In the past few years, 3D electron microscopy (3DEM) has undergone a revolution in instrumentation and methodology. One of the central players in this wide-reaching change is the continuous ...development of image processing software. Here we present Scipion, a software framework for integrating several 3DEM software packages through a workflow-based approach. Scipion allows the execution of reusable, standardized, traceable and reproducible image-processing protocols. These protocols incorporate tools from different programs while providing full interoperability among them. Scipion is an open-source project that can be downloaded from http://scipion.cnb.csic.es.
Calcium sulfate minerals such as gypsum play important roles in natural and industrial processes, but their precipitation mechanisms remain largely unexplored. We used time-resolved sample quenching ...and high-resolution microscopy to demonstrate that gypsum forms via a three-stage process: (i) homogeneous precipitation of nanocrystalline hemihydrate bassanite below its predicted solubility, (ii) self-assembly of bassanite into elongated aggregates co-oriented along their c axis, and (iii) transformation into dihydrate gypsum. These findings indicate that a stable nanocrystalline precursor phase can form below its bulk solubility and that in the CaSO₄ system, the self-assembly of nanoparticles plays a crucial role. Understanding why bassanite forms prior to gypsum can lead to more efficient anti-scaling strategies for water desalination and may help to explain the persistence of CaS0 4 phases in regions of low water activity on Mars.
Here, we investigated for the first time the frequency and number of circulating tumor plasma cells (CTPC) in peripheral blood (PB) of newly diagnosed patients with localized and systemic plasma cell ...neoplasms (PCN) using next-generation flow cytometry (NGF) and correlated our findings with the distinct diagnostic and prognostic categories of the disease. Overall, 508 samples from 264 newly diagnosed PCN patients, were studied. CTPC were detected in PB of all active multiple myeloma (MM; 100%), and smoldering MM (SMM) patients (100%), and in more than half (59%) monoclonal gammopathy of undetermined significance (MGUS) cases (p <0.0001); in contrast, CTPC were present in a small fraction of solitary plasmacytoma patients (18%). Higher numbers of CTPC in PB were associated with higher levels of BM infiltration and more adverse prognostic features, together with shorter time to progression from MGUS to MM (p <0.0001) and a shorter survival in MM patients with active disease requiring treatment (p ≤ 0.03). In summary, the presence of CTPC in PB as assessed by NGF at diagnosis, emerges as a hallmark of disseminated PCN, higher numbers of PB CTPC being strongly associated with a malignant disease behavior and a poorer outcome of both MGUS and MM.
Previously, it has been shown that pancreatic ductal adenocarcinoma (PDA) tumors exhibit high levels of hypoxia, characterized by low oxygen pressure (pO2) and decreased O2 intracellular perfusion. ...Chronic hypoxia is strongly associated with resistance to cytotoxic chemotherapy and chemoradiation in an understudied phenomenon known as hypoxia-induced chemoresistance. The hypoxia-inducible, pro-oncogenic, serine-threonine kinase PIM1 (Proviral Integration site for Moloney murine leukemia virus 1) has emerged as a key regulator of hypoxia-induced chemoresistance in PDA and other cancers. Although its role in therapeutic resistance has been described previously, the molecular mechanism behind PIM1 overexpression in PDA is unknown. Here, we demonstrate that cis-acting AU-rich elements (ARE) present within a 38-base pair region of the PIM1 mRNA 3'-untranslated region mediate a regulatory interaction with the mRNA stability factor HuR (Hu antigen R) in the context of tumor hypoxia. Predominantly expressed in the nucleus in PDA cells, HuR translocates to the cytoplasm in response to hypoxic stress and stabilizes the PIM1 mRNA transcript, resulting in PIM1 protein overexpression. A reverse-phase protein array revealed that HuR-mediated regulation of PIM1 protects cells from hypoxic stress through phosphorylation and inactivation of the apoptotic effector BAD and activation of MEK1/2. Importantly, pharmacological inhibition of HuR by MS-444 inhibits HuR homodimerization and its cytoplasmic translocation, abrogates hypoxia-induced PIM1 overexpression and markedly enhances PDA cell sensitivity to oxaliplatin and 5-fluorouracil under physiologic low oxygen conditions. Taken together, these results support the notion that HuR has prosurvival properties in PDA cells by enabling them with growth advantages in stressful tumor microenvironment niches. Accordingly, these studies provide evidence that therapeutic disruption of HuR's regulation of PIM1 may be a key strategy in breaking an elusive chemotherapeutic resistance mechanism acquired by PDA cells that reside in hypoxic PDA microenvironments.
We compared the effects of two resistance training (RT) programs only differing in the repetition velocity loss allowed in each set: 20% (VL20) vs 40% (VL40) on muscle structural and functional ...adaptations. Twenty‐two young males were randomly assigned to a VL20 (n = 12) or VL40 (n = 10) group. Subjects followed an 8‐week velocity‐based RT program using the squat exercise while monitoring repetition velocity. Pre‐ and post‐training assessments included: magnetic resonance imaging, vastus lateralis biopsies for muscle cross‐sectional area (CSA) and fiber type analyses, one‐repetition maximum strength and full load‐velocity squat profile, countermovement jump (CMJ), and 20‐m sprint running. VL20 resulted in similar squat strength gains than VL40 and greater improvements in CMJ (9.5% vs 3.5%, P < 0.05), despite VL20 performing 40% fewer repetitions. Although both groups increased mean fiber CSA and whole quadriceps muscle volume, VL40 training elicited a greater hypertrophy of vastus lateralis and intermedius than VL20. Training resulted in a reduction of myosin heavy chain IIX percentage in VL40, whereas it was preserved in VL20. In conclusion, the progressive accumulation of muscle fatigue as indicated by a more pronounced repetition velocity loss appears as an important variable in the configuration of the resistance exercise stimulus as it influences functional and structural neuromuscular adaptations.
