Rab3D is critical for secretory granule maturation in PC12 cells.

Neuropeptide- and hormone-containing secretory granules (SGs) are synthesized at the trans-Golgi network (TGN) as immature secretory granules (ISGs) and complete their maturation in the F-actin-rich cell cortex. This maturation process is characterized by acidification-dependent processing of cargo proteins, condensation of the SG matrix and removal of membrane and proteins not destined to mature secretory granules (MSGs). Here we addressed a potential role of Rab3 isoforms in these maturation steps by expressing their nucleotide-binding deficient mutants in PC12 cells. Our data show that the presence of Rab3D(N135I) decreases the restriction of maturing SGs to the F-actin-rich cell cortex, blocks the removal of the endoprotease furin from SGs and impedes the processing of the luminal SG protein secretogranin II. This strongly suggests that Rab3D is implicated in the subcellular localization and maturation of ISGs

Volume Flow Rate Estimation for Small Explosions at Mt. Etna, Italy, From Acoustic Waveform Inversion

Rapid assessment of the volume and the rate at which gas and pyroclasts are injected into the atmosphere during volcanic explosions is key to effective eruption hazard mitigation. Here, we use data from a dense infrasound network deployed in 2017 on Mt. Etna, Italy, to estimate eruptive volume flow rates (VFRs) during small gas-and-ash explosions.We use a finite-difference time-domain approximation to compute the acoustic Green's functions and perform a full waveform inversion for a multipole source, combining monopole and horizontal dipole terms. The inversion produces realistic estimates of VFR, on the order of 4 × 104 m3/s and well-defined patterns of source directivity. This is the first application of acoustic waveform inversion at Mt. Etna. Our results demonstrate that acoustic waveform inversion is a mature and robust tool for assessment of source parameters and holds potential as a tool to provide rapid estimates of VFR in near real time.This study was supported by NERC Grant NE/P00105X/1 and by European Unions Horizon 2020 Research and Innovation Programme Under the Marie Sklodowska-Curie Grant Agreement 798480

Spatial migration of temporal earthquake clusters driven by the transfer of differential stress between neighbouring fault/shear-zone structures

Uncertainty concerning the processes responsible for slip-rate fluctuations associated with temporal clustering of surface faulting earthquakes is a fundamental, unresolved issue in tectonics, because strain-rates accommodated by fault/shear-zone structures are the key to understanding the viscosity structure of the crust and seismic hazard. We constrain the timing and amplitude of slip-rate fluctuations that occurred on three active normal faults in central Italy over a time period of 20–30 kyrs, using in situ 36Cl cosmogenic dating of fault planes. We identify five periods of rapid slip on individual faults lasting a few millennia, separated time periods of up to 10 millennia with low or zero slip-rate. The rapid slip pulses migrated across the strike between the faults in two waves from SW to NE. We replicate this migration with a model where rapid slip induces changes in differential stress that drive changes in strain-rate on viscous shear zones that drive slip-rate variability on overlying brittle faults. Earthquakes increase the differential stress and strain-rate on underlying shear zones, which in turn accumulate strain, re-loading stress onto the overlying brittle fault. This positive feedback produces high strain-rate episodes containing several large magnitude surface faulting earthquakes (earthquake clusters), but also reduce the differential stress on the viscous portions of neighbouring fault/shear-zones slowing the occurrence of large-magnitude surface faulting earthquakes (earthquake anticlusters). Shear-zones on faults experiencing anticlusters continue to accumulate viscous strain at a lowered rate, and eventually this loads the overlying brittle fault to failure, initiating a period of rapid slip through the positive feedback process described above, and inducing lowered strain-rates onto neighbouring fault/shear-zones. We show that these patterns of differential stress change can replicate the measured earthquake clustering implied by the 36Cl data. The stress changes are related to the fault geometry in terms of distance and azimuth from the slipping structure, implying that (a) strain-rate and viscosity fluctuations for studies of continental rheology, and (b) slip-rates for seismic hazard purposes are to an extent predictable given knowledge of the fault system geometry

High-rate very-long-period seismicity at Yasur volcano, Vanuatu: source mechanism and decoupling from surficial explosions and infrasound

