Mitogenomes from Egyptian Cattle Breeds: New Clues on the Origin of Haplogroup Q and the Early Spread of Bos taurus from the Near East

Background Genetic studies support the scenario that Bos taurus domestication occurred in the Near East during the Neolithic transition about 10 thousand years (ky) ago, with the likely exception of a minor secondary event in Italy. However, despite the proven effectiveness of whole mitochondrial genome data in providing valuable information concerning the origin of taurine cattle, until now no population surveys have been carried out at the level of mitogenomes in local breeds from the Near East or surrounding areas. Egypt is in close geographic and cultural proximity to the Near East, in particular the Nile Delta region, and was one of the first neighboring areas to adopt the Neolithic package. Thus, a survey of mitogenome variation of autochthonous taurine breeds from the Nile Delta region might provide new insights on the early spread of cattle rearing outside the Near East. Methodology Using Illumina high-throughput sequencing we characterized the mitogenomes from two cattle breeds, Menofi (N = 17) and Domiaty (N = 14), from the Nile Delta region. Phylogenetic and Bayesian analyses were subsequently performed. Conclusions Phylogenetic analyses of the 31 mitogenomes confirmed the prevalence of haplogroup T1, similar to most African cattle breeds, but showed also high frequencies for haplogroups T2, T3 and Q1, and an extremely high haplotype diversity, while Bayesian skyline plots pointed to a main episode of population growth ~12.5 ky ago. Comparisons of Nile Delta mitogenomes with those from other geographic areas revealed that (i) most Egyptian mtDNAs are probably direct local derivatives from the founder domestic herds which first arrived from the Near East and the extent of gene flow from and towards the Nile Delta region was limited after the initial founding event(s); (ii) haplogroup Q1 was among these founders, thus proving that it underwent domestication in the Near East together with the founders of the T clades

AKR1C enzymes sustain therapy resistance in paediatric T-ALL

BACKGROUND: Despite chemotherapy intensification, a subgroup of high-risk paediatric T-cell acute lymphoblastic leukemia (TALL) patients still experience treatment failure. In this context, we hypothesised that therapy resistance in T-ALL might involve aldo-keto reductase 1C (AKR1C) enzymes as previously reported for solid tumors.METHODS: Expression of NRF2-AKR1C signaling components has been analysed in paediatric T-ALL samples endowed with different treatment outcomes as well as in patient-derived xenografts of T-ALL. The effects of AKR1C enzyme modulation has been investigated in T-ALL cell lines and primary cultures by combining AKR1C inhibition, overexpression, and gene silencing approaches.RESULTS: We show that T-ALL cells overexpress AKR1C1-3 enzymes in therapy-resistant patients. We report that AKR1C1-3 enzymes play a role in the response to vincristine (VCR) treatment, also ex vivo in patient-derived xenografts. Moreover, we demonstrate that the modulation of AKR1C1-3 levels is sufficient to sensitise T-ALL cells to VCR. Finally, we show that T-ALL chemotherapeutics induce overactivation of AKR1C enzymes independent of therapy resistance, thus establishing a potential resistance loop during T-ALL combination treatment.CONCLUSIONS: Here, we demonstrate that expression and activity of AKR1C enzymes correlate with response to chemotherapeutics in T-ALL, posing AKR1C1-3 as potential targets for combination treatments during T-ALL therapy

Cancer data quality and harmonization in Europe: the experience of the BENCHISTA Project – international benchmarking of childhood cancer survival by stage

