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Genetic conditions, traumatic injuries, carious lesions and periodontal diseases are all responsible for dental pathologies. The current clinical approaches are based on the substitution of damaged dental tissues with inert materials, which, however, do not ensure full physiological recovery of the teeth. Different populations of dental mesenchymal stem cells have been isolated from dental tissues and several attempts have already been made at using these stem cells for the regeneration of human dental tissues. Despite encouraging progresses, dental regenerative therapies are very far from any clinical applications. This is tightly connected with the absence of proper platforms that would model and faithfully mimic human dental tissues in their complexity. Therefore, in the last decades, many efforts have been dedicated for the development of innovative systems capable of emulating human tooth physiology in vitro. This review focuses on the use of in vitro culture systems, such as bioreactors and “organ-on-a-chip” microfluidic devices, for the modelling of human dental tissues and their potential use for dental regeneration and drug testing.

Stem cells are essential for tissue homeostasis and regeneration throughout the lifespan of multicellular rganisms. The decline in stem cell function during advanced age is associated with a reduced regenerative potential of tissues that leads to an increased frequency of diseases. Age-related changes also occur in the dental pulp tissue that represents a reliable model tissue, with high regenerative capability, for studying senescence mechanisms. However, little information is available concerning the effects of ageing on dental stem-cell function. In this mini-review, recent data on how the molecular and functional alterations that accumulate in stem cell populations during ageing result in modifications of dental pulp physiology are discussed. Changes that accumulate during ageing such as how reduction of pulp chamber volume, decreased vascular supply and modifications to the stem cell niches affect stem cell functions and, therefore, dental pulp regenerative potential in response to various stressful agents. Dental pulp cells from aged individuals are still metabolically active and secrete pro-inflammatory and matrix-degrading molecules. Furthermore, miRNAs and exosomes derived from dental pulp stem cells constitute an attractive source of nanovesicles for the treatment of age-related dental pathologies. Further investigation of the epigenetic alterations in dental pulp stem cells, accumulating during ageing, might reveal crucial information for potential stem cell-based therapeutic approaches in the elderly.

Stem cell-based mediated therapies represent very promising approaches for tissue regeneration and are already applied with success in clinics. These therapeutic approaches consist of the in vitro manipulation of stem cells and their consequent administration to patients as living and dynamic biological agents. Nevertheless, the deregulation of stem cells function might result in the generation of pathologies such as tumours or accelerated senescence. Moreover, different stem cells sources are needed for regeneration of specific tissues. It is thus fundamental to understand the mechanisms regulating the physiology of stem cells. Microfluidic technology can be used to mimic in vivo scenarios and allow the study of stem cell physiology at both single cell and whole stem cell niche levels.This review focuses on the potential sources of stem and progenitor cells for orofacial regeneration and the use of microfluidic technologies for the study of stem cells behaviour and stem cell niches, in the light of regenerative medicine.

Staphylococcus aureus is the most common cause of skin and soft tissue infections (SSTIs) with Methicillin-Resistant S. aureus (MRSA) strains being a major contributor in both community and hospital settings. S. aureus relies on metabolic diversity and a large repertoire of virulence factors to cause disease. This includes α-hemolysin (Hla), an integral player in tissue damage found in various models, including SSTIs. Previously, we identified a role for the Spx adapter protein, YjbH, in the regulation of several virulence factors and as an inhibitor of pathogenesis in a sepsis model. In this study, we found that YjbH is critical for tissue damage during SSTI, and its absence leads to decreased proinflammatory chemokines and cytokines in the skin. We identified no contribution of YjbI, encoded on the same transcript as YjbH. Using a combination of reporters and quantitative hemolysis assays, we demonstrated that YjbH impacts Hla expression and activity both in vitro and in vivo. Additionally, expression of Hla from a non-native promoter reversed the tissue damage phenotype of the ΔyjbIH mutant. Lastly, we identified reduced Agr activity as the likely cause for reduced Hla production in the ΔyjbH mutant. This work continues to define the importance of YjbH in the pathogenesis of S. aureus infection as well as identify a new pathway important for Hla production.

