Power shift and connectivity changes in healthy aging during resting-state EEG.

The neural activity of human brain changes in healthy individuals during aging. The most frequent variation in patterns of neural activity are a shift from posterior to anterior areas and a reduced asymmetry between hemispheres. These patterns are typically observed during task execution and by using functional magnetic resonance imaging data. In the present study we investigated whether analogous effects can also be detected during rest and by means of source-space time series reconstructed from electroencephalographic recordings. By analyzing oscillatory power distribution across the brain we indeed found a shift from posterior to anterior areas in older adults. We additionally examined this shift by evaluating connectivity and its changes with age. The findings indicated that inter-area connections among frontal, parietal and temporal areas were strengthened in older individuals. A more complex pattern was shown in intra-area connections, where age-related activity was enhanced in parietal and temporal areas, and reduced in frontal areas. Finally, the resulting network exhibits a loss of modularity with age. Overall, the results extend to resting-state condition the evidence of an age-related shift of brain activity from posterior to anterior areas, thus suggesting that this shift is a general feature of the aging brain rather than being task-specific. In addition, the connectivity results provide new information on the reorganization of resting-state brain activity in aging.

Decoding location-specific and location-invariant stages of numerosity processing in subitizing.

Extracting the number of objects in perceived scenes is a fundamental cognitive ability. Number processing is proposed to rely on two consecutive stages: an early object location map that captures individuated objects in a location-specific way and a subsequent location-invariant representation that captures numerosity at an abstract level. However, it is unclear whether this framework applies to small numerosities that can be individuated at once ("subitized"). Here, we reanalyzed data from two electroencephalography (EEG) experiments using multivariate pattern decoding to identify location-specific and location-invariant stages of numerosity processing in the subitizing range. In these experiments, one to three targets were presented in the left or right hemifield, which allowed for decoding target numerosity within each hemifield separately (location specific) or across hemifields (location invariant). Experiment 1 indicated the presence of a location-specific stage (180-200 ms after stimulus), followed by a location-invariant stage (300 ms after stimulus). A time-by-channel searchlight analysis revealed that the early location-specific stage is most evident at occipital channels, whereas the late location-invariant stage is most evident at parietal channels. Experiment 2 showed that both location-specific and location-invariant components are engaged only during tasks that explicitly require numerosity processing, ruling out automatic, and passive recording of numerosity. These results suggest that numerosity coding in subitizing is strongly grounded on an attention-based, location-specific stage. This stage overlaps with the subsequent activation of a location-invariant stage, where a full representation of numerosity is finalized. Taken together, our findings provide clear evidence for a temporal and spatial segregation of location-specific and location-invariant numerosity coding of small object numerosities.

Frequency and power of human alpha oscillations drift systematically with time-on-task.

Oscillatory neural activity is a fundamental characteristic of the mammalian brain spanning multiple levels of spatial and temporal scale. Current theories of neural oscillations and analysis techniques employed to investigate their functional significance are based on an often implicit assumption: In the absence of experimental manipulation, the spectral content of any given EEG- or MEG-recorded neural oscillator remains approximately stationary over the course of a typical experimental session (∼1 h), spontaneously fluctuating only around its dominant frequency. Here, we examined this assumption for ongoing neural oscillations in the alpha-band (8-13 Hz). We found that alpha peak frequency systematically decreased over time, while alpha-power increased. Intriguingly, these systematic changes showed partial independence of each other: Statistical source separation (independent component analysis) revealed that while some alpha components displayed concomitant power increases and peak frequency decreases, other components showed either unique power increases or frequency decreases. Interestingly, we also found these components to differ in frequency. Components that showed mixed frequency/power changes oscillated primarily in the lower alpha-band (∼8-10 Hz), while components with unique changes oscillated primarily in the higher alpha-band (∼9-13 Hz). Our findings provide novel clues on the time-varying intrinsic properties of large-scale neural networks as measured by M/EEG, with implications for the analysis and interpretation of studies that aim at identifying functionally relevant oscillatory networks or at driving them through external stimulation.

Influence of the Insertion Method of Aryl-Extended Calix[4]pyrroles into Liposomal Membranes on Their Properties as Anion Carriers.

