Molecular Mechanisms of Programmed Necrotic Death Initiated by Intrinsic Death Signals

Proper regulation of cell death is critical for tissue development and homeostasis, with deregulation implicated in many illnesses. Cell death is morphologically categorised as apoptosis, autophagy, and necrosis, with apoptosis being the best studied. BCL-2 family members are critical apoptosis regulators. Death signals induce upstream activator BH3-only molecules to activate the essential mitochondrion apoptosis effectors BAX and BAK to execute death. Yet, combined loss of Bax and Bak causes developmental and homeostatic defects in restricted tissues, indicating the existence of additional death program(s). By using Bax-/-Bak-/- double- knockout (DKO) mouse embryonic fibroblasts (MEFs) to study non-apoptotic death, we discovered DNA double strand breaks (DSBs) activate a genetic program that upregulates reactive oxygen species (ROS) and the lysosomal protease cathepsin to execute a form of programmed necrotic death (PND). This refutes the long-held view that necrosis is a passive reponse to unmanageable physico-chemical stress. However, the PND execution pathways triggered by death signals and the determinants of death versus long-term survival are unclear. Here, I demonstrated a critical role for the transcription factor DeltaNp63alpha in determining long-term survival in the face of oxidative stress, a central necrotic mediator. DeltaNp63alpha protected DKO MEFs against PND and enhanced long-term survival via a novel ability to control intracellular redox homeostasis by regulating glutathione metabolism. DeltaNp63alpha overexpression protected from oxidative stress induced by oxidants, DNA damage, and anoikis, while deficiency of DeltaNp63alpha increased oxidative stress and sensitized to oxidant-induced death. I further found that long-term survival of anchorage-dependent cells following loss of matrix attachment was enhanced by combined inhibition of apoptosis and oxidative stress by BCL-2 and DeltaNp63alpha, respectively. Furthermore, I showed that in DKO MEFs, DSBs triggered an ATM-mediated DNA damage response that increased ROS production by upregulating the activity of complex III of the electron transport chain. My work concluded a key role for oxidative stress in the loss of long-term survival triggered by intrinsic death signals and revealed an important role for DeltaNp63alpha in regulating redox homeostasis. These findings laid the groundwork for future studies on programmed necrotic death initiated by intrinsic death signals

COMPARISON OF RECENT FIBER ORIENTATION MODELS IN AUTODESK MOLDFLOW INSIGHT SIMULATIONS WITH MEASURED FIBER ORIENTATION DATA

Abstract -The reduced strain closure (RSC) and anisotropic rotary diffusion (ARD) models have been implemented in a research version of Autodesk Moldflow Insight software to improve the accuracy of fiber orientation predictions in simulations of injection-molded parts. The RSC model captures the slow fiber orientation kinetics, which are observed in experiments but over-predicted by the widely used Folgar-Tucker model. The ARD model accounts for fiber-fiber interactions using anisotropic diffusion to rectify the problem that for long-fiber materials, the Folgar-Tucker model does not match all aspects of measured fiber orientation data. Simulating the injection molding process in Autodesk Moldflow Insight software, the fiber orientation is predicted for a number of end-gated ISO plaques and center-gated disks of different thicknesses (from 1.5 to 6 mm) filled at different injection rates, with Midplane meshes as well as 3D meshes, using the RSC model for short-fiber materials and the ARD-RSC model for long-fiber materials. In Midplane models, with an appropriate inlet condition for fiber orientation applied at the gate, the RSC and ARD models show good agreement with measured fiber orientation data. In 3D models with random inlet orientation applied at the gate, the RSC model gives good agreement with one orientation component of the experimental data for short-fiber materials