This case study explores the utilization of distributed fiber optic sensors (DFOS) in wooden foundation piles, for assessing and monitoring the stress distribution along their length. Three spruce and three pine foundation piles instrumented with DFOS were driven into the soil in a testing field in Amsterdam and axially loaded in compression. Since DFOS provided strain information, calculating the stress distribution in the piles required knowledge of their stiffness properties, which inherently vary from the head to the tip. Consequently, the piles were extracted and their overall wet dynamic elastic modulus (Ec,0,dyn,wet) was determined through frequency response measurements. Subsequently, the piles were segmented, transported to the TU Delft Laboratory and subjected to mechanical testing. For each segment, the mechanical properties were determined and their variability along the pile was studied, in particular for the static modulus of elasticity (Ec,0,stat,wet). This enabled a comprehensive assessment of the actual in-situ stress distribution (Δσactual,stat and Δσactual,dyn) along the length of the piles, calculated with DFOS strains and the pile stiffness (Ec,0,stat,wet and Ec,0,stat,dyn). Given the novelty of the DFOS application to timber piles, a validation of the accuracy was conducted on 3 pile segments equipped with DFOS. These segments underwent laboratory compression testing, allowing for a direct comparison between DFOS strain readings and strains measured with linear potentiometers attached to the pile segments. The results revealed good accuracy of DFOS in controlled lab conditions, with a maximum stress deviation of 0.65 MPa. Since the testing field featured a 6-meter-deep predrilled layer, where negligible shaft friction was mobilized, the no-friction stress (Δσno-friction) approximately aligned with Δσactual,stat on the piles. At pile tips, the maximum applied 300–350 kN compressive load (i.e. Δσno-friction = 20–26 MPa), resulted in Δσactual,stat = 4–7 MPa, highlighting shaft friction effect. The calculated Δσactual,dyn with a single Ec,0,stat,dyn for the whole pile, led to 3 MPa stress overestimation at pile tip. Although this calculation is conservative, the detailed knowledge of the variation of stiffness properties along the pile would result in a more efficient structural use.

Abstract The potassium chloride cotransporter KCC2 is crucial for Cl- extrusion from mature neurons and thus key to hyperpolarizing inhibition. Auditory brainstem circuits contain well-understood inhibitory projections and provide a potent model to study the regulation of synaptic inhibition. Two peculiarities of the auditory brainstem are (i) posttranslational activation of KCC2 during development and (ii) extremely negative reversal potentials in specific circuits. To investigate the role of the potent phospho-site serine 937 therein, we generated a KCC2 Thr934Ala/Ser937Asp double mutation, in which Ser937 is replaced by aspartate mimicking the phosphorylated state, and the neighbouring Thr934 arrested in the dephosphorylated state. This double mutant showed a twofold increased transport activity in HEK293 cells, raising the hypothesis that auditory brainstem neurons show lower [Cl−]i. and increased glycinergic inhibition. This was tested in a mouse model carrying the same KCC2 Thr934Ala/Ser937Asp mutation by the use of the CRISPR/Cas9 technology. Homozygous KCC2 Thr934Ala/Ser937Asp mice showed an earlier developmental onset of hyperpolarisation in the auditory brainstem. Mature neurons displayed stronger glycinergic inhibition due to hyperpolarized ECl−. These data demonstrate that phospho-regulation of KCC2 Ser937 is a potent way to interfere with the excitation-inhibition balance in neural circuits.

