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Abstract We present an innovative approach that combines a unique real‐time data set documenting absolute dissolution rates of a calcite crystal with an original reactive transport model tailored to the analysis of the dynamics of nano‐scale mineral dissolution processes. Providing robust and physically based fundamental understanding on the kinetics of mineral dissolution is at the core of various geo‐engineered strategies to quantify chemical weathering patterns across diverse spatial and temporal scales. Here, we rely on data obtained through Atomic Force Microscopy. We provide a mathematical framework to describe three‐dimensional dynamics of the mineral surface topography, and show convergence of the numerical approach for vertical grid spacing down to sub‐nm resolution.

Abstract Chemical weathering associated with dissolution/precipitation at interfaces between minerals and flowing fluids is key for the evolution of geologic systems, including groundwater contamination and storage capacity. Relying on Atomic Force Microscopy (AFM) yields reaction rates at nanoscale resolutions. Challenges limiting our ability to quantify heterogeneity associated with these processes include establishing reliable platforms allowing AFM imaging of real‐time and in situ absolute material fluxes across mineral surfaces under continuous flow conditions to complement typically acquired surface topography images. We provide an experimental workflow and heterogeneous absolute rates at the nanoscale across the surface of a calcite crystal under dissolution. These high‐quality experimental observations are then interpreted through a stochastic approach. The latter is geared to embed diverse kinetic modes driving the degree of spatial heterogeneity of the reaction and corresponding to different mechanistic processes documented across the crystal surface.

Summary: The largest multi-gene family in metazoans is the family of olfactory receptor (OR) genes. Human ORs are organized in clusters over most chromosomes and seem to include >0.1% the human genome. Because 369 out of 856 OR genes are mapped on chromosome 11 (HSA11), we sought to determine whether they mediate structural rearrangements involving this chromosome. To this aim, we analyzed 220 specimens collected during diagnostic procedures involving structural rearrangements of chromosome 11. A total of 222 chromosomal abnormalities were included, consisting of inversions, deletions, translocations, duplications, and one insertion, detected by conventional chromosome analysis and/or fluorescence in situ hybridization (FISH) and array comparative genomic hybridization (array-CGH). We verified by bioinformatics and statistical approaches the occurrence of breakpoints in cytobands with or without OR genes. We found that OR genes are not involved in chromosome 11 reciprocal translocations, suggesting that different DNA motifs and mechanisms based on homology or non-homology recombination can cause chromosome 11 structural alterations. We also considered the proximity between the chromosomal territories of chromosome 11 and its partner chromosomes involved in the translocations by using the deposited Hi-C data concerning the possible occurrence of chromosome interactions. Interestingly, most of the breakpoints are located in regions highly involved in chromosome interactions. Further studies should be carried out to confirm the potential role of chromosome territories’ proximity in promoting genome structural variation, so fundamental in our understanding of the molecular basis of medical genetics and evolutionary genetics.

Background: Postmenopausal dyspareunia and vulvar pain are common complaints, affecting about 60% of women within a few years after hormone levels begin to decline (such as estrogen and androgen). Atrophic changes mainly located in the vulvar vestibule and vulnerability to vulvovaginal infections in postmenopause could be predisposing factors to the development of vulvar burning/pain and introital dyspareunia (vestibulodynia secondary to atrophy). Tibolone is the most effective and safe alternative for treating menopausal symptoms. The role of Lactobacilli and lactoferrin shows its effectiveness in the treatment of vaginal microbiota dysbiosis. The aim of the present study was to assess the efficacy of the combination of tibolone and an oral-specific Lactobacilli mixture in combination with bovine lactoferrin as synergistic therapy for the treatment of vestibulodynia related to atrophy. Methods: In this study, we included 35 postmenopausal women with at least 1 year of amenorrhea, affected by vulvar burning/pain and introital dyspareunia. All participants received treatment with open-label, oral Tibolone 2.5 mg and Lactobacilli mixture (5 × 109 CFU per capsule) in combination with bovine lactoferrin (Respecta®). Each product was taken once daily for 90 days. Results: After 90 d of therapy with TIB+ Respecta®, in 30 women that completed the treatment, there was a statistically significant decrease from the baseline in the mean of the Visual Analog Scale for vulvar burning/pain and a reduction in scores in the pain evaluation test. Conclusions: This study provides evidence that the combination of TIB+ Respecta® was effective in reducing symptoms related to vestibular pain and hypersensitivity in a postmenopausal setting.

