assess the thermal stability and compatibility of wine lees and coconut oil in formulations. Compared to NE-OC, NE-OC-Ext showed a greater hydration effect on bleached-colored hair. DTA showed that NE-OC-Ext presented a smaller number of exothermic degradation events than those of NE-OC, suggesting good interaction and compatibility of the wine lees extract in this formulation. This study highlights the value of wine lees, a residue from the winemaking process, and its possibility of use as raw material for the cosmetic hair industry since it shows a greater moisturizing potential in colored hair.

Development of the Fit&Fab Exercise Intervention for Women With Obesity: A Community Advisory Board Informed Process.

BACKGROUND: Women with higher body mass index report low rates of and face unique barriers to exercise. Increasing exercise participation can improve mental and physical health independent of weight loss; however, most exercise programs targeting this population focus predominately on losing weight. This paper aims to describe the development of Fit&Fab, a community-based exercise intervention focused on increasing exercise participation and enjoyment for women with obesity. METHODS: In partnership with the YMCA, we recruited women ages 35-64 years (body mass index ≥ 30) to participate in 4 focus groups to understand exercise preferences. Formative work was used to identify theory constructs and associated intervention components. Women from the focus groups were recruited for a community advisory board that finalized the intervention design, recruitment, and evaluation plan. RESULTS: Focus groups participants (N = 29) preferred to exercise without men and wanted a cohort-style class that included women of similar exercise levels and body types, incorporated social support, fun activities, and broke exercise into smaller bouts. They wanted a supportive instructor who was fit but understood weight-related challenges. The community advisory board and research team used focus group findings to inform design of the final intervention including group exercise classes, psychosocial support sessions, personalized training, exercise tracking, outcome monitoring, and rewards. CONCLUSIONS: Our findings emphasize the need to focus on exercise enjoyment and benefits other than losing weight to improve exercise participation among women with higher body mass index. In addition to having outcomes other than weight loss, exercise interventions with this population should also consider group composition, instructor, and class format.

Therapeutic inhibition of monocyte recruitment prevents checkpoint inhibitor-induced hepatitis.

BACKGROUND: Checkpoint inhibitor-induced hepatitis (CPI-hepatitis) is an emerging problem with the widening use of CPIs in cancer immunotherapy. Here, we developed a mouse model to characterize the mechanism of CPI-hepatitis and to therapeutically target key pathways driving this pathology. METHODS: C57BL/6 wild-type (WT) mice were dosed with toll-like receptor (TLR)9 agonist (TLR9-L) for hepatic priming combined with anti-cytotoxic T lymphocyte antigen-4 (CTLA-4) plus anti-programmed cell death 1 (PD-1) ("CPI") or phosphate buffered saline (PBS) control for up to 7 days. Flow cytometry, histology/immunofluorescence and messenger RNA sequencing were used to characterize liver myeloid/lymphoid subsets and inflammation. Hepatocyte damage was assessed by plasma alanine transaminase (ALT) and cytokeratin-18 (CK-18) measurements. In vivo investigations of CPI-hepatitis were carried out in Rag2-/- and Ccr2rfp/rfp transgenic mice, as well as following anti-CD4, anti-CD8 or cenicriviroc (CVC; CCR2/CCR5 antagonist) treatment. RESULTS: Co-administration of combination CPIs with TLR9-L induced liver pathology closely resembling human disease, with increased infiltration and clustering of granzyme B+perforin+CD8+ T cells and CCR2+ monocytes, 7 days post treatment. This was accompanied by apoptotic hepatocytes surrounding these clusters and elevated ALT and CK-18 plasma levels. Liver RNA sequencing identified key signaling pathways (JAK-STAT, NF-ΚB) and cytokine/chemokine networks (Ifnγ, Cxcl9, Ccl2/Ccr2) as drivers of CPI-hepatitis. Using this model, we show that CD8+ T cells mediate hepatocyte damage in experimental CPI-hepatitis. However, their liver recruitment, clustering, and cytotoxic activity is dependent on the presence of CCR2+ monocytes. The absence of hepatic monocyte recruitment in Ccr2rfp/rfp mice and CCR2 inhibition by CVC treatment in WT mice was able to prevent the development and reverse established experimental CPI-hepatitis. CONCLUSION: This newly established mouse model provides a platform for in vivo mechanistic studies of CPI-hepatitis. Using this model, we demonstrate the central role of liver infiltrating CCR2+ monocyte interaction with tissue-destructive CD8+ T cells in the pathogenesis of CPI-hepatitis and highlight CCR2 inhibition as a novel therapeutic target.

