Dynamically Tunable All-Weather Daytime Cellulose Aerogel Radiative Supercooler for Energy-Saving Building.

A passive cooling strategy without any electricity input has shown a significant impact on overall energy consumption globally. However, designing tunable daytime radiative cooler to meet requirement of different weather conditions is still a big challenge, especially in hot, humid regions. Here, a novel type of tunable, thermally insulating and compressible cellulose nanocrystal (CNC) aerogel coolers is prepared via chemical cross-linking and unidirectional freeze casting process. Such aerogel coolers can achieve a subambient temperature drop of 9.2 °C under direct sunlight and promisingly reached the reduction of ∼7.4 °C even in hot, moist, and fickle extreme surroundings. The tunable cooling performance can be realized via controlling the compression ratio of shape-malleable aerogel coolers. Furthermore, energy consumption modeling of using such aerogel coolers in buildings in China shows 35.4% reduction of cooling energy. This work can pave the way toward designing high-performance, thermal-regulating materials for energy consumption savings.

Biokinetic modeling of nanoparticle interactions with lung alveolar epithelial cells: uptake, intracellular processing, and egress.

Studies on health effects of engineered nanomaterials (ENMs) in the lung have provided information on ENM toxicity and translocation across airway and alveolar epithelial barriers. Various inhaled ENMs (e.g., gold and iridium nanoparticles) have been reported to partially cross the air-blood barrier in the lung, enter the vasculature, and distribute in several end organs, including the heart, liver, spleen, and kidney. Using an in vitro primary rat alveolar epithelial cell (AEC) monolayer model, we reported transport rates of relatively nontoxic polystyrene nanoparticles (PNPs), which appear to be taken up via nonendocytic processes into AECs. PNPs internalized into cytoplasm then trigger autophagy, followed by delivery of PNPs from autophagosomes into lysosomes, from where PNPs are exocytosed. We used the data from these experiments to perform biokinetic modeling that incorporates the processes associated with internalization and intracellular distribution of PNPs, autophagy, lysosomal exocytosis of PNPs, and several putative mechanisms of action that extend our previous understanding of AEC processing of PNPs. Results suggest that entry of PNPs into AECs, subsequent activation of autophagy by cytosolic PNPs, accumulation of PNPs in lysosomes, and lysosomal exocytosis are interwoven by proposed regulatory mechanisms.

A physiological model of granulopoiesis to predict clinical drug induced neutropenia from in vitro bone marrow studies: with application to a cell cycle inhibitor.

Neutropenia is one of the most common dose-limiting toxocities associated with anticancer drug therapy. The ability to predict the probability and severity of neutropenia based on in vitro studies of drugs in early drug development will aid in advancing safe and efficacious compounds to human testing. Toward this end, a physiological model of granulopoiesis and its regulation is presented that includes the bone marrow progenitor cell cycle, allowing for a mechanistic representation of the action of relevant anticancer drugs based on in vitro studies. Model development used data from previously reported tracer kinetic studies of granulocyte disposition in healthy humans to characterize the dynamics of neutrophil margination in the presence of endogenous granulocyte-colony stimulating factor (G-CSF). In addition, previously published data from healthy volunteers following pegfilgrastim and filgrastim were used to quantify the regulatory effects of support G-CSF therapies on granulopoiesis. The model was evaluated for the cell cycle inhibitor palbociclib, using an in vitro system of human bone marrow mononuclear cells to quantify the action of palbociclib on proliferating progenitor cells, including its inhibitory effect on G1 to S phase transition. The in vitro results were incorporated into the physiological model of granulopoiesis and used to predict the time course of absolute neutrophil count (ANC) and the incidence of neutropenia observed in three previously reported clinical trials of palbociclib. The model was able to predict grade 3 and 4 neutropenia due to palbociclib treatment with 86% accuracy based on in vitro data.

A mesoporous theranostic platform for ultrasound and photoacoustic dual imaging-guided photothermal and enhanced starvation therapy for cancer.

