HSV-1 infection induces phosphorylated tau propagation among neurons via extracellular vesicles.

Extracellular vesicles (EV), key players in cell-to-cell communication, may contribute to disease propagation in several neurodegenerative diseases, including Alzheimer's disease (AD), by favoring the dissemination of neurotoxic proteins within the brain. Interestingly, growing evidence supports the role of herpes simplex virus type 1 (HSV-1) infection in the pathogenesis of AD. Here, we investigated whether HSV-1 infection could promote the spread of phosphorylated tau (ptau) among neurons via EV. We analyzed the ptau species that were secreted via EV following HSV-1 infection in neuroblastoma cells and primary neurons, focusing particularly on T205, T181, and T217, the phosphorylation sites mainly associated with AD. Moreover, by overexpressing human tau tagged with GFP (htauGFP), we found that recipient tau knockout (KO) neurons uptook EV that are loaded with HSV-1-induced phtauGFP. Finally, we exploited an in vivo model of acute infection and assessed that cerebral HSV-1 infection promotes the release of ptau via EV in the brain of infected mice. Overall, our data suggest that, following HSV-1 infection, EV play a role in tau spreading within the brain, thus contributing to neurodegeneration.IMPORTANCEHerpes simplex virus type 1 (HSV-1) infection that reaches the brain has been repeatedly linked with the appearance of the pathognomonic markers of Alzheimer's disease (AD), including accumulation of amyloid beta and hyperphosphorylated tau proteins, and cognitive deficits. AD is a multifactorial neurodegenerative disease representing the most common form of dementia in the elderly, and no cure is currently available, thus prompting additional investigation on potential risk factors and pathological mechanisms. Here, we demonstrate that the virus exploits the extracellular vesicles (EV) to disseminate phosphorylated tau (ptau) among brain cells. Importantly, we provide evidence that the HSV-1-induced EV-bearing ptau can be undertaken by recipient neurons, thus likely contributing to misfolding and aggregation of native tau, as reported for other AD models. Hence, our data highlight a novel mechanism exploited by HSV-1 to propagate tau-related damage in the brain.

A geo-chemo-mechanical study of a highly polluted marine system (Taranto, Italy) for the enhancement of the conceptual site model.

The paper presents the results of the analysis of the geo-chemo-mechanical data gathered through an innovative multidisciplinary investigation campaign in the Mar Piccolo basin, a heavily polluted marine bay aside the town of Taranto (Southern Italy). The basin is part of an area declared at high environmental risk by the Italian government. The cutting-edge approach to the environmental characterization of the site was promoted by the Special Commissioner for urgent measures of reclamation, environmental improvements and redevelopment of Taranto and involved experts from several research fields, who cooperated to gather a new insight into the origin, distribution, mobility and fate of the contaminants within the basin. The investigation campaign was designed to implement advanced research methodologies and testing strategies. Differently from traditional investigation campaigns, aimed solely at the assessment of the contamination state within sediments lying in the top layers, the new campaign provided an interpretation of the geo-chemo-mechanical properties and state of the sediments forming the deposit at the seafloor. The integrated, multidisciplinary and holistic approach, that considered geotechnical engineering, electrical and electronical engineering, geological, sedimentological, mineralogical, hydraulic engineering, hydrological, chemical, geochemical, biological fields, supported a comprehensive understanding of the influence of the contamination on the hydro-mechanical properties of the sediments, which need to be accounted for in the selection and design of the risk mitigation measures. The findings of the research represent the input ingredients of the conceptual model of the site, premise to model the evolutionary contamination scenarios within the basin, of guidance for the environmental risk management. The study testifies the importance of the cooperative approach among researchers of different fields to fulfil the interpretation of complex polluted eco-systems.

Experimental Determination of Irreversible Entropy Production in out-of-Equilibrium Mesoscopic Quantum Systems.

By making use of a recently proposed framework for the inference of thermodynamic irreversibility in bosonic quantum systems, we experimentally measure and characterize the entropy production rates in the nonequilibrium steady state of two different physical systems-a micromechanical resonator and a Bose-Einstein condensate-each coupled to a high finesse cavity and hence also subject to optical loss. Key features of our setups, such as the cooling of the mechanical resonator and signatures of a structural quantum phase transition in the condensate, are reflected in the entropy production rates. Our work demonstrates the possibility to explore irreversibility in driven mesoscopic quantum systems and paves the way to a systematic experimental assessment of entropy production beyond the microscopic limit.

