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Neuronal ceroid lipofuscinosis (NCL) is an umbrella term referring to the most frequent childhood-onset neurodegenerative diseases, which are also the main cause of childhood dementia. Although the molecular mechanisms underlying the NCLs remain elusive, evidence is increasingly pointing to shared disease pathways and common clinical features across the disease forms. The characterization of pathological mechanisms, disease modifiers, and biomarkers might facilitate the development of treatment strategies. The DEM-AGING project aims to define molecular signatures in NCL and expedite biomarker discovery with a view to identifying novel targets for monitoring disease status and progression and accelerating clinical trial readiness in this field. In this study, we fused multiomic assessments in established NCL models with similar data on the more common late-onset neurodegenerative conditions in order to test the hypothesis of shared molecular fingerprints critical to the underlying pathological mechanisms. Our aim, ultimately, is to combine data analysis, cell models, and omic strategies in an effort to trace new routes to therapies that might readily be applied in the most common forms of dementia. [ABSTRACT FROM AUTHOR]

During neuronal development, neuronal cells read extracellular stimuli from the micro/nano-environment within which they exist, retrieving essential directionality and wiring information. Here, focal adhesions (FAs -protein clusters anchoring integrins to cytoskeleton) act as sensors, by integrating signals from both the extracellular matrix environment and chemotactic factors, contributing to the final neuronal pathfinding and migration. In the processes that orchestrate neuronal development, the important function of ubiquitin E3A ligase (UBE3A) is emerging. UBE3A has crucial functions in the brain and changes in its expression levels lead to neurodevelopmental disorders: the lack of UBE3A leads to Angelman syndrome (AS, OMIN 105830), while its increase causes autisms (Dup15q-autism). By using nano/micro-structured anisotropic substrates we previously showed that UBE3A-deficient neurons have deficits in contact guidance (Tonazzini et al, Mol Autism 2019). Here, we investigate the adhesion and migration dynamics of UBE3A-silenced SH-SY5Y neuroblastoma cells in vitro by exploiting nano/micro-grooved substrates. We analyze the molecular processes regulating the development of FAs by transfection with EGFP-vector encoding for paxillin, a protein of FA clusters, and by live-cell total-internal-reflection-fluorescence microscopy. We show that UBE3A-silenced SH-SY5Y cells have impaired FA morphological development and pathway activation, which lead to a delayed adhesion and also explain the defective contact guidance in response to directional topographical stimuli. However, UBE3A-silenced SH-SY5Y cells show an overall normal migration behavior, in terms of speed and ability to follow the GRs directional stimulus. Only the collective cell migration upon cell gaps was slightly delayed for UBE3Ash SHs. Overall, the deficits of UBE3Ash SHS-SY5Y cells in FA maturation/sensing and in collective migration may have patho-physiological implications, in AS condition, considering the much more complex stimuli that neurons find in vivo during the neurodevelopment. [ABSTRACT FROM AUTHOR]

The replica exchange molecular dynamics (REMD) approach is applied to four oligomeric peptide systems. At physiologically relevant temperature values REMD samples conformation space and aggregation transitions more efficiently than constant temperature molecular dynamics (CTMD). During the aggregation process the energetic and structural properties are essentially the same in REMD and CTMD. A condensation stage toward disordered aggregates precedes the β-sheet formation. Two order parameters, borrowed from anisotropic fluid analysis, are used to monitor the aggregation process. The order parameters do not depend on the peptide sequence and length and therefore allow to compare the amyloidogenic propensity of different peptides.© 2004 American Institute of Physics. [ABSTRACT FROM AUTHOR]

We study the relation between the chirality of a discotic mesogen and that of the chiral columnar aggregates that they can spontaneously form by self-assembly. We discuss first the different types of chiral columns that can be in principle obtained. We introduce then a simple two-site Gay–Berne dissymmetric molecular model where chirality can be easily varied and perform extensive NPT Monte Carlo simulations of samples of these particles for different chiralities. At low temperatures we find nematic discotic and columnar mesophases formed by overall chiral columns and we analyze the results in terms of suitably defined observables and chiral correlation functions. We find that, at least for our model system, the columnar chirality is not originating from a regular helical or spiral arrangement of particles but it is mainly due to one-particle high-chirality defects separated by low-chirality domains. © 2003 American Institute of Physics. [ABSTRACT FROM AUTHOR]

