Universal mean-field upper bound for the generalization gap of deep neural networks.

Modern deep neural networks (DNNs) represent a formidable challenge for theorists: according to the commonly accepted probabilistic framework that describes their performance, these architectures should overfit due to the huge number of parameters to train, but in practice they do not. Here we employ results from replica mean field theory to compute the generalization gap of machine learning models with quenched features, in the teacher-student scenario and for regression problems with quadratic loss function. Notably, this framework includes the case of DNNs where the last layer is optimized given a specific realization of the remaining weights. We show how these results-combined with ideas from statistical learning theory-provide a stringent asymptotic upper bound on the generalization gap of fully trained DNN as a function of the size of the dataset P. In particular, in the limit of large P and N_{out} (where N_{out} is the size of the last layer) and N_{out}≪P, the generalization gap approaches zero faster than 2N_{out}/P, for any choice of both architecture and teacher function. Notably, this result greatly improves existing bounds from statistical learning theory. We test our predictions on a broad range of architectures, from toy fully connected neural networks with few hidden layers to state-of-the-art deep convolutional neural networks.

European Council of Legal Medicine (ECLM) on-site inspection forms for forensic pathology, anthropology, odontology, genetics, entomology and toxicology for forensic and medico-legal scene and corpse investigation: the Parma form.

Further to a previous publication by the European Council of Legal Medicine (ECLM) concerning on-site forensic and medico-legal scene and corpse investigation, this publication provides guidance for forensic medical specialists, pathologists and, where present, coroners' activity at a scene of death inspection and to harmonize the procedures for a correct search, detection, collection, sampling and storage of all elements which may be useful as evidence, and ensure documentation of all these steps. This ECLM's inspection form provides a checklist to be used on-site for the investigation of a corpse present at a crime or suspicious death scene. It permits the collection of all relevant data not only for the pathologist, but also for forensic anthropologists, odontologists, geneticists, entomologists and toxicologists, thus supporting a collaborative work approach. Detailed instructions for the completion of forms are provided.

Criticality and conformality in the random dimer model.

In critical systems, the effect of a localized perturbation affects points that are arbitrarily far from the perturbation location. In this paper, we study the effect of localized perturbations on the solution of the random dimer problem in two dimensions. By means of an accurate numerical analysis, we show that a local perturbation of the optimal covering induces an excitation whose size is extensive with finite probability. We compute the fractal dimension of the excitations and scaling exponents. In particular, excitations in random dimer problems on nonbipartite lattices have the same statistical properties of domain walls in spin glass. Excitations produced in bipartite lattices, instead, are compatible with a loop-erased self-avoiding random walk process. In both cases, we find evidence of conformal invariance of the excitations that is compatible with SLE_{κ} with parameter κ depending on the bipartiteness of the underlying lattice only.

Cooperative effects on the compaction of DNA fragments by the nucleoid protein H-NS and the crowding agent PEG probed by Magnetic Tweezers.

BACKGROUND: DNA bridging promoted by the H-NS protein, combined with the compaction induced by cellular crowding, plays a major role in the structuring of the E. coli genome. However, only few studies consider the effects of the physical interplay of these two factors in a controlled environment. METHODS: We apply a single molecule technique (Magnetic Tweezers) to study the nanomechanics of compaction and folding kinetics of a 6 kb DNA fragment, induced by H-NS bridging and/or PEG crowding. RESULTS: In the presence of H-NS alone, the DNA shows a step-wise collapse driven by the formation of multiple bridges, and little variations in the H-NS concentration-dependent unfolding force. Conversely, the DNA collapse force observed with PEG was highly dependent on the volume fraction of the crowding agent. The two limit cases were interpreted considering the models of loop formation in a pulled chain and pulling of an equilibrium globule respectively. CONCLUSIONS: We observed an evident cooperative effect between H-NS activity and the depletion of forces induced by PEG. GENERAL SIGNIFICANCE: Our data suggest a double role for H-NS in enhancing compaction while forming specific loops, which could be crucial in vivo for defining specific mesoscale domains in chromosomal regions in response to environmental changes.

Informing MS patients on treatment options: a consensus on the process of consent taking.

In the last years, change in multiple sclerosis (MS) therapeutic scenario has highlighted the need for an improved doctor-patient communication in advance of treatment initiation in order to allow patient's empowerment in the decision-making process. AIMS: The aims of our project were to review the strategies used by Italian MS specialists to inform patients about treatment options and to design a multicentre shared document that homogenizes the information about disease-modifying treatment (DMTs) and the procedure of taking informed consent in clinical practice. RESULTS: The new resource, obtained by consensus among 31 neurologists from 27 MS Centres in Italy with the supervision of a medico-legal advisor, received the aegis of Italian Neurological Society (SIN) and constitutes a step toward a standardized decision process around DMTs in MS.

