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Circulating vitamin B12 concentrations during pregnancy are associated with offspring health. Foetal DNA methylation changes could underlie these associations. Within the Pregnancy And Childhood Epigenetics Consortium, we meta-analysed epigenome-wide associations of circulating vitamin B12 concentrations in mothers during pregnancy (n = 2,420) or cord blood (n = 1,029), with cord blood DNA methylation. Maternal and newborn vitamin B12 concentrations were associated with DNA methylation at 109 and 7 CpGs, respectively (False Discovery Rate P-value

Among the relevant aspects of the family resemblance approach (FRA), our study focuses on the potential of the approach to elaborate on disciplinary identities in an interdisciplinary context, specifically regarding the interplay between physics and mathematics. We present and discuss how the FRA wheel can be used and intertwined with the framework of boundary objects and boundary crossing mechanisms (Akkerman & Bakker, "Review of Educational Research," 81, 132-169, 2011), which is well-known in STEM education for dealing with interdisciplinarity. The role of the FRA discussed in the article is dual: both practical and theoretical. It is practical in that we show how its use, in combination with the Akkerman and Bakker framework, appears effective in fostering productive discussions among prospective teachers on disciplinary identities and interdisciplinarity in historical cases. It is theoretical in that the combination of the two frameworks provides the vocabulary to characterise the 'ambiguous nature' of interdisciplinarity: like boundaries, interdisciplinarity both separates disciplines, making their identities emerge, and connects them, fostering mechanisms of crossing and transgressing the boundaries. This empirical study reveals how the theoretical elaboration took advantage of the prospective teachers' contributions. We initially presented the FRA to characterise disciplinary identities, but the prospective teachers highlighted its potential to characterise also the boundary zone and the dialogue between physics and mathematics. The data analysis showed that the combinination of the two frameworks shaped a complex learning space where there was room for very different epistemic demands of the prospective teachers: from those who feel better within the identity cores of the disciplines, to those who like to inhabit the boundary zone and others who like to re-shape boundary spaces and move dynamically across them.

Abstract The benefits of breastfeeding for the health and wellbeing of both infants and mothers are well documented, yet global breastfeeding rates are low. One factor associated with low breast feeding is maternal body mass index (BMI), which is used as a measure of obesity. The negative relationship between maternal obesity and breastfeeding is likely caused by a variety of social, psychological, and physiological factors. Maternal obesity may also have a direct biological association with breastfeeding through changes in maternal DNA methylation. Here, we investigate this potential biological association using data from a UK-based cohort study, the Avon Longitudinal Study of Parents and Children (ALSPAC). We find that pre-pregnancy body mass index (BMI) is associated with lower initiation to breastfeed and shorter breastfeeding duration. We conduct epigenome-wide association studies (EWAS) of pre-pregnancy BMI and breastfeeding outcomes, and run candidate-gene analysis of methylation sites associated with BMI identified via previous meta-EWAS. We find that DNA methylation at cg11453712, annotated to PHTP1, is associated with pre-pregnancy BMI. From our results, neither this association nor those at candidate-gene sites are likely to mediate the link between pre-pregnancy BMI and breastfeeding.

ABSTRACT The limited temporal completeness and taxonomic accuracy of species lists, made available in a traditional manner in scientific publications, has always represented a problem. These lists are invariably limited to a few taxonomic groups and do not represent up-to-date knowledge of all species and classifications. In this context, the Brazilian megadiverse fauna is no exception, and the Catálogo Taxonômico da Fauna do Brasil (CTFB) (http://fauna.jbrj.gov.br/), made public in 2015, represents a database on biodiversity anchored on a list of valid and expertly recognized scientific names of animals in Brazil. The CTFB is updated in near real time by a team of more than 800 specialists. By January 1, 2024, the CTFB compiled 133,691 nominal species, with 125,138 that were considered valid. Most of the valid species were arthropods (82.3%, with more than 102,000 species) and chordates (7.69%, with over 11,000 species). These taxa were followed by a cluster composed of Mollusca (3,567 species), Platyhelminthes (2,292 species), Annelida (1,833 species), and Nematoda (1,447 species). All remaining groups had less than 1,000 species reported in Brazil, with Cnidaria (831 species), Porifera (628 species), Rotifera (606 species), and Bryozoa (520 species) representing those with more than 500 species. Analysis of the CTFB database can facilitate and direct efforts towards the discovery of new species in Brazil, but it is also fundamental in providing the best available list of valid nominal species to users, including those in science, health, conservation efforts, and any initiative involving animals. The importance of the CTFB is evidenced by the elevated number of citations in the scientific literature in diverse areas of biology, law, anthropology, education, forensic science, and veterinary science, among others.

PurposeEven today, melanoma is a highly aggressive neoplasm with a high mortality rate. The nodular type is very aggressive and has cerebroid nests of melanocytes (CNMs) at the growth edge, morphologically similar to the poorly differentiated neoplastic epithelial cell clusters described in colorectal, breast, and endometrioid endometrial cancers.Patients and methodsWe selected 25 nodular melanomas (NMs) with known molecular profiles, of which the entire paraffin-embedded lesion was available. We counted CNMs under a microscopic at a magnification of 20x (i.e., a microscopic field with a major axis of 1 mm). Based on the number of CNMs in the area, melanomas were classified into three groups: G1 (CNMs ranging from 0 to 4), G2 (CNMs ranging from 5 to 9), and G3 (CNMs ≥ 10). The presence of CNMs and their counts were compared with molecular and histopathological data.ResultsSeventeen (NMs) were grouped as G1 (68%), 5 as G2 (20%), and 3 as G3 (12%) based on CNMs count. The presence of CNMs correlated with epithelioid cell morphology (p < 0.05), Clark IV and V levels (p < 0.05), vascular invasion (p < 0.05), and biological mutants (p < 0.05). Melanomas with ≥ 10 CNMs more frequently show ulceration (p < 0.02) and the BRAF V600E mutation (p < 0.02).ConclusionCNMs count has a predictive role regardless of tumor size; their association with the BRAF V600E mutation suggests their predictive significance in response to biologics. However, further investigations are needed to strengthen this hypothesis.

