Inequality Constrained State-Space Models

<p>The standard Kalman filter cannot handle inequality constraints imposed on the state variables, as state truncation induces a nonlinear and non-Gaussian model. We propose a Rao-Blackwellized particle filter with the optimal importance function for forward filtering and the likelihood function evaluation. The particle filter effectively enforces the state constraints when the Kalman filter violates them. Monte Carlo experiments demonstrate excellent performance of the proposed particle filter with Rao-Blackwellization, in which the Gaussian linear sub-structure is exploited at both the cross-sectional and temporal levels.</p

Isothermal Self-Assembly of Spermidine–DNA Nanostructure Complex as a Functional Platform for Cancer Therapy

Programmable DNA nanostructure self-assembly offers great potentials in nanomedicine, drug delivery, biosensing, and bioimaging. However, due to the intrinsically negatively charged DNA backbones, the instability of DNA nanostructures in physiological settings poses serious challenges to their practical applications. To overcome this challenge, a strategy that combines the magnesium-free DNA self-assembly and functionalization is proposed in this study. We hypothesize that naturally abundant spermidine may not only mediate the self-assembly of DNA nanostructures, but also shield them from harsh physiological environments. As a proof of concept, a DNA nanoprism is designed and synthesized successfully through spermidine. It is found that spermidine can mediate the isothermal self-assembly of DNA nanoprisms. Compared to conventional Mg²⁺-assembled DNA nanostructures, the spermidine–DNA nanoprism complex shows higher thermal stability and better enzymatic resistance than Mg²⁺-assembled DNA nanoprisms, and more importantly, it has a much higher cellular uptake efficacy in multiple cancerous cell lines. The internalization mechanism is identified as clathrin-mediated endocytosis. To demonstrate the suitability of this new nanomaterial for biomedical applications, an mTOR siRNA, after being conjugated into the complex, is efficiently delivered into cancer cells and shows excellent gene knockdown efficacy and anticancer capability. These findings indicate that the spermidine–DNA complex nanomaterials might be a promising platform for biomedical applications in the future

Sleep and day-to-day PTSD symptom variability: an ecological momentary assessment and actigraphy monitored study in trauma-exposed young adults

Disrupted sleep and post-traumatic stress disorder (PTSD) are bi-directionally linked and have been found to mutually reinforce each other on a day-to-day basis. However, most of the previous research has focused on subjective measures of sleep only. Here, we investigated the temporal relationship between sleep and PTSD symptoms using both subjective (sleep diary) and objective measures of sleep (actigraphy). Forty-one non-treatment seeking, trauma exposed young adults (age M = 24.68, SD = 8.15) with a range of PTSD symptom severities (PTSS, 0–53 on PCL-5) were recruited. Participants completed two surveys per day over four weeks to measure day-time PTSD symptoms (i.e. PTSS and number of intrusions) and night-time sleep subjectively, while wearing an actigraphy watch to measure sleep objectively. Linear mixed models revealed that subjectively reported sleep disruptions were associated with elevated next-day PTSS and increasing number of intrusive memories both within and between participants. Similar results were found for daytime PTSD symptoms on night-time sleep. However, these associations were not found using objective sleep data. Exploratory moderator analyses including sex (male vs. female) found that these associations differed in strength between sexes but were generally in the same direction. These results were in line with our hypothesis with regards to the sleep diary (subjective sleep), but not actigraphy (objective sleep). Several factors which have implications on both PTSD and sleep, such as the COVID-19 pandemic and/ or sleep-state misperception, may be potential reasons behind those discrepancies. However, this study had limited power and needs to be replicated in larger samples. Nonetheless, these results add to the current literature about the bi-directional relationship between sleep and PTSD and have clinical implications for treatment strategies. Elevated day-time PTSD symptom severity (PTSS) and more frequent intrusive memories were generally associated with subjectively reported disruptions in sleep and vice versa, but not with objective measures of sleep.While longer subjective sleep duration predicted reductions in PTSS and shorter sleep onset latency predicted reduced numbers of intrusions the next day, reduced daytime PTSS was only associated with reductions in distress associated with nightmares during the following night.Exploratory analyses showed that sex (men vs. women) moderated the bi-directional relationships between night-time sleep and day-time PTSD symptoms with longer sleep onset latency and lower sleep efficiency being related to worse PTSD symptoms the next day in women, but was not associated with men. Elevated day-time PTSD symptom severity (PTSS) and more frequent intrusive memories were generally associated with subjectively reported disruptions in sleep and vice versa, but not with objective measures of sleep. While longer subjective sleep duration predicted reductions in PTSS and shorter sleep onset latency predicted reduced numbers of intrusions the next day, reduced daytime PTSS was only associated with reductions in distress associated with nightmares during the following night. Exploratory analyses showed that sex (men vs. women) moderated the bi-directional relationships between night-time sleep and day-time PTSD symptoms with longer sleep onset latency and lower sleep efficiency being related to worse PTSD symptoms the next day in women, but was not associated with men.</p

