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During normal ageing a low rate of division of pre-existing cardiomyocytes, rather than progenitor cells, is responsible for cardiomyocyte genesis; this process is increased fourfold during myocardial infarction. Heart-cell replacement in the adult There is controversy in the cardiovascular field regarding the extent of existing cardiomyocyte turnover versus progenitor cell contributions during mammalian cardiac homeostasis throughout adult life. This study takes a novel approach to settling the debate by using a combination of prospective labelling with the nitrogen-15 isotope and genetic pulse–chase to measure DNA synthesis in the adult mammalian heart. The authors conclude that during normal ageing, preexisting cardiomyocytes are the dominant source of cardiomyocyte replacement in normal mammalian myocardial homeostasis, a process that is increased fivefold during recovery from myocardial infarction. Although recent studies have revealed that heart cells are generated in adult mammals, the frequency of generation and the source of new heart cells are not yet known. Some studies suggest a high rate of stem cell activity with differentiation of progenitors to cardiomyocytes 1 . Other studies suggest that new cardiomyocytes are born at a very low rate 2 , 3 , 4 , and that they may be derived from the division of pre-existing cardiomyocytes. Here we show, by combining two different pulse–chase approaches—genetic fate-mapping with stable isotope labelling, and multi-isotope imaging mass spectrometry—that the genesis of cardiomyocytes occurs at a low rate by the division of pre-existing cardiomyocytes during normal ageing, a process that increases adjacent to areas of myocardial injury. We found that cell cycle activity during normal ageing and after injury led to polyploidy and multinucleation, but also to new diploid, mononucleate cardiomyocytes. These data reveal pre-existing cardiomyocytes as the dominant source of cardiomyocyte replacement in normal mammalian myocardial homeostasis as well as after myocardial injury.

We present a 1:25,000 scale map of the coseismic surface ruptures following the 30 October 2016 M w 6.5 Norcia normal-faulting earthquake, central Italy. Detailed rupture mapping is based on almost 11,000 oblique photographs taken from helicopter flights, that has been verified and integrated with field data (>7000 measurements). Thanks to the common efforts of the Open EMERGEO Working Group (130 people, 25 research institutions and universities from Europe), we were able to document a complex surface faulting pattern with a dominant strike of N135°-160° (SW-dipping) and a subordinate strike of N320°-345° (NE-dipping) along about 28 km of the active Mt. Vettore-Mt. Bove fault system. Geometric and kinematic characteristics of the rupture were observed and recorded along closely spaced, parallel or subparallel, overlapping or step-like synthetic and antithetic fault splays of the activated fault systems, comprising a total surface rupture length of approximately 46 km when all ruptures were considered.

We provide a database of the surface ruptures produced by the 26 December 2018 Mw 4.9 earthquake that struck the eastern flank of Mt. Etna volcano in Sicily (southern Italy). Despite its relatively small magnitude, this shallow earthquake caused about 8 km of surface faulting, along the trace of the NNW-trending active Fiandaca Fault. Detailed field surveys have been performed in the epicentral area to map the ruptures and to characterize their kinematics. The surface ruptures show a dominant right-oblique sense of displacement with an average slip of about 0.09 m and a maximum value of 0.35 m. We have parsed and organized all observations in a concise database, with 932 homogeneous georeferenced records. The Fiandaca Fault is part of the complex active Timpe faults system affecting the eastern flank of Etna, and its seismic history indicates a prominent surface-faulting potential. Therefore, this database is essential for unravelling the seismotectonics of shallow earthquakes in volcanic areas, and contributes updating empirical scaling regressions that relate magnitude and extent of surface faulting.Measurement(s)coseismic surface rupture • surface rupture kinematics • surface rupture displacement • surface rupture locationTechnology Type(s)field survey • GPS navigation systemFactor Type(s)offset • strike • angle • length • latitude • longitude • elevationSample Characteristic - Environmentvolcanic fieldSample Characteristic - LocationIsland of Sicily • Mount EtnaMachine-accessible metadata file describing the reported data: 10.6084/m9.figshare.11673027

Abstract Introduction: We recently demonstrated that the sleep-wake cycle is severely altered in the acute stage of moderate to severe traumatic brain injuries (TBI). In general, these patients have short sleep and wake bouts dispersed over the 24 h. This study aimed to explore whether early markers of TBI severity predict acute sleep-wake cycle disturbances. Moreover, it aimed to verify the relationship between the sleep-wake cycle and the acute cognitive recovery. Methods: We included 37 non-sedated patients (age 30 ± 14 yo, 25 males) hospitalized for moderate to severe TBI. We used two severity markers that are available in the first hours following TBI, namely the initial Glasgow Coma Scale (GCS) score and the delay to recover the ability to sustain visual fixation. Once patients had reached medical stability, we used continuous actigraphy to document the sleep-wake cycle, and a consolidated sleep-wake cycle was defined by a daytime activity ratio > 80%. A short neuropsychological assessment was performed in a subsample of 13 patients. Correlation analyses were conducted between sleep-wake variables, TBI severity markers and performance on neuropsychological tests. Results: Patients had a median GCS score of 7 (range 3–13) and spent 6 ± 6 days without visual fixation in the intensive care unit. Once patient had reached medical stability, they had 5 ± 4 days of non-consolidated sleep-wake cycle. The number of days without sleep-wake cycle consolidation correlated with the initial GCS score (ρ=0.35; p=0.04) and the delay before recovering visual fixation (r=0.45; p<0.01). Moreover, more altered sleep-wake cycle was associated with poorer performance on cognitive screening, episodic memory, language and logical reasoning tests carried before hospital discharge (r varying from -0.5 to -0.7, p<0.05, n=13). Conclusion: Our results support emerging evidence showing that early markers of TBI severity gathered in the first few hours after TBI can predict acute sleep-wake cycle alterations. The reappearance of consolidated sleep-wake cycle was associated with better cognitive recovery; still the directionality (or bidirectionality) of this relationship needs to be further investigated. Support (If Any): The research was supported by the Canadian Institutes of Health Research (CIHR) and by the Fonds pour la recherche du Québec, Santé (FRQS)