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Background: Rhabdoid colorectal carcinoma (RC) is a rare lesion localized to the proximal colon of patients with a mean age at diagnosis of around 70 years. This tumor shows an aggressive behavior with an overall survival period shorter than 12 months. The diagnostic hallmark is the presence of rhabdoid cells. Alterations in chromatin remodeling (SMARCB1) and in the centrosome structure (CROCC) are reported in RC usually BRAFmut and MSI-H. RKO intestinal neoplastic cells culture (BRAFmut, SMARCB1wt, MSI-H) with CROCC knockdown exhibit rhabdoid features and develop prominent projections from the edge of the cell.Methods: Here, we investigated two cases of CROCCmutSMARCB1wt RC by scanning and transmission electron microscopy (SEM, TEM).Results: TEM confirmed the diagnostic presence of intermediate cytoplasmic filaments and nucleolar margination. SEM showed cellular protrusions (lamellipodia) in the intercellular spaces not evident at light microscopy.Conclusions: These protrusions CROCC-related might represent the pathogenetic mechanism underlying the rhabdoid aggressive behavior, independently of tumor staging. To our knowledge, the SEM technique was applied in the study of this neoplasm for the first time. [ABSTRACT FROM AUTHOR]

Summary: Introduction: Physical inactivity is a risk factor for obesity, overweight and for a number of chronic diseases. Although primary care may be an ideal setting to encourage people to do more exercise, there are still significant gaps in the literature on the effectiveness of primary care‐initiated policies to promote physical activity. Methods: In this paper, we systematically review and meta‐analyse the evidence on the impact of primary care‐initiated interventions to promote exercise on the body mass index and on physical activity energy expenditure levels among people at an increased risk of having potentially disabling non‐communicable diseases (but healthy enough to exercise). Results: We find that such interventions reduce body mass index by about 0.21 kg m−2 (95% confidence interval: −0.41 to −0.01) and increase physical activity‐related energy expenditure (based mostly on self‐recall) by about 1.77 metabolic equivalent of task‐hours a week (95% confidence interval: 0.58 to 2.95). Discussion: This study suggests that primary care‐initiated interventions promoting physical activity can be an effective strategy to reduce weight and increase exercise levels in this population group, although the question remains about whether such interventions can be cost‐effective. [ABSTRACT FROM AUTHOR]

Human papillomavirus-associated (HPV+) head and neck squamous cell carcinoma (HNSCC) is the fastest rising cancer in North America, with generally favourable prognosis. There is significant interest in treatment de-escalation for these patients, but 15-30% of patients recur after primary treatment, reflecting a need for improved risk-stratification tools. We sought to develop a molecular test to predict survival of patients with newly diagnosed HPV+ HNSCC. We created an RNA-based prognostic score which was successfully validated in six cohorts comprising a total of 906 patients, including blinded external validations in a large retrospective cohort (n = 269) and in a prospective cohort (BD2Decide, NCT02832102, n = 286). We assessed the feasibility of using IHC to calculate the UWO3 score using an immunohistochemistry-based tissue microarray cohort (n = 197). Transcriptomic data from two aggressive treatment de-escalation cohorts were used to assess ability of UWO3 to identify patients who recur. Multivariate Cox models were used to assess the associations between the UWO3 score and outcomes, adjusting for potential confounders. Analysis of HPV+ HNSCC tumours revealed three distinct tumor microenvironment subtypes: immune rich, immune desert, and mixed. A three gene immune score (UWO3) classified patients into the three immune groups and was strongly associated with disease-free survival in six datasets, including blinded validation in a retrospective and a prospective dataset. Pooled analysis (n = 906) demonstrated that the immune rich group had superior disease-free survival at 5 years. The association between UWO3 immune class and time to recurrence was independent of patient age, sex, smoking status, alcohol intake status, and AJCC 8th edition clinical stage. Finally, UWO3 was able to identify patients who respond to aggressive treatment de-escalation to 30 Gy radiation in two treatment de-escalation cohorts. The UWO3 immune score could inform clinical decision making for patients with HPV+ HNSCC based on robust outcome prediction across six independent cohorts. The superior survival of immune rich patients supports de-intensification strategies for this cohort, while the inferior outcomes of the immune desert patients suggest potential for intensification and/or immunotherapy. Prospective de-escalation and intensification clinical trials are currently being planned. [ABSTRACT FROM AUTHOR]

A surface acoustic wave (SAW)-enhanced, surface plasmon resonance (SPR) microfluidic biosensor in which SAW-induced mixing and phase-interrogation grating-coupling SPR are combined in a single lithium niobate lab-on-a-chip is demonstrated. Thiol-polyethylene glycol adsorption and avidin/biotin binding kinetics were monitored by exploiting the high sensitivity of grating-coupling SPR under azimuthal control. A time saturation binding kinetics reduction of 82% and 24% for polyethylene and avidin adsorption was obtained, respectively, due to the fluid mixing enhancement by means of the SAW-generated chaotic advection. These results represent the first implementation of a nanostructured SAW–SPR microfluidic biochip capable of significantly improving the molecule binding kinetics on a single, portable device. In addition, the biochip here proposed is suitable for a great variety of biosensing applications. [ABSTRACT FROM AUTHOR]

