Changes in Blood Cell Deformability in Chorea-Acanthocytosis and Effects of Treatment With Dasatinib or Lithium

Misshaped red blood cells (RBCs), characterized by thorn-like protrusions known as acanthocytes, are a key diagnostic feature in Chorea-Acanthocytosis (ChAc), a rare neurodegenerative disorder. The altered RBC morphology likely influences their biomechanical properties which are crucial for the cells to pass the microvasculature. Here, we investigated blood cell deformability of five ChAc patients compared to healthy controls during up to 1-year individual off-label treatment with the tyrosine kinase inhibitor dasatinib or several weeks with lithium. Measurements with two microfluidic techniques allowed us to assess RBC deformability under different shear stresses. Furthermore, we characterized leukocyte stiffness at high shear stresses. The results showed that blood cell deformability–including both RBCs and leukocytes - in general was altered in ChAc patients compared to healthy donors. Therefore, this study shows for the first time an impairment of leukocyte properties in ChAc. During treatment with dasatinib or lithium, we observed alterations in RBC deformability and a stiffness increase for leukocytes. The hematological phenotype of ChAc patients hinted at a reorganization of the cytoskeleton in blood cells which partly explains the altered mechanical properties observed here. These findings highlight the need for a systematic assessment of the contribution of impaired blood cell mechanics to the clinical manifestation of ChAc

An Integrated Multiscale Method for the Characterisation of Active Faults in Offshore Areas. The Case of Sant\u2019Eufemia Gulf (Offshore Calabria, Italy)

Diagnostic morphological features (e.g., rectilinear seafloor scarps) and lateral offsets of the Upper Quaternary deposits are used to infer active faults in offshore areas. Although they deform a significant seafloor region, the active faults are not necessarily capable of producing large earthquakes as they correspond to shallow structures formed in response to local stresses. We present a multiscale approach to reconstruct the structural pattern in offshore areas and distinguish between shallow, non-seismogenic, active faults, and deep blind faults, potentially associated with large seismic moment release. The approach is based on the interpretation of marine seismic reflection data and quantitative morphometric analysis of multibeam bathymetry, and tested on the Sant\u2019Eufemia Gulf (southeastern Tyrrhenian Sea). Data highlights the occurrence of three major tectonic events since the Late Miocene. The first extensional or transtensional phase occurred during the Late Miocene. Since the Early Pliocene, a right-lateral transpressional tectonic event caused the positive inversion of deep (>3 km) tectonic features, and the formation of NE-SW faults in the central sector of the gulf. Also, NNE-SSW to NE-SW trending anticlines (e.g., Maida Ridge) developed in the eastern part of the area. Since the Early Pleistocene (Calabrian), shallow (<1.5 km) NNE-SSW oriented structures formed in a left-lateral transtensional regime. The new results integrated with previous literature indicates that the Late Miocene to Recent transpressional/transtensional structures developed in an 3cE-W oriented main displacement zone that extends from the Sant\u2019Eufemia Gulf to the Squillace Basin (Ionian offshore), and likely represents the upper plate response to a tear fault of the lower plate. The quantitative morphometric analysis of the study area and the bathymetric analysis of the Angitola Canyon indicate that NNE-SSW to NE-SW trending anticlines were negatively reactivated during the last tectonic phase. We also suggest that the deep structure below the Maida Ridge may correspond to the seismogenic source of the large magnitude earthquake that struck the western Calabrian region in 1905. The multiscale approach contributes to understanding the tectonic imprint of active faults from different hierarchical orders and the geometry of seismogenic faults developed in a lithospheric strike-slip zone orthogonal to the Calabrian Arc

Influence of eye movement on lens dose and optic nerve target coverage during craniospinal irradiation

PURPOSE: Optic nerves are part of the craniospinal irradiation (CSI) target volume. Modern radiotherapy techniques achieve highly conformal target doses while avoiding organs-at-risk such as the lens. The magnitude of eye movement and its influence on CSI target- and avoidance volumes are unclear. We aimed to evaluate the movement-range of lenses and optic nerves and its influence on dose distribution of several planning techniques. METHODS: Ten volunteers underwent MRI scans in various gaze directions (neutral, left, right, cranial, caudal). Lenses, orbital optic nerves, optic discs and CSI target volumes were delineated. 36-Gy cranial irradiation plans were constructed on synthetic CT images in neutral gaze, with Volumetric Modulated Arc Therapy, pencil-beam scanning proton therapy, and 3D-conventional photons. Movement-amplitudes of lenses and optic discs were analyzed, and influence of gaze direction on lens and orbital optic nerve dose distribution. RESULTS: Mean eye structures’ shift from neutral position was greatest in caudal gaze; −5.8±1.2 mm (±SD) for lenses and 7.0±2.0 mm for optic discs. In 3D-conventional plans, caudal gaze decreased Mean Lens Dose (MLD). In VMAT and proton plans, eye movements mainly increased MLD and diminished D98 orbital optic nerve (D98(OON)) coverage; mean MLD increased up to 5.5 Gy [total ΔMLD range −8.1 to 10.0 Gy], and mean D98(OON) decreased up to 3.3 Gy [total ΔD98(OON) range −13.6 to 1.2 Gy]. VMAT plans optimized for optic disc Internal Target Volume and lens Planning organ-at-Risk Volume resulted in higher MLD over gaze directions. D98(OON) became ≥95% of prescribed dose over 95/100 evaluated gaze directions, while all-gaze bilateral D98(OON) significantly changed in 1 of 10 volunteers. CONCLUSION: With modern CSI techniques, eye movements result in higher lens doses and a mean detriment for orbital optic nerve dose coverage of <10% of prescribed dose

