Glucocorticoid receptor regulates protein chaperone, circadian clock and affective disorder genes in the zebrafish brain.

Glucocorticoid resistance is commonly observed in depression, and has been linked to reduced expression and/or function of the glucocorticoid receptor (NR3C1 in human, hereafter referred to as GR). Previous studies have shown that GR-mutant zebrafish exhibit behavioural abnormalities that are indicative of an affective disorder, suggesting that GR plays a role in brain function. We compared the brain methylomes and brain transcriptomes of adult wild-type and GR-mutant zebrafish, and identified 249 differentially methylated regions (DMRs) that are regulated by GR. These include a cluster of CpG sites within the first intron of fkbp5, the gene encoding the glucocorticoid-inducible heat shock protein co-chaperone Fkbp5. RNA-sequencing analysis revealed that genes associated with chaperone-mediated protein folding, the regulation of circadian rhythm and the regulation of metabolism are particularly sensitive to loss of GR function. In addition, we identified subsets of genes exhibiting GR-regulated transcription that are known to regulate behaviour, and are linked to unipolar depression and anxiety. Taken together, our results identify key biological processes and novel molecular mechanisms through which the GR is likely to mediate responses to stress in the adult zebrafish brain, and they provide further support for the zebrafish GR mutant as a model for the study of affective disorders.

6 mm short versus 11 mm long inter-foraminal implants in the full-arch rehabilitation of edentulous non-atrophic mandibles: 5-year results from a multicenter randomized controlled trial.

OBJECTIVE: The aim of this multicenter parallel-group randomized controlled trial is to compare, in the same clinical scenario, 6 mm short with 11 mm long implants for the rehabilitation of completely edentulous non-atrophic mandibles. MATERIALS AND METHODS: Thirty patients in three study centers received a fixed full-arch mandibular rehabilitation supported by five inter-foraminal implants, with no need for bone augmentation procedures. Patients were randomly allocated (1:1 ratio), at the time of surgery, to test (6 mm implants) or control group (11 mm implants). After 3 months, a screw-retained full-arch prosthesis was positioned (baseline). Peri-implant marginal bone level change (MBLc, primary outcome) together with implant and prosthesis survival rate, and biological/technical complications (secondary outcomes) were evaluated up to 5 years. RESULTS: Twenty seven patients were controlled at 5 years (3 drop-outs). No implant or prosthesis loss occurred. No significant intergroup difference for biological/technical complications (p > .05, Fisher's exact test) and no significant intragroup and intergroup difference in the MBLc values were registered (test -0.03 ± 0.17 mm and control -0.13 ± 0.32 mm at 5-years; p > .025, one-sided Mann-Whitney U-test). CONCLUSIONS: When used in comparable anatomic, surgical, and prosthetic conditions, no difference in the clinical and radiographic outcomes between 6-mm and 11-mm implants was observed at 5 years of follow-up. Short implants showed to be a reliable option for the rehabilitation of completely edentulous non-atrophic mandibles. There is growing clinical evidence supporting the use of short implants, even in the case of non-atrophic sites.

Analytical Workflows to Unlock Predictive Power in Biotherapeutic Developability.

PURPOSE: Forming accurate data models that assist the design of developability assays is one area that requires a deep and practical understanding of the problem domain. We aim to incorporate expert knowledge into the model building process by creating new metrics from instrument data and by guiding the choice of input parameters and Machine Learning (ML) techniques. METHODS: We generated datasets from the biophysical characterisation of 5 monoclonal antibodies (mAbs). We explored combinations of techniques and parameters to uncover the ones that better describe specific molecular liabilities, such as conformational and colloidal instability. We also employed ML algorithms to predict metrics from the dataset. RESULTS: We found that the combination of Differential Scanning Calorimetry (DSC) and Light Scattering thermal ramps enabled us to identify domain-specific aggregation in mAbs that would be otherwise overlooked by common developability workflows. We also found that the response to different salt concentrations provided information about colloidal stability in agreement with charge distribution models. Finally, we predicted DSC transition temperatures from the dataset, and used the order of importance of different metrics to increase the explainability of the model. CONCLUSIONS: The new analytical workflows enabled a better description of molecular behaviour and uncovered links between structural properties and molecular liabilities. In the future this new understanding will be coupled with ML algorithms to unlock their predictive power during developability assessment.

Temporal population structure, a genetic dating method for ancient Eurasian genomes from the past 10,000 years.