The FRIGG project: From intermediate galactic scales to self-gravitating cores

Abridged. Understanding the detailed structure of the interstellar gas is essential for our knowledge of the star formation process. The small-scale structure of the interstellar medium (ISM) is a direct consequence of the galactic scales and making the link between the two is essential. We perform adaptive mesh simulations that aim to bridge the gap between the intermediate galactic scales and the self-gravitating prestellar cores. For this purpose we use stratified supernova regulated ISM magneto-hydrodynamical (MHD) simulations at the kpc scale to set up the initial conditions. We then zoom, performing a series of concentric uniform refinement and then refining on the Jeans length for the last levels. This allows us to reach a spatial resolution of a few $10^{-3}$ pc. The cores are identified using a clump finder and various criteria based on virial analysis. Their most relevant properties are computed and, due to the large number of objects formed in the simulations, reliable statistics are obtained. The cores properties show encouraging agreements with observations. The mass spectrum presents a clear powerlaw at high masses with an exponent close to $\simeq -1.3$ and a peak at about 1-2 $M_\odot$. The velocity dispersion and the angular momentum distributions are respectively a few times the local sound speed and a few $10^{-2}$ pc km s$^{-1}$. We also find that the distribution of thermally supercritical cores present a range of magnetic mass-to-flux over critical mass-to-flux ratio which typically ranges between $\simeq$0.3 and 3.Comment: accepted for publication in A&

Validation of New Process Models for Large Injection-Molded Long-Fiber Thermoplastic Composite Structures

This report describes the work conducted under the CRADA Nr. PNNL/304 between Battelle PNNL and Autodesk whose objective is to validate the new process models developed under the previous CRADA for large injection-molded LFT composite structures. To this end, the ARD-RSC and fiber length attrition models implemented in the 2013 research version of Moldflow was used to simulate the injection molding of 600-mm x 600-mm x 3-mm plaques from 40% glass/polypropylene (Dow Chemical DLGF9411.00) and 40% glass/polyamide 6,6 (DuPont Zytel 75LG40HSL BK031) materials. The injection molding was performed by Injection Technologies, Inc. at Windsor, Ontario (under a subcontract by Oak Ridge National Laboratory, ORNL) using the mold offered by the Automotive Composite Consortium (ACC). Two fill speeds under the same back pressure were used to produce plaques under slow-fill and fast-fill conditions. Also, two gating options were used to achieve the following desired flow patterns: flows in edge-gated plaques and in center-gated plaques. After molding, ORNL performed measurements of fiber orientation and length distributions for process model validations. The structure of this report is as follows. After the Introduction (Section 1), Section 2 provides a summary of the ARD-RSC and fiber length attrition models. A summary of model implementations in the latest research version of Moldflow is given in Section 3. Section 4 provides the key processing conditions and parameters for molding of the ACC plaques. The validations of the ARD-RSC and fiber length attrition models are presented and discussed in Section 5. The conclusions will be drawn in Section 6

Monitoring of the central blood pressure waveform via a conformal ultrasonic device.

Continuous monitoring of the central-blood-pressure waveform from deeply embedded vessels, such as the carotid artery and jugular vein, has clinical value for the prediction of all-cause cardiovascular mortality. However, existing non-invasive approaches, including photoplethysmography and tonometry, only enable access to the superficial peripheral vasculature. Although current ultrasonic technologies allow non-invasive deep-tissue observation, unstable coupling with the tissue surface resulting from the bulkiness and rigidity of conventional ultrasound probes introduces usability constraints. Here, we describe the design and operation of an ultrasonic device that is conformal to the skin and capable of capturing blood-pressure waveforms at deeply embedded arterial and venous sites. The wearable device is ultrathin (240 μm) and stretchable (with strains up to 60%), and enables the non-invasive, continuous and accurate monitoring of cardiovascular events from multiple body locations, which should facilitate its use in a variety of clinical environments

A Study on the Effect of the Structural Parameters and Internal Mechanism of a Bilateral Gate-Controlled S/D Symmetric and Interchangeable Bidirectional Tunnel Field Effect Transistor

A bilateral gate-controlled S/D symmetric and interchangeable bidirectional tunnel field effect transistor (B-TFET) is proposed in this paper, which shows the advantage of bidirectional switching characteristics and compatibility with CMOS integrated circuits compared to the conventional asymmetrical TFET. The effects of the structural parameters, e.g., the doping concentrations of the N+ region and P+ region, length of the N+ region and length of the intrinsic region, on the device performances, e.g., the transfer characteristics, Ion–Ioff ratio and subthreshold swing, and the internal mechanism are discussed and explained in detail.The Natural Science Foundation of Liaoning Province No. 2019-MS-250. This fund is used to pay for the publication of papers

Mindfulness for mediating the relationship between self-control and alexithymia among Chinese medical students: A structural equation modeling analysis