Cognitive skills are a strong predictor of a wide range of later life outcomes. Genetic and epigenetic associations across the genome explain some of the variation in general cognitive abilities in the general population and it is plausible that epigenetic associations might arise from prenatal environmental exposures and/or genetic variation early in life. We investigated the association between cord blood DNA methylation at birth and cognitive skills assessed in children from eight pregnancy cohorts within the Pregnancy And Childhood Epigenetics (PACE) Consortium across overall (total N = 2196), verbal (total N = 2206) and non-verbal cognitive scores (total N = 3300). The associations at single CpG sites were weak for all of the cognitive domains investigated. One region near DUSP22 on chromosome 6 was associated with non-verbal cognition in a model adjusted for maternal IQ. We conclude that there is little evidence to support the idea that variation in cord blood DNA methylation at single CpG sites is associated with cognitive skills and further studies are needed to confirm the association at DUSP22.

The World Health Organization (WHO) promotes research aimed at developing new drugs from natural compounds. Fungi are important producers of bioactive molecules, and they are often effective against other fungi and/or bacteria and are thus a potential source of new antibiotics. Basidiomycota crude extracts, which have previously been proven to be active against Pseudomonas aeruginosa ATCC27853, were subjected to liquid chromatographic separation by RP-18, leading to six macro-fractions for each fungal extract. The various fractions were tested for their bioactivities against P. aeruginosa ATCC27853, and ten of them were characterized by HPLC-HRMS and NMR. Further chromatographic separations were performed for a few selected macro-fractions, yielding seven pure compounds. Bioactivity was mainly found in the lipophilic fractions containing fatty acids and their derivatives, such as hydroxy or keto C-18 unsaturated acids, and in various complex lipids, such as glycolipids and related compounds. More hydrophilic molecules, such as GABA, phenethylamine, two chromogenic anthraquinoids and pistillarin, were also isolated, and their antibacterial activities were recorded. The novelties of this research are as follows: (i) the genera Cortinarius and Mycena have never been investigated before for the synthesis of antibiotic compounds; (ii) the molecules produced by these genera are known, but their production has never been reported in the investigated fungi; (iii) the determination of bacterial siderophore synthesis inhibition by certain compounds from Cortinarius and Mycena.

As a result of technological advancements, functional capacity assessments, such as the 6-minute walk test, can be performed remotely, at home and in the community. Current studies, however, tend to overlook the crucial aspect of data quality, often limiting their focus to idealised scenarios. Challenging conditions may arise when performing a test given the risk of collecting poor-quality GNSS signal, which can undermine the reliability of the results. This work shows the impact of applying filtering rules to avoid noisy samples in common algorithms that compute the walked distance from positioning data. Then, based on signal features, we assess the reliability of the distance estimation using logistic regression from the following two perspectives: error-based analysis, which relates to the estimated distance error, and user-based analysis, which distinguishes conventional from unconventional tests based on users’ previous annotations. We highlight the impact of features associated with walked path irregularity and direction changes to establish data quality. We evaluate features within a binary classification task and reach an F1-score of 0.93 and an area under the curve of 0.97 for the user-based classification. Identifying unreliable tests is helpful to clinicians, who receive the recorded test results accompanied by quality assessments, and to patients, who can be given the opportunity to repeat tests classified as not following the instructions.

OBJECTIVES: Acrodermatitis Enteropathica (AE) is a rare disease that can be transmitted by autosomal recessive inheritance, it can be related to parenteral nutrition without zinc, or it can be secondary to malabsorptive syndromes. Clinically, it is characterized by the triad of acral and periorificial dermatitis, alopecia and diarrhea, accompanied by growth restriction. The condition can be fatal if left untreated. METHODS: We describe the case of a child with AE and Crohns Disease (CD), with AE being a known complication, secondary to malabsorption caused by CD. RESULTS: Treatment for CD was started with systemic steroids, Azathioprine and Mesalazine, and local care with the diaper area. Oral zinc replacement was also started. The child showed significant clinical and dermatological improvement within a few weeks. CONCLUSIONS: The diagnosis of AE is made with serum zinc levels lower than 70 ug/dL. Treatment involves zinc supplementation, at a dose ranging from 1 to 3 mg/kg/day. In the case described, the zinc value was 65 ug/dL. In this case, we started replacement with 2mg/kg/day, with rapid clinical improvement. Zinc deficiency AE is a well-known complication of CD, secondary to malabsorption. In the case described, the cutaneous condition came after the intestinal condition, with the deficiency in the absorption of zinc being secondary to Crohns Disease, leading to a condition with extensive lesions, but with a quick response to the treatment and with an important improvement of the condition.