Yasur volcano, Vanuatu is a continuously active open-vent basaltic-andesite stratocone with persistent and long-lived eruptive activity. We present results from a seismo-acoustic field experiment at Yasur, providing locally dense broad-band seismic and infrasonic network coverage from 2016 July 27 to August 3. We corroborate our seismo-acoustic observations with coincident video data from cameras deployed at the crater and on an unoccupied aircraft system (UAS). The waveforms contain a profusion of signals reflecting Yasur's rapidly occurring and persistent explosive activity. The typical infrasonic signature of Yasur explosions is a classic short-duration and often asymmetric explosion waveform characterized by a sharp compressive onset and wideband frequency content. The dominant seismic signals are numerous repetitive very-long-period (VLP) signals with periods of ∼2-10 s. The VLP seismic events are 'high-rate', reoccurring near-continuously throughout the data set with short interevent times (∼20-60 s). We observe variability in the synchronization of seismic VLP and acoustic sources. Explosion events clearly delineated by infrasonic waveforms are underlain by seismic VLPs. However, strong seismic VLPs also occur with only a weak infrasonic expression. Multiplet analysis of the seismic VLPs reveals a systematic progression in the seismo-acoustic source decoupling. The same dominant seismic VLP multiplet occurs with and without surficial explosions and infrasound, and these transitions occur over a timescale of a few days during our field campaign. We subsequently employ template matching, stacking, and full-waveform inversion to image the source mechanism of the dominant VLP multiplet. Inversion of the dominant VLP multiplet stack points to a composite source consisting of either a dual-crack (plus forces) or pipe-crack (plus forces) mechanism. The derived mechanisms correspond to a point-source directly beneath the summit vents with centroid depths in the range ∼900-1000 m below topography. All mechanisms suggest a northeast trending crack dipping relatively shallowly to the northwest and indicate a VLP source centroid and mechanism controlled by a stable structural geologic feature beneath Yasur. We interpret the results in the framework of gas slug ascent through the conduit responsible for Yasur explosions. The VLP mechanism and timing with infrasound (when present) are explained by a shallow-buffered top-down model in which slug ascent is relatively aseismic until reaching the base of a shallow section. Slug disruption in this shallow zone triggers a pressure disturbance that propagates downward and couples at the conduit base (VLP centroid). If the shallow section is open, an explosion propagates to the surface, producing infrasound. In the case of (the same multiplet) VLPs occurring without surficial explosions and weak or no infrasound, the decoupling of the dominant VLPs at ∼900-1000 m depth from surficial explosions and infrasound strongly indicates buffering of the terminal slug ascent. This buffering could be achieved by a variety of conditions at or directly beneath the vents, such as a high-viscosity layer of crystal-rich magma, a debris cap from backfill, a foam layer, or a combination of these. The dominant VLP at Yasur captured by our experiment has a source depth and mechanism separated from surface processes and is stable over time.fals

Dual control of fault intersections on stop-start rupture in the 2016 Central Italy seismic sequence

Large continental earthquakes necessarily involve failure of multiple faults or segments. But these same critically-stressed systems sometimes fail in drawn-out sequences of smaller earthquakes over days or years instead. These two modes of failure have vastly different implications for seismic hazard and it is not known why fault systems sometimes fail in one mode or the other, or what controls the termination and reinitiation of slip in protracted seismic sequences. A paucity of modern observations of seismic sequences has hampered our understanding to-date, but a series of three Mw > 6 earthquakes from August to November 2016 in Central Italy represents a uniquely well-observed example. Here we exploit a wealth of geodetic, seismological and field data to understand the spatio-temporal evolution of the sequence. Our results suggest that intersections between major and subsidiary faults controlled the extent and termination of rupture in each event in the sequence, and that fluid diffusion, channelled along these same fault intersections, may have also determined the timing of rupture reinitiation. This dual control of subsurface structure on the stop-start rupture in seismic sequences may be common; future efforts should focus on investigating its prevalence

CREB Is Activated by Muscle Injury and Promotes Muscle Regeneration

The cAMP response element binding protein (CREB) plays key roles in differentiation of embryonic skeletal muscle progenitors and survival of adult skeletal muscle. However, little is known about the physiologic signals that activate CREB in normal muscle. Here we show that CREB phosphorylation and target genes are induced after acute muscle injury and during regeneration due to genetic mutation. Activated CREB localizes to both myogenic precursor cells and newly regenerating myofibers within regenerating areas. Moreover, we found that signals from damaged skeletal muscle tissue induce CREB phosphorylation and target gene expression in primary mouse myoblasts. An activated CREB mutant (CREBY134F) potentiates myoblast proliferation as well as expression of early myogenic transcription factors in cultured primary myocytes. Consistently, activated CREB-YF promotes myoblast proliferation after acute muscle injury in vivo and enhances muscle regeneration in dystrophic mdx mice. Our findings reveal a new physiologic function for CREB in contributing to skeletal muscle regeneration