BackgroundsMedical students are prone to experience alexithymia due to academic work overload, which could increase the prevalence of mental illness such as anxiety and depression. The purpose of our study was to estimate the levels of alexithymia and to explore the relationships between alexithymia, self-control, and mindfulness among medical students.Materials and methodsFrom March 18th, 2021 to April 9th, 2021, a cross-sectional study with stratified sampling was carried out in China Medical University, Liaoning Province, China. A total of 1,013 medical students participated in this study. The questionnaires pertaining to the Toronto Alexithymia Scale (TAS-26), the Five Facet Mindfulness Questionnaire (FFMQ), and the Self-control Scale (SCS) were used to assess the levels of alexithymia, mindfulness and self-control. We used Hierarchical Multiple Regression (HMR) and structural equation modeling to explore the mediating role of mindfulness between self-control and alexithymia.ResultsThe mean score of alexithymia in medical students was 69.39 ± 9.9. After controlling for confounders, males were more likely to experience alexithymia. Self-control, acting with awareness, describing, and observing in mindfulness were negatively associated with alexithymia (P < 0.01). Mindfulness mediated the relationship between self-control and alexithymia (a*b = −0.06, BCa 95% CI: −0.09 to −0.031, Percentile 95% CI: −0.089 to −0.031).ConclusionChinese medical students experienced high levels of alexithymia. Self-control could directly attenuate alexithymia for medical students and indirectly affect alexithymia through the mediating path of mindfulness. Initiatives for self-control ability enhancement should be provided to medical students to combat alexithymia. And interventions on mindfulness training should be developed to prevent from alexithymia and promote their mental health

JourneyDB: A Benchmark for Generative Image Understanding

While recent advancements in vision-language models have had a transformative impact on multi-modal comprehension, the extent to which these models possess the ability to comprehend generated images remains uncertain. Synthetic images, in comparison to real data, encompass a higher level of diversity in terms of both content and style, thereby presenting significant challenges for the models to fully grasp. In light of this challenge, we introduce a comprehensive dataset, referred to as JourneyDB, that caters to the domain of generative images within the context of multi-modal visual understanding. Our meticulously curated dataset comprises 4 million distinct and high-quality generated images, each paired with the corresponding text prompts that were employed in their creation. Furthermore, we additionally introduce an external subset with results of another 22 text-to-image generative models, which makes JourneyDB a comprehensive benchmark for evaluating the comprehension of generated images. On our dataset, we have devised four benchmarks to assess the performance of generated image comprehension in relation to both content and style interpretation. These benchmarks encompass prompt inversion, style retrieval, image captioning, and visual question answering. Lastly, we evaluate the performance of state-of-the-art multi-modal models when applied to the JourneyDB dataset, providing a comprehensive analysis of their strengths and limitations in comprehending generated content. We anticipate that the proposed dataset and benchmarks will facilitate further research in the field of generative content understanding. The dataset is publicly available at https://journeydb.github.io.Comment: Accepted to the Thirty-seventh Conference on Neural Information Processing Systems (NeurIPS 2023

Characterization of BRD4 during mammalian post-meiotic sperm development

During spermiogenesis, the post-meiotic phase of mammalian spermatogenesis, transcription is progressively repressed as nuclei of haploid spermatids are compacted through a dramatic chromatin reorganization involving hyper-acetylation and replacement of most histones with protamines. Although BRDT functions in transcription and histone removal in spermatids, it is unknown whether other BET family proteins play a role. Immunofluorescence of spermatogenic cells revealed BRD4 in a ring around the nuclei of spermatids containing hyper-acetylated histones. The ring lies directly adjacent to the acroplaxome, the cytoskeletal base of the acrosome, previously linked to chromatin reorganization. The BRD4 ring does not form in acrosomal mutant mice. ChIP sequencing in spermatids revealed enrichment of BRD4 and acetylated histones at the promoters of active genes. BRD4 and BRDT show distinct and synergistic binding patterns, with a pronounced enrichment of BRD4 at spermatogenesis-specific genes. Direct association of BRD4 with acetylated H4 decreases in late spermatids as acetylated histones are removed from the condensing nucleus in a wave following the progressing acrosome. These data provide evidence for a prominent transcriptional role of BRD4 and suggest a possible removal mechanism for chromatin components from the genome via the progressing acrosome as transcription is repressed in response to chromatin condensation during spermiogenesis