We disclose the results of our investigations on the influence that the insertion method of aryl-extended calix[4]pyrrole into liposomal membranes exerts on their properties as anion carriers. We use the standard HPTS assay to assess the transport properties of the carriers. We show that the post-insertion of the carrier, as DMSO solution, assigns better transport activities to the "two-wall" α,α-aryl-extended calix[4]pyrrole 1 compared to the "four-wall" α,α,α,α-counterpart 2. Notably, opposite results were obtained when the carriers were pre-inserted into the liposomal membranes. We assign this difference to an improved incorporation of carrier 2 into the membrane when delivered by the pre-insertion method. On the other hand, carrier 1 shows comparable levels of transport independently of the method used for its incorporation. Thus, an accurate comparison of the chloride transport activities featured by these two carriers demands their pre-incorporation in the liposomal membranes. In contrast, using the lucigenin assay with the pre-insertion method both carriers displayed similar transport efficiencies.

Astrocytes in Motor Neuron Diseases.

Motor neuron disorders are highly debilitating and mostly fatal conditions for which only limited therapeutic options are available. To overcome this limitation and develop more effective therapeutic strategies, it is critical to discover the pathogenic mechanisms that trigger and sustain motor neuron degeneration with the greatest accuracy and detail. In the case of Amyotrophic Lateral Sclerosis (ALS), several genes have been associated with familial forms of the disease, whilst the vast majority of cases develop sporadically and no defined cause can be held responsible. On the contrary, the huge majority of Spinal Muscular Atrophy (SMA) occurrences are caused by loss-of-function mutations in a single gene, SMN1. Although the typical hallmark of both diseases is the loss of motor neurons, there is increasing awareness that pathological lesions are also present in the neighbouring glia, whose dysfunction clearly contributes to generating a toxic environment in the central nervous system. Here, ALS and SMA are sequentially presented, each disease section having a brief introduction, followed by a focussed discussion on the role of the astrocytes in the disease pathogenesis. Such a dissertation is substantiated by the findings that built awareness on the glial involvement and how the glial-neuronal interplay is perturbed, along with the appraisal of this new cellular site for possible therapeutic intervention.

Disruption of the astrocytic TNFR1-GDNF axis accelerates motor neuron degeneration and disease progression in amyotrophic lateral sclerosis.

Considerable evidence indicates that neurodegeneration in amyotrophic lateral sclerosis (ALS) can be conditioned by a deleterious interplay between motor neurons and astrocytes. Astrocytes are the major glial component in the central nervous system (CNS) and fulfill several activities that are essential to preserve CNS homeostasis. In physiological and pathological conditions, astrocytes secrete a wide range of factors by which they exert multimodal influences on their cellular neighbours. Among others, astrocytes can secrete glial cell line-derived neurotrophic factor (GDNF), one of the most potent protective agents for motor neurons. This suggests that the modulation of the endogenous mechanisms that control the production of astrocytic GDNF may have therapeutic implications in motor neuron diseases, particularly ALS. In this study, we identified TNF receptor 1 (TNFR1) signalling as a major promoter of GDNF synthesis/release from human and mouse spinal cord astrocytes in vitro and in vivo To determine whether endogenously produced TNFα can also trigger the synthesis of GDNF in the nervous system, we then focused on SOD1G93A ALS transgenic mice, whose affected tissues spontaneously exhibit high levels of TNFα and its receptor 1 at the onset and symptomatic stage of the disease. In SOD1G93A spinal cords, we verified a strict correlation in the expression of the TNFα, TNFR1 and GDNF triad at different stages of disease progression. Yet, ablation of TNFR1 completely abolished GDNF rises in both SOD1G93A astrocytes and spinal cords, a condition that accelerated motor neuron degeneration and disease progression. Our data suggest that the astrocytic TNFR1-GDNF axis represents a novel target for therapeutic intervention in ALS.

A group study on the effects of a short multi-domain cognitive training in healthy elderly Italian people.