Tunable Polarons in Bose-Einstein Condensates.

A toolbox for the quantum simulation of polarons in ultracold atoms is presented. Motivated by the impressive experimental advances in the area of ultracold atomic mixtures, we theoretically study the problem of ultracold atomic impurities immersed in a Bose-Einstein condensate mixture (BEC). The coupling between impurity and BEC gives rise to the formation of polarons whose mutual interaction can be effectively tuned using an external laser driving a quasi-resonant Raman transition between the BEC components. Our scheme allows one to change the effective interactions between polarons in different sites from attractive to zero. This is achieved by simply changing the intensity and the frequency of the two lasers. Such arrangement opens new avenues for the study of strongly correlated condensed matter models in ultracold gases.

Measuring the characteristic function of the work distribution.

We propose an interferometric setting for the ancilla-assisted measurement of the characteristic function of the work distribution following a time-dependent process experienced by a quantum system. We identify how the configuration of the effective interferometer is linked to the symmetries enjoyed by the Hamiltonian ruling the process and provide the explicit form of the operations to implement in order to accomplish our task. We finally discuss two physical settings, based on hybrid optomechanical-electromechanical devices, where the theoretical proposals discussed in our work could find an experimental demonstration.

Low molecular weight, non-peptidic agonists of TrkA receptor with NGF-mimetic activity.

Exploitation of the biologic activity of neurotrophins is desirable for medical purposes, but their protein nature intrinsically bears adverse pharmacokinetic properties. Here, we report synthesis and biologic characterization of a novel class of low molecular weight, non-peptidic compounds with NGF (nerve growth factor)-mimetic properties. MT2, a representative compound, bound to Trk (tropomyosin kinase receptor)A chain on NGF-sensitive cells, as well as in cell-free assays, at nanomolar concentrations and induced TrkA autophosphorylation and receptor-mediated internalization. MT2 binding involved at least two amino-acid residues within TrkA molecule. Like NGF, MT2 increased phosphorylation of extracellular signal-regulated kinase 1/2 and Akt proteins and production of MKP-1 phosphatase (dual specificity phosphatase 1), modulated p38 mitogen-activated protein kinase activation,sustained survival of serum-starved PC12 or RDG cells, and promoted their differentiation. However, the intensity of such responses was heterogenous, as the ability of maintaining survival was equally possessed by NGF and MT2, whereas the induction of differentiation was expressed at definitely lower levels by the mimetic. Analysis of TrkA autophosphorylation patterns induced by MT2 revealed a strong tyrosine (Tyr)490 and a limited Tyr785 and Tyr674/675 activation, findings coherent with the observed functional divarication. Consistently, in an NGF-deprived rat hippocampal neuronal model of Alzheimer Disease, MT2 could correct the biochemical abnormalities and sustain cell survival. Thus, NGF mimetics may reveal interesting investigational tools in neurobiology, as well as promising drug candidates.

Low molecular weight, non-peptidic agonists of TrkA receptor with NGF-mimetic activity.

Exploitation of the biologic activity of neurotrophins is desirable for medical purposes, but their protein nature intrinsically bears adverse pharmacokinetic properties. Here, we report synthesis and biologic characterization of a novel class of low molecular weight, non-peptidic compounds with NGF (nerve growth factor)-mimetic properties. MT2, a representative compound, bound to Trk (tropomyosin kinase receptor)A chain on NGF-sensitive cells, as well as in cell-free assays, at nanomolar concentrations and induced TrkA autophosphorylation and receptor-mediated internalization. MT2 binding involved at least two amino-acid residues within TrkA molecule. Like NGF, MT2 increased phosphorylation of extracellular signal-regulated kinase1/2 and Akt proteins and production of MKP-1 phosphatase (dual specificity phosphatase 1), modulated p38 mitogen-activated protein kinase activation, sustained survival of serum-starved PC12 or RDG cells, and promoted their differentiation. However, the intensity of such responses was heterogenous, as the ability of maintaining survival was equally possessed by NGF and MT2, whereas the induction of differentiation was expressed at definitely lower levels by the mimetic. Analysis of TrkA autophosphorylation patterns induced by MT2 revealed a strong tyrosine (Tyr)490 and a limited Tyr785 and Tyr674/675 activation, findings coherent with the observed functional divarication. Consistently, in an NGF-deprived rat hippocampal neuronal model of Alzheimer Disease, MT2 could correct the biochemical abnormalities and sustain cell survival. Thus, NGF mimetics may reveal interesting investigational tools in neurobiology, as well as promising drug candidates.