Radiocarbon dating is the gold standard in archeology to estimate the age of skeletons, a key to studying their origins. Many published ancient genomes lack reliable and direct dates, which results in obscure and contradictory reports. We developed the temporal population structure (TPS), a DNA-based dating method for genomes ranging from the Late Mesolithic to today, and applied it to 3,591 ancient and 1,307 modern Eurasians. TPS predictions aligned with the known dates and correctly accounted for kin relationships. TPS dating of poorly dated Eurasian samples resolved conflicting reports in the literature, as illustrated by one test case. We also demonstrated how TPS improved the ability to study phenotypic traits over time. TPS can be used when radiocarbon dating is unfeasible or uncertain or to develop alternative hypotheses for samples younger than 10,000 years ago, a limitation that may be resolved over time as ancient data accumulate.

Dental Emergencies and Coronavirus Disease-2019: Scoping Review of the Literature and Single Centre Experience.

Understanding the impact of the COVID-19 pandemic on dental emergencies. A systematic review of the literature (PubMed/Scopus) searching for articles on COVID-19 and dental abscess and a retrospective cohort study with quantitative/qualitative data analysis of our hospital E.R. patients admitted for cervico-facial abscess of dental origin were performed. Thirteen studies could be included in the review, concerning characteristics/management of patients with dental emergencies in hospitals/private practices, generally with poor evidence. For the retrospective analysis, 232 consecutive patients were included (100 study vs. 132 control). The prevalence of dental emergencies (abscess) and relative complications (mediastinitis, exitus) increased. Dental care availability was limited, with strong heterogeneity amongst regions/nations. At-risk (aerosol-generating) procedures were generally avoided, and hospitalization length reduced. Comorbidity patients and males seem less likely to restore regular dentist attendance during the post-lockdown pandemic. Despite the poor scientific evidence, COVID-19 seems to have impacted dental emergencies through limited routine dental care availability and influence on physicians' and patients' behaviour.

Germline rare variants of lectin pathway genes predispose to asymptomatic SARS-CoV-2 infection in elderly individuals.

PURPOSE: Emerging evidence suggest that infection-dependent hyperactivation of complement system (CS) may worsen COVID-19 outcome. We investigated the role of predicted high impact rare variants - referred as qualifying variants (QVs) - of CS genes in predisposing asymptomatic COVID-19 in elderly individuals, known to be more susceptible to severe disease. METHODS: Exploiting exome sequencing data and 56 CS genes, we performed a gene-based collapsing test between 164 asymptomatic subjects (aged ≥60 years) and 56,885 European individuals from the Genome Aggregation Database. We replicated this test comparing the same asymptomatic individuals with 147 hospitalized patients with COVID-19. RESULTS: We found an enrichment of QVs in 3 genes (MASP1, COLEC11, and COLEC10), which belong to the lectin pathway, in the asymptomatic cohort. Analyses of complement activity in serum showed decreased activity of lectin pathway in asymptomatic individuals with QVs. Finally, we found allelic variants associated with asymptomatic COVID-19 phenotype and with a decreased expression of MASP1, COLEC11, and COLEC10 in lung tissue. CONCLUSION: This study suggests that genetic rare variants can protect from severe COVID-19 by mitigating the activity of lectin pathway and prothrombin. The genetic data obtained through ES of 786 asymptomatic and 147 hospitalized individuals are publicly available at http://espocovid.ceinge.unina.it/.

Dental Trauma in Children with Autistic Disorder: A Retrospective Study.

BACKGROUND: The oral health care of autistic children is elaborated; they often fail to define dental problems, and a family-centered approach can be useful to improve and intercept these disorders. AIM: To assess the oral status of autistic children, comparing it with no autistic patients. MATERIALS AND METHODS: A retrospective study analyzed the oral health status of 70 children, 35 with autism and 35 without the disorder. Conditions assessed were dental trauma type, periodontal tissue injuries, soft tissue lip injuries, different treatments carried out, associated soft tissue findings and disorders, and the long-term management. All patients (≤15 years of age) were chosen consecutively. RESULTS: Females (57%) suffered more traumatic injuries than males (43%) in the autistic group, whereas males affected by dental trauma (54%) are predominant in the control group. The enamel fracture was the main finding among the dental trauma types in both groups followed by enamel/dentin/pulp fracture (31%), root fracture (11%), and avulsions (3%) in the autistic group and by avulsions (20%), root fracture (11%), and enamel/dentin/pulp fracture (6%) in the control group. The comparison of all variables of the two groups showed a statistically significant difference (P < 0.012). The lower lip was statistically more injured than the upper lip (P < 0.005). CONCLUSIONS: The composite restorative technique was the most common approach carried out; the long-term evaluation, when possible, was predominantly managed through root canal therapy in the control group (81%), and root canal therapy (50%) and tooth extraction (50%) in the sample group.