Iron is an essential nutrient for growth among all branches of life, but while iron is among the most common elements, bioavailable iron is a relatively scarce nutrient. Since iron is fundamental for several biological processes, iron deficiency can be deleterious. On the other hand, excess iron may lead to cell and tissue damage. Consequently, iron balance is strictly regulated. As iron excretion is not physiologically controlled, systemic iron homeostasis is maintained at the level of absorption, which is mainly influenced by the amount of iron stores and the level of erythropoietic activity, the major iron consumer. Here, we outline recent advances that increased our understanding of the molecular aspects of iron absorption. Moreover, we examine the impact of these recent insights on dietary strategies for maintaining iron balance.

Die Coronakrise hat in den vergangenen Jahren ein erbittertes Ringen um Freiheit hervorgerufen. Dabei wird Freiheit von den Impf-, Masken- und Lockdown-Gegner:innen vor allem als Freiheit im individuellen Sinn verstanden. Der vorliegende Beitrag dekonstruiert eine solche Idee der Freiheit und setzt ihr ein Paradigma der Solidarität entgegen. Mithilfe von Charles Darwin und Karl Marx entlarvt er das Freiheitsverständnis der No-Vaxund No-Green-Pass-Bewegung als narzisstisch-adoleszente Haltung, die zu keiner echten Verantwortungsübernahme für das eigene Handeln fähig ist. Analysiert werden die Rhetoriken der freiheitspredigenden Demagog: innen ebenso wie die verschiedenen Formen von Ängsten, die seit Ausbruch der Pandemie die einzelnen Subjekte und die Gesellschaften als Ganze in ihrem Vermögen und ihren Zukunftsperspektiven in Frage stellen. Was wir morgen sein werden, ist angesichts der gegenwärtigen Krise noch nicht ausgemacht, dass ein Wiedergewinnen der Freiheit nur im Übernehmen der Grenze gelingt, jedoch sicher.

Background: Vestibulodynia (VBD) is the most common form of vulvodynia. Because VBD is a pain disorder, transcutaneous electrical nerve stimulation (TENS) can be used as treatment. This study aims to evaluate the effects of two-parameter combinations (frequency and pulse duration) of TENS in reducing pain intensity and dyspareunia in VBD. Methods: A randomized, double-blind, controlled trial was conducted to study the effect of two different electrical stimulation treatment regimens on women with VBD receiving domiciliary TENS. Outcomes were the mean change from baseline at 60 and 120 days of burning/pain and dyspareunia (VAS), Vulvar Pain Functional Questionnaire (V-Q), Female Sexual Functioning Index (FSFI) and vaginal electromyography measurements. Results: A total of 78 subjects, 39 in each group, completed the trial. Patients in Groups 1 and 2 received a mean of 46.9 and 48.4 TENS sessions. By day 120, there was a 38.2% reduction in the burning/pain and a 52.1% reduction in the dyspareunia VAS scores in Group 1, as compared to 21.3% (p = 0.003) and 23.1% in Group 2 (p = 0.01), respectively. FSFI, V-Q, and muscle-strength measures also improved but were not statistically significant. Conclusions: Our findings showed the potential of TENS in the treatment of VBD.

The 5q deletion syndrome is a relatively rare condition caused by the monoallelic interstitial deletion of the long arm of chromosome 5. Patients described in literature usually present variable dysmorphic features, behavioral disturbance, and intellectual disability (ID); moreover, the involvement of the APC gene (5q22.2) in the deletion predisposes them to tumoral syndromes (Familial Adenomatous Polyposis and Gardner syndrome). Although the development of gastrointestinal tract malignancies has been extensively described, the genetic causes underlying neurologic manifestations have never been investigated. In this study, we described a new patient with a 19.85 Mb interstitial deletion identified by array-CGH and compared the deletions and the phenotypes reported in other patients already described in the literature and the Decipher database. Overlapping deletions allowed us to highlight a common region in 5q22.1q23.1, identifying KCNN2 (5q22.3) as the most likely candidate gene contributing to the neurologic phenotype.

Petrified ears is an uncommon clinical entity. It describes auricular cartilage hardening, due usually to ectopic calcification or, less commonly, ossification. The most common causes are frostbite and mechanical trauma. However, endocrinopathies have also been reported to cause ectopic calcium deposition through an unknown mechanism. Addison’s disease is the systemic disease most frequently associated, but the exact pathogenesis remains unclear. Patients are usually asymptomatic, and the diagnosis is made incidentally when rigid helices are noted on palpation and can be confirmed by radiological imaging. A biopsy can also help to differentiate between calcification and ossification. The presence of this condition may be a useful clinical sign, which in some cases precedes the development of endocrinopathies by many years. We report on a case, and we review the current literature.