Introduction. A postsurgical ciliated cyst (PSCC) is an epithelial cyst that usually develops in the maxilla, although in rare cases, it can affect the mandible or other facial bones. The typical age of diagnosis is 40-50 years, with no gender prevalence, and the mean cyst development occurs approximately 10-15 years following a surgical or traumatic event. Some epithelial respiratory cells can be trapped into the bone tissue during maxillary surgical procedures or maxillary fractures. The pathogenetic mechanism can be attributed to an inflammatory process that stimulates epithelial proliferation, leading to cyst expansion caused by osmotic pressure difference. Methods. This study presents case series involving three surgical ciliated cysts located in the left maxilla, affecting two female patients (aged 49 and 55 years) and one male patient (aged 39 years). In all three cases, symptoms such as pain or swelling were mild and not consistently present. Two cases showed cyst development 10 and 15 years after implant placement, while one case was not associated with any surgical or traumatic event. CT scan identified well-defined unilocular lesions in the maxillary bone in each patient. Results. Histopathological examination of the surgical specimens confirmed the suspected diagnosis of a PSCC of maxilla. The cystic walls consisted of fibrous connective tissue with chronic inflammatory infiltrate, lined exclusively by a thin layer of ciliated pseudostratified columnar epithelium. In the third patient, it was not possible to rule out an unusual radicular cyst. Conclusions. Although PSCCs are not commonly encountered in daily practice, clinicians should consider this possibility including it in the differential diagnosis of odontogenic jaw cysts and benign jaw tumors, particularly in patients who have undergone previous surgeries in the maxillary area.

In the heterogenous category of digital healthcare technologies, software with a medical purpose - i.e. therapy, diagnosis, prevention of a disease or monitoring of adherence to treatment - is expected have a strong impact. Indeed, it conforms to models of development and market access which are typical of information technology and unusual for healthcare. Avoiding any regulatory uncertainty is crucial for companies and competent authorities. In the European Union (EU), software with a medical purpose qualifies as a medical device, for which a strong regulatory framework is already in place. However, for patient-managed digital medical devices (pDMDs), i.e. software with a medical purpose intended to be used directly by patients, some open issues are still on the ground. These issues arise both at the EU level, related to risk-based classification and clinical evaluation, and the national level, related to prescription and reimbursement policies. The aim of this article is to analyse the classification and regulation of pDMDs in the EU, exploring the need of additional definitions, legislation or guidance.

Introduction: Orbital pathologies requiring surgery are traditionally treated by open approach with different techniques depending on the lesion location. Recently, minimally invasive endoscopic approaches, such as the Endoscopic Endonasal Approach (EEA) and the Endoscopic Transorbital Approach (ETA) have been introduced in orbital surgery. Research question: The purpose of this study is to report the combined experience of the Neurosurgical and Ear-Nose-Throat (ENT) Units in the endoscopic approach of orbital pathologies. Material and methods: We retrospectively retrieved data on patients treated at our Institution between 2016 and 2021 with endoscopic approach for orbital pathologies. The Clavien-Dindo classification and the Scar Cosmesis Assessment and Rating (SCAR) Scale have been used to assess complications and cosmetic outcomes. Results: 39 patients met the inclusion criteria. EEA (15 patients) or ETA (20 patients) were chosen to approach the lesions. In three cases we used a combination of endoscopic and anterior orbitotomy and in one patient a combination of EEA + ETA. The type of procedure performed was orbital biopsy (9 cases), orbital decompression (6 cases), subtotal resection of the lesion (STR) (8 cases) and total resection of the lesion (GTR) (16 cases). The more frequent postoperative complications were diplopia (5.1%, with 1 case of permanent diplopia), trigeminal paraesthesia and dysesthesia (5.1%), palpebral edema (17.9%), periorbital ecchymosis (7.7%). Mean follow up time was 21 months (range 2–63 months). Discussion and conclusion: Endoscopic approaches to orbital compartments provide minimally invasive access to every orbital compartment with low complications rate and good cosmetic outcome.

The classical model of tissue renewal posits that small numbers of quiescent stem cells (SCs) give rise to proliferating transit-amplifying cells before terminal differentiation. However, many organs house pools of SCs with proliferative and differentiation potentials that diverge from this template. Resolving SC identity and organization is therefore central to understanding tissue renewal. Here, using a combination of single-cell RNA sequencing (scRNA-seq), mouse genetics and tissue injury approaches, we uncover cellular hierarchies and mechanisms that underlie the maintenance and repair of the continuously growing mouse incisor. Our results reveal that, during homeostasis, a group of actively cycling epithelial progenitors generates enamel-producing ameloblasts and adjacent layers of non-ameloblast cells. After injury, tissue repair was achieved through transient increases in progenitor-cell proliferation and through direct conversion of Notch1-expressing cells to ameloblasts. We elucidate epithelial SC identity, position and function, providing a mechanistic basis for the homeostasis and repair of a fast-turnover ectodermal appendage.