Entanglement spectrum, critical exponents, and order parameters in quantum spin chains.

We investigate the entanglement spectrum near criticality in finite quantum spin chains. Using finite size scaling we show that when approaching a quantum phase transition, the Schmidt gap, i.e., the difference between the two largest eigenvalues of the reduced density matrix λ(1), λ(2), signals the critical point and scales with universal critical exponents related to the relevant operators of the corresponding perturbed conformal field theory describing the critical point. Such scaling behavior allows us to identify explicitly the Schmidt gap as a local order parameter.

Cold-atom-induced control of an optomechanical device.

We consider a cavity with a vibrating end mirror and coupled to a Bose-Einstein condensate. The cavity field mediates the interplay between mirror and collective oscillations of the atomic density. We study the implications of this dynamics and the possibility of an indirect diagnostic. Our predictions can be observed in a realistic setup that is central to the current quest for mesoscopic quantumness.

Structural defects in ion chains by quenching the external potential: the inhomogeneous Kibble-Zurek mechanism.

The nonequilibrium dynamics of an ion chain in a highly anisotropic trap is studied when the transverse trap frequency is quenched across the value at which the chain undergoes a continuous phase transition from a linear to a zigzag structure. Within Landau theory, an equation for the order parameter, corresponding to the transverse size of the zigzag structure, is determined when the vibrational motion is damped via laser cooling. The number of structural defects produced during a linear quench of the transverse trapping frequency is predicted and verified numerically. It is shown to obey the scaling predicted by the Kibble-Zurek mechanism, when extended to take into account the spatial inhomogeneities of the ion chain in a linear Paul trap.

A new radioguided procedure for localization and surgical treatment of neck node metastasis of papillary thyroid cancer.

AIM OF THE STUDY: We intended to use a radioguided technique for pre-operative localization of neck node recurrences in patients with papillary thyroid cancer (PTC) already submitted to thyroidectomy and radioiodine treatment. PATIENTS AND METHODS: We selected 20 patients affected by PTC with evidence of neck nodes recurrences at ultrasound examination. Our method has been derived from the Radioguided Occult Lesion Localization technique used for pre-operative localization of occult breast lesions. The technique involves the inoculation of human albumin macroaggregates labeled with radioactive technetium (0.4 mCi in a volume of 0.05 ml) directly in the suspicious lesion, under ultrasound guidance. The persistence of the radioactive tracer in the nodes is confirmed by a scintigraphy performed 2 h after injection. During surgery, a gamma detecting probe is used to locate the suspicious lesions as "hot spots". RESULTS: Fifty lymph-nodes were injected with the tracer. All radiolabeled lymph-nodes were located and removed during surgery. At histology, metastasis of PTC was confirmed in 38/50 (76%) lymph-nodes. At least one metastatic lymph-node per patient was removed. In 8/20 (40%) patients, reactive lymphoid hyperplasia was found in 12/50 (24%) lymph-nodes. CONCLUSIONS: This radioguided technique has been highly effective for localization and surgical treatment of suspicious lymph-node detected at neck ultrasound and may play a valuable role in case of node metastases of thyroid cancer that show no radioiodine uptake.

[Renal biopsy: outpatient procedure?]. / Biopsia renale: possibile procedura ambulatoriale?

BACKGROUND: The renal biopsy is usually performed as an in-patient procedure, with patients admitted to hospital for at least 24 hours. We have carried out renal biopsies on two groups of patients. In the first group, patients rest in the hospital for 8 hours following the procedure. They are discharged after undergoing ultrasonography and a TC scan. These patients return to the hospital after 24 hours to verify possible post-biopsy complications. In the comparison group, patients remain in hospital for 24 hours. RESULTS: In both groups, the only observed complication was asymptomatic postbiopsy hematoma. No major complications were present in either group. CONCLUSIONS: In selected cases, renal biopsy performed by an expert practitioner as an outpatient procedure is safe and does not require 24-hour observation.

Nerve growth factor inhibits apoptosis in memory B lymphocytes via inactivation of p38 MAPK, prevention of Bcl-2 phosphorylation, and cytochrome c release.