Effective options in the quiescent, scantily inflammatory phase of localized scleroderma (morphea) are lacking. A cohort study in patients with histologically confirmed fibroatrophic morphea explored the therapeutic value of the anti-dystrophic A2A adenosine agonist polydeoxyribonucleotide (PDRN, one daily 5.625 mg/3 mL ampoule for 90 days with a three-month follow-up). Primary efficacy endpoints: Localized Scleroderma Cutaneous Assessment Tool mLoSSI and mLoSDI subscores for disease activity and damage in eighteen areas; Physicians Global Assessment for Activity (PGA-A) and Damage (PGA-D) VAS scores; skin echography. Secondary efficacy endpoints: mLoSSI, mLoSDI, PGA-A, PGA-D, and morphea areas (photographs) over time; Dermatology Life Quality Index (DLQI); skin biopsy scores and induration over time. Twenty-five patients enrolled; 20 completed the follow-up period. Highly significant improvements at the end of the 3-month treatment period: mLoSSI–73.7%, mLoSDI–43.9%, PGA-A–60.4%, PGA-D–40.3%, with further improvements at follow-up visit for all disease activity and damage indexes. Overall, the outcomes suggest that a daily PDRN ampoule intramuscularly for 90 days reduces disease activity and damage rapidly and significantly in quiescent, modestly inflammatory morphea with few currently therapeutic options. The COVID-19 pandemic and lockdowns caused difficulties in enrollment, and some patients were lost to follow-up. Due to low final enrollment, the study outcomes may have only an exploratory value, yet they appear impressive. The anti-dystrophic potential of the PDRN A2A adenosine agonist deserves further in-depth exploration.

Late-onset focal dermal elastosis is a rare cutaneous condition classified within the disorders of increased dermal elastic tissue. It is characterized clinically by multiple papules with predilection for the neck and other flexures, without systemic alterations, and histologically by focally increased elastic fibers in the reticular dermis. Several elastic tissue disorders share a similar clinical presentation in the skin. Distinction of late-onset focal dermal elastosis and other pseudoxanthoma elasticum mimickers from pseudoxanthoma elasticum is critical, as they are not associated to systemic lesions. We report here on a case of late-onset focal dermal elastosis and review the scientific literature on this unusual condition.

The text takes up almost literally, except for some inevitable formal changes, the content of the Lectio magistralis held by the author on June 2019 in Reggio Emilia at the church of San Filippo Neri in Reggio Emilia. The article examines the relationship between Claudio Parmiggiani’s work and the dimension of spirituality: “That which is spiritual of Parmiggiani - the author writes - is a spiritual rooted in the immanence of life, in the mystery of life.” In the article several works by the artist are taken into consideration: starting from the High Altar of the Cathedral of Reggio Emilia in 2011 going back to the Delocations of 1970.

Primary liver cancer (PLC) is one of the most devastating cancers worldwide. Extensive phenotypical and functional heterogeneity is a cardinal hallmark of cancer, including PLC, and is related to the cancer stem cell (CSC) concept. CSCs are responsible for tumor growth, progression, relapse and resistance to conventional therapies. Metabolic reprogramming represents an emerging hallmark of cancer. Cancer cells, including CSCs, are very plastic and possess the dynamic ability to constantly shift between different metabolic states depending on various intrinsic and extrinsic stimuli, therefore amplifying the complexity of understanding tumor heterogeneity. Besides the well-known Warburg effect, several other metabolic pathways including lipids and iron metabolism are altered in PLC. An increasing number of studies supports the role of the surrounding tumor microenvironment (TME) in the metabolic control of liver CSCs. In this review, we discuss the complex metabolic rewiring affecting liver cancer cells and, in particular, liver CSCs. Moreover, we highlight the role of TME cellular and noncellular components in regulating liver CSC metabolic plasticity. Deciphering the specific mechanisms regulating liver CSC–TME metabolic interplay could be very helpful with respect to the development of more effective and innovative combinatorial therapies for PLC treatment.

Der Kapitalismus gilt in seinem klassischen Verständnis nicht nur als Produkt rationaler Wirtschaftlichkeit, sondern scheint heute paradigmatisch die liberale Freiheit der Moderne zu verbürgen. Dem kapitalistischen Subjekt ist es erstmals möglich, ohne Einschränkung aufgrund äußerer Zwänge und ohne Verbote durch religiöse oder moralische Systeme, frei seine Bedürfnisse zu stillen und sein Wollen zu verfolgen. Der vorliegende Beitrag dekonstruiert diese Idee der Freiheit durch die Interpretation des psychoanalytischen Diskurses des Kapitalisten von Jacques Lacan. Er entlarvt den Kapitalismus selbst als totalitäre Ideologie, die anstatt eines gemeinschaftlichen „Herrn“ den Imperativ des Genießens ins Zentrum rückt. Analysiert werden die listigen Mechanismen der Warenzirkulation, die nicht nur mit der Idee einer ständig beschleunigten Akkumulation und Konsumption neue Pathologien befördern, sondern die Beziehungen des Menschen zu seiner Umwelt, den anderen und zu sich selbst tiefgreifend transformieren. Demgegenüber steht der Verweis auf den Diskurs der Liebe, der zur Verwirklichung von Freiheit die negativen Momente von Mangel und Unterbrechung wahrt.