During normal ageing a low rate of division of pre-existing cardiomyocytes, rather than progenitor cells, is responsible for cardiomyocyte genesis; this process is increased fourfold during myocardial infarction.

Current standard of care for muscle-invasive urothelial cell carcinoma (UCC) is surgery along with perioperative platinum-based chemotherapy. UCC is sensitive to cisplatin-based regimens, but acquired resistance eventually occurs, and a subset of tumors is intrinsically resistant. Thus, there is an unmet need for new therapeutic approaches to target chemotherapy-resistant UCC. Yes-associated protein (YAP) is a transcriptional co-activator that has been associated with bladder cancer progression and cisplatin resistance in ovarian cancer. In contrast, YAP has been shown to induce DNA damage associated apoptosis in non-small cell lung carcinoma. However, no data have been reported on the YAP role in UCC chemo-resistance. Thus, we have investigated the potential dichotomous role of YAP in UCC response to chemotherapy utilizing two patient-derived xenograft models recently established. Constitutive expression and activation of YAP inversely correlated with in vitro and in vivo cisplatin sensitivity. YAP overexpression protected while YAP knockdown sensitized UCC cells to chemotherapy and radiation effects via increased accumulation of DNA damage and apoptosis. Furthermore, pharmacological YAP inhibition with verteporfin inhibited tumor cell proliferation and restored sensitivity to cisplatin. In addition, nuclear YAP expression was associated with poor outcome in UCC patients who received perioperative chemotherapy. In conclusion, these results suggest that YAP activation exerts a protective role and represents a pharmacological target to enhance the anti-tumor effects of DNA damaging modalities in the treatment of UCC.

Injury to one cerebral hemisphere can result in paresis of the contralesional hand and subsequent preference of the ipsilesional hand in daily activities. However, forced use therapy in humans can improve function of the contralesional paretic hand and increase its use in daily activities, although the ipsilesional hand may remain preferred for fine motor activities. Studies in monkeys have shown that minimal forced use of the contralesional hand, which was the preferred hand prior to brain injury, can produce remarkable recovery of function. Here we tested the hypothesis that long-term forced use of the contralesional hand during the post-lesion period can return it to preferred status. Four rhesus monkeys received tests of hand preference prior to surgical lesions of primary motor cortex, lateral premotor cortex and anterior parietal cortex (F2P2 lesion) contralateral to the preferred hand. Beginning two weeks after the lesion, forced use therapy involving contralateral hand reaches to acquire food targets occurred 3X weekly with at least 300 reaches/session until 24 weeks post-lesion. Despite initial paresis of the contralesional hand, its manipulation skill returned to near pre-lesion levels or higher and all four monkeys returned to a contralesional hand preference late in the post-lesion period. Favorable reorganization of spared cortical and subcortical neural networks may promote recovery of hand function and preference. These results have relevance for the use of extensive forced-use therapy in humans who experience unilateral periRolandic injury to potentially support better recovery of contralesional hand function.

Our objective was to investigate the capacity to control a P3-based brain-computer interface (BCI) device for communication and its related (temporal) attention processing in a sample of amyotrophic lateral sclerosis (ALS) patients with respect to healthy subjects. The ultimate goal was to corroborate the role of cognitive mechanisms in event-related potential (ERP)-based BCI control in ALS patients. Furthermore, the possible differences in such attentional mechanisms between the two groups were investigated in order to unveil possible alterations associated with the ALS condition. Thirteen ALS patients and 13 healthy volunteers matched for age and years of education underwent a P3-speller BCI task and a rapid serial visual presentation (RSVP) task. The RSVP task was performed by participants in order to screen their temporal pattern of attentional resource allocation, namely: (i) the temporal attentional filtering capacity (scored as T1%); and (ii) the capability to adequately update the attentive filter in the temporal dynamics of the attentional selection (scored as T2%). For the P3-speller BCI task, the online accuracy and information transfer rate (ITR) were obtained. Centroid Latency and Mean Amplitude of N200 and P300 were also obtained. No significant differences emerged between ALS patients and Controls with regards to online accuracy ( = 0.13). Differently, the performance in controlling the P3-speller expressed as ITR values (calculated offline) were compromised in ALS patients ( < 0.05), with a delay in the latency of P3 when processing BCI stimuli as compared with Control group ( < 0.01). Furthermore, the temporal aspect of attentional filtering which was related to BCI control ( = 0.51; < 0.05) and to the P3 wave amplitude ( = 0.63; < 0.05) was also altered in ALS patients ( = 0.01). These findings ground the knowledge required to develop sensible classes of BCI specifically designed by taking into account the influence of the cognitive characteristics of the possible candidates in need of a BCI system for communication.