Reversibly Switching the Surface Porosity of a DNA Tetrahedron

The ability to reversibly switch the surface porosity of nanocages would allow controllable matter transport in and out of the nanocages. This would be a desirable property for many technological applications, such as drug delivery. To achieve such capability, however, is challenging. Herein we report a strategy for reversibly changing the surface porosity of a self-assembled DNA nanocage (a DNA tetrahedron) that is based on DNA hydridization and strand displacement. The involved DNA nanostructures were thoroughly characterized by multiple techniques, including polyacrylamide gel electrophoresis, dynamic light scattering, atomic force microscopy, and cryogenic electron microscopy. This work may lead to the design and construction of stimuli-responsive nanocages that might find applications as smart materials

RAB26-dependent autophagy protects adherens junctional integrity in acute lung injury

<p>Microvascular barrier dysfunction is the central pathophysiological feature of acute lung injury (ALI). RAB26 is a newly identified small GTPase involved in the regulation of endothelial cell (EC) permeability. However, the mechanism behind this protection has not been clearly elucidated. Here we found that RAB26 promoted the integrity of adherens junctions (AJs) in a macroautophagy/autophagy-dependent manner in ALI. RAB26 is frequently downregulated in mouse lungs after LPS treatment. Mice lacking <i>Rab26</i> exhibited phosphorylated SRC expression and increased CDH5/VE-cadherin phosphorylation, leading to AJ destruction. <i>rab26</i>-null mice showed further aggravation of the effects of endotoxin insult on lung vascular permeability and water content. Depletion of <i>RAB26</i> resulted in upregulation of phosphorylated SRC, enhancement of CDH5 phosphorylation, and aggravation of CDH5 internalization, thereby weakening AJ integrity and endothelial barrier function in human pulmonary microvascular endothelial cells (HPMECs). <i>RAB26</i> overexpression caused active interaction between SRC and the autophagy marker LC3-II and promoted degradation of phosphorylated SRC. Furthermore, RAB26 was involved in a direct and activation-dependent manner in autophagy induction through interaction with ATG16L1 in its GTP-bound form. These findings demonstrate that RAB26 exerts a protective effect on endothelial cell (EC) permeability, which is in part dependent on autophagic targeting of active SRC, and the resultant CDH5 dephosphorylation maintains AJ stabilization. Thus, RAB26-mediated autophagic targeting of phosphorylated SRC can maintain barrier integrity when flux through the RAB26-SRC pathway is protected. These findings suggest that activation of RAB26-SRC signaling provides a new therapeutic opportunity to prevent vascular leakage in ALI.</p> <p><b>Abbreviations:</b> AJs: adherens junctions; ALI: acute lung injury; ARDS: acute respiratory distress syndrome; ATG5: autophagy related 5; ATG12: autophagy related 12; ATG 16L1: autophagy related 16 like; 1 BALF: bronchoalveolar lavage fluidCQ: chloroquine; Ctrl: control; EC: endothelial cell; GFP: green fluorescent protein; HA-tagged; RAB26^WT: HA-tagged wild-type; RAB26  HA-tagged; RAB26^QL: HA-tagged; RAB26^Q123LHA-tagged; RAB26^NI: HA-tagged; RAB26^N177IHPMECs: human pulmonary microvascular endothelial cells; H&E: hematoxylin & eosin; IgG: immunoglobulin; GIF: immunofluorescence; IP: immunoprecipitationi;. p.: intraperitoneal; LPS: lipopolysaccharide; PBS: phosphate-buffered salinesi; RNA: small interfering;RNASQSTM1/p62, sequestosome; 1TBS: Tris-buffered saline; VEGF: vascular endothelial growth factor; WB: western blot; WT: wild-type</p