BACKGROUND: Alongside physiological cognitive ageing, nowadays there is an alarming increase in the incidence of dementia that requires communities to invest in its prevention. The engagement in cognitively stimulating activities and strong social networks has been identified among those protective factors promoting successful cognitive ageing. One aspect regarding cognitive stimulation concerns the relevance of the frequency of an external intervention. For this reason, the aim of this study was to evaluate the efficacy of a 3-month cognitive training program, once per week, in a group of healthy elderly aged over 60 years old. Their results were compared with those of a passive control group. METHODS: The training consisted of a weekly session of multi-domain and ecological cognitive exercises performed in small homogenous (i.e. same cognitive level) groups. The scores obtained in a neuropsychological assessment by the experimental and control groups were compared at pre- and post-training. In addition, by means of a questionnaire, we also evaluated the indirect effect of the program on participants' mood, socialization and perceived impact on everyday activities. RESULTS: Overall, the experimental group showed a general improvement in cognitive functioning following the training program, even with the frequency of once per week. Greater improvements were observed mainly on executive functions and short-term memory, but general cognitive functioning and non-verbal reasoning also showed a tendency to an improvement. It is noteworthy that a majority of the participants reported to have subjectively experienced an improvement in their everyday life and a positive influence on both mood and socialization. CONCLUSIONS: These results show that even a low-intensity training program is able to promote some of the protective factors that support successful cognitive ageing. Moreover, this multi-domain approach proved to be an excellent training method to transfer gains not only to other cognitive domains, but also to everyday living. TRIAL REGISTRATION: NCT03771131 ; the study was retrospectively registered on December 7th 2018.

Performance Testing of Hydraulic Cements: Measuring Sulfate Resistance.

The sulfate resistance of cements used in the construction industry is traditionally assessed by measuring the expansion of a prism of 280 mm (11inch) length and 25 mm (1 inch) square cross section immersed in a sodium sulfate solution for at least one year. The duration of the experiment limits this test from being used as a performance-based determination of innovative mixtures of cementitious materials. In response to the need for a more rapid test protocol, the National Institute of Standards and Technology (NIST) has developed a new test method that measures the expansion of smaller bars (10 mm × 10 mm × 60 mm) made with neat cement paste. With these bars, similar expansion is achieved in less than 3 months, reducing the test duration by a factor of at least 4. This accelerated test method provides more rapid results consistent with the traditional test procedure, allowing for a shorter decision time and the screening of more materials.

Role of Materials Selection in the Resilience of the Built Environment.

The resilience of U.S. communities, defined as the "ability to withstand and recover rapidly from disruptive events," is directly dependent upon the ability of the built environment to maintain and support the functions upon which modern society relies. The built environment includes both buildings and infrastructure systems. Buildings are important to the extent that they provide critical services (e.g., hospitals, police stations, and mercantile/office buildings). Infrastructure systems include the physical networks, systems, and structures that make up transportation, energy, communications, water, wastewater, and other systems that support the functionality of community social institutions. As local decision makers consider resilience, choices often involve cost-benefit decisions among materials with differing initial and lifetime costs, as well as differing performance characteristics. This paper will describe the important role that materials science plays in enabling informed local decisions for resilience, as well as identify knowledge gaps, such as the service life of the materials designed for new construction or system repair.

Redirecting T cells with Chimeric Antigen Receptor (CAR) for the treatment of childhood acute lymphoblastic leukemia.

Acute lymphoblastic leukemia (ALL) is the most common cancer in children. Nowadays the survival rate is around 85%. Nevertheless, an urgent clinical need is still represented by primary refractory and relapsed patients who do not significantly benefit from standard approaches, including chemo-radiotherapy and hematopoietic stem cell transplantation (HSCT). For this reason, immunotherapy has so far represented a challenging novel treatment opportunity, including, as the most validated therapeutic options, cancer vaccines, donor-lymphocyte infusions and tumor-specific immune effector cells. More recently, unexpected positive clinical results in ALL have been achieved by application of gene-engineered chimeric antigen expressing (CAR) T cells. Several CAR designs across different trials have generated similar response rates, with Complete Response (CR) of 60-90% at 1 month and an Event-Free Survival (EFS) of 70% at 6 months. Relevant challenges anyway remain to be addressed, such as amelioration of technical, cost and feasibility aspects of cell and gene manipulation and the necessity to face the occurrence of relapse mechanisms. This review describes the state of the art of ALL immunotherapies, the novelties in terms of gene manipulation approaches and the problems emerged from early clinical studies. We describe and discuss the process of clinical translation, including the design of a cell manufacturing protocol, vector production and regulatory issues. Multiple antigen targeting and combination of CAR T cells with molecular targeted drugs have also been evaluated as latest strategies to prevail over immune-evasion.