Abstract The Notch signaling pathway is a fundamental regulator of cell fate determination in homeostasis and regeneration. In this work, we aimed to determine how Notch signaling mediates the interactions between perivascular stem cells and their niches in human dental mesenchymal tissues, both in homeostatic and regenerative conditions. By single cell RNA sequencing analysis, we showed that perivascular cells across the dental pulp and periodontal human tissues all express NOTCH3, and that these cells are important for the response to traumatic injuries in vivo in a transgenic mouse model. We further showed that the behavior of perivascular NOTCH3‐expressing stem cells could be modulated by cellular and molecular cues deriving from their microenvironments. Taken together, the present studies, reinforced by single‐cell analysis, reveal the pivotal importance of Notch signaling in the crosstalk between perivascular stem cells and their niches in tissue homeostasis and regeneration.

Abstract Hereditary haemorrhagic telangiectasia (HHT) is a multisystemic vascular dysplasia inherited as an autosomal dominant trait. Approximately 10 % of patients have cerebral vascular malformations, a proportion being cerebral arteriovenous malformations (AVMs) and fistulae that may lead to potentially devastating consequences in case of rupture. On the other hand, detection and treatment related-risks are not negligible, and immediate. While successful treatment can be undertaken in individual cases, current data do not support the treatment of unruptured AVMs, which also present a low risk of bleeding in HHT patients. Screening for these AVMs is therefore controversial. Structured discussions, distinctions of different cerebrovascular abnormalities commonly grouped into an “AVM” bracket, and clear guidance by neurosurgical and neurointerventional radiology colleagues enabled the European Reference Network for Rare Vascular Disorders (VASCERN-HHT) to develop the following agreed Position Statement on cerebral screening: 1) First, we emphasise that neurological symptoms suggestive of cerebral AVMs in HHT patients should be investigated as in general neurological and emergency care practice. Similarly, if an AVM is found accidentally, management approaches should rely on expert discussions on a case-by-case basis and individual risk-benefit evaluation of all therapeutic possibilities for a specific lesion. 2) The current evidence base does not favour the treatment of unruptured cerebral AVMs, and therefore cannot be used to support widespread screening of asymptomatic HHT patients. 3) Individual situations encompass a wide range of personal, cultural and clinical states. In order to enable informed patient choice, and avoid conflicting advice, particularly arising from non-neurovascular interpretations of the evidence base, we suggest that all HHT patients should have the opportunity to discuss knowingly brain screening issues with their healthcare provider. 4) Any screening discussions in asymptomatic individuals should be preceded by informed pre-test review of the latest evidence regarding preventative and therapeutic efficacies of any interventions. The possibility of harm due to detection of, or intervention on, a vascular malformation that would not have necessarily caused any consequence in later life should be stated explicitly. We consider this nuanced Position Statement provides a helpful, evidence-based framework for informed discussions between healthcare providers and patients in an emotionally charged area.

Summary: Teeth and the surrounding periodontal tissues are affected by many pathologies that compromise their integrity and significantly affect life quality. The study of the main dental tissues, the dental pulp and periodontium, is made arduous by their close association with highly mineralized tissues (dentin, cementum, and alveolar bone). Here we describe a protocol to isolate all cells composing human dental pulp and periodontium for single-cell RNA sequencing analysis.For complete details on the use and execution of this protocol, please refer to Pagella et al. (2021).