Mid-to-late Holocene upper slope contourite deposits off Capo Vaticano (Mediterranean Sea): High-resolution record of contourite cyclicity, bottom current variability and sandy facies

none13noThe upper continental slope offshore Capo Vaticano (southern Tyrrhenian Sea) is characterized by a contourite depositional system with well-developed elongated sediment drifts. This system is related to a northward paleo-bottom current, similar to the present-day modified-Levantine Intermediate Water (modified-LIW) flowing from the Messina Strait. In this work, we show results from an integrated analysis of descriptive oceanography, high-resolution seismic profiles and core data (i.e., grain size, foraminiferal assemblages, tephrostratigraphy and AMS radiocarbon dating) collected from the crest and moat sectors of drift deposits. The studied succession formed since the mid Holocene, under the action of the modified-LIW and the stratigraphic architecture indicates an upslope migration of the moat and rather stable position of the crest sector. Grain-size features recorded from two sediment cores indicate the occurrence of a succession of complete bi-gradational sand-rich contourite sequences. Sandy facies were observed both as lag deposits formed in active moat channel and as coarser intervals of bi-gradational sequences forming drift deposits close to its crest. Their occurrence would highlight that upper slope environments impacted by intermediate water masses and proximal to sandy sources may represent favorable settings for accumulation of sandy sediment. The moat sector is characterized by a more complex stratigraphic record, where either moat sedimentation or lateral deposition of finer sediment occur, suggesting that further investigation is required to better understand this complex element of contourite systems. Based on available age information, some of the bi-gradational sequences probably formed during the Dark Age Cold Period, providing example of a small-scale cyclicity of contourite deposition, likely related to short-term (possibly multicentennial scale) fluctuations of the paleo modified-LIW. According to age constraints and analysis of foraminiferal assemblages, these fluctuations were likely governed by climate variations, with a weaker activity during warmer periods and faster currents during colder events.openMartorelli E., Bosman A., Casalbore D., Chiocci F., Conte A.M., Di Bella L., Ercilla G., Falcini F., Falco P., Frezza V., Gaglianone G., Giaccio B., Mancini M.Martorelli, E.; Bosman, A.; Casalbore, D.; Chiocci, F.; Conte, A. M.; Di Bella, L.; Ercilla, G.; Falcini, F.; Falco, P.; Frezza, V.; Gaglianone, G.; Giaccio, B.; Mancini, M

FIVA:Functional Information Viewer and Analyzer extracting biological knowledge from transcriptome data of prokaryotes

FIVA (Function Information Viewer and Analyzer) aids researchers in the prokaryotic community to quickly identify relevant biological processes following transcriptome analysis. Our software assists in functional profiling of large sets of genes and generates a comprehensive overview of affected biological processes.

Novel risk calculator performance in athletes with arrhythmogenic right ventricular cardiomyopathy

Background: Disease progression and ventricular arrhythmias (VAs) in arrhythmogenic right ventricular cardiomyopathy (ARVC) are correlated with physical exercise, and clinical detraining and avoidance of competitive sport practice are suggested for ARVC patients. An algorithm assessing primary arrhythmic risk in ARVC patients was recently developed by Cadrin-Tourigny et al. Data regarding its transferability to athletes are lacking. Objective: The purpose of this study was to assess the reliability of the Cadrin-Tourigny risk prediction algorithm in a cohort of athletes with ARVC and to describe the impact of clinical detraining on disease progression. Methods: All athletes undergoing clinical detraining after ARVC diagnosis at our institution were enrolled. Baseline and follow-up clinical characteristics and data on VA events occurring during follow-up were collected. The Cadrin-Tourigny algorithm was used to calculate the a priori predicted VA risk, which was compared with the observed outcomes. Results: Twenty-five athletes (age 36.1 \ub1 14.0 years; 80% male) with definite ARVC who were undergoing clinical detraining were enrolled. Over median (interquartile range) follow-up of 5.3 (3.2\u20136.6) years, a reduction in premature ventricular complex (PVC) burden (P = .001) was assessed, and 10 VA events (40%) were recorded. The a priori algorithm-predicted risk seemed to fit with the observed cohort arrhythmic risk [mean observed\u2013predicted risk difference over 5 years \u20130.85% (interquartile range \u20134.8% to +3.1%); P = .85]. At 1-year follow-up, 11 patients (44%) had an improved stress ECG response, and no significant changes in right ventricular ejection fraction were observed. Conclusion: Clinical detraining is associated with PVC burden reduction in athletes with ARVC. The novel risk prediction algorithm does not seem to require any correction for its application to ARVC athletes