Survival of memory B lymphocytes is tightly linked to the integrity of the Bcl-2 protein and is regulated by a nerve growth factor (NGF) autocrine circuit. In factor-starved memory B cells, the addition of exogenous NGF promptly induced p38 mitogen-activated protein kinase (MAPK), but not c-Jun N-terminal kinase (JNK), dephosphorylation. Conversely, withdrawal of endogenous NGF was followed by p38 MAPK activation and translocation onto mitochondria, whereby it combined with and phosphorylated Bcl-2, as assessed by co-immunoprecipitation and kinase assays in vivo and in vitro. Mitochondria isolated from human memory B cells, then exposed to recombinant p38 MAPK, released cytochrome c, as did mitochondria from Bcl-2-negative MDCK cells loaded with recombinant Bcl-2. Apoptosis induced by NGF neutralization could be blocked by the specific p38 MAPK inhibitor SB203580 or by Bcl-2 mutations in Ser-87 or Thr-56. These data demonstrate that the molecular mechanisms underlying the survival factor function of NGF critically rely upon the continuous inactivation of p38 MAPK, a Bcl-2-modifying enzyme.

NGF withdrawal induces apoptosis in CESS B cell line through p38 MAPK activation and Bcl-2 phosphorylation.

The sIgG(+) lymphoblastoid B cell line CESS spontaneously produces a high amount of NGF and expresses both high affinity (p140(Trk-A)) and low affinity (p75(NTR)) NGF receptors. Blocking NGF signals with neutralizing antibodies or specific Trk-A inhibitors induces a rapid phosphorylation of antiapoptotic Bcl-2 protein, followed by caspase activation, and apoptotic death of CESS cells. Bcl-2 phosphorylation in several sites within a approximately 60 aa "loop" domain of protein is known to regulate its antiapoptotic function. Accordingly, CESS cells expressing the loop deletional mutant cDNA constructs Bcl-2 Delta40-91 were completely resistant to apoptosis induced by NGF withdrawal, indicating that Bcl-2 phosphorylation is a critical event. NGF withdrawal induces p38 MAPK, but not JNK, activation in CESS cells, and SB203580, a specific inhibitor of p38 MAPK, is able to prevent both Bcl-2 phosphorylation and apoptosis, indicating that p38 MAPK is the enzyme responsible for these events.

Antibody response to Helicobacter pylori CagA and heat-shock proteins in determining the risk of gastric cancer development.

OBJECTIVE: To investigate whether the systemic antibody response to Helicobacter pylori heat shock protein B can be considered, in addition to anti cytotoxin-associated protein [CagA) antibody determination, a further serological marker of increased risk of gastric cancer development. METHODS: A total of 98 Giemsa positive Helicobacter pylori patients (28 with gastric cancer, 30 with duodenal ulcer and 40 with nonulcer dyspepsia) were studied. Serum samples obtained from all patients were tested for IgG antibodies to CagA (116 kDa), VacA [89kDa) and heat skock protein B (54 kDa) antigens of Helicobacter pylori by the Western blot technique. RESULTS: 26/28 patients [(92.9% with gastric carcinoma, 29/30 patients [96.7%) with duodenal ulcer and 30/40 patients (75.0%) with non-ulcer dyspepsia were seropositive for CagA protein. The prevalence of serum IgG antibody to CagA in the cancer patients was not significantly higher than in duodenal ulcer and non-ulcer dyspepsia patients. The prevalence of antibodies to VacA was not significantly different between gastric carcinoma and non-ulcer dyspepsia patients. In contrast the prevalence of systemic antibodies to heat skock protein B was significantly higher in gastric cancer patients (78.6%) than in duodenal ulcer (36.7%, p=0.002) or nonulcer dyspepsia patients (52.5%, p=0.029). CONCLUSIONS: The detection of antibodies to heat shock protein B is proposed as an additional test which, in association with the determination of serum antibodies to CagA, could help in determining the risk of developing severe gastroduodenal disease, and gastric cancer, in particular.

An outbreak in Italy of botulism associated with a dessert made with mascarpone cream cheese.

In the late 1996, an outbreak of botulism affected eight young people (age of patients ranged from 6 to 23 years) in Italy. The onset of the illness was the same for all of these patients: gastrointestinal symptoms (nausea and vomiting) followed by neurologic symptoms. The most common neurologic symptoms were dysphagia, respiratory failure (100%), diplopia (87%), dysarthria, ptosis (75%) and mydriasis (50%). All patients required mechanical ventilation. Botulinum toxin was detected from two of respectively five sera and six stool samples analysed, while spores of Clostridium botulinum type A were recovered from all patient' faeces. The epidemiological investigation led to suspect a commercial cream cheese ('mascarpone') as a source of botulinum toxin: indeed, it had been eaten by all the patients before onset of the symptoms, either alone or as the (uncooked) ingredient of a dessert, 'tiramisù'. Botulinum toxin type A was found in the 'tiramisù' leftover consumed by two patients and in some mascarpone cheese samples collected from the same retail stores where the other patients had previously bought their cheeses. A break in the cold-chain at the retail has likely caused germination of C. botulinum spores contaminating the products, with subsequent production of the toxin. One of the patients died, while the others recovered very slowly. Prompt international alerting and recall of the mascarpone cheese prevented the spread of the outbreak due to the wide range of distribution, demonstrating the importance of a rapid surveillance system. None of the people complaining of symptoms after the public alert resulted positive for botulinum spores and toxin.