Sensory systems have to be malleable to context-dependent modulations occurring over different time scales, in order to serve their evolutionary function of informing about the external world while also eliciting survival-promoting behaviors. Stress is a major context-dependent signal that can have fast and delayed effects on sensory systems, especially on the auditory system. Urocortin 3 (UCN3) is a member of the corticotropin-releasing factor family. As a neuropeptide, UCN3 regulates synaptic activity much faster than the classic steroid hormones of the hypothalamic-pituitary-adrenal axis. Moreover, due to the lack of synaptic re-uptake mechanisms, UCN3 can have more long-lasting and far-reaching effects. To date, a modest number of studies have reported the presence of UCN3 or its receptor CRFR2 in the auditory system, particularly in the cochlea and the superior olivary complex, and have highlighted the importance of this stress neuropeptide for protecting auditory function. However, a comprehensive map of all neurons synthesizing UCN3 or CRFR2 within the auditory pathway is lacking. Here, we utilize two reporter mouse lines to elucidate the expression patterns of UCN3 and CRFR2 in the auditory system. Additional immunolabelling enables further characterization of the neurons that synthesize UCN3 or CRFR2. Surprisingly, our results indicate that within the auditory system, UCN3 is expressed predominantly in principal cells, whereas CRFR2 expression is strongest in non-principal, presumably multisensory, cell types. Based on the presence or absence of overlap between UCN3 and CRFR2 labeling, our data suggest unusual modes of neuromodulation by UCN3, involving volume transmission and autocrine signaling.

Abstract Background Hereditary hemorrhagic telangiectasia (HHT) is a rare vascular dysplasia resulting in visceral arteriovenous malformations and smaller mucocutaneous telangiectasia. Most patients experience recurrent nosebleeds and become anemic without iron supplementation. However, thousands may require anticoagulation for conditions such as venous thromboembolism and/or atrial fibrillation. Over decades, tolerance data has been published for almost 200 HHT-affected users of warfarin and heparins, but there are no published data for the newer direct oral anticoagulants (DOACs) in HHT. Methods To provide such data, a retrospective audit was conducted across the eight HHT centres of the European Reference Network for Rare Multisystemic Vascular Diseases (VASCERN), in Denmark, France, Germany, Italy, the Netherlands and the UK. Results Although HHT Centres had not specifically recommended the use of DOACs, 32 treatment episodes had been initiated by other clinicians in 28 patients reviewed at the Centres, at median age 65 years (range 30–84). Indications were for atrial fibrillation (16 treatment episodes) and venous thromboembolism (16 episodes). The 32 treatment episodes used Apixaban (n = 15), Rivaroxaban (n = 14), and Dabigatran (n = 3). HHT nosebleeds increased in severity in 24/32 treatment episodes (75%), leading to treatment discontinuation in 11 (34.4%). Treatment discontinuation was required for 4/15 (26.7%) Apixaban episodes and 7/14 (50%) Rivaroxaban episodes. By a 4 point scale of increasing severity, there was a trend for Rivaroxaban to be associated with a greater bleeding risk both including and excluding patients who had used more than one agent (age-adjusted coefficients 0.61 (95% confidence intervals 0.11, 1.20) and 0.74 (95% confidence intervals 0.12, 1.36) respectively. Associations were maintained after adjustment for gender and treatment indication. Extreme hemorrhagic responses, worse than anything experienced previously, with individual nosebleeds lasting hours requiring hospital admissions, blood transfusions and in all cases treatment discontinuation, occurred in 5/14 (35.7%) Rivaroxaban episodes compared to 3/15 (20%) Apixaban episodes and published rates of ~ 5% for warfarin and heparin. Conclusions Currently, conventional heparin and warfarin remain first choice anticoagulants in HHT. If newer anticoagulants are considered, although study numbers are small, at this stage Apixaban appears to be associated with lesser bleeding risk than Rivaroxaban.

Exophiala dermatitidis is a dematiaceous fungus with yeast-like and hyphal growth states that may cause cutaneous and visceral infections. Recently, E. dermatitidis has been linked to central line associated blood stream infection (CLABSI), probably due to its ability to produce extracellular polysaccharides and grow as biofilm. We describe an E. dermatitidis CLASBI. The strain was identified by morphological and molecular methods. E. dermatitidis CLASBI is highly uncommon, but seems to be increasing. Keywords: Exophiala dermatitidis, Melanized fungi, Black yeast, Fungemia, Wangiella dermatitidis