Fractal Folding and Medium Viscoelasticity Contribute Jointly to Chromosome Dynamics.

Chromosomes are key players of cell physiology, their dynamics provides valuable information about its physical organization. In both prokaryotes and eukaryotes, the short-time motion of chromosomal loci has been described with a Rouse model in a simple or viscoelastic medium. However, little emphasis has been put on the influence of the folded organization of chromosomes on the local dynamics. Clearly, stress propagation, and thus dynamics, must be affected by such organization, but a theory allowing us to extract such information from data, e.g., on two-point correlations, is lacking. Here, we describe a theoretical framework able to answer this general polymer dynamics question. We provide a scaling analysis of the stress-propagation time between two loci at a given arclength distance along the chromosomal coordinate. The results suggest a precise way to assess folding information from the dynamical coupling of chromosome segments. Additionally, we realize this framework in a specific model of a polymer whose long-range interactions are designed to make it fold in a fractal way and immersed in a medium characterized by subdiffusive fractional Langevin motion with a tunable scaling exponent. This allows us to derive explicit analytical expressions for the correlation functions.

Effects of potential neurotoxic pesticides on hearing loss: a review.

Several pesticides are supposed to be neurotoxic for humans, consequently, they may also affect the auditory system. This review analyzes human and experimental animal studies testing the hypothesis that exposure to pesticides is associated with hearing loss. The literature on this topic is still sparse and methodological limitations of some papers evaluated are identified. As a whole, available data indicate a possible ototoxic action of pesticides, but alternative hypotheses could not be ruled out, also considering some confounders, such as the co-exposure to noise. Therefore, further studies are necessary in order to clarify the association between pesticides exposure and hearing loss. While awaiting more evidence, for precautionary action we recommend considering pesticides as possible ototoxic agents, in particular for vulnerable targets, such as pregnant women and children during early development.

Otoacoustic emission sensitivity to exposure to styrene and noise.

The ototoxic effect of the exposure to styrene is evaluated, also in the presence of simultaneous exposure to noise, using otoacoustic emissions as biomarkers of mild cochlear damage. Transient-evoked and distortion product otoacoustic emissions were recorded and analyzed in a sample of workers (15 subjects) exposed to styrene and noise in a fiberglass manufacturing facility and in a control group of 13 non-exposed subjects. Individual exposure monitoring of the airborne styrene concentrations was performed, as well as biological monitoring, based on the urinary concentration of two styrene metabolites, the Mandelic and Phenylglyoxylic acids. Noise exposure was evaluated using wearable phonometers, and hearing loss with pure tone audiometry. Due to their different job tasks, one group of workers was exposed to high noise and low styrene levels, another group to higher styrene levels, close to the limit of 20 ppm, and to low noise levels. A significant negative correlation was found between the otoacoustic emission levels and the concentration of the styrene urinary metabolites. Otoacoustic emissions, and particularly distortion products, were able to discriminate the exposed workers from the controls, providing also a rough estimate of the slope of the dose-response relation between otoacoustic levels and styrene exposure.

Theta-point polymers in the plane and Schramm-Loewner evolution.

We study the connection between polymers at the θ temperature on the lattice and Schramm-Loewner chains with constant step length in the continuum. The second of these realize a useful algorithm for the exact sampling of tricritical polymers, where finite-chain effects are excluded. The driving function computed from the lattice model via a radial implementation of the zipper method is shown to converge to Brownian motion of diffusivity κ=6 for large times. The distribution function of an internal portion of walk is well approximated by that obtained from Schramm-Loewner chains. The exponent of the correlation length ν and the leading correction-to-scaling exponent Δ_{1} measured in the continuum are compatible with ν=4/7 (predicted for the θ point) and Δ_{1}=72/91 (predicted for percolation). Finally, we compute the shape factor and the asphericity of the chains, finding surprising accord with the θ-point end-to-end values.

T-cell immune responses against Env from CRF12_BF and subtype B HIV-1 show high clade-specificity that can be overridden by multiclade immunizations.