Circulating vitamin B12 concentrations during pregnancy are associated with offspring health. Foetal DNA methylation changes could underlie these associations. Within the Pregnancy And Childhood Epigenetics Consortium, we meta-analysed epigenome-wide associations of circulating vitamin B12 concentrations in mothers during pregnancy (n = 2,420) or cord blood (n = 1,029), with cord blood DNA methylation. Maternal and newborn vitamin B12 concentrations were associated with DNA methylation at 109 and 7 CpGs, respectively (False Discovery Rate P-value

The article describes the analysis of the Italian physics curriculum documents in terms of the coverage of nature of science (NOS). NOS is not explicitly presented as part of the Italian high-school physics curriculum. The article focuses on analysing the implicit aspects of the curriculum documents. The Family Resemblance Approach (FRA) to NOS was used as an analytical lens. FRA was chosen because of the broad range of categories that it provides to trace curriculum content. Curriculum documents were analysed using the FRA categories as well as an Epistemic Network Analysis (ENA) which has shown important limitations in the FRA categories 'Political Power Structures, Scientific Ethos, Professional Activities'. These aspects of NOS belong to the social-institutional aspects of the FRA framework. There were also some inconsistencies between the general section and the specific sections of the curriculum. The study elaborates on how FRA and ENA can be used to analyse NOS content in a science curriculum. The epistemic networks provide concrete illustrations of where curriculum revision can best be carried out to promote underrepresented aspects of NOS. Implications for future research and recommendations for curriculum reform internationally are suggested.

SARS-CoV-2 virulence is known to increase with lowering of environmental temperature and solar ultraviolet radiation; therefore, we have focused our real-world nationwide study concerning with COVID-19 trend and dynamics on the coldest seasons of the year in Italy, the Western country hardest hit at the onset of the pandemic, comparing the autumn–winter of 2020 (before mass vaccination but when the emergency machinery was fully operative in terms of tracing and swabs) with the autumn–winter of 2021 (after mass vaccination), and analyzing the mortality burden by age groups and life stages in the years 2019 (pre-COVID-19), 2020 (before mass vaccination), and 2021 (after mass vaccination). Methods: During the state of national health emergency, the Civil Defense Department released the aggregate data coming from the Higher Institute of Health, the Ministry of Health, the Italian Regions, and the Independent Provinces, to inform the population about the pandemic situation, daily. Among these data, there were the number of contagions, performed swabs, hospitalizations in Intensive Care Units (ICU), non-ICU patients, and deaths. By means of a team effort, we have collected and elaborated all these data, comparing the COVID-19 pandemic in Italy during the autumn–winter of 2020 with the autumn–winter of 2021. Moreover, we have extracted from the database of the National Institute of Statistics the total number of annual deaths in Italy during the years 2019, 2020, and 2021, comparing them to each other in order to evaluate the mortality burden attributable to COVID-19. Results: From the autumn–winter of 2020 to the autumn–winter of 2021, the contagions increased by ≈285%, against a ≈290% increase in the performed swabs; therefore, the mean positivity rate passed from 8.74% before mass vaccination to 8.59% after mass vaccination. The unprecedent vaccination campaign allowed a ≈251% abatement in COVID-19 deaths, and a reduction of ≈224% and ≈228% in daily ICU and non-ICU hospitalizations due to COVID-19, respectively. Regarding COVID-19 deaths, in 2020, there was a mortality excess of ≈14.3% quantifiable in 105,900 more deaths compared to 2019, the pre-COVID-19 year; 103,183 out of 105,900 deaths occurred in older adults (≥60 years), which is equivalent to ≈97.4%, while in adults over 50, the segment of population just below older adults, in 2020, there were 2807 more deaths than in 2019. Surprisingly, from the analysis of our data, it is emerged that in people under the age of 40 in the years 2019, 2020, and 2021, there were 7103, 6808, and 7165 deaths, respectively. This means that in subjects under 40 during 2020, there were 295 fewer deaths than in 2019, while during 2021, there were 357 more deaths than in 2020, equivalent to ≈5.2% more. Conclusions: COVID-19 is a potential life-threatening disease mainly in older adults, as they are the most vulnerable due to inherent immunosenescence and inflammaging. Extensive vaccination in this segment of population with up-to-date vaccines is the means to reduce deaths, hospitalizations, and ICU pressure in the public interest. In the event of future threats, a new mass vaccination campaign should not be implemented without taking into account the individual age; it should primarily be aimed at people over 60 and at patients of any age with immune deficits, and secondly at people over 50. COVID-19 vaccination shows a favorable benefit–risk ratio in older adults, while the balance steps down under the age of 40; this younger segment of the population should be therefore exempt from any mandatory vaccination.

Abstract Background Leukoencephalopathy with vanishing white matter (VWM) is an autosomal recessive neurological disease. The physiopathology of disease is still little understood, but it seems to involve impairment in maturation of astrocytes; as a consequence white matter is more prone to cellular stress. Disease is caused by mutations in five genes encoding subunits of the translation initiation factor eIF2B. We know five different types of VWM syndrome classified based different ages of onset (prenatal, infantile, childhood, juvenile and adult onset). Case presentation We report the case of a 4-month-old boy with early seizure onset, recurrent hypoglycemia and post mortem diagnosis of vanishing white matter disease (VMD). At the admission he presented suspected critical episodes, resolved after intravenous administration of benzodiazepines. The brain MRI showed total absence of myelination that suggested hypomyelination leukoencephalopathy. The whole exome sequencing (WES) revealed a variant of EIF2B2 gene (p. Val308Met) present in homozygosity. In this case report we also describe the clinical evolution of seizures, in fact the epileptic seizures had a polymorphic aspect, from several complex partial seizures secondarily generalized to status epilepticus. Conclusion Infantile and early childhood onset forms are associated with chronic progressive neurological signs, with episodes of rapid neurological worsening, and poor prognosis, with death in few months or years. Clinical presentation of epilepsy is poorly documented and do not include detailed information about the type, time of onset and severity of seizures. No therapeutic strategies for VWM disease have been reported.