Advancing genomics to improve health equity.

Health equity is the state in which everyone has fair and just opportunities to attain their highest level of health. The field of human genomics has fallen short in increasing health equity, largely because the diversity of the human population has been inadequately reflected among participants of genomics research. This lack of diversity leads to disparities that can have scientific and clinical consequences. Achieving health equity related to genomics will require greater effort in addressing inequities within the field. As part of the commitment of the National Human Genome Research Institute (NHGRI) to advancing health equity, it convened experts in genomics and health equity research to make recommendations and performed a review of current literature to identify the landscape of gaps and opportunities at the interface between human genomics and health equity research. This Perspective describes these findings and examines health equity within the context of human genomics and genomic medicine.

Incident Use of Hydroxychloroquine for the Treatment of Rheumatoid Arthritis and Systemic Lupus Erythematosus During the COVID-19 Pandemic.

OBJECTIVE: We studied whether the use of hydroxychloroquine (HCQ) for COVID-19 resulted in supply shortages for patients with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). METHODS: We used US claims data (IQVIA PHARMETRICS® Plus for Academics [PHARMETRICS]) and hospital electronic records from Spain (Institut Municipal d'Assistència Sanitària Information System [IMASIS]) to estimate monthly rates of HCQ use between January 2019 and March 2022, in the general population and in patients with RA and SLE. Methotrexate (MTX) use was estimated as a control. RESULTS: More than 13.5 million individuals (13,311,811 PHARMETRICS, 207,646 IMASIS) were included in the general population cohort. RA and SLE cohorts enrolled 135,259 and 39,295 patients, respectively, in PHARMETRICS. Incidence of MTX and HCQ were stable before March 2020. On March 2020, the incidence of HCQ increased by 9- and 67-fold in PHARMETRICS and IMASIS, respectively, and decreased in May 2020. Usage rates of HCQ went back to prepandemic trends in Spain but remained high in the United States, mimicking waves of COVID-19. No significant changes in HCQ use were noted among patients with RA and SLE. MTX use rates decreased during HCQ approval period for COVID-19 treatment. CONCLUSION: Use of HCQ increased dramatically in the general population in both Spain and the United States during March and April 2020. Whereas Spain returned to prepandemic rates after the first wave, use of HCQ remained high and followed waves of COVID-19 in the United States. However, we found no evidence of general shortages in the use of HCQ for both RA and SLE in the United States.

A longitudinal causal graph analysis investigating modifiable risk factors and obesity in a European cohort of children and adolescents.

Childhood obesity is a complex disorder that appears to be influenced by an interacting system of many factors. Taking this complexity into account, we aim to investigate the causal structure underlying childhood obesity. Our focus is on identifying potential early, direct or indirect, causes of obesity which may be promising targets for prevention strategies. Using a causal discovery algorithm, we estimate a cohort causal graph (CCG) over the life course from childhood to adolescence. We adapt a popular method, the so-called PC-algorithm, to deal with missing values by multiple imputation, with mixed discrete and continuous variables, and that takes background knowledge such as the time-structure of cohort data into account. The algorithm is then applied to learn the causal structure among 51 variables including obesity, early life factors, diet, lifestyle, insulin resistance, puberty stage and cultural background of 5112 children from the European IDEFICS/I.Family cohort across three waves (2007-2014). The robustness of the learned causal structure is addressed in a series of alternative and sensitivity analyses; in particular, we use bootstrap resamples to assess the stability of aspects of the learned CCG. Our results suggest some but only indirect possible causal paths from early modifiable risk factors, such as audio-visual media consumption and physical activity, to obesity (measured by age- and sex-adjusted BMI z-scores) 6 years later.