6-mm-short and 11-mm-long implants compared in the full-arch rehabilitation of the edentulous mandible: A 3-year multicenter randomized controlled trial.

OBJECTIVE: The aim of this multicenter parallel-group randomized controlled trial is to compare 6-mm-short with 11-mm-long implants in the rehabilitation of totally edentulous mandible in a completely comparable clinical situation, from anatomical, surgical, and prosthetic point of view. MATERIAL AND METHODS: Thirty patients were selected in three study centers to receive a fixed full-arch mandibular rehabilitation supported by five inter-foraminal implants. Patients were randomly allocated, at the time of surgery, half to the test group (6-mm-long implants) and half to the control group (11-mm-long implants). No bone augmentation procedure was performed. After 3 months, a screw-retained full-arch prosthesis with distal cantilevers was positioned (baseline). Peri-implant marginal bone level change (MBLc), implant and prosthesis survival rate, and biological/technical complications were evaluated after 1 and 3 years. RESULTS: Thirty subjects (150 implants) were evaluated after 1 year and 28 (140 implants) after 3 years. No implant or prosthesis loss occurred. No significant inter-group difference for biological/technical complications was registered. No statistically significant (p > .025) intra-group or inter-group difference in the mean MBLc values was registered. The mean MBLc was 0.01 ± 0.19 mm and -0.04 ± 0.21 mm at 1 year, and -0.10 ± 0.24 mm and 0.02 ± 0.25 mm at 3 years (test and control groups, respectively). CONCLUSIONS: 6-mm-short implants may be a reliable option when used in the rehabilitation of total edentulous mandibles. These results need to be confirmed by longer follow-up data from well-designed randomized controlled clinical trials.

A 5-year longitudinal cohort study on crown to implant ratio effect on marginal bone level in single implants.

BACKGROUND: A 5-year longitudinal cohort study was carried out to evaluate the influence of anatomical crown to implant ratio (CIR) on peri-implant marginal bone level (MBL) in single implants. MATERIALS AND METHODS: The longest possible implants, according to the availability of pristine bone, were inserted, one per patient, among periodontally healthy teeth in consecutively recruited subjects. CIR and MBL changes were measured on standardized radiographs. The relationship between MBL and multiple predictors was investigated. A statistical analysis suitable for mixed type distributions was conducted: for the discrete component a logistic regression model was used and for the continuous component the impact of the variables on MBL was examined by using robust nonparametric comparison tests. RESULTS: Seventy-eight dental implants were inserted in 34 mandibles and 44 maxillae, with one stage procedure in 40 cases and two stage in 38 cases. Thirty-five implants were <10 mm, while 43 were ≥ 10 mm long; 28 implants had a CIR ≤1 and 50 had a CIR >1. No drop-outs or implant loss were observed. Bone loss occurred only in a few cases, measuring less than 0.5 mm and being significantly more pronounced for implant length ≥10 mm, for lower CIR values and for the two stage procedure. CONCLUSION: Higher CIR values were not related to increased peri-implant bone loss; a <10 mm long implant insertion may be safely considered for reduced bone heights.

Ancient Ancestry Informative Markers for Identifying Fine-Scale Ancient Population Structure in Eurasians.

The rapid accumulation of ancient human genomes from various areas and time periods potentially enables the expansion of studies of biodiversity, biogeography, forensics, population history, and epidemiology into past populations. However, most ancient DNA (aDNA) data were generated through microarrays designed for modern-day populations, which are known to misrepresent the population structure. Past studies addressed these problems by using ancestry informative markers (AIMs). It is, thereby, unclear whether AIMs derived from contemporary human genomes can capture ancient population structures, and whether AIM-finding methods are applicable to aDNA, provided that the high missingness rates in ancient-and oftentimes haploid-DNA can also distort the population structure. Here, we define ancient AIMs (aAIMs) and develop a framework to evaluate established and novel AIM-finding methods in identifying the most informative markers. We show that aAIMs identified by a novel principal component analysis (PCA)-based method outperform all of the competing methods in classifying ancient individuals into populations and identifying admixed individuals. In some cases, predictions made using the aAIMs were more accurate than those made with a complete marker set. We discuss the features of the ancient Eurasian population structure and strategies to identify aAIMs. This work informs the design of single nucleotide polymorphism (SNP) microarrays and the interpretation of aDNA results, which enables a population-wide testing of primordialist theories.