Like all RNA viruses, SARS-CoV-2 shows a high mutation rate, which has led to the emergence of new variants. Among them, Gamma and Delta developed at the turn of 2020–2021 in Amazonas and India, two ecoregions characterized by hot-humid weather, very similar to that of the summer season in Italy due to climate change, the first Western country to be hit hard by COVID-19 and to experience lockdown restrictions in a democratic framework of 58.85 million people. The aim of our research has been to evaluate the impact of climate on the COVID-19 pandemic in Italy during the summers of 2020 (before mass vaccination), 2021 (after primary mass vaccination) and 2022 (after booster mass vaccination), also taking into account the emergence of these two variants. Methods: During the state of national health emergency and the Draghi government, the Civil Defense Department released the aggregate data coming from the Ministry of Health, the Higher Institute of Health, the Independent Provinces and the Italian Regions daily, in order to inform about the pandemic situation in Italy. Among these data there were the number of deaths, hospitalizations in intensive care units (ICU), non-ICU patients, contagions and performed swabs. By means of a team effort, we have collected and elaborated all these data, comparing the COVID-19 pandemic in Italy during the summers of 2020 (following the nationwide lockdown), 2021 and 2022. Results: from the summer of 2020 to the summers of 2021 and 2022 all pandemic trend indicators have shown a sharp worsening in Italy. COVID-19 deaths increased by ≈298% and ≈834%, ICU hospitalizations by ≈386% and ≈310%, non-ICU hospitalizations by ≈224% and ≈600%, contagions by ≈627% and ≈6850% (i.e., ≈68.50 times), swabs by ≈354% and ≈370%, and the mean positivity rate passed from ≈1% to ≈2% and ≈20%, respectively. Conclusions: SARS-CoV-2 can be transmitted in any climate, including areas with hot and humid weather, and the emergence of variants adapted to hot-humid climates may result in summer COVID-19 outbreaks, even in neither tropical nor subtropical countries. Although COVID-19 vaccines can confer cross-protection against newly emerging variants, this cross-immunity is naturally not absolute but limited, considering that vaccine protection wanes significantly after 6 months. It follows that a subject vaccinated at the beginning of the winter will not be completely covered in the height of the summer, and we should not forget the unvaccinated. As a final remark, the long and strict nationwide lockdown made it possible to flatten SARS-CoV-2 circulation and, therefore, its negative impact on Italy during the summer of 2020.

Abstract Handedness has low heritability and epigenetic mechanisms have been proposed as an etiological mechanism. To examine this hypothesis, we performed an epigenome-wide association study of left-handedness. In a meta-analysis of 3914 adults of whole-blood DNA methylation, we observed that CpG sites located in proximity of handedness-associated genetic variants were more strongly associated with left-handedness than other CpG sites (P = 0.04), but did not identify any differentially methylated positions. In longitudinal analyses of DNA methylation in peripheral blood and buccal cells from children (N = 1737), we observed moderately stable associations across age (correlation range [0.355–0.578]), but inconsistent across tissues (correlation range [− 0.384 to 0.318]). We conclude that DNA methylation in peripheral tissues captures little of the variance in handedness. Future investigations should consider other more targeted sources of tissue, such as the brain.

Promotion of oral health has an essential role in the maintenance of teeth in adults. However, health education must start from an early age, in order to monitor the child's growth and prevent pathologies. Schools are in charge of the overall education of children and of guidance to parents but could also be engaged in the promotion of oral health, supported and counseled by pediatricians and dentists. The purpose of this pilot study is to evaluate whether school age children could be taught, successfully, basic oral sciences and dental hygiene, by a professional, during school hours. In this pilot study, an anonymized test was administered to 45 children of age between 8 and 10, both before and after an interactive lecture on oral health, to assess the effectiveness of the lesson and acquisition by the children of knowledge on oral health. After the presentation, the majority of the children were able to answer correctly to the questionnaire that was given to them (test, retest) which was related to dental anatomy and pathology (number of teeth, cavities, halitosis), and dental hygiene tools and practices (brushes, floss, mouth wash, tongue scrapers). The children seemed to be receptive to learning while in school, and a specific educational session of dental hygiene and oral health seems to be the right approach to ensure children can identify dental hygiene tools and use them appropriately.

Abstract: Aim Long-term ecological research often integrates many research groups and subjects in one or few sites sampled systematically along the time. In the Amazon, there is a tradition of long-term research in terrestrial habitats, but this has been less common in floodplain lakes. This study systematically reviews 35 years of research (1988-2022) in Batata Lake, a clear water flood plain lake impacted by bauxite mining tailings for ten years (1979-1989) and discuss some research opportunities and challenges for the future. Methods The review covered 99 scientific reports (78 papers and 21 book chapters) comprising a large spectrum of data from snapshot observations and experiments to enduring quarterly observational and hypothesis-testing studies. Soil, sediments, and the water column were consistently sampled in natural and impacted areas. Results Research topics were quite diverse and covered biological communities from aquatic virus to igapó flooded forests and provided an overview of ecological processes such as primary and secondary production. Ecological variables monitored along the project were constrained by a strong seasonality of the flood pulse and the effect of sampling areas (natural and impacted), which was performed by very connected research groups. Conclusions Despite the extensive information, long-term ecosystem function trends are still incomplete.