IntroductionVariation in stage at diagnosis of childhood cancers (CC) may explain differences in survival rates observed across geographical regions. The BENCHISTA project aims to understand these differences and to encourage the application of the Toronto Staging Guidelines (TG) by Population-Based Cancer Registries (PBCRs) to the most common solid paediatric cancers.MethodsPBCRs within and outside Europe were invited to participate and identify all cases of Neuroblastoma, Wilms Tumour, Medulloblastoma, Ewing Sarcoma, Rhabdomyosarcoma and Osteosarcoma diagnosed in a consecutive three-year period (2014-2017) and apply TG at diagnosis. Other non-stage prognostic factors, treatment, progression/recurrence, and cause of death information were collected as optional variables. A minimum of three-year follow-up was required. To standardise TG application by PBCRs, on-line workshops led by six tumour-specific clinical experts were held. To understand the role of data availability and quality, a survey focused on data collection/sharing processes and a quality assurance exercise were generated. To support data harmonization and query resolution a dedicated email and a question-and-answers bank were created.Results67 PBCRs from 28 countries participated and provided a maximally de-personalized, patient-level dataset. For 26 PBCRs, data format and ethical approval obtained by the two sponsoring institutions (UCL and INT) was sufficient for data sharing. 41 participating PBCRs required a Data Transfer Agreement (DTA) to comply with data protection regulations. Due to heterogeneity found in legal aspects, 18 months were spent on finalizing the DTA. The data collection survey was answered by 68 respondents from 63 PBCRs; 44% of them confirmed the ability to re-consult a clinician in cases where stage ascertainment was difficult/uncertain. Of the total participating PBCRs, 75% completed the staging quality assurance exercise, with a median correct answer proportion of 92% [range: 70% (rhabdomyosarcoma) to 100% (Wilms tumour)].ConclusionDifferences in interpretation and processes required to harmonize general data protection regulations across countries were encountered causing delays in data transfer. Despite challenges, the BENCHISTA Project has established a large collaboration between PBCRs and clinicians to collect detailed and standardised TG at a population-level enhancing the understanding of the reasons for variation in overall survival rates for CC, stimulate research and improve national/regional child health plans

Eye controlled semi-Robotic Wheelchair for quadriplegic users embedding Mixed Reality tools

Mobile assistive robotics can play a key role to improve the autonomy and lifestyle of patients. In this context, RoboEye project aims to support people affected by mobility problems that range from very impairing pathologies (like ALS, amyotrophic lateral sclerosis) to old age. Any severe motor disability is a condition that limits the capability of interacting with the environment, even the domestic one, caused by the loss of the control on our own mobility. Although these pathologies are relatively rare, the number of people affected by this disease are increasing during the years. The focus of this project is the restore of persons’ mobility using novel technologies based on the gaze on a power wheelchair designed to enable the user to move easily and autonomously inside his home. A novel and intuitive control system was designed to achieve such a goal, in which a non-invasive eye tracker, a monitor, and a 3D camera represent some of the core elements. The developed prototype integrates, on a standard power wheelchair, functionalities from the mobile robotics field, with the main benefit of providing to the user two driving options and comfortable navigation. The most intuitive, and direct, modality foresees the continuous control of the frontal and angular velocities of the wheelchair by gazing at different areas of the monitor. The second, semi-autonomous, enables the navigation toward a selected point in the environment by just pointing and activating the wished destination while the system autonomously plans and follows the trajectory that brings the wheelchair there. The main goal is the development of shared control, combining direct control by the user with the comfort of autonomous navigation based on augmented reality markers. A first evaluation has been performed on a real test bed where specific motion metrics are evaluated. The designs of the control structure and driving interfaces were tuned thanks to the testing of some volunteers, habitual users of standard power wheelchairs. The driving modalities, especially the semi-autonomous one, were modelled and qualified to verify their efficiency, reliability, and safety for domestic usage

Self-Weighted Multilateration for Indoor Positioning Systems

The paper proposes an improved method for calculating the position of a movable tag whose distance to a (redundant) set of fixed beacons is measured by some suitable physical principle (typically ultra wide band or ultrasound propagation). The method is based on the multilateration technique, where the contribution of each individual beacon is weighed on the basis of a recurring, self-supported calibration of the measurement repeatability of each beacon at a given distance range. The work outlines the method and its implementation, and shows the improvement in measurement quality with respect to the results of a commercial Ultra-Wide-Band (UWB) system when tested on the same set of raw beacon-to-tag distances. Two versions of the algorithm are proposed: one-dimensional, or isotropic, and 3D. With respect to the standard approach, the isotropic solution managed to reduce the maximum localization error by around 25%, with a maximum error of 0.60 m, while the 3D version manages to improve even further the localization accuracy, with a maximum error of 0.45 m

Information Dynamics of the Brain, Cardiovascular and Respiratory Network during Different Levels of Mental Stress