Tetanus vaccination, antibody persistence and decennial booster: a serosurvey of university students and at-risk workers.

The aim of the present research is to verify the immune status against tetanus in students and workers exposed to risk and to ascertain whether a decennial booster is necessary. Antibodies against tetanus were measured in 1433 workers and students of Padua University (Italy). The enrolment criterion was the ability to provide a booklet of vaccinations released by a public health office. The influence of age, gender, the number of vaccine doses, and the interval since the last dose was determined. Ten years after the last dose, the majority of subjects (95·0%) displayed an antibody titre above the protective level (⩾0·10 IU/ml), and half of these (49·1%) had a long-term protective level (⩾1·0 IU/ml). According to our data, titre depends on both the number of vaccine doses and the interval since the last dose (P < 0·0001). Five vaccine doses and an interval of at least 10 years since the last dose are predictive of a long-term protective titre in absence of a booster (1·97 IU/ml). These data suggest that when primary series are completed, a decennial booster is unnecessary for up to 20 years. Furthermore, we recommend measuring the antibody level before a new booster is given to prevent problems related to over-immunisation.

Arginine methylation next to the PY-NLS modulates Transportin binding and nuclear import of FUS.

Fused in sarcoma (FUS) is a nuclear protein that carries a proline-tyrosine nuclear localization signal (PY-NLS) and is imported into the nucleus via Transportin (TRN). Defects in nuclear import of FUS have been implicated in neurodegeneration, since mutations in the PY-NLS of FUS cause amyotrophic lateral sclerosis (ALS). Moreover, FUS is deposited in the cytosol in a subset of frontotemporal lobar degeneration (FTLD) patients. Here, we show that arginine methylation modulates nuclear import of FUS via a novel TRN-binding epitope. Chemical or genetic inhibition of arginine methylation restores TRN-mediated nuclear import of ALS-associated FUS mutants. The unmethylated arginine-glycine-glycine domain preceding the PY-NLS interacts with TRN and arginine methylation in this domain reduces TRN binding. Inclusions in ALS-FUS patients contain methylated FUS, while inclusions in FTLD-FUS patients are not methylated. Together with recent findings that FUS co-aggregates with two related proteins of the FET family and TRN in FTLD-FUS but not in ALS-FUS, our study provides evidence that these two diseases may be initiated by distinct pathomechanisms and implicates alterations in arginine methylation in pathogenesis.

PTEN depletion decreases disease severity and modestly prolongs survival in a mouse model of spinal muscular atrophy.

Spinal muscular atrophy (SMA) is the second most common genetic cause of death in childhood. However, no effective treatment is available to halt disease progression. SMA is caused by mutations in the survival motor neuron 1 (SMN1) gene. We previously reported that PTEN depletion leads to an increase in survival of SMN-deficient motor neurons. Here, we aimed to establish the impact of PTEN modulation in an SMA mouse model in vivo. Initial experiments using intramuscular delivery of adeno-associated vector serotype 6 (AAV6) expressing shRNA against PTEN in an established mouse model of severe SMA (SMNΔ7) demonstrated the ability to ameliorate the severity of neuromuscular junction pathology. Subsequently, we developed self-complementary AAV9 expressing siPTEN (scAAV9-siPTEN) to allow evaluation of the effect of systemic suppression of PTEN on the disease course of SMA in vivo. Treatment with a single injection of scAAV9-siPTEN at postnatal day 1 resulted in a modest threefold extension of the lifespan of SMNΔ7 mice, increasing mean survival to 30 days, compared to 10 days in untreated mice. Our data revealed that systemic PTEN depletion is an important disease modifier in SMNΔ7 mice, and therapies aimed at lowering PTEN expression may therefore offer a potential therapeutic strategy for SMA.

Comparative study of methods to measure the density of Cementious powders.