Massimiliano Salati,1,2 Luigi Marcheselli,1 Carlo Messina,3 Valeria Merz,3,4 Marco Messina,5 Pietro Carotenuto,6 Francesco Caputo,1 Fabio Gelsomino,1 Andrea Spallanzani,1 Luca Reggiani Bonetti,7 Stefania Caramaschi,7 Gabriele Luppi,1 Massimo Dominici,1 Michele Ghidini8 1Division of Oncology, Department of Oncology and Hematology, University Hospital of Modena, Modena, Italy; 2PhD Program Clinical and Experimental Medicine, University of Modena and Reggio Emilia, Modena, Italy; 3Department of Medical Oncology, Santa Chiara Hospital, Trento, Italy; 4Digestive Molecular Clinical Oncology Research Unit, University of Verona, Verona, Italy; 5Oncology Unit, Fondazione San Raffaele-Giglio, Cefalu’, Palermo, Italy; 6Telethon Institute of Genetics and Medicine, Pozzuoli, 80078, Napoli, Italy; 7Pathology Section, University Hospital of Modena, Modena, Italy; 8Medical Oncology Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, ItalyCorrespondence: Massimiliano Salati, PhD Program Clinical and Experimental Medicine, University Hospital of Modena, Modena Cancer Centre, via del Pozzo 71, Modena, 41125, Italy, Tel +39/0594223808, Fax +39/0594222647, Email massimiliano.salati@unimore.itBackground: The role of second-line chemotherapy in advanced biliary cancers (ABCs) has only recently been established in phase III randomized trial and the optimal selection of patients most likely to benefit from it remains challenging.Methods: A cohort of 98 ABC treated second-line chemotherapy was used as a developmental dataset to identify covariates independently associated with overall survival (OS). Kaplan–Meier analysis was used to investigate the association between variables and OS and those retaining statistically significance were combined in a multiplexed score.Results: The following pretreatment variables were independently associated with OS: ECOG PS > 0, peritoneal disease, LDH > 430 UI/L, albumin < 3.5 gr/dL, gamma-GT > 100 UI/L, sodium < 140 mEq/L, absolute lymphocyte count < 1000/mmc, and PFS to first-line < 6 months. Based on these results, a scoring system was developed that identified three subgroups with statistically different OS: low-risk (mOS 18 months), intermediate-risk (mOS 9.4 months) and high-risk (mOS 2.9 months) (p < 0.001). The prognostic model was both internally and externally validated in a multicentre cohort of 120 ABCs.Conclusion: The Modena score is a multiplexed scoring system capable of accurately risk-stratified ABCs treated with second-line chemotherapy. Based on its reproducibility, usability and generalizability, it has the potential for assisting therapeutic decision-making in the clinic and risk-stratification in future trials.Graphical Abstract: Keywords: biliary tract cancer, chemotherapy, second-line, prognostic score, survival

Abstract Background Depression is a disabling and highly prevalent condition where genetic and epigenetic, such as DNA methylation (DNAm), differences contribute to disease risk. DNA methylation is influenced by genetic variation but the association between polygenic risk of depression and DNA methylation is unknown. Methods We investigated the association between polygenic risk scores (PRS) for depression and DNAm by conducting a methylome-wide association study (MWAS) in Generation Scotland (N = 8898, mean age = 49.8 years) with replication in the Lothian Birth Cohorts of 1921 and 1936 and adults in the Avon Longitudinal Study of Parents and Children (ALSPAC) (N combined = 2049, mean age = 79.1, 69.6 and 47.2 years, respectively). We also conducted a replication MWAS in the ALSPAC children (N = 423, mean age = 17.1 years). Gene ontology analysis was conducted for the cytosine-guanine dinucleotide (CpG) probes significantly associated with depression PRS, followed by Mendelian randomisation (MR) analysis to infer the causal relationship between depression and DNAm. Results Widespread associations (N CpG = 71, p Bonferroni < 0.05, p < 6.3 × 10−8) were found between PRS constructed using genetic risk variants for depression and DNAm in CpG probes that localised to genes involved in immune responses and neural development. The effect sizes for the significant associations were highly correlated between the discovery and replication samples in adults (r = 0.79) and in adolescents (r = 0.82). Gene Ontology analysis showed that significant CpG probes are enriched in immunological processes in the human leukocyte antigen system. Additional MWAS was conducted for each lead genetic risk variant. Over 47.9% of the independent genetic risk variants included in the PRS showed associations with DNAm in CpG probes located in both the same (cis) and distal (trans) locations to the genetic loci (p Bonferroni < 0.045). Subsequent MR analysis showed that there are a greater number of causal effects found from DNAm to depression than vice versa (DNAm to depression: p FDR ranged from 0.024 to 7.45 × 10−30; depression to DNAm: p FDR ranged from 0.028 to 0.003). Conclusions PRS for depression, especially those constructed from genome-wide significant genetic risk variants, showed methylome-wide differences associated with immune responses. Findings from MR analysis provided evidence for causal effect of DNAm to depression.