BACKGROUND: The extreme genetic diversity of the human immunodeficiency virus type 1 (HIV-1) poses a daunting challenge to the generation of an effective AIDS vaccine. In Argentina, the epidemic is characterized by the high prevalence of infections caused by subtype B and BF variants. The aim of this study was to characterize in mice the immunogenic and antigenic properties of the Env protein from CRF12_BF in comparison with clade B, employing prime-boost schemes with the combination of recombinant DNA and vaccinia virus (VV) vectors. METHODOLOGY/PRINCIPAL FINDINGS: As determined by ELISPOT from splenocytes of animals immunized with either EnvBF or EnvB antigens, the majority of the cellular responses to Env were found to be clade-specific. A detailed peptide mapping of the responses reveal that when there is cross-reactivity, there are no amino acid changes in the peptide sequence or were minimal and located at the peptide ends. In those cases, analysis of T cell polifunctionality and affinity indicated no differences with respect to the cellular responses found against the original homologous sequence. Significantly, application of a mixed immunization combining both clades (B and BF) induced a broader cellular response, in which the majority of the peptides targeted after the single clade vaccinations generated a positive response. In this group we could also find significant cellular and humoral responses against the whole gp120 protein from subtype B. CONCLUSIONS/SIGNIFICANCE: This work has characterized for the first time the immunogenic peptides of certain EnvBF regions, involved in T cell responses. It provides evidence that to improve immune responses to HIV there is a need to combine Env antigens from different clades, highlighting the convenience of the inclusion of BF antigens in future vaccines for geographic regions where these HIV variants circulate.

Interplay between modified vaccinia virus Ankara and dendritic cells: phenotypic and functional maturation of bystander dendritic cells.

Modified vaccinia virus Ankara (MVA) is an attenuated poxvirus strain, currently under evaluation as a vaccine vector in various clinical settings. It has been reported that human dendritic cells (DCs) mature after infection with MVA, but reports on the functionality of DCs have so far been controversial. In this work, we studied the phenotype and functionality of MVA-infected DCs. As previously reported, we found that human monocyte-derived DCs upregulated CD86 and HLA-DR in response to MVA infection. Moreover, infected DCs produced a broad array of chemokines and cytokines and were able to activate and induce gamma interferon (IFN-γ) production both in CD4(+) and in CD8(+) allogeneic T cells and in specific autologous peripheral blood lymphocytes (PBLs). Analysis of DC maturation following infection with a recombinant green fluorescent protein (GFP)-expressing MVA revealed that upregulation of CD86 expression was mainly observed in GFP(neg) (bystander) cells. While GFP(pos) (infected) DCs produced tumor necrosis factor alpha (TNF-α), they were unable to produce CXCL10 and were less efficient at inducing IFN-γ production in CEF-specific autologous PBLs. Maturation of bystander DCs could be achieved by incubation with supernatant from infected cultures or with apoptotic infected cells. Type I IFNs were partially responsible for the induction of CXCL10 on bystander DCs. Our findings demonstrate for the first time that, in MVA-infected DC cultures, the leading role with respect to functionality and maturation characteristics is achieved by the bystander DCs.

Insects found on a human cadaver in central Italy including the blowfly Calliphora loewi (Diptera, Calliphoridae), a new species of forensic interest.

In the case of unidentified bodies the estimation of the period since death or of the season of death plays an important role to focus the attention on a reduced number of people among the ones reported missing. Forensic entomology can be one of the most important methods for these estimations, as occurred in this case. Flies are typically the first insects to colonize a dead body. The case reported here concerns the colonisation by insects of a male body in advanced decay found during the winter in Central Italy. This case is of particular interest as few data are available on the entomological evidence in the cold season. In particular, in this case we recovered Calliphora loewi (Calliphoridae), a species never collected before on dead bodies in Southern Europe. Larvae of the black soldier fly Hermetia illucens (Stratiomyidae), pupae and larvae belonging to genus Hydrothea (Muscidae), and Necrobia rufipes (Cleridae) specimens were also collected. The estimated PMI enabled identification of the cadaver, confirmed by DNA analysis.

[Synergistic exposure to noise and styrene and cochlear functionality in a sample of exposed workers: preliminary results]. / Esposizione sinergica a rumore e stirene e funzionalità cocleare in un campione di lavoratori esposti: risultati preliminari.

This study is aimed at testing the cochlear functionality using otoacoustic emissions, analyzing the synergistic effects of simultaneous exposure to noise and organic solvents EBTx on workers of a glass-reinforced plastic products factory. Exposure to organic solvents was assessed using ambiental measurements and evaluation of the salivary concentration. Biological monitoring was performed evaluating the urinary concentration of the styrene metabolites. Statistical analysis shows that otoacoustic tests can discriminate between different exposure groups. Significant differences were found between controls and subjects exposed to high styrene and low noise levels, showing the ototoxic effect (at sub-clinical level) of the styrene exposure.