The accurate measurement of the density of hydraulic cement has an essential role in the determination of concrete mixture proportions. As more supplementary cementitious materials (SCM), such as fly ash, and slag, or cement replacements materials such as limestone and calcium carbonate are used in blended cements, knowledge of the density of each powder or of the blended cement would allow a more accurate calculation of the proportions of a concrete mixture by volume instead of by mass. The current ASTM standard for measuring cement density is the "Test Method for Density of Hydraulic Cements" (ASTM C188-14), which utilizes a liquid displacement method to measure the volume of the cement. This paper will examine advantageous modifications of the current ASTM test, by alcohol substitutions for kerosene. In addition, a gas (helium) pycnometry method is evaluated as a possible alternative to the current standard. The described techniques will be compared to determine the most precise and reproducible method for measuring the density of hydraulic cements and other powders.

The multifaceted role of glial cells in amyotrophic lateral sclerosis.

Despite indisputable progress in the molecular and genetic aspects of amyotrophic lateral sclerosis (ALS), a mechanistic comprehension of the neurodegenerative processes typical of this disorder is still missing and no effective cures to halt the progression of this pathology have yet been developed. Therefore, it seems that a substantial improvement of the outcome of ALS treatments may depend on a better understanding of the molecular mechanisms underlying neuronal pathology and survival as well as on the establishment of novel etiological therapeutic strategies. Noteworthy, a convergence of recent data from multiple studies suggests that, in cellular and animal models of ALS, a complex pathological interplay subsists between motor neurons and their non-neuronal neighbours, particularly glial cells. These observations not only have drawn attention to the physiopathological changes glial cells undergo during ALS progression, but they have moved the focus of the investigations from intrinsic defects and weakening of motor neurons to glia-neuron interactions. In this review, we summarize the growing body of evidence supporting the concept that different glial populations are critically involved in the dreadful chain of events leading to motor neuron sufferance and death in various forms of ALS. The outlined observations strongly suggest that glial cells can be the targets for novel therapeutic interventions in ALS.

Better safe than sorry? The safety margin surrounding the body is increased by anxiety.

The defensive peripersonal space represents a "safety margin" advantageous for survival. Its spatial extension and the possible relationship with personality traits have never been investigated. Here, in a population of 15 healthy human participants, we show that the defensive peripersonal space has a sharp boundary, located between 20 and 40 cm from the face, and that within such space there is a thin, "highest-risk area" closest to the face (i.e., an "ultra-near" defensive space). Single-subject analysis revealed clear interindividual differences in the extension of such peripersonal space. These differences are positively related to individual variability in trait anxiety. These findings point to the potential for measuring a range of defensive behaviors in relation to individual levels of anxiety. Such measures will allow developing procedures to test risk assessment abilities, particularly in professions that require reacting quickly to aversive stimuli near the body, such as firemen, policemen, and military officers. This may also lead to possible interventions to improve their performance under pressure.

The BH4 domain of Bcl-X(L) rescues astrocyte degeneration in amyotrophic lateral sclerosis by modulating intracellular calcium signals.

Collective evidence indicates that motor neuron degeneration in amyotrophic lateral sclerosis (ALS) is non-cell-autonomous and requires the interaction with the neighboring astrocytes. Recently, we reported that a subpopulation of spinal cord astrocytes degenerates in the microenvironment of motor neurons in the hSOD1(G93A) mouse model of ALS. Mechanistic studies in vitro identified a role for the excitatory amino acid glutamate in the gliodegenerative process via the activation of its inositol 1,4,5-triphosphate (IP(3))-generating metabotropic receptor 5 (mGluR5). Since non-physiological formation of IP(3) can prompt IP(3) receptor (IP(3)R)-mediated Ca(2+) release from the intracellular stores and trigger various forms of cell death, here we investigated the intracellular Ca(2+) signaling that occurs downstream of mGluR5 in hSOD1(G93A)-expressing astrocytes. Contrary to wild-type cells, stimulation of mGluR5 causes aberrant and persistent elevations of intracellular Ca(2+) concentrations ([Ca(2+)](i)) in the absence of spontaneous oscillations. The interaction of IP(3)Rs with the anti-apoptotic protein Bcl-X(L) was previously described to prevent cell death by modulating intracellular Ca(2+) signals. In mutant SOD1-expressing astrocytes, we found that the sole BH4 domain of Bcl-X(L), fused to the protein transduction domain of the HIV-1 TAT protein (TAT-BH4), is sufficient to restore sustained Ca(2+) oscillations and cell death resistance. Furthermore, chronic treatment of hSOD1(G93A) mice with the TAT-BH4 peptide reduces focal degeneration of astrocytes, slightly delays the onset of the disease and improves both motor performance and animal lifespan. Our results point at TAT-BH4 as a novel glioprotective agent with a therapeutic potential for ALS.