Since December 2019, a novel coronavirus, known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been rapidly spreading across the world, leading to the declared pandemic of COVID-19 [...]

Iron is necessary for essential processes in every cell of the body, but the erythropoietic compartment is a privileged iron consumer. In fact, as a necessary component of hemoglobin and myoglobin, iron assures oxygen distribution; therefore, a considerable amount of iron is required daily for hemoglobin synthesis and erythroid cell proliferation. Therefore, a tight link exists between iron metabolism and erythropoiesis. The liver-derived hormone hepcidin, which controls iron homeostasis via its interaction with the iron exporter ferroportin, coordinates erythropoietic activity and iron homeostasis. When erythropoiesis is enhanced, iron availability to the erythron is mainly ensured by inhibiting hepcidin expression, thereby increasing ferroportin-mediated iron export from both duodenal absorptive cells and reticuloendothelial cells that process old and/or damaged red blood cells. Erythroferrone, a factor produced and secreted by erythroid precursors in response to erythropoietin, has been identified and characterized as a suppressor of hepcidin synthesis to allow iron mobilization and facilitate erythropoiesis.

Ring chromosome 20 [r(20)] syndrome is a rare condition characterized by a non-supernumerary ring chromosome 20 replacing a normal chromosome 20. It is commonly seen in a mosaic state and is diagnosed by means of karyotyping. r(20) syndrome is characterized by a recognizable epileptic phenotype with typical EEG pattern, intellectual disability manifesting after seizure onset in otherwise normally developing children, and behavioral changes. Despite the distinctive phenotype, many patients still lack a diagnosis—especially in the genomic era—and the pathomechanisms of ring formation are poorly understood. In this review we address the genetic and clinical aspects of r(20) syndrome, and discuss differential diagnoses and overlapping phenotypes, providing the reader with useful tools for clinical and laboratory practice. We also discuss the current issues in understanding the mechanisms through which ring 20 chromosome causes the typical manifestations, and present unpublished data about methylation studies. Ultimately, we explore future perspectives of r(20) research. Our intended audience is clinical and laboratory geneticists, child and adult neurologists, and genetic counselors.

Interstitial deletions of the long arm of chromosome 12 are rare, with a dozen patients carrying a deletion in 12q21 being reported. Recently a critical region (CR) has been delimited and could be responsible for the more commonly described clinical features, such as developmental delay/intellectual disability, congenital genitourinary and brain malformations. Other, less frequent, clinical signs do not seem to be correlated to the proposed CR. We present seven new patients harboring non-recurrent deletions ranging from 1 to 18.5 Mb differentially scattered across 12q21. Alongside more common clinical signs, some patients have rarer features such as heart defects, hearing loss, hypotonia and dysmorphisms. The correlation of haploinsufficiency of genes outside the CR to specific signs contributes to our knowledge of the effect of the deletion of this gene-poor region of chromosome 12q. This work underlines the still important role of copy number variations in the diagnostic setting of syndromic patients and the positive reflection on management and family genetic counseling.

Improvements in microarray-based comparative genomic hybridization technology have allowed for high-resolution detection of genome wide copy number alterations, leading to a better definition of rearrangements and supporting the study of pathogenesis mechanisms. In this study, we focused our attention on chromosome 8p. We report 12 cases of 8p rearrangements, analyzed by molecular karyotype, evidencing a continuum of fragility that involves the entire short arm. The breakpoints seem more concentrated in three intervals: one at the telomeric end, the others at 8p23.1, close to the beta-defensin gene cluster and olfactory receptor low-copy repeats. Hypothetical mechanisms for all cases are described. Our data extend the cohort of published patients with 8p aberrations and highlight the need to pay special attention to these sequences due to the risk of formation of new chromosomal aberrations with pathological effects.