Abstract Background Hereditary hemorrhagic telangiectasia (HHT) is a multisystemic inherited vascular dysplasia that leads to nosebleeds and visceral arteriovenous malformations (AVMs). Anti-angiogenic drugs thalidomide and bevacizumab have been increasingly used off-label with variable results. The HHT working group within the ERN for Rare Multisystemic Vascular Diseases (VASCERN), developed a questionnaire-based retrospective capture of adverse events (AEs) classified using the Common Terminology Criteria for Adverse Events. Results Sixty-nine HHT patients received bevacizumab, 37 (50.6%) for high output cardiac failure/hepatic AVMs, and 32 (49.4%) for bleeding; the 69 patients received bevacizumab for a mean of 11 months for a total of 63.8 person/years treatment. 67 received thalidomide, all for epistaxis and/or gastrointestinal bleeding; they received thalidomide for a mean of 13.4 months/patient for a total of 75 person/years treatment. AEs were reported in 58 patients, 33 with bevacizumab, 37 with thalidomide. 32 grade 1–3 AEs related to bevacizumab were reported with an average incidence rate of 50 per 100 person-years. 34 grade 1–3 AEs related to thalidomide were reported with an average incidence rate of 45.3 per 100 person-years. Bevacizumab AEs were more common in females (27 AEs in 46 women) than males (6 in 23, p

Our understanding of food security in sub-Saharan Africa (SSA) has been hampered by limitations in the temporal and spatial representativeness of data. Food balance sheets provide scalable estimates of per capita food availability, but fail to represent food access, stability and their causal linkages. In contrast, rural household surveys represent detailed conditions for one or multiple points in time, but are influenced by survey timing and are often limited in geographical coverage. This study draws on a large sample of rural land-holding households in SSA (n = 6,353) to identify household level food access deficiencies and to understand the associations with rural livelihoods and food sourcing behavior throughout the year. Food access deficiencies were identified using food security of access and diet diversity indicators. Dietary diversity and channel of access (farm or purchased) were enumerated for the “flush” and “lean” periods and food security of access was enumerated for the lean period only - making the results of this study independent of survey timing. As many as 39% of households were classified as severely food insecure (in terms of food access) and as many as 49% of households were likely to be deficient in micronutrients in the lean period. Vulnerability to food insecurity and micronutrient deficiencies differed by household composition, agricultural livelihood characteristics and agro-ecological zone. Dairy, fruit and vitamin A-rich produce were predominantly accessed through the farm channel. Households with a livestock component to their farm had a lower prevalence of severe food insecurity and higher diet diversity scores. These findings have implications for the development of nutrition-sensitive and nutrition-specific interventions. Interventions need to be tailored to agro-ecological zone, household composition, scale of operation and production mix. Increasing income will not necessarily result in improved diet diversity or healthy dietary choices. Interventions focused on income generation should monitor and promote crop and livestock production diversity and provide nutrition education.

Solar-induced chlorophyll fluorescence (SIF) is increasingly known as an effective proxy for plant photosynthesis, and therefore, has great potential in monitoring gross primary production (GPP). However, the relationship between SIF and GPP remains highly uncertain across space and time. Here, we analyzed the SIF (reconstructed, SIFc)–GPP relationships and their spatiotemporal variability, using GPP estimates from FLUXNET2015 and two spatiotemporally contiguous SIFc datasets (CSIF and GOSIF). The results showed that SIFc had significant positive correlations with GPP at the spatiotemporal scales investigated (p < 0.001). The generally linear SIFc–GPP relationships were substantially affected by spatial and temporal scales and SIFc datasets. The GPP/SIFc slope of the evergreen needleleaf forest (ENF) biome was significantly higher than the slopes of several other biomes (p < 0.05), while the other 11 biomes showed no significant differences in the GPP/SIFc slope between each other (p > 0.05). Therefore, we propose a two-slope scheme to differentiate ENF from non-ENF biome and synopsize spatiotemporal variability of the GPP/SIFc slope. The relative biases were 7.14% and 11.06% in the estimated cumulative GPP across all EC towers, respectively, for GOSIF and CSIF using a two-slope scheme. The significantly higher GPP/SIFc slopes of the ENF biome in the two-slope scheme are intriguing and deserve further study. In addition, there was still considerable dispersion in the comparisons of CSIF/GOSIF and GPP at both site and biome levels, calling for discriminatory analysis backed by higher spatial resolution to systematically address issues related to landscape heterogeneity and mismatch between SIFc pixel and the footprints of flux towers and their impacts on the SIF–GPP relationship.