Altered maternal haemoglobin levels during pregnancy are associated with pre-clinical and clinical conditions affecting the fetus. Evidence from animal models suggests that these associations may be partially explained by differential DNA methylation in the newborn with possible long-term consequences. To test this in humans, we meta-analyzed the epigenome-wide associations of maternal haemoglobin levels during pregnancy with offspring DNA methylation in 3,967 newborn cord blood and 1,534 children and 1,962 adolescent whole-blood samples derived from 10 cohorts. DNA methylation was measured using Illumina Infinium Methylation 450K or MethylationEPIC arrays covering 450,000 and 850,000 methylation sites, respectively. There was no statistical support for the association of maternal haemoglobin levels with offspring DNA methylation either at individual methylation sites or clustered in regions. For most participants, maternal haemoglobin levels were within the normal range in the current study, whereas adverse perinatal outcomes often arise at the extremes. Thus, this study does not rule out the possibility that associations with offspring DNA methylation might be seen in studies with more extreme maternal haemoglobin levels.

Aromatic L-amino acid decarboxylase deficiency (AADCd) is a rare recessive metabolic disorder caused by pathogenic homozygous or compound heterozygous variants in the dopa decarboxylase (DDC) gene. Adeno-associated viral vector-mediated gene transfer of the human DDC gene injected into the putamen is available. The typical presentation is characterized by early-onset hypotonia, severe developmental delay, movement disorders, and dysautonomia. Recently, mild and even atypical phenotypes have been reported, increasing the diagnostic challenge. The aim of this multicentric study is to identify the prevalence of AADCd in a population of patients with phenotypic clusters characterized by neurodevelopmental disorders (developmental delay/intellectual disability, and/or autism) by 3-O-methyldopa (3-OMD) detection in dried blood spots (DBS). It is essential to identify AADCd promptly, especially within non-typical phenotypic clusters, because better results are obtained when therapy is quickly started in mild-moderate phenotypes. Between 2021 and 2023, 390 patients with non-specific phenotypes possibly associated with AADCd were tested; none resulted in a positive result. This result highlights that the population to be investigated for AADCd should have more defined clinical characteristics: association with common signs (hypotonia) and/or pathognomonic symptoms (oculogyric crisis and dysautonomia). It is necessary to continue to screen selected clusters for reaching diagnosis and improving long-term outcomes through treatment initiation. This underscores the role of newborn screening in identifying AADCd.

Background. Biobanks are vital research infrastructures aiming to collect, process, store, and distribute biological specimens along with associated data in an organized and governed manner. Exploiting diverse datasets produced by the biobanks and the downstream research from various sources and integrating bioinformatics and “omics” data has proven instrumental in advancing research such as cancer research. Biobanks offer different types of biological samples matched with rich datasets comprising clinicopathologic information. As digital pathology and artificial intelligence (AI) have entered the precision medicine arena, biobanks are progressively transitioning from mere biorepositories to integrated computational databanks. Consequently, the application of AI and machine learning on these biobank datasets holds huge potential to profoundly impact cancer research. Methods. In this paper, we explore how AI and machine learning can respond to the digital evolution of biobanks with flexibility, solutions, and effective services. We look at the different data that ranges from specimen-related data, including digital images, patient health records and downstream genetic/genomic data and resulting “Big Data” and the analytic approaches used for analysis. Results. These cutting-edge technologies can address the challenges faced by translational and clinical research, enhancing their capabilities in data management, analysis, and interpretation. By leveraging AI, biobanks can unlock valuable insights from their vast repositories, enabling the identification of novel biomarkers, prediction of treatment responses, and ultimately facilitating the development of personalized cancer therapies. Conclusions. The integration of biobanking with AI has the potential not only to expand the current understanding of cancer biology but also to pave the way for more precise, patient-centric healthcare strategies.

Massimiliano Salati,1,2 Francesco Caputo,1 Cinzia Baldessari,1 Pietro Carotenuto,3 Marco Messina,4 Stefania Caramaschi,5 Massimo Dominici,1 Luca Reggiani Bonetti5 1Department of Oncology and Hematology, University Hospital of Modena, Modena, Italy; 2PhD Program Clinical and Experimental Medicine, University of Modena and Reggio Emilia, Modena, Italy; 3Department of Genomics, Telethon Institute of Genetics and Medicine (TIGEM), Naples, Italy; 4Department of Oncology, Fondazione Istituto G. Giglio, Cefalu, Italy; 5Department of Medical and Surgical Sciences for Children and Adults, University of Modena and Reggio Emilia – AOU Policlinico of Modena, Modena, ItalyCorrespondence: Massimiliano SalatiDepartment of Oncology and Hematology, University Hospital of Modena, Via del Pozzo 71, Modena, 41125, ItalyTel +390594223808Fax +390594222647Email massimiliano.salati@unimore.itAbstract: Intrahepatic cholangiocarcinoma (iCCA) is an anatomically and biologically distinct entity with a rising incidence and a poor prognosis on conventional treatments. Surgery followed by adjuvant chemotherapy is a potentially curative option in resectable cases, while palliative-intent chemotherapy is the standard-of-care in the advanced setting. Technological advances through massive parallel sequencing have enabled a deeper understanding of disease biology with the identification of several druggable molecular vulnerabilities in nearly 50% of cases. Among them, gene fusions involving the fibroblast growth factor receptor 2 (FGFR2) are the most therapeutically exploited so far with a number of Phase II clinical trials investigating FGFR2 inhibitors showing unprecedented efficacy results in this molecular subgroup. Over the last year, these efforts have culminated in the US FDA-approval of pemigatinib and infigratinib, the first two oral selective FGFR2 targeted agents for previously treated, locally advanced or metastatic iCCA driven by FGFR2 fusion or rearrangements. While first-line Phase III trials are currently underway to test these targeted approach against standard-of-care chemotherapy, translational studies are trying to better understand primary and secondary resistance mechanisms in order to optimize FGFR2 blockade in iCCA. In this article, we extensively reviewed the current evidence on the biological rationale, as well as preclinical and clinical development of FGFR inhibitors in iCCA.Keywords: biliary cancer, cholangiocarcinoma, intrahepatic, FGFR2, targeted therapy, precision medicine