Highly active antiretroviral therapy (HAART) results in potent and durable suppression of HIV-1 viremia. However, HIV-1 replication resumes if therapy is interrupted. Although it is generally ...believed that active replication has been halted in individuals on HAART, immune activation and inflammation continue at abnormal levels, suggesting continued, low-level viral replication. To assess whether active replication might be driving immune activation in HAART, we examined the impact of treatment intensification with the integrase inhibitor raltegravir on viral complementary DNA and immune activation parameters. In the presence of raltegravir, linear HIV-1 cDNA is prevented from integrating into chromatin and is subsequently converted to episomal cDNAs. Raltegravir intensification of a three-drug suppressive HAART regimen resulted in a specific and transient increase in episomal DNAs in a large percentage of HAART-suppressed subjects. Furthermore, in subjects with these episomal DNAs, immune activation was higher at baseline and was subsequently normalized after raltegravir intensification. These results suggest that, despite suppressive HAART, active replication persists in some infected individuals and drives immune activation. The ability of raltegravir intensification to perturb the reservoir that supports active replication has implications for therapeutic strategies aimed at achieving viral eradication.
Here we provide a theoretical framework revealing that the radius
$R_{d}$
of the top droplet ejected from a bursting bubble of radius
$R_{b}$
and
$Bo\leqslant 0.05$
can be expressed as
...$R_{d}/R_{b}=K_{b}(1-(Oh/Oh_{c}^{\prime })^{1/2})$
for
$Oh\lesssim Oh_{c}^{\prime }$
or as
$R_{d}\approx 18\,\unicodeSTIX{x1D707}_{l}^{2}/(\unicodeSTIX{x1D70C}_{l}\unicodeSTIX{x1D70E})$
for
$Oh\gtrsim Oh_{c}^{\prime }$
, with the numerically fitted constants
$K_{b}\approx 0.2$
,
$Oh_{c}^{\prime }\approx 0.03$
,
$Oh=\unicodeSTIX{x1D707}_{l}/\sqrt{\unicodeSTIX{x1D70C}_{l}\,R_{b}\,\unicodeSTIX{x1D70E}}\ll 1$
the Ohnesorge number,
$Bo=\unicodeSTIX{x1D70C}_{l}\,g\,R_{b}^{2}/\unicodeSTIX{x1D70E}$
the Bond number, and
$\unicodeSTIX{x1D70C}_{l}$
,
$\unicodeSTIX{x1D707}_{l}$
and
$\unicodeSTIX{x1D70E}$
indicating the liquid density, dynamic viscosity and interfacial tension coefficient, respectively. These predictions, which do not only have solid theoretical roots but are also much more accurate than the usual 10 % rule used in the context of marine spray generation via whitecaps for
$R_{b}\lesssim 1$
mm, agree very well with both experimental data and numerical simulations for the values of
$Oh$
and
$Bo$
investigated. Moreover, making use of a criterion which reveals the mechanism that controls the growth rate of capillary instabilities, we also explain here why no droplets are ejected from the tip of the fast Worthington jet for
$Oh\gtrsim 0.04$
. In addition, our results predict the generation of submicron-sized aerosol particles with diameters below 100 nm and velocities
${\sim}\unicodeSTIX{x1D70E}/\unicodeSTIX{x1D707}_{l}$
for bubble radii
$10~\unicodeSTIX{x03BC}\text{m}\lesssim R_{b}\lesssim 20~\unicodeSTIX{x03BC}\text{m}$
, within the range found in natural conditions and in good agreement with experiments – a fact suggesting that our study could be applied in the modelling of sea spray aerosol production.
Subsidence related to multiple natural and human-induced processes affects an increasing number of areas worldwide. Although this phenomenon may involve surface deformation with 3D displacement ...components, negative vertical movement, either progressive or episodic, tends to dominate. Over the last decades, differential SAR interferometry (DInSAR) has become a very useful remote sensing tool for accurately measuring the spatial and temporal evolution of surface displacements over broad areas. This work discusses the main advantages and limitations of addressing active subsidence phenomena by means of DInSAR techniques from an end-user point of view. Special attention is paid to the spatial and temporal resolution, the precision of the measurements, and the usefulness of the data. The presented analysis is focused on DInSAR results exploitation of various ground subsidence phenomena (groundwater withdrawal, soil compaction, mining subsidence, evaporite dissolution subsidence, and volcanic deformation) with different displacement patterns in a selection of subsidence areas in Spain. Finally, a cost comparative study is performed for the different techniques applied.
We present a phenomenological model for granular suspension rheology in which particle interactions enter as constraints to relative particle motion. By considering constraints that are formed and ...released by stress respectively, we derive a range of experimental flow curves in a single treatment and predict singularities in viscosity and yield stress consistent with literature data. Fundamentally, we offer a generic description of suspension flow that is independent of bespoke microphysics.
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