Abstract Nerve growth factor (NGF) is a key regulator of the development and differentiation of neuronal and non-neuronal cells. In the present study we examined the distribution of NGF and its low and high-affinity receptors, p75NTR and TrkA respectively, in permanent human teeth under normal and pathological conditions. In intact functional teeth, NGF, p75NTR and TrkA are weakly expressed in dental pulp fibroblasts and odontoblasts that are responsible for dentine formation, while the NGF and p75NTR molecules are strongly expressed in nerve fibres innervating the dental pulp. In carious and injured teeth NGF and TrkA expression is upregulated in a selective manner in odontoblasts surrounding the injury sites, indicating a link between NGF signalling and dental tissue repair events. Accordingly, NGF and TrkA expression is strongly upregulated in cultured primary human dental mesenchymal cells during their differentiation into odontoblasts. Targeted release of NGF in cultured human tooth slices induced extensive axonal growth and migration of Schwann cells towards the NGF administration site. These results show that NGF signalling is strongly linked to pathological and regenerative processes in human teeth and suggest a potential role for this neurotrophic molecule in pulp regeneration.

Tiziano Mannoni osservava come fosse frequente trovare date incise sui portali delle case di abitazione delle zone alpine e appenniniche, quasi si trattasse di una tradizione specifica dei paesi di montagna. Non sappiamo se e in quale misura tale affermazione corrisponda al vero, ma non vi è dubbio che in molti abitati di montagna la tradizione di scolpire nella pietra la data della costruzione sia assai diffusa. Il catalogo informatico delle aperture redatto da Mannoni e da altri membri dell’Istituto di Storia della Cultura Materiale a partire dagli anni ‘80 del secolo scorso permette di tracciare una prima mappa di tale fenomeno che, seppure non sistematica e non esaustiva, fornisce alcuni dati quantitativi e spunti di riflessione. L’articolo non ha la pretesa di spiegare le ragioni sociali e culturali che hanno indotto molte popolazioni a lasciare una traccia materiale della propria storia, ma intende proporre all’attenzione dei lettori questa interessante tradizione e fornire alcune ipotesi di lavoro. Tiziano Mannoni observed how frequently dates were engraved on the doorways and windows (normally made by stone) of the houses built in the Alps and in the Apennines mountains. In his opinion, this tradition was specific of the mountains region. We don’t know whether and to what extent this statement can be generalised, but it cannot be denied that in several mountainous areas the tradition of engraving the construction date in stone is extremely common. Thanks to the digital catalogue of apertures compiled by Tiziano Mannoni and by other members of the Institute for the History of Material Culture (ISCUM) since the 1980s, it is possible to outline a map of this phenomenon, which provides interesting and thought provoking quantitative data, even if it is not yet systematic and exhaustive. The present article does not seek to explain the social and cultural reasons that led many populations to leave a material trace of their history, but it aims to draw the reader’s attention to this interesting tradition and to propose some reflection about it.

Ameloblastomas are locally invasive and aggressive odontogenic tumors treated via surgical resection, which results in facial deformity and significant morbidity. Few studies have addressed the cellular and molecular events of ameloblastoma onset and progression, thus hampering the development of non-invasive therapeutic approaches. Tumorigenesis is driven by a plethora of factors, among which innervation has been long neglected. Recent findings have shown that innervation directly promotes tumor progression. On this basis, we investigated the molecular characteristics and neurotrophic properties of human ameloblastomas. Our results showed that ameloblastomas express dental epithelial stem cell markers, as well as components of the Notch signaling pathway, indicating persistence of stemness. We demonstrated that ameloblastomas express classical stem cell markers, exhibit stem cell potential, and form spheres. These tumors express also molecules of the Notch signaling pathway, fundamental for stem cells and their fate. Additionally, we showed that ameloblastomas express the neurotrophic factors NGF and BDNF, as well as their receptors TRKA, TRKB, and P75/NGFR, which are responsible for their innervation by trigeminal axons in vivo. In vitro studies using microfluidic devices showed that ameloblastoma cells attract and form connections with these nerves. Innervation of ameloblastomas might play a key role in the onset of this malignancy and might represent a promising target for non-invasive pharmacological interventions.