Characterization of DNA and MVA vectors expressing Nef from HIV-1 CRF12_BF revealed high immune specificity with low cross-reactivity against subtype B.

The HIV epidemic in Argentina is characterized by the high prevalence of infections caused by subtype B and BF variants. In this study, the Nef protein was used as a tool to study the impact of HIV-1 BF variants in the design of future vaccines. DNA and MVA vectors expressing Nef of the CRF12_BF recombinant form of HIV-1 were generated and characterized. After the administration of single DNAprime/MVAboost immunization schedules in Balb/c mice we found that NefBF delivered from these vectors generated a response of high specificity with low cross-reactivity against subtype B. But, when a more potent response was induced after 3 priming DNA doses and a booster with MVA virus, cross-reactivity against NefB was detected, although of lower magnitude than the NefBF specific. These results will be pivotal for vaccines designs in our region, indicating that antigens from these viral variants must be considered for a future vaccine.

Chronic respiratory care for neuromuscular diseases in adults.

Neuromuscular diseases (NMD) may affect respiratory muscles, leading to respiratory failure. Studies show that long-term noninvasive mechanical ventilation (NIV) improves symptoms, gas exchange, quality of life and survival. NIV improved these parameters in muscular dystrophies and also in patients with amyotrophic lateral sclerosis without severe bulbar dysfunction. NIV should be started at the onset of nocturnal hypoventilation. In selected cases, NIV may be simpler, better accepted by patients and cheaper than invasive mechanical ventilation, but it cannot be used as an alternative. Tracheostomy may be preferred by patients unable to protect their airways and wishing to survive as long as possible, or by ventilator-dependent patients. Glossopharyngeal breathing consists of taking air and propelling it into the lungs. Chest percussions and vibrations can help to mobilise airway secretions but they cannot substitute coughing. Manually assisted coughing requires substantial lung inflation through air stacking or deep lung insufflation, followed by an abdominal thrust with open glottis. The combination of mechanical in-exsufflation with an abdominal thrust is a mechanically assisted cough. In conclusion, recent advances in respiratory care of NMD have improved prognosis and many caregivers have changed from a traditional noninterventional to a more aggressive, supportive approach.

[Occupational exposure to hexavalent chromium during aircraft painting]. / Esposizione occupazionale a cromo esavalente nelle operazioni di verniciatura degli aeromobili.

Hygienists are interested in hexavalent chromium due to its genotoxic and carcinogenic effect on humans. The use of products containing hexavalent chromium is decreasing in many industrial fields because of the substitution with less-toxic compounds. In the aeronautical industry, however, the chromate are added to primer paint as a corrosion inhibitor of aircrafts surfaces: so hexavalent chromium compounds are available in many primers with a composition ranging from 10% to 13%. The application of these primers by using electrostatic guns potentially exposes painting and coating workers at high concentrations of aerosols containing Cr(VI). The aim of the present study is the evaluation of professional exposure to hexavalent chromium during aircraft painting, by adopting both environmental personal sampling and biological monitoring. To valuate workers exposure levels the personal measurements results have been compared with the exposure limit values (TLV-TWA) and the urinary chromium contents with the biological exposure indices (IBE). Moreover the strategy of coupling environmental sampling with biological monitoring seems to be a useful instrument to measure the validity of the individual protection devices.

The epidermis of Timarete filigera (Polychaeta, Cirratulidae): histochemical and ultrastructural analysis of the gland cells.

The aim of this study was to verify whether different living conditions of Polychaeta are correlated with morphological and functional differences in the organization of the integument. For this purpose, we decided to study the epidermis of Timarete filigera, a non-tubicolous polychaete. With this objective in mind, we have identified the various cellular types responsible for mucous secretion in the epidermis of this species and defined the histochemical composition of the mucus produced by different types of gland cells. Three types of gland cells have been identified by histochemical and ultrastructural studies in the epidermis of this polychaete. The histochemistry was carried out using standard techniques and peroxidase-labelled lectins. In type 1 cells, the secretory granules contain neutral glycoproteins with glucosidic residues of GalNAc, Galbeta 1,3 GalNAc, glucosidic and/or mannosidic residues. In type 2 cells, the secretory granules contain acid glycoproteins mainly sulphated with glucosidic residues of GalNAc, Galbeta 1,3 GalNAc, glucosidic and/or mannosidic residues, and some terminal sialic acid. In type 3 cells, the residual granules have the same chemical composition as that of granules present in type 2 cells. The secretion of these glandular mucous cells consists of mainly sulphated acidic glycoproteins and GAG resistant to testis jaluronidase. In these cells, the residual granules have the same chemical composition as that of their secretion. The heterogeneity of mucus composition may be correlated with its different functions.