Profile of Central and Effector Memory T Cells in the Progression of Chronic Human Chagas Disease

Chagas disease is a parasitic infection caused by protozoan Trypanosoma cruzi that affects approximately 11 million people in Latin America. The involvement of the host's immune response on the development of severe forms of Chagas disease has not been fully elucidated. Studies on the immune response against T. cruzi infection show that the immunoregulatory mechanisms are necessary to prevent the deleterious effect of excessive immune response stimulation and consequently the fatal outcome of the disease. A recall response against parasite antigens observed in in vitro peripheral blood cell culture clearly demonstrates that memory response is generated during infection. Memory T cells are heterogeneous and differ in both the ability to migrate and exert their effector function. This heterogeneity is reflected in the definition of central (TCM) and effector memory (TEM) T cells. Our results suggest that a balance between regulatory and effectors T cells may be important for the progression and development of the disease. Furthermore, the high percentage of central memory CD4+ T cells in indeterminate patients after stimulation suggests that these cells may modulate host's inflammatory response by controlling cell migration to tissues and their effector role during chronic phase of the disease

Coulomb pre-stress and fault bends are ignored yet vital factors for earthquake triggering and hazard

Successive locations of individual large earthquakes (Mw>5.5) over years to centuries can be difficult to explain with simple Coulomb Stress Transfer (CST) because it is common for seismicity to circumvent nearest-neighbour along-strike faults where coseismic CST is greatest. We demonstrate that Coulomb pre-stress (the cumulative CST from multiple earthquakes and interseismic loading on non-planar faults) may explain this, evidenced by study of a 667-year historical record of earthquakes in central Italy. Heterogeneity in Coulomb pre-stresses across the fault system is >±50 bars, whereas coseismic CST is <±2 bars, so the latter will rarely overwhelm the former, explaining why historical earthquakes rarely rupture nearest neighbor faults. However, earthquakes do tend to occur where the cumulative coseismic and interseismic CST is positive, although there are notable examples where earthquake propagate across negatively stressed portions of faults. Hence Coulomb pre-stress calculated for non-planar faults is an ignored yet vital factor for earthquake triggering

A retrospective multicentric observational study of trastuzumab emtansine in HER2 positive metastatic breast cancer: a real- world experience

We addressed trastuzumab emtansine (T-DM1) e cacy in HER2+ metastatic breast cancer patients treated in real-world practice, and its activity in pertuzumab- pretreated patients. We conducted a retrospective, observational study involving 23 cancer centres, and 250 patients. Survival data were analyzed by Kaplan Meier curves and log rank test. Factors testing signi cant in univariate analysis were tested in multivariate models. Median follow-up was 15 months and median T-DM1 treatment-length 4 months. Response rate was 41.6%, clinical bene t 60.9%. Median progression-free and median overall survival were 6 and 20 months, respectively. Overall, no di erences emerged by pertuzumab pretreatment, with median progression-free and median overall survival of 4 and 17 months in pertuzumab- pretreated (p=0.13), and 6 and 22 months in pertuzumab-naïve patients (p=0.27). Patients who received second-line T-DM1 had median progression-free and median overall survival of 3 and 12 months (p=0.0001) if pertuzumab-pretreated, and 8 and 26 months if pertuzumab-naïve (p=0.06). In contrast, in third-line and beyond, median progression-free and median overall survival were 16 and 18 months in pertuzumab- pretreated (p=0.05) and 6 and 17 months in pertuzumab-naïve patients (p=0.30). In multivariate analysis, lower ECOG performance status was associated with progression-free survival bene t (p<0.0001), while overall survival was positively a ected by lower ECOG PS (p<0.0001), absence of brain metastases (p 0.05), and clinical bene t (p<0.0001). Our results are comparable with those from randomized trials. Further studies are warranted to con rm and interpret our data on apparently lower T-DM1 e cacy when given as second-line treatment after pertuzumab, and on the optimal sequence order