Interferon-alpha-induced inhibition of B16 melanoma cell proliferation: interference with the bFGF autocrine growth circuit.

The molecular mechanisms underlying the growth inhibition induced by interferon-alpha (IFN-alpha) in B16 murine melanoma cells were investigated. IFN-alpha did not induce cell apoptosis, but strongly interfered with the synthesis of basic fibroblast growth factor (bFGF), which acts as an autocrine growth factor in this system. Inhibition of bFGF synthesis was observed at the same concentrations (50-500 pM, 10-100 U/ml) of IFN-alpha able to induce growth arrest of B16 melanoma cells. Although the synthesis of acidic (a)FGF was only slightly affected by IFN-alpha, the cytokine induced release of an aFGF-related low-molecular-weight peptide, which was able to interfere with bFGF binding to surface receptors. Thus, the molecular mechanisms of IFN-alpha activity on melanoma cells include a specific modulation of the bFGF autocrine circuit.

[Solitary breast metastasis from a plasmacytoma: fine needle cytological diagnosis]. / Metastasi mammaria solitaria di un Plasmocitoma: diagnosi citologica con ago sottile.

We report a case of an extramedullary plasmocytoma of the breast in a 71 years old woman who suffered from six years of an osseous plasmocytoma. This lesion is rare and is associated with a serum monoclonal lambda gammopathy. A correct diagnosis of metastasis to the breast is important since the treatment of primary and secondary malignancies of the breast is different.

Functional epitope mapping of human interleukin-1 beta by surface plasmon resonance.

A panel of monoclonal antibodies to human IL-1 beta has been used to probe its conformational and functional characteristics. Real time antibody-protein interaction was assessed by surface plasmon resonance with a BIAcore apparatus, in order to determine the kinetic and thermodynamic parameters of the interaction and to map the recognition sites of the antibodies on the IL-1 beta surface. Topological analysis was thus compared to the inhibitory capacity of antibodies for IL-1 beta bioactivity and binding to the activating receptor IL-1RI. This functional mapping analysis allows the following hypothesis. At least two discrete areas of IL-1 beta, located within the sequences 133-147 and 177-186 (as defined by mAbs MhC1 and BRhD2, respectively), are apparently involved in IL-1RI-independent agonist activity, and thus possibly take part in the interaction with the receptor accessory protein IL-1RAcP. Another area in the 133-147 sequence (defined by mAb BRhC3) is involved in agonist binding to its receptor CDw121a (IL-1RI), whereas a site recognized by mAb BRhG5 within the sequence 218-243 is selectively responsible for non-agonist binding to the activating receptor. The loop between the 4th and the 5th beta-strand, at the open end of the IL-1 beta-barrel structure, may possibly take part in both non-agonist binding to IL-1RI and in the interaction with IL-1RAcP.

[Effectiveness of and tolerability to oral desmopressin in the treatment of central diabetes insipidus]. / Efficacia e tollerabilità della desmopressina in formulazione orale nel trattamento del diabete insipido centrale.

Intranasal desmopressin represents the treatment of choice in Central Diabetes Insipidus. Nevertheless, this route of administration bears some practical disadvantage, linked to either difficult delivering technique, or the status of nasal mucose. The antidiuretic effectiveness of oral desmopressin has been recently demonstrated, both in experimental animals and in man. In our study we compared oral vs. intranasal desmopressin efficacy in 13 patients affected by Central Diabetes Insipidus. The results show that the peroral administration of Desmopressin at a mean dose of 500-600 micrograms/die determines an antidiuretic effect comparable to that of intranasal route, without affecting body weight, arterial pressure and chemical analysis. Side effects, generally limited to the first week of treatment, were described (nausea, vomiting, headache, dizziness [corrected], bitter taste, epygastralgia, asthenia, epystassis), inducing 4/13 patients to withdrawal the trial.