Viral delivery of antioxidant genes as a therapeutic strategy in experimental models of amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder with no effective treatment to date. Despite its multi-factorial aetiology, oxidative stress is hypothesized to be one of the key pathogenic mechanisms. It is thus proposed that manipulation of the expression of antioxidant genes that are downregulated in the presence of mutant SOD1 may serve as a therapeutic strategy for motor neuronal protection. Lentiviral vectors expressing either PRDX3 or NRF2 genes were tested in the motor neuronal-like NSC34 cell line, and in the ALS tissue culture model, NSC34 cells expressing the human SOD1(G93A) mutation. The NSC34 SOD1(G93A) cells overexpressing either PRDX3 or NRF2 showed a significant decrease in endogenous oxidation stress levels by 40 and 50% respectively compared with controls, whereas cell survival was increased by 30% in both cases. The neuroprotective potential of those two genes was further investigated in vivo in the SOD1(G93A) ALS mouse model, by administering intramuscular injections of adenoassociated virus serotype 6 (AAV6) expressing either of the target genes at a presymptomatic stage. Despite the absence of a significant effect in survival, disease onset or progression, which can be explained by the inefficient viral delivery, the promising in vitro data suggest that a more widespread CNS delivery is needed.

Pharmacogenetics of tenofovir drug transporters in the context of HBV: Is there an impact?

BACKGROUND: Current treatments for chronic hepatitis B management include orally administered nucleos(t)ide analogues, such as tenofovir (TDF), which is an acyclic adenine nucleotide analogue used both in HBV and human immune deficiency virus (HIV). The course of HBV infection is mainly dependent on viral factors, such as HBV genotypes, immunological features and host genetic variables, but a few data are available in the context of HBV, in particular for polymorphisms of genes encoding proteins involved in drug metabolism and elimination. Consequently, the aim of this study was to evaluate the potential impact of genetic variants on TDF plasma and urine concentrations in patients with HBV, considering the role of HBV genotypes. METHODS: A retrospective cohort study at the Infectious Disease Unit of Amedeo di Savoia Hospital, Torino, Italy, was performed. Pharmacokinetic analyses were performed through liquidi chromatography, whereas pharmacogenetic analyses through real-time PCR. FINDINGS: Sixty - eight patients were analyzed: ABCC4 4976 C>T genetic variant showed an impact on urine TDF drug concentrations (p = 0.014). In addition, SLC22A6 453 AA was retained in the final regression multivariate model considering factors predicting plasma concentrations, while ABCC4 4976 TC/CC was the only predictor of urine concentrations in the univariate model. INTERPRETATION: In conclusion, this is the first study showing a potential impact of genetic variants on TDF plasma and urine concentrations in the HBV context, but further studies in different and larger cohorts of patients are required.

The MyD88 rs6853 and TIRAP rs8177374 polymorphic sites are associated with resistance to human pulmonary tuberculosis.

Toll-like receptors recognize several components of Mycobacterium tuberculosis, the main causative agent of tuberculosis. The signaling pathways leading to activation of the immune response require the MyD88 and TIRAP genes. The hypothesis that polymorphic variants of these genes influenced resistance to pulmonary tuberculosis was tested by a case-control study (400 cases and 400 controls). Heterozygosity at the polymorphic sites MyD88 rs6853 (alleles: A, G) or TIRAP rs8177374 (S180L) (alleles: C, T) is associated with resistance to pulmonary tuberculosis (P: 7.8 × 10(-8) and 2 × 10(-6), respectively). Double heterozygosity confers higher protection levels (P: 10(-14) to 2 × 10(-16)). The logistic regression model displayed that the double homozygous genotype GG/TT predisposes to the disease (odds ratio (OR): 5.78) and the AG/TT genotype combination neutralizes the protective activity exerted by AG (OR: 3.05). The same model showed that the risk of developing the disease increases with age from 31-40 years to 71-80 years (OR: 1.32-13.59).