Neoadjuvant chemoradiotherapy with or without panitumumab in patients with wild-type KRAS, locally advanced rectal cancer (LARC): a randomized, multicenter, phase II trial SAKK 41/07

Background We conducted a randomized, phase II, multicenter study to evaluate the anti-epidermal growth factor receptor (EGFR) mAb panitumumab (P) in combination with chemoradiotherapy (CRT) with standard-dose capecitabine as neoadjuvant treatment for wild-type KRAS locally advanced rectal cancer (LARC). Patients and methods Patients with wild-type KRAS, T3-4 and/or N+ LARC were randomly assigned to receive CRT with or without P (6 mg/kg). The primary end-point was pathological near-complete or complete tumor response (pNC/CR), defined as grade 3 (pNCR) or 4 (pCR) histological regression by Dworak classification (DC). Results Forty of 68 patients were randomly assigned to P + CRT and 28 to CRT. pNC/CR was achieved in 21 patients (53%) treated with P + CRT [95% confidence interval (CI) 36%-69%] versus 9 patients (32%) treated with CRT alone (95% CI: 16%-52%). pCR was achieved in 4 (10%) and 5 (18%) patients, and pNCR in 17 (43%) and 4 (14%) patients. In immunohistochemical analysis, most DC 3 cells were not apoptotic. The most common grade ≥3 toxic effects in the P + CRT/CRT arm were diarrhea (10%/6%) and anastomotic leakage (15%/4%). Conclusions The addition of panitumumab to neoadjuvant CRT in patients with KRAS wild-type LARC resulted in a high pNC/CR rate, mostly grade 3 DC. The results of both treatment arms exceeded prespecified thresholds. The addition of panitumumab increased toxicit

The Bortoluzzi Mud Volcano (Ionian Sea, Italy) and its potential for tracking the seismic cycle of active faults

The Ionian Sea in southern Italy is at the center of active interaction and convergence between the Eurasian and African-Adriatic plates in the Mediterranean. This area is seismically active with instrumentally and/or historically recorded Mw &gt; 7:0 earthquakes, and it is affected by recently discovered long strike-slip faults across the active Calabrian accretionary wedge. Many mud volcanoes occur on top of the wedge. A recently discovered one (called the Bortoluzzi Mud Volcano or BMV) was surveyed during the Seismofaults 2017 cruise (May 2017). High-resolution bathymetric backscatter surveys, seismic reflection profiles, geochemical and earthquake data, and a gravity core are used here to geologically, geochemically, and geophysically characterize this structure. The BMV is a circular feature ' 22 m high and ' 1100 m in diameter with steep slopes (up to a dip of 22). It sits atop the Calabrian accretionary wedge and a system of flower-like oblique-slip faults that are probably seismically active as demonstrated by earthquake hypocentral and focal data. Geochemistry of water samples from the seawater column on top of the BMV shows a significant contamination of the bottom waters from saline (evaporite-type) CH4-dominated crustal-derived fluids similar to the fluids collected from a mud volcano located on the Calabria mainland over the same accretionary wedge. These results attest to the occurrence of open crustal pathways for fluids through the BMV down to at least the Messinian evaporites at about-3000 m. This evidence is also substantiated by helium isotope ratios and by comparison and contrast with different geochemical data from three seawater columns located over other active faults in the Ionian Sea area. One conclusion is that the BMV may be useful for tracking the seismic cycle of active faults through geochemical monitoring. Due to the widespread diffusion of mud volcanoes in seismically active settings, this study contributes to indicating a future path for the use of mud volcanoes in the monitoring and mitigation of natural hazards

Ethylene augments root hypoxia tolerance via growth cessation and reactive oxygen species amelioration

Flooded plants experience impaired gas diffusion underwater, leading to oxygen deprivation (hypoxia). The volatile plant hormone ethylene is rapidly trapped in submerged plant cells and is instrumental for enhanced hypoxia acclimation. However, the precise mechanisms underpinning ethylene-enhanced hypoxia survival remain unclear. We studied the effect of ethylene pretreatment on hypoxia survival of Arabidopsis (Arabidopsis thaliana) primary root tips. Both hypoxia itself and re-oxygenation following hypoxia are highly damaging to root tip cells, and ethylene pretreatments reduced this damage. Ethylene pretreatment alone altered the abundance of transcripts and proteins involved in hypoxia responses, root growth, translation, and reactive oxygen species (ROS) homeostasis. Through imaging and manipulating ROS abundance in planta, we demonstrated that ethylene limited excessive ROS formation during hypoxia and subsequent re-oxygenation and improved oxidative stress survival in a PHYTOGLOBIN1-dependent manner. In addition, we showed that root growth cessation via ethylene and auxin occurred rapidly and that this quiescence behavior contributed to enhanced hypoxia tolerance. Collectively, our results show that the early flooding signal ethylene modulates a variety of processes that all contribute to hypoxia surviva