Human teeth have a limited capacity to regenerate and thus biological reconstruction of damaged or lost dental tissues remains a significant challange in modern dentistry. Recent efforts focus on alternative therapeutic approaches for partial or whole tooth regeneration that complement traditional dental treatments using sophisticated materials and dental implants. These multidisciplinary approaches are based on the combination of stem cells with advanced tissue engineer products and computing technology, and they hold great promise for future applications in dentistry. The administration to patients of dynamic biological agents composed by stem cells and scaffolds will certainly increase the regenerative capacity of dental pathological tissues. The design of innovative materials for tissue restoration, diagnostics, imaging, and targeted pharmaceutical treatment will significantly improve the quality of dental care and will have a major societal impact. This review depicts the current challenges in dentistry and describes the possibilities for novel and succesful therapeutic applications in the near future.

Hereditary hemorrhagic telangiectasia (HTT) is an autosomal dominant disease, most frequently caused by a mutation in either ENG or ACVRL1 , which can be associated with pulmonary arterial hypertension (PAH). In this report, we describe a new unpublished ACVRL1 mutation segregating in three members of the same family, showing three different types of pulmonary hypertension (PH) in the absence of BMPR2 mutations. The first patient has a form of heritable PAH (HPAH) in the absence of hepatic arteriovenous malformations (AVMs); the second one has a severe form of portopulmonary hypertension (PoPAH) associated with multiple hepatic AVMs; the third one has hepatopulmonary syndrome (HPS) with numerous hepatic arteriovenous fistulas and a form of post-capillary PH due to high cardiac output. In summary, a single mutation in the ACVRL1 gene can be associated, in the same family, with an extreme phenotypic variability regarding not only the clinical presentation of HHT but also the type of PH in the absence of BMPR2 mutations. More studies are needed to evaluate if this variability can be explained by the presence of additional variants in other genes relevant for the pathogenesis of HHT.

Odontogenesis results from the continuous and reciprocal interaction between cells of the oral epithelium and cranial neural crest-derived mesenchyme. The canonical Wnt signaling pathway plays a fundamental role in mediating these interactions from the earliest stages of tooth development. Here we analyze by in situ hybridization the expression patterns of the extracellular Wnt antagonist Frzb/Sfrp3. Although Frzb is expressed in dental mesenchymal cells from the earliest stages of odontogenesis, its expression is absent from a tiny population of mesenchymal cells immediately adjacent to the invaginating dental epithelium. Cell proliferation studies using BrdU showed that the Frzb expressing and Frzb non-expressing cell populations display different proliferative behavior during the initial stages of odontogenesis. DiI-mediated cell-fate tracing studies demonstrated that the Frzb expressing cells contribute to the formation of the dental follicle, the future periodontium. In contrast, the Frzb non-expressing cells give rise to the dental pulp. The present results indicate that Frzb is discriminating the presumptive periodontal territory from the rest of the dental mesenchyme from the very beginning of odontogenesis, where it might act as a barrier for the diffusion of Wnt molecules, thus regulating the activation of Wnt-dependent transcription within dental tissues.

The continuous growth of rodent incisors is ensured by clusters of mesenchymal and epithelial stem cells that are located at the posterior part of these teeth. Genetic lineage tracing studies have shown that dental epithelial stem cells (DESCs) are able to generate all epithelial cell populations within incisors during homeostasis. However, it remains unclear whether these cells have the ability to adopt alternative fates in response to extrinsic factors. Here, we have studied the plasticity of DESCs in the context of mammary gland regeneration. Transplantation of DESCs together with mammary epithelial cells into the mammary stroma resulted in the formation of chimeric ductal epithelial structures in which DESCs adopted all the possible mammary fates including milk-producing alveolar cells. In addition, when transplanted without mammary epithelial cells, DESCs developed branching rudiments and cysts. These in vivo findings demonstrate that when outside their niche, DESCs redirect their fates according to their new microenvironment and thus can contribute to the regeneration of non-dental tissues.