Neste artigo apresentamos os resultados de uma investigação qualitativa, em que o objetivo foi investigar, por meio dos designs de enunciados de problemas, para a (re)formulação e resolução com o uso de tecnologias digitais, quais aspectos matemáticos, metodológicos, tecnológicos e relativos à abordagem de temas de relevância social, que se apresentam em tais processos. Para tanto, foram produzidos três enunciados de problemas, com o uso de planilhas eletrônicas, do Microsoft Office Excel, a partir do tema Situações na Escola, para apresentar situações problemáticas abertas e fictícias e proporcionar, por meio das (re)formulações e resoluções, o ensino e a aprendizagem da resolução de Expressões Numéricas. Conforme os enunciados, concluímos que esses podem favorecer a Educação Matemática Crítica e/ou Financeira, por meio de informações, dados numéricos, imagens, frases incompletas e questionamentos e da simulação, experimentação, entre outros aspectos.

Abstract is missing (Short communication)

The erythropoietin (Epo)-erythroferrone (ERFE)-hepcidin axis coordinates erythropoiesis and iron homeostasis. While mouse studies have established that Epo-induced ERFE production represses hepcidin synthesis by inhibiting hepatic BMP/SMAD signaling, evidence for the role of ERFE in humans is limited. To investigate the role of ERFE as a physiological erythroid regulator in humans, we conducted two studies: first, 24 males received six injections of saline (placebo), recombinant Epo (rhEpo) 20 UI kg-1 (micro-dose) or 50 UI kg-1 (low-dose). Second, we quantified ERFE in 22 subjects exposed to high altitude (3800 m) for 15 hours. In the first study, total hemoglobin mass (Hbmass) increased after low- but not after micro-dose injections, when compared to placebo. Serum ERFE levels were enhanced by rhEpo, remaining higher than after placebo for 48 (micro-dose) or 72 hours (low-dose) post-injections. Conversely, hepcidin levels decreased when Epo and ERFE arose, before any changes in serum iron parameters occurred. In the second study, serum Epo and ERFE increased at high altitude. The present results demonstrate that in healthy humans ERFE responds to slightly increased Epo levels not associated with Hbmass expansion and down-regulates hepcidin in an apparently iron-independent way. Notably, ERFE flags micro-dose Epo, thus holding promise as novel anti-doping biomarker.

Abstract Background Chromosomal microarray analysis (CMA) is nowadays widely used in the diagnostic path of patients with clinical phenotypes. However, there is no ascertained evidence to date on how to assemble single/combined clinical categories of developmental phenotypic findings to improve the array‐based detection rate. Methods The Italian Society of Human Genetics coordinated a retrospective study which included CMA results of 5,110 Italian patients referred to 17 genetics laboratories for variable combined clinical phenotypes. Results Non‐polymorphic copy number variants (CNVs) were identified in 1512 patients (30%) and 615 (32%) present in 552 patients (11%) were classified as pathogenic. CNVs were analysed according to type, size, inheritance pattern, distribution among chromosomes, and association to known syndromes. In addition, the evaluation of the detection rate of clinical subgroups of patients allowed to associate dysmorphisms and/or congenital malformations combined with any other single clinical sign to an increased detection rate, whereas non‐syndromic neurodevelopmental signs and non‐syndromic congenital malformations to a decreased detection rate. Conclusions Our retrospective study resulted in confirming the high detection rate of CMA and indicated new clinical markers useful to optimize their inclusion in the diagnostic and rehabilitative path of patients with developmental phenotypes.

Abstract Background Mutations occurring in the orthodenticle homeobox 2 gene (OTX2) are responsible for a rare genetic syndrome, characterized mainly by microphthalmia/anophthalmia associated with extra-ocular defects such as brain malformations, pituitary abnormalities, short stature and intellectual disability. To date, the spectrum of radiological features observed in patients with OTX2 mutations has never been summarized. Case presentation In this report, we describe a case of large microdeletion encompassing OTX2 but not BMP4 presenting with a syndromic anophthalmia with corpus callosum hypoplasia, pituitary gland hypoplasia and vermian hypoplasia. Conclusion Our case report provides an illustration of the neuroradiological spectrum in a case of OTX2-related syndrome and the first radiological evidence of 14q22.2q23.1 deletion associated posterior cranial fossa anomalies.

Macrophages perform a variety of different biological functions and are known for their essential role in the immune response. In this context, a principal function is phagocytic clearance of pathogens, apoptotic and senescent cells. However, the major targets of homeostatic phagocytosis by macrophages are old/damaged red blood cells. As such, macrophages play a crucial role in iron trafficking, as they recycle the large quantity of iron obtained by hemoglobin degradation. They also seem particularly adapted to handle and store amounts of iron that would be toxic to other cell types. Here, we examine the specific and peculiar iron metabolism of macrophages.