[Chemical risk of exposure to volatile organic compounds in the field of restoration of art objects]. / Il rischio chimico di esposizione a composti organici volatili nel settore del restauro di oggetti d'arte.

The use of chemicals during restoration practices involves emissions of toxics depending on both the amount of original products used and the specific techniques applied. Restorers perform a great variety of techniques by using not standardized operative procedures: moreover, they are exposed to mixtures and very rarely to single chemicals. In this study we evaluated workers' exposure to solvent mixture which were generated during restoration of archaeological metal handcraft. Exposure to low levels of twelve organic compounds has been experimented inside a public restoration laboratory: based on the data presented in this article we assume that inside restoration workplaces a diffused indoor contamination can take place. The indoor pollution can generate a risk of an uncontrolled exposure to volatile mixtures: therefore the emissions of solvents during restoration practices has to be avoided even if they cause a low level of exposure.

MVA-LACK as a safe and efficient vector for vaccination against leishmaniasis.

An optimal vaccine against leishmaniasis should elicit parasite specific CD4+ and cytotoxic CD8+ T cells. In this investigation, we described a prime/boost immunization approach based on DNA and on poxvirus vectors (Western Reserve, WR, and the highly attenuated modified vaccinia virus Ankara, MVA), both expressing the LACK antigen of Leishmania infantum, that triggers different levels of specific CD8+ T cell responses and protection (reduction in lesion size and parasitemia) against L. major infection in mice. A prime/boost vaccination with DNA-LACK/MVA-LACK elicits higher CD8+ T cell responses than a similar protocol with the replication competent VV-LACK. Both CD4+ and CD8+ T cells were induced by DNA-LACK/MVA-LACK immunization. The levels of IFN-gamma and TNF-alpha secreting CD8+ T cells were higher in splenocytes from DNA-LACK/MVA-LACK than in DNA-LACK/VV-LACK immunized animals. Moreover, protection against L. major was significantly higher in DNA-LACK/MVA-LACK than in DNA-LACK/VV-LACK immunized animals when boosted with the same virus dose, and correlated with high levels of IFN-gamma and TNF-alpha secreting CD8+ T cells. In DNA-LACK/MVA-LACK vaccinated animals, the extent of lesion size reduction ranged from 65 to 92% and this protection was maintained for at least 17 weeks after challenge with the parasite. These findings demonstrate that in heterologous prime/boost immunization approaches, the protocol DNA-LACK/MVA-LACK is superior to DNA-LACK/VV-LACK in triggering specific CD8+ T cell immune responses and in conferring protection against cutaneous leishmaniasis. Thus, MVA-LACK is a safe and efficient vector for vaccination against leishmaniasis.

Recombinant poxviruses as mucosal vaccine vectors.

The majority of infections initiate their departure from a mucosal surface, such as Human immunodeficiency virus (HIV), a sexually transmitted virus. Therefore, the induction of mucosal immunity is a high priority in the development of vaccines against mucosal pathogens. The selection of an appropriate antigen delivery system is necessary to induce an efficient mucosal immune response. Poxvirus vectors have been the most intensively studied live recombinant vector, and numerous studies have demonstrated their ability to induce mucosal immune responses against foreign expressed antigens. Previous studies have demonstrated that recombinants based on the attenuated modified vaccinia virus Ankara (MVA) vector were effective in inducing protective responses against different respiratory viruses, such as influenza and respiratory syncytial virus, following immunization via mucosal routes. Recent studies performed in the murine and macaque models have shown that recombinant MVA (rMVA) does not only stimulate HIV-specific immunity in the genital and rectal tracts following mucosal delivery, but can also control simian/human immunodeficiency viraemia and disease progression. In addition, a prime-boost vaccination approach against tuberculosis emphasized the importance of the intranasal rMVA antigen delivery to induce protective immunity against Mycobacterium tuberculosis. The aim of this review is to summarize the studies employing recombinant poxviruses, specifically rMVA as a mucosal delivery vector. The results demonstrate that rMVAs can activate specific immune responses at mucosal surfaces, and encourage further studies to characterize and improve the MVA mucosal immunogenicity of poxvirus vectors.