Distinctive cell-free DNA methylation characterizes presymptomatic genetic frontotemporal dementia.

OBJECTIVE: Methylation of plasma cell-free DNA (cfDNA) has potential as a marker of brain damage in neurodegenerative diseases such as frontotemporal dementia (FTD). Here, we study methylation of cfDNA in presymptomatic and symptomatic carriers of genetic FTD pathogenic variants, next to healthy controls. METHODS: cfDNA was isolated from cross-sectional plasma of 10 presymptomatic carriers (4 C9orf72, 4 GRN, and 2 MAPT), 10 symptomatic carriers (4 C9orf72, 4 GRN, and 2 MAPT), and 9 healthy controls. Genome-wide methylation of cfDNA was determined using a high-resolution sequencing technique (MeD-seq). Cumulative scores based on the identified differentially methylated regions (DMRs) were estimated for presymptomatic carriers (vs. controls and symptomatic carriers), and reevaluated in a validation cohort (8 presymptomatic: 3 C9orf72, 3 GRN, and 2 MAPT; 26 symptomatic: 7 C9orf72, 6 GRN, 12 MAPT, and 1 TARDBP; 13 noncarriers from genetic FTD families). RESULTS: Presymptomatic carriers showed a distinctive methylation profile compared to healthy controls and symptomatic carriers. Cumulative DMR scores in presymptomatic carriers enabled to significantly differentiate presymptomatic carriers from healthy controls (p < 0.001) and symptomatic carriers (p < 0.001). In the validation cohort, these scores differentiated presymptomatic carriers from symptomatic carriers (p ≤ 0.007) only. Transcription-start-site methylation in presymptomatic carriers, generally associated with gene downregulation, was enriched for genes involved in ubiquitin-dependent processes, while gene body methylation, generally associated with gene upregulation, was enriched for genes involved in neuronal cell processes. INTERPRETATION: A distinctive methylation profile of cfDNA characterizes the presymptomatic stage of genetic FTD, and could reflect neuronal death in this stage.

Interleukin-4 downregulates transcription factor BCL6 to promote memory B cell selection in germinal centers.

Germinal center (GC)-derived memory B cells (MBCs) are critical for humoral immunity as they differentiate into protective antibody-secreting cells during re-infection. GC formation and cellular interactions within the GC have been studied in detail, yet the exact signals that allow for the selection and exit of MBCs are not understood. Here, we showed that IL-4 cytokine signaling in GC B cells directly downregulated the transcription factor BCL6 via negative autoregulation to release cells from the GC program and to promote MBC formation. This selection event required additional survival cues and could therefore result in either GC exit or death. We demonstrate that both increasing IL-4 bioavailability or limiting IL-4 signaling disrupted MBC selection stringency. In this way, IL-4 control of BCL6 expression serves as a tunable switch within the GC to tightly regulate MBC selection and affinity maturation.

Shades of white: The Petunia long corolla tube clade evolutionary history.

Delimiting species is challenging in recently diverged species, and adaptive radiation is fundamental to understanding the evolutionary processes because it requires multiple ecological opportunities associated with adaptation to biotic and abiotic environments. The young Petunia genus (Solanaceae) is an excellent opportunity to study speciation because of its association with pollinators and unique microenvironments. This study evaluated the phylogenetic relationships among a Petunia clade species with different floral syndromes that inhabit several environments. We based our work on multiple individuals per lineage and employed nuclear and plastid phylogenetic markers and nuclear microsatellites. The phylogenetic tree revealed two main groups regarding the elevation of the distribution range, whereas microsatellites showed high polymorphism-sharing splitting lineages into three clusters. Isolation by distance, migration followed by new environment colonization, and shifts in floral syndrome were the motors for lineage differentiation, including infraspecific structuring, which suggests the need for taxonomic revision in the genus.