The presence of thousands of repetitive sequences makes the centromere a fragile region subject to breakage. In this study we collected 31 cases of rearrangements of chromosome 18, of which 16 involved an acrocentric chromosome, during genetic screening done in three centers. We noticed a significant enrichment of reciprocal translocations between the centromere of chromosome 18 and the centromeric or pericentromeric regions of the acrocentrics. We describe five cases with translocation between chromosome 18 and an acrocentric chromosome, and one case involving the common telomere regions of chromosomes 18p and 22p. In addition, we bring evidence to support the hypothesis that chromosome 18 preferentially recombines with acrocentrics: (i) the presence on 18p11.21 of segmental duplications highly homologous to acrocentrics, that can justify a NAHR mechanism; (ii) the observation by 2D-FISH of the behavior of the centromeric regions of 18 respect to the centromeric regions of acrocentrics in the nuclei of normal subjects; (iii) the contact analysis among these regions on published Hi-C data from the human lymphoblastoid cell line (GM12878).

Neste trabalho apresentamos os resultados obtidos com uma proposta de Educação Financeira Escolar, que envolveu o planejamento, desenvolvimento e implementação de um enunciado de problema aberto, com o uso de uma planilha do Microsoft Office Excel, e a proposta desse problema a alunos de um sexto ano do Ensino Fundamental. O objetivo pretendido era propiciar as ações de (re)formulação e resolução de problemas, com o uso de recursos tecnológicos digitais, para promover a aprendizagem de conhecimentos relativos às Expressões Numéricas e à Matemática Financeira. No processo de (re)formulação e resolução, os alunos puderam trabalhar em duplas, realizar cálculos mentais e por escrito, representar os valores na planilha eletrônica e analisá-los, conforme as suas decisões e empregando ou aprendendo os conhecimentos matemáticos almejados.

Cancer stem cells (CSC) which have been identified in several tumors, including liver cancer, represent a particular subpopulation of tumor cells characterized by properties similar to those of adult stem cells. Importantly, CSC are resistant to standard therapies, thereby leading to metastatic dissemination and tumor relapse. Given the increasing evidence that iron homeostasis is deregulated in cancer, here we describe the iron homeostasis alterations in cancer cells, particularly in liver CSC. We also discuss two paradoxically opposite iron manipulation-strategies for tumor therapy based either on iron chelation or iron overload-mediated oxidant production leading to ferroptosis. A better understanding of iron metabolism modifications occurring in hepatic tumors and particularly in liver CSC cells may offer new therapeutic options for this cancer, which is characterized by increasing incidence and unfavorable prognosis.

Iron recycling by macrophages is essential for erythropoiesis, but may also be relevant for iron redistribution to neighboring cells at the local tissue level. Using mice with iron retention in macrophages due to targeted inactivation of the iron exporter ferroportin, we investigated the role of macrophage iron release in hair follicle cycling and wound healing, a complex process leading to major clinical problems, if impaired. Genetic deletion of ferroportin in macrophages resulted in iron deficiency and decreased proliferation in epithelial cells, which consequently impaired hair follicle growth and caused transient alopecia. Hair loss was not related to systemic iron deficiency or anemia, thus indicating the necessity of local iron release from macrophages. Inactivation of macrophage ferroportin also led to delayed skin wound healing with defective granulation tissue formation and diminished fibroplasia. Iron retention in macrophages had no impact on the inflammatory processes accompanying wound healing, but affected stromal cell proliferation, blood and lymphatic vessel formation, and fibrogenesis. Our findings reveal that iron/ferroportin plays a largely underestimated role in macrophage trophic function in skin homeostasis and repair.

Pendred syndrome (PS) is an autosomal recessive disorder due to mutations in the SLC26A4 gene (chr7q22. 3) and characterized by sensorineural hearing loss and variable thyroid phenotype. Silver-Russell syndrome (SRS) is a heterogeneous imprinting disorder including severe intrauterine and postnatal growth retardation, and dysmorphic features. Maternal uniparental disomy of either the whole chromosome 7 (upd(7)mat) or 7q (upd(7q)mat) is one of the multiple mechanisms impacting the expression of imprinted genes in SRS, and is associated with milder clinical features. Here, we report genetic and clinical characterization of a female child with PS, postnatal growth retardation, and minor dysmorphic features. A gross homozygous deletion of SLC26A4 exons 17-20 was suspected by Sanger sequencing and then confirmed by array-CGH. Moreover, an insertion of about 1 kb of the CCDC126 gene (7p15.3), which does not appear to be clinically relevant, was detected. The possible occurrence of a balanced rearrangement between 7p and 7q was excluded. The absence of the deletion in the father led to the investigation of upd, and microsatellite segregation analysis revealed a segmental 7q (upd(7q)mat), leading to SLC26A4 homozygosity and responsible for both PS and SRS-like traits. The proband matched 3 out of 6 major SRS criteria. In conclusion, this is the first report of uniparental isodisomy encompassing almost the whole long arm of chromosome 7 resulting in PS and SRS-like features. Whereas, the inner ear phenotype of PS is typical, the clinical features suggestive of SRS might have been overlooked.