Considerado uma das expressões faciais mais complexas, o sorriso é produto da manifestação de diversos estados emocionais e apresenta diferenças sexuais significativas. O objetivo deste estudo foi comparar a frequência do sorriso entre homens e mulheres durante a fala, com base na observação dinâmica da exibição da arcada dentária superior. A amostra foi composta por 88 participantes (41 homens e 47 mulheres), que foram convidados a descrever imagens previamente selecionadas, sendo filmados durante esse procedimento. A partir das gravações obtidas, foi realizada a aferição da frequência de exibição das arcadas dentárias superiores em recurso de câmera lenta (4.0x slow) e a comparação por meio do Test t de Student. Os resultados apontam frequência média maior entre as mulheres (M=23; DP=8,22), em comparação aos homens (M=12; DP=6,76), com diferença estatisticamente significativa (t = 6,44; p

In this era of great uncertainty, imagining the future may be challenging, especially for young people. In science education, the interest in future-oriented education is now emerging, research needs, however, to keep eyes on youngsters’ future perceptions and on the development of a future literacy. In this article, starting from a sample of individual students’ narratives about their future daily life in 2040, we aim to delineate which ways of grappling with the future can be observed in the essays and which methodological tools are suited to operationalize their identification and characterization. The analysis led to the definition of “polarization” and “complexification” attitudes that represent the ways in which the students’ narratives are positioned with respect to a bunch of dichotomies: personal–societal, functional–aesthetics oriented, good–bad, natural–artificial, and certain–uncertain. Moreover, with this study, we provide a contribution to the methodological reflection that deals with the collection and analysis of data, when students’ future perceptions need to be investigated. Discussing the limits of the current data collection tool, we introduce the design of a SenseMaker® questionnaire which contributed to feeding a collaboration with #OurFutures project, recently launched by the European Commission to collect future narratives all around Europe.

Nowadays, in the case of suspected prostate cancer (PCa), tissue needle biopsy remains the benchmark for diagnosis despite its invasiveness and poor tolerability, as serum prostate-specific antigen (PSA) is limited by low specificity. The aim of this proteomic study was to identify new diagnostic biomarkers in urine, an easily and non-invasively available sample, able to selectively discriminate cancer from benign prostatic hyperplasia (BPH), evaluating whether the presence of inflammation may be a confounding parameter. The analysis was performed by two-dimensional gel electrophoresis (2-DE), mass spectrometry (LC-MS/MS) and Enzyme-Linked Immunosorbent Assay (ELISA) on urine samples from PCa and BPH patients, divided into subgroups based on the presence or absence of inflammation. Significant quantitative and qualitative differences were found in the urinary proteomic profile of PCa and BPH groups. Of the nine differentially expressed proteins, only five can properly be considered potential biomarkers of PCa able to discriminate the two diseases, as they were not affected by the inflammatory process. Therefore, the proteomic research of novel and reliable urinary biomarkers of PCa should be conducted considering the presence of inflammation as a realistic interfering element, as it could hinder the detection of important protein targets.

Abstract The Neotropical zone stands out for having the greatest richness of amphibians in the world. About 625 species of anurans are known on Atlantic Forest. The southeastern mountainous regions of Brazil called Serra do Mar and Serra da Mantiqueira, are very important areas for the diversity of anurans in the country because they shelter remaining strata of the Atlantic Forest that have several endemic species. The present study aims to expand the knowledge about the Serra da Mantiqueira anurans, specifically from the Rio Preto and Rio Grande upper basins. The study area comprised 10 sample centers. We realized 38 campaigns, lasting two days each. During this period, we used active search as visual and auditory cues. The passive search was comprised of pitfall traps. Bioacoustic analyses were used to determine the cryptic species. The sufficiency of the sampling effort was estimated through the accumulation curve using Bootstrap and Jackknife-1 as estimators. During the study 55 species were found, 40 of them in the basin of the Rio Preto, and 44 in the basin of the Rio Grande. Twenty-nine species were found in both areas. The Hylidae family was predominant, followed by Leptodactylidae. In addition to species of the Atlantic Forest, the place houses typical components of the Cerrado biome and altitudinal swamps with unexpected sympatries. This inventory expands the area of occurrence of Scinax duartei, a species considered threatened. Although adjacent to the oldest national park in Brazil, the composition of anuran species of this area was unknown until then.