The development of biomaterials ensuring proper cell adhesion, polarization, migration and differentiation represents a true enabler for successful tissue-engineering applications. Surface nanostructuring was suggested as a promising method for improving cell-substrate interaction. Here, we study Wharton's Jelly human Mesenchymal Stem Cells (WJ-hMSC) interacting with nanogratings (NGs) having a controlled amount of nanotopographical noise (nTN). Our data demonstrate that unperturbed NGs induce cell polarization, alignment and migration along NG lines. The introduction of nTN dramatically modifies this behavior and leads to a marked loss of cell polarization and directional migration, even at low noise levels. High-resolution focal adhesions (FAs) imaging showed that this behavior is caused by the release of the geometrical vinculum imposed by the NGs to FA shaping and maturation. We argue that highly anisotropic nanopatterned scaffolds can be successfully exploited to drive stem cell migration in regenerative medicine protocols and discuss the impact of scaffold alterations or wear. [ABSTRACT FROM AUTHOR]

The paper deals with a series of tests conducted on a PV-DC pump in Viterbo 42°24' North, 12°06' East). The tests lasted from January 2003 up to November 2004 and involved measurements of solar radiation, on both a horizontal surface and the tilted module surface, flow rates, volumes, and total dynamic heads. In total, up to 3000 data were collected every day whose analysis allowed us to find empirical relationships among system efficiencies, solar radiations, and total dynamic heads. In the second part of the paperwe develop a simplemethod that allows both the assessment of performances of the whole system when installed in a different site from that in which the tests were performed and the optimal inclination angle of the panel to be determined in relation to annual or seasonal use (see irrigation). [ABSTRACT FROM AUTHOR]

Modern agriculture is an extremely energy intensive process. However, high agricultural productivities and the growth of green revolution has been possible only by large amount of energy inputs, especially those coming from fossil fuels. These energy resources have not been able to provide an economically viable solution for agricultural applications. Biomass energy-based systems had been extensively used for transportation and on farm systems during World War II: the most common and reliable solution was wood or biomass gasification. The latter means incomplete combustion of biomass resulting in production of combustible gases which mostly consist of carbon monoxide (CO), hydrogen (H2) and traces of methane (CH4). This mixture is called syngas, which can be successfully used to run internal combustion engines (both compression and spark ignition) or as substitute for furnace oil in direct heat applications. The aim of the present paper is to help the experimentation of innovative plants for electric power production using agro-forest biomass derived by hazelnut cultivations. An additional purpose is to point out a connection among the chemical and physical properties of the outgoing syngas by biomass characterization and gas-chromatography analysis. [ABSTRACT FROM AUTHOR]

A square-wave anodic-stripping voltammetric method for the analysis of lead and cadmium in chicken muscle and liver was developed and validated, and the results of a monitoring study relative to chicken and pigeon meat are reported. The voltammetric method allows the analysis of lead and cadmium at the same time in samples after acid digestion. The use of perchloric acid for digestion and of acetate buffer in the supporting electrolyte are suitable to reduce matrix interferences and obtain limits of quantification which were below 10 ng g−1 for meat and liver samples. The regression between the analytical signal and the concentration of the target analytes in spiked samples and Certified Reference Materials proved to be linear within the 10–100 ng g−1 range for meat and within the 50–500 ng g−1 range for liver. The analytical method was verified using available Certified Reference Materials BCR-184 (cattle meat) and BCR-185R (cattle liver) as well as with spiked chicken samples. Precision (i.e. repeatability and intermediate precision) and accuracy (percentage recovery and bias) were of the order of 0.3–4.5% for both lead and cadmium The level of lead in muscle was in the range between 6.4 and 59.8 ng g−1 in chickens and between 7.9 and 63.6 ng g−1 in farmed pigeons, whereas it was between 8.0 and 84.4 ng g−1 in chicken liver. The cadmium concentration was 0.4–10.4 ng g−1 in chicken muscle, 10.4–90.6 ng g−1 in chicken liver and 2.2–8.0 ng g−1 in farmed pigeons. [ABSTRACT FROM AUTHOR]

The article presents a study on the risks of exposure to microclimatic condition for harvesters of fruits and vegetables in Italy by applying methods set by international standards. The study involves measuring air temperature, radiative temperature and air speed, using instruments that conform to International Organization for Standardization (ISO) 7726, to estimate the risk for workers. Furthermore, the results show a slight risk for workers that perform manual harvesting in the field.