The Diversity of REcent and Ancient huMan (DREAM): A New Microarray for Genetic Anthropology and Genealogy, Forensics, and Personalized Medicine.

The human population displays wide variety in demographic history, ancestry, content of DNA derived from hominins or ancient populations, adaptation, traits, copy number variation, drug response, and more. These polymorphisms are of broad interest to population geneticists, forensics investigators, and medical professionals. Historically, much of that knowledge was gained from population survey projects. Although many commercial arrays exist for genome-wide single-nucleotide polymorphism genotyping, their design specifications are limited and they do not allow a full exploration of biodiversity. We thereby aimed to design the Diversity of REcent and Ancient huMan (DREAM)-an all-inclusive microarray that would allow both identification of known associations and exploration of standing questions in genetic anthropology, forensics, and personalized medicine. DREAM includes probes to interrogate ancestry informative markers obtained from over 450 human populations, over 200 ancient genomes, and 10 archaic hominins. DREAM can identify 94% and 61% of all known Y and mitochondrial haplogroups, respectively, and was vetted to avoid interrogation of clinically relevant markers. To demonstrate its capabilities, we compared its FST distributions with those of the 1000 Genomes Project and commercial arrays. Although all arrays yielded similarly shaped (inverse J) FST distributions, DREAM's autosomal and X-chromosomal distributions had the highest mean FST, attesting to its ability to discern subpopulations. DREAM performances are further illustrated in biogeographical, identical by descent, and copy number variation analyses. In summary, with approximately 800,000 markers spanning nearly 2,000 genes, DREAM is a useful tool for genetic anthropology, forensic, and personalized medicine studies.

Measuring symmetry, asymmetry and randomness in neural network connectivity.

Cognitive functions are stored in the connectome, the wiring diagram of the brain, which exhibits non-random features, so-called motifs. In this work, we focus on bidirectional, symmetric motifs, i.e. two neurons that project to each other via connections of equal strength, and unidirectional, non-symmetric motifs, i.e. within a pair of neurons only one neuron projects to the other. We hypothesise that such motifs have been shaped via activity dependent synaptic plasticity processes. As a consequence, learning moves the distribution of the synaptic connections away from randomness. Our aim is to provide a global, macroscopic, single parameter characterisation of the statistical occurrence of bidirectional and unidirectional motifs. To this end we define a symmetry measure that does not require any a priori thresholding of the weights or knowledge of their maximal value. We calculate its mean and variance for random uniform or Gaussian distributions, which allows us to introduce a confidence measure of how significantly symmetric or asymmetric a specific configuration is, i.e. how likely it is that the configuration is the result of chance. We demonstrate the discriminatory power of our symmetry measure by inspecting the eigenvalues of different types of connectivity matrices. We show that a Gaussian weight distribution biases the connectivity motifs to more symmetric configurations than a uniform distribution and that introducing a random synaptic pruning, mimicking developmental regulation in synaptogenesis, biases the connectivity motifs to more asymmetric configurations, regardless of the distribution. We expect that our work will benefit the computational modelling community, by providing a systematic way to characterise symmetry and asymmetry in network structures. Further, our symmetry measure will be of use to electrophysiologists that investigate symmetry of network connectivity.

Adaptation of short-term plasticity parameters via error-driven learning may explain the correlation between activity-dependent synaptic properties, connectivity motifs and target specificity.

The anatomical connectivity among neurons has been experimentally found to be largely non-random across brain areas. This means that certain connectivity motifs occur at a higher frequency than would be expected by chance. Of particular interest, short-term synaptic plasticity properties were found to colocalize with specific motifs: an over-expression of bidirectional motifs has been found in neuronal pairs where short-term facilitation dominates synaptic transmission among the neurons, whereas an over-expression of unidirectional motifs has been observed in neuronal pairs where short-term depression dominates. In previous work we found that, given a network with fixed short-term properties, the interaction between short- and long-term plasticity of synaptic transmission is sufficient for the emergence of specific motifs. Here, we introduce an error-driven learning mechanism for short-term plasticity that may explain how such observed correspondences develop from randomly initialized dynamic synapses. By allowing synapses to change their properties, neurons are able to adapt their own activity depending on an error signal. This results in more rich dynamics and also, provided that the learning mechanism is target-specific, leads to specialized groups of synapses projecting onto functionally different targets, qualitatively replicating the experimental results of Wang and collaborators.