To date only five patients with 8p23.2-pter microdeletions manifesting a mild-to-moderate cognitive impairment and/or developmental delay, dysmorphisms and neurobehavioral issues were reported. The smallest microdeletion described by Wu in 2010 suggested a critical region (CR) of 2.1 Mb including several genes, out of which FBXO25, DLGAP2, CLN8, ARHGEF10 and MYOM2 are the main candidates. Here we present seven additional patients with 8p23.2-pter microdeletions, ranging from 71.79 kb to 4.55 Mb. The review of five previously reported and nine Decipher patients confirmed the association of the CR with a variable clinical phenotype characterized by intellectual disability/developmental delay, including language and speech delay and/or motor impairment, behavioral anomalies, autism spectrum disorder, dysmorphisms, microcephaly, fingers/toes anomalies and epilepsy. Genotype analysis allowed to narrow down the 8p23.3 candidate region which includes only DLGAP2, CLN8 and ARHGEF10 genes, accounting for the main signs of the broad clinical phenotype associated to 8p23.2-pter microdeletions. This region is more restricted compared to the previously proposed CR. Overall, our data favor the hypothesis that DLGAP2 is the actual strongest candidate for neurodevelopmental/behavioral phenotypes. Additional patients will be necessary to validate the pathogenic role of DLGAP2 and better define how the two contiguous genes, ARHGEF10 and CLN8, might contribute to the clinical phenotype.

Body iron levels are regulated by hepcidin, a liver-derived peptide that exerts its function by controlling the presence of ferroportin (FPN), the sole cellular iron exporter, on the cell surface. Hepcidin binding leads to FPN internalization and degradation, thereby inhibiting iron release, in particular from iron-absorbing duodenal cells and macrophages involved in iron recycling. Disruption in this regulatory mechanism results in a variety of disorders associated with iron-deficiency or overload. In recent years, increasing evidence has emerged to indicate that, in addition to its role in systemic iron metabolism, FPN may play an important function in local iron control, such that its dysregulation may lead to tissue damage despite unaltered systemic iron homeostasis. In this review, we focus on recent discoveries to discuss the role of FPN-mediated iron export in the microenvironment under both physiological and pathological conditions.

Maternal uniparental disomy of chromosome 7 is present in 5–10% of patients with Silver-Russell syndrome (SRS), and duplication of 7p including GRB10 (Growth Factor Receptor-Bound Protein 10), an imprinted gene that affects pre-and postnatal growth retardation, has been associated with the SRS phenotype. Here, we report on a 17 year old girl referred to array-CGH analysis for short stature, psychomotor delay, and relative macrocephaly. Array-CGH analysis showed two copy number variants (CNVs): a ~12.7 Mb gain in 7p13-p11.2, involving GRB10 and an ~9 Mb loss in 7q11.21-q11.23. FISH experiments performed on the proband’s mother showed a chromosome 7 pericentric inversion that might have mediated the complex rearrangement harbored by the daughter. Indeed, we found that segmental duplications, of which chromosome 7 is highly enriched, mapped at the breakpoints of both the mother’s inversion and the daughter’s CNVs. We postulate that pairing of highly homologous sequences might have perturbed the correct meiotic chromosome segregation, leading to unbalanced outcomes and acting as the putative meiotic mechanism that was causative of the proband’s rearrangement. Comparison of the girl’s phenotype to those of patients with similar CNVs supports the presence of 7p in a locus associated with features of SRS syndrome.

This article aims to analyse the COVID-19 coping strategies adopted by municipal health managers in two regions. A mixed method study of the sequential explanatory type was carried out with municipal health managers and primary care coordinators. The quantitative stage was developed with the application of an instrument to 42 managers to identify coping actions and associations with demographic and epidemiological data of COVID-19 in the municipalities. The results aimed at the definition of 15 participants and the collection of data in the qualitative stage, enabling approximation of the meta inferences of the study. Of the actions implemented, there were immediate actions to monitor cases, organize new care flows and encourage the population to adopt nonpharmacological measures. Regional articulation was the device that allowed for expansion and municipal autonomy for testing, reducing contamination and deaths among citizens. Municipal coping strategies that focused on the surveillance of cases and expansion of testing showed positive outcomes in terms of the number of infections and deaths from COVID-19. [ABSTRACT FROM AUTHOR]