The article presents a study which evaluates the risk of Italian tomato harvesting workers for musculoskeletal disorders using the occupational repetitive actions (OCRA) index method. The study shows that participating workers garnered an exposure index greater than 20 which is defined by OCRA as unacceptable. The study stresses that the replacement of manual sorting with optical sorters will reduce the risk of work-related musculoskeletal disorders (WMSDs).

The rigor to post-rigor transition in myosin, a consequence of ATP binding, plays an essential role in the Lymn-Taylor functional cycle because it results in the dissociation of the actomyosin complex after the powerstroke. On the basis of the X-ray structures of myosin V, we have developed a new normal mode superposition model for the transition path between the two states. Rigid-body motions of the various subdomains and specific residues at the subdomain interfaces are key elements in the transition. The allosteric communication between the nucleotide binding site and the U50/L50 cleft is shown to result from local changes due to ATP binding, which induce large amplitude motions that are encoded in the structure of the protein. The triggering event is the change in the interaction of switch I and the P-loop, which is stabilized by ATP binding. The motion of switch I, which is a relatively rigid element of the U50 subdomain, leads directly to a partial opening of the U50/L50 cleft; the latter is expected to weaken the binding of myosin to actin. The calculated transition path demonstrates the nature of the subdomain coupling and offers an explanation for the mutual exclusion of ATP and actin binding. The mechanism of the uncoupling of the converter from the motor head, an essential part of the transition, is elucidated. The origin of the partial untwisting of the central b-sheet in the rigor to post-rigor transition is described. [ABSTRACT FROM AUTHOR]

A novel computational approach to the structural analysis of ordered β-aggregation is presented and validated on three known amyloidogenic polypeptides. The strategy is based on the decomposition of the sequence into overlapping stretches and equilibrium implicit solvent molecular dynamics (MD) simulations of an oligomeric system for each stretch. The structural stability of the in-register parallel aggregates sampled in the implicit solvent runs is further evaluated using explicit water simulations for a subset of the stretches. The β-aggregation propensity along the sequence of the Alzheimer''s amyloid-β peptide (Aβ42) is found to be highly heterogeneous with a maximum in the segment V12HHQKLVFFAE22 and minima at S8G9, G25S26, G29A30, and G38V39, which are turn-like segments. The simulation results suggest that these sites may play a crucial role in determining the aggregation tendency and the fibrillar structure of Aβ42. Similar findings are obtained for the human amylin, a 37-residue peptide that displays a maximal β-aggregation propensity at Q10RLANFLVHSSNN22 and two turn-like sites at G24A25 and G33S34. In the third application, the MD approach is used to identify β-aggregation “hot-spots” within the N-terminal domain of the yeast prion Ure2p (Ure2p1–94) and to design a double-point mutant (Ure2p-N4748S1–94) with lower β-aggregation propensity. The change in the aggregation propensity of Ure2p-N4748S1–94 is verified in vitro using the thioflavin T binding assay. [Copyright &y& Elsevier]

The article discusses workers' safety in milking premises. Dairy cattle rearing techniques have evolved, with stall housing being replaced by open housing on deeper litter and/or cubicles, which saves labor and improves the animals' environmental conditions. Milking moved from stalls to ad hoc premises, which, however, were often arranged in farm buildings that had been set up for other purposes. The shift has reduced the workers' danger due to direct contact with animals, thanks to the presence of segregation fences. In fact, no fatal accidents were registered in recent years during milking operations, and the number of temporary and permanent disabilities was reduced by 63%. However, other sources of accident and professional health risks, such as noise from milking machines, adverse indoor microclimatic conditions, posture, and other work-related musculoskeletal disorders are still present. The survey involved milking premises at ten dairy farms in central Italy. Farms had between 40 and 60 milking animals throughout the year.

Mycorrhizas of Tuber brumale on Quercus pubescens and Tilia americana were obtained in vitro using micropropagated plantlets. Mycelium pure cultures were used for inoculation. Both the mycelium used for the inoculations, as well as the mycorrhizas which were obtained, were identified using several molecular approaches: analysis of the ITS region, polymerase chain reaction (PCR) specific primers and sequencing. The mycorrhizas were described from a morphological standpoint. Some of their biometric characteristics were different in bass-wood than they were in oak, thus showing the influence of the host plant on several of the morphological features believed to be necessary for the identification of the species. Considering the variability of their morphological characteristics, molecular analysis proved to be a necessary tool for the recognition of the mycorrhizas of Tuber spp. [Copyright &y& Elsevier]