In this study, an analysis of brain, cardiovascular and respiratory dynamics was conducted combining information-theoretic measures with the Network Physiology paradigm during different levels of mental stress. Starting from low invasive recordings of electroencephalographic, electrocardiographic, respiratory, and blood volume pulse signals, the dynamical activity of seven physiological systems was probed with one-second time resolution measuring the time series of the δ , θ , α and β brain wave amplitudes, the cardiac period (RR interval), the respiratory amplitude, and the duration of blood pressure wave propagation (pulse arrival time, PAT). Synchronous 5-min windows of these time series, obtained from 18 subjects during resting wakefulness (REST), mental stress induced by mental arithmetic (MA) and sustained attention induced by serious game (SG), were taken to describe the dynamics of the nodes composing the observed physiological network. Network activity and connectivity were then assessed in the framework of information dynamics computing the new information generated by each node, the information dynamically stored in it, and the information transferred to it from the other network nodes. Moreover, the network topology was investigated using directed measures of conditional information transfer and assessing their statistical significance. We found that all network nodes dynamically produce and store significant amounts of information, with the new information being prevalent in the brain systems and the information storage being prevalent in the peripheral systems. The transition from REST to MA was associated with an increase of the new information produced by the respiratory signal time series (RESP), and that from MA to SG with a decrease of the new information produced by PAT. Each network node received a significant amount of information from the other nodes, with the highest amount transferred to RR and the lowest transferred to δ , θ , α and β . The topology of the physiological network underlying such information transfer was node- and state-dependent, with the peripheral subnetwork showing interactions from RR to PAT and between RESP and RR, PAT consistently across states, the brain subnetwork resulting more connected during MA, and the subnetwork of brain–peripheral interactions involving different brain rhythms in the three states and resulting primarily activated during MA. These results have both physiological relevance as regards the interpretation of central and autonomic effects on cardiovascular and respiratory variability, and practical relevance as regards the identification of features useful for the automatic distinction of different mental states

Cardiovascular Response to Posture Changes: Multiscale Modeling and in vivo Validation During Head-Up Tilt

In spite of cardiovascular system (CVS) response to posture changes have been widely studied, a number of mechanisms and their interplay in regulating central blood pressure and organs perfusion upon orthostatic stress are not yet clear. We propose a novel multiscale 1D-0D mathematical model of the human CVS to investigate the effects of passive (i.e., through head-up tilt without muscular intervention) posture changes. The model includes the main short-term regulation mechanisms and is carefully validated against literature data and in vivo measures here carried out. The model is used to study the transient and steady-state response of the CVS to tilting, the effects of the tilting rate, and the differences between tilt-up and tilt-down. Passive upright tilt led to an increase of mean arterial pressure and heart rate, and a decrease of stroke volume and cardiac output, in agreement with literature data and present in vivo experiments. Pressure and flow rate waveform analysis along the arterial tree together with mechano-energetic and oxygen consumption parameters highlighted that the whole system approaches a less stressed condition at passive upright posture than supine, with a slight unbalance of the energy supply-demand ratio. The transient dynamics is not symmetric in tilt-up and tilt-down testing, and is non-linearly affected by the tilting rate, with stronger under- and overshoots of the hemodynamic parameters as the duration of tilt is reduced. By enriching the CVS response to posture changes, the present modeling approach shows promise in a number of applications, ranging from autonomic system disorders to spaceflight deconditioning

Cardiovascular Response to Posture Changes: Multiscale Modeling and in vivo Validation During Head-Up Tilt

In spite of cardiovascular system (CVS) response to posture changes have been widely studied, a number of mechanisms and their interplay in regulating central blood pressure and organs perfusion upon orthostatic stress are not yet clear. We propose a novel multiscale 1D-0D mathematical model of the human CVS to investigate the effects of passive (i.e., through head-up tilt without muscular intervention) posture changes. The model includes the main short-term regulation mechanisms and is carefully validated against literature data and in vivo measures here carried out. The model is used to study the transient and steady-state response of the CVS to tilting, the effects of the tilting rate, and the differences between tilt-up and tilt-down. Passive upright tilt led to an increase of mean arterial pressure and heart rate, and a decrease of stroke volume and cardiac output, in agreement with literature data and present in vivo experiments. Pressure and flow rate waveform analysis along the arterial tree together with mechano-energetic and oxygen consumption parameters highlighted that the whole system approaches a less stressed condition at passive upright posture than supine, with a slight unbalance of the energy supply-demand ratio. The transient dynamics is not symmetric in tilt-up and tilt-down testing, and is non-linearly affected by the tilting rate, with stronger under- and overshoots of the hemodynamic parameters as the duration of tilt is reduced. By enriching the CVS response to posture changes, the present modeling approach shows promise in a number of applications, ranging from autonomic system disorders to spaceflight deconditioning