Lunar phases remarkably influence the circadian cycle of living beings. Early amphibian studies date back to the 1960s, but only recently has more research been conducted in this field. Much still needs to be understood to establish the behavioral pattern of this group according to the synodic cycle. In the present study, we sought to determine (i) whether the vocalization activity was influenced by the lunar phases and (ii) whether the influence was species-specific or affects the community with equal intensity. We expected a great diversity of behaviors and adaptations. Rayleigh's test was used to verify whether the sample differs significantly from the null hypothesis; Rao's test was used to check sample size sufficiency; and the Kiviat diagram was used to evaluate the activity of the species in relation to the complete synodic cycle. We have observed 1691 individuals of 37 species over 882 d. The lunar cycle influenced 78 % of the species, with 32 % preferring the lower-albedo phases. The activity pattern of each species was established. These results suggest that the lunar phases influence the vocalization activity of most species. Therefore, there is a general pattern of activity related to the synodic cycles; however, the specificities still need to be better understood.

Tracking a person’s activities is relevant in a variety of contexts, from health and group-specific assessments, such as elderly care, to fitness tracking and human–computer interaction. In a clinical context, sensor-based activity tracking could help monitor patients’ progress or deterioration during their hospitalization time. However, during routine hospital care, devices could face displacements in their position and orientation caused by incorrect device application, patients’ physical peculiarities, or patients’ day-to-day free movement. These aspects can significantly reduce algorithms’ performances. In this work, we investigated how shifts in orientation could impact Human Activity Recognition (HAR) classification. To reach this purpose, we propose an HAR model based on a single three-axis accelerometer that can be located anywhere on the participant’s trunk, capable of recognizing activities from multiple movement patterns, and, thanks to data augmentation, can deal with device displacement. Developed models were trained and validated using acceleration measurements acquired in fifteen participants, and tested on twenty-four participants, of which twenty were from a different study protocol for external validation. The obtained results highlight the impact of changes in device orientation on a HAR algorithm and the potential of simple wearable sensor data augmentation for tackling this challenge. When applying small rotations (0.85±0.11 against a baseline model f1-score equal to 0.49±0.12.

Antimicrobial resistance related to the misuse of antibiotics is a well-known current topic. Their excessive use in several fields has led to enormous selective pressure on pathogenic and commensal bacteria, driving the evolution of antimicrobial resistance genes with severe impacts on human health. Among all the possible strategies, a viable one could be the development of medical features that employ essential oils (EOs), complex natural mixtures extracted from different plant organs, rich in organic compounds showing, among others, antiseptic properties. In this work, green extracted essential oil of Thymus vulgaris was included in cyclic oligosaccharides cyclodextrins (CD) and prepared in the form of tablets. This essential oil has been shown to have a strong transversal efficacy both as an antifungal and as an antibacterial agent. Its inclusion allows its effective use because an extension of the exposure time to the active compounds is obtained and, therefore, a more marked efficacy, especially against biofilm-producing microorganisms such as P. aeruginosa and S. aureus, was registered. The efficacy of the tablet against candidiasis opens their possible use as a chewable tablet against oral candidiasis and as a vaginal tablet against vaginal candidiasis. Moreover, the registered wide efficacy is even more positive since the proposed approach can be defined as effective, safe, and green. In fact, the natural mixture of the essential oil is produced by the steam current method; therefore, the manufacturer employs substances that are not harmful, with very low production and management costs.

Background: Stress experienced by mothers during pregnancy can have both immediate and long-term effects on child development, potentially mediated by breastfeeding. Aim: Using a UK birth cohort study, we asked how maternal stress relates to breastfeeding and consequences for growth and puberty onset. Subjects and methods: We analysed data from the Avon Longitudinal Study of Parents and Children, collected via questionnaires and clinic visits (N: 698–8,506). We used reports of prenatal anxiety, breastfeeding, early growth and age at menarche or first voice change. Confounding by maternal age, parity, smoking, education and body mass index (BMI) was considered. Results: Mothers with higher levels of reported anxiety were less likely to breastfeed (Odds ratio (OR): 0.83, 95% confidence interval (CI): 0.71, 0.97). Breastfed infants had slower growth before weaning, although growth differences were unclear thereafter. Being breastfed for more than six months was associated with later puberty onset in females (2.76 months later than non-breastfed; CI: 0.9, 4.63), although the association was attenuated by confounders and BMI (1.51 months, CI: −0.38, 3.40). No association between breastfeeding and puberty onset in males was found. Conclusion: Our studies fit results shown previously, and we consider these in light of evolutionary life history theory while discussing key challenges in such an approach.

Temporomandibular disorders (TMDs) are a condition which has multifactorial etiology. The most acknowledged method to classify TMDs is the diagnostic criteria (DC) introduced firstly by Dworkin. This protocol considers different aspects that are not only biological, but even psychosocial. Diagnosis is often based on anamnesis, physical examination and instrumental diagnosis. TMDs are classified as intra-articular and/or extra-articular disorders. Common signs and symptoms include jaw pain and dysfunction, earache, headache, facial pain, limitation to opening the mouth, ear pain and temporomandibular joint (TMJ) noises. This study regards two kind of clinicians that started in the last years to be more involved in the treatment of TMDs: osteopaths (OOs) and physiotherapists (PTs). The purpose is to analyze their attitude and clinical approach on patients affected by TMDs. Four hundred therapists answered an anonymous questionnaire regarding TMJ and TMDs. OOs showed greater knowledges on TMDs and TMJ and, the therapists with both qualifications seemed to be most confident in treating patients with TMDs. In conclusion this study highlights OOs and all the clinicians with this qualification, have a higher confidence in treating patients with TMD than the others. Dentists and orthodontists, according to this study, should co-work with OOs and PTs, because they are the specialists more requested by them than other kinds of specialists.