G0S2 causes lipid accumulation in hepatocyte cell lines.

<p>(A) L02 cells were transfected with the Ad-GFP-G0S2 plasmid and incubated under normal growth conditions for 24 h. The cells were fixed and stained with Oil Red O and then observed under fluorescence microscopy. (B) G0S2 protein levels in the L02 cells were determined with western blotting. (C) HepG2 or L02 cells were infected with Ad-LacZ or Ad-G0S2 for 48 h before they were fixed and stained with Oil Red O. Representative images are shown (magnification 400×). (D) Oil Red O content in HepG2 and L02 cells. (E and F) Triglyceride and cholesterol levels in L02 cells. Each bar represents the mean ± SEM (n = 3). *<i>P</i> < 0.05; ns, not significant.</p

Effects of G0S2 overexpression on lipid accumulation in mice.

<p>The mice were injected via the tail vein with an Ad vector at a dose of 3.0 × 10⁹ pfu and were killed at various time points. (A) G0S2 protein levels in the liver and fat tissues were determined with western blotting. (B) Livers of mice infected with Ad-G0S2 (right) or Ad-LacZ (left) for 4 days. Scale bar = 10 mm. (C) The liver weight of mice infected with Ad-LacZ or Ad-G0S2. (D) The liver sections were stained with Oil Red O (magnification 400×). Fasting hepatic and plasma lipid levels were measured. (E) Liver triglyceride content. (F) Plasma triglyceride levels. (G) Liver glycerol content. (H) Liver free fatty acid levels. Each bar represents the mean ± SEM (n = 6). *<i>P</i> < 0.05; **<i>P</i> < 0.01.</p

Effects of G0S2 overexpression on hepatic glucose uptake.

<p>The fluorescence intensity of 6-NBDG in Ad-G0S2- or Ad-LacZ-infected livers was detected. Each bar represents the mean ± SEM (n = 5). *<i>P</i> < 0.05.</p

G0S2 binds to ATGL in the liver.

<p>Mice were injected via the tail vein with an Ad-G0S2 vector and killed 4 days later. (A) Immunofluorescent analysis of liver sections with the anti-G0S2 and anti-ATGL antibodies. Bound primary antibodies were visualized, respectively, with FITC-conjugated anti-rabbit IgG or TRITC-conjugated anti-mouse IgG. The sections were visualized under laser confocal microscopy. LDs in the livers were visualized under a phase-contrast microscope. The arrows indicate positive staining. Scale bar = 10 µm. (B) Anti-G0S2 and anti-ATGL western blot (WB) analyses were performed on ATGL or mouse monoclonal IgG immunoprecipitates (IP) prepared with the anti-ATGL antibody or IgG affinity Dynabeads (left panel). To control for equal loading, equal amounts by volume of crude extract for the immunoprecipitation experiments were loaded onto the SDS-PAGE gel for immunoblotting (right panel).</p

Changes in PPAR-α activated gene expression in mice overexpressing G0S2 in the liver.

<p>Mice were injected via the tail vein with the Ad-G0S2 vector and killed 4 days later. Relative mRNA levels of aP2 (A), Cyp4a10 (B), Ehhadh (C), Aldh3a2 (D), Cgi58 (E), Atgl (F), and Lipe (G) in the liver after fasting. *<i>P</i> < 0.05, compared with the Ad-LacZ-infected mice (n = 5); ns, not significant.</p