Satellited non-acrocentric autosomal chromosomes (ps–qs-chromosomes) are the result of an interchange between sub- or telomeric regions of autosomes and the p arm of acrocentrics. The sequence homology at the rearrangement breakpoints appears to be, among others, the most frequent mechanism generating these variant chromosomes. The unbalanced carriers of this type of translocation may or may not display phenotypic abnormalities. With the aim to understand the causative mechanism, we revised all the ps–qs-chromosomes identified in five medical genetics laboratories, which used the same procedures for karyotype analysis, reporting 24 unrelated cases involving eight chromosomes. In conclusion, we observed three different scenarios: true translocation, benign variant and complex rearrangement. The detection of translocation partners is essential to evaluate possible euchromatic unbalances and to infer their effect on phenotype. Moreover, we emphasize the importance to perform both, molecular and conventional cytogenetics methods, to better understand the behavior of our genome.

Cholangiocarcinoma (CCA) is a deadly tumor without an effective therapy. Unique metabolic and bioenergetics features are important hallmarks of tumor cells. Metabolic plasticity allows cancer cells to survive in poor nutrient environments and maximize cell growth by sustaining survival, proliferation, and metastasis. In recent years, an increasing number of studies have shown that specific signaling networks contribute to malignant tumor onset by reprogramming metabolic traits. Several evidences demonstrate that numerous metabolic mediators represent key-players of CCA progression by regulating many signaling pathways. Besides the well-known Warburg effect, several other different pathways involving carbohydrates, proteins, lipids, and nucleic acids metabolism are altered in CCA. The goal of this review is to highlight the main metabolic processes involved in the cholangio-carcinogeneis that might be considered as potential novel druggable candidates for this disease.

Il volume contiene alcuni esiti delle ricerche condotte nell’ambito del progetto PRIN 2012 I cattolici e il cinema in Italia tra gli anni ’40 e gli anni ’70, coordinato dall’Università degli Studi di Milano, capitalizzando riflessioni emerse nel corso di una serie di convegni che si sono succeduti dal 2014 al 2016. The issue contains some outcomes of the research project PRIN 2012 The Catholics and Cinema in Italy between the 40s and the 70s, coordinated by University of Milan, capitalizing reflections shared during a series of congresses between 2014 and 2016.

Il contributo si propone di indagare il profondo legame di Diego Fabbri con l’opera di Dostoevskij che influenza la saggistica, la drammaturgia e l’impegno istituzionale dello sceneggiatore forlivese presso il Centro Cattolico Cinematografico (CCC). In particolare, si mira a definire il contributo personale di Fabbri negli sceneggiati Rai I fratelli Karamazov (1969) e I demoni (1972), in cui l’autore porta sullo schermo anni di studio e riflessione sull’opera dostoevskiana. Per meglio comprendere la relazione che corre tra la sceneggiatura, la produzione e la regia di Sandro Bolchi si analizza infine nel dettaglio il caso de I fratelli Karamazov. The essay aims to investigate Diego Fabbri’s strong connection to Dostoyevsky’s work, which influenced the writer’s theatre, theoretical reflections and institutional work at the Centro Cattolico Cinematografico. In particular, the article aims to define Fabbri’s contribution to the RAI television productions "The Brothers Karamazov" (1969) and "The Demons" (1972), which represent many years of the author’s reflections on Dostoyevsky’s novels. It analyses The Brothers Karamazov in detail, in order to highlight the relationship between the screenplay, its production, and Sandro Bolchi’s direction.

These pages are from Massimo Recalcati’s book Il Mistero delle cose. Nove ritratti di artista (Feltrinelli, Milano 2016). They are dedicated to Claudio Parmiggiani, whose work is read through the approach of the Lacanian psychoanalysis, starting from some artist’s works of art and texts.

Il presente contributo è volto a presentare scavi e ricerche dell’Università degli Studi di Milano alla Civita di Tarquinia, iniziati nel 1982 e sempre forieri di scoperte scientificamente rilevanti sul piano internazionale. Il “Progetto Tarquinia” si avvale di numerose collaborazioni strette con Università italiane e internazionali e altri enti. Questo approccio interdisciplinare arricchisce il percorso formativo degli studenti che vi partecipano.

Over the last decade, increasing evidence has reinforced the key role of metabolic reprogramming in macrophage activation. In addition to supporting the specific immune response of different subsets of macrophages, intracellular metabolic pathways also directly control the specialized effector functions of immune cells. In this context, iron metabolism has been recognized as an important component of macrophage plasticity. Since macrophages control the availability of this essential metal, changes in the expression of genes coding for the major proteins of iron metabolism may result in different iron availability for the macrophage itself and for other cells in the microenvironment. In this review, we discuss how macrophage iron can also play a role in immunometabolism.