Tumor starvation therapy utilizing glucose oxidase (GOx), has gained traction due to its non-invasive and bio-safe attributes. However, its effectiveness is often hampered by severe hypoxia in the tumor microenvironment (TME), limiting GOx's catalytic activity. To address this issue, a multifunctional nanosystem based on mesoporous polydopamine nanoparticles (MPDA NPs) was developled to alleviate TME hypoxia. This nanosystem integrated GOx modification and oxygenated perfluoropentane (PFP) encapsulation to address hypoxia-related challenges in the TME. Under NIR laser irradiation, the MPDA NPs exhibit significant photothermal conversion efficacy, activating targeted tumor photothermal therapy (PTT), while also serving as proficient photoacoustic (PA) imaging agents. The ensuing temperature rise facilitates oxygen (O2) release and induces liquid-gas conversion of PFP, generating microbubbles for enhanced ultrasound (US) imaging signals. The supplied oxygen alleviates local hypoxia, thereby enhancing GOx-mediated endogenous glucose consumption for tumor starvation. Overall, the integration of ultrasound/photoacoustic dual imaging-guided PTT and starvation therapy within MPDA-GOx@PFP@O2 nanoparticles (MGPO NPs) presents a promising platform for enhancing the efficacay of tumor treatment by overcoming the complexities of the TME. STATEMENT OF SIGNIFICANCE: A multifunctional MPDA-based theranostic nanoagent was developed for US/PAI imaging-guided PTT and starvation therapy against tumor hypoxia by direct O2 delivery. The incorporation of oxygenated perfluoropentane (PFP) within the mesoporous structure of MGPO not only enables efficient US imaging but also helps in alleviating tumor hypoxia. Moreover, the strong near-infrared (NIR) absorption of MGPO NPs promote the generation of PFP microbubbles and release of oxygen, thereby enhancing US imaging and GOx-mediated starvation therapy. Such a multifunctional nanosystem leverages synergistic effects to enhance therapeutic efficacy while incorporating US/PA imaging for precise visualization of the tumor.

Serotonergic Neurons in the Brain and Gnathal Ganglion of Larval Spodoptera frugiperda.

The fall armyworm Spodoptera frugiperda (S. frugiperda) (Lepidoptera: Noctuidae) is a worldwide, disruptive, agricultural pest species. The larvae of S. frugiperda feed on seedling, leave, and kernel of crops with chewing mouthparts, resulting in reduced crop yields. Serotonin is an important biogenic amine acting as a neural circuit modulator known to mediate lots of behaviors including feeding in insects. In order to explore the serotonergic neural network in the nervous system of larval S. frugiperda, we performed immunohistochemical experiments to examine the neuropil structure of the brain and the gnathal ganglion with antisynapsin and to examine their serotonergic neurons with antiserotonin serum. Our data show that the brain of larval S. frugiperda contains three neuromeres: the tritocerebrum, the deutocerebrum, and the protocerebrum. The gnathal ganglion also contains three neuromeres: the mandibular neuromere, the maxillary neuromere, and the labial neuromere. There are about 40 serotonergic neurons in the brain and about 24 serotonergic neurons in the gnathal ganglion. Most of these neurons are wide-field neurons giving off processes in several neuropils of the brain and the gnathal ganglion. Serotonergic neuron processes are mainly present in the protocerebrum. A pair of serotonergic neurons associated with the deutocerebrum has arborizations in the contralateral antennal lobe and bilateral superior lateral protocerebra. In the gnathal ganglion, the serotonergic neuron processes are also widespread throughout the neuropil and some process projections extend to the tritocerebrum. These findings on the serotonergic neuron network in larval S. frugiperda allow us to explore the important roles of serotonin in feeding and find a potential approach to modulate the feeding behavior of the gluttonous pest and reduce its damage.

A whole-body circulatory neutrophil model with application to predicting clinical neutropenia from in vitro studies.

A circulatory model of granulopoiesis and its regulation is presented that includes neutrophil trafficking in the lungs, liver, spleen, bone marrow, lymph nodes, and blood. In each organ, neutrophils undergo transendothelial migration from vascular to interstitial space, clearance due to apoptosis, and recycling via the lymphatic flow. The model includes cell cycling of progenitor cells in the bone marrow, granulocyte colony-stimulating factor (G-CSF) kinetics and its neutrophil regulatory action, as well as neutrophil margination in the blood. From previously reported studies, 111 In-labeled neutrophil kinetic data in the blood and sampled organs were used to estimate the organ trafficking parameters in the model. The model was further developed and evaluated using absolute neutrophil count (ANC), band cell, and segmented neutrophil time course data from healthy volunteers following four dose levels of pegfilgrastim (r2  = 0.77-0.99), along with ANC time course responses following filgrastim (r2  = 0.96). The baseline values of various cell types in bone marrow and blood, as well as G-CSF concentration in the blood, predicted by the model are consistent with available literature reports. After incorporating the mechanism of action of both paclitaxel and carboplatin, as determined from an in vitro bone marrow studies, the model reliably predicted the observed ANC time course following paclitaxel plus carboplatin observed in a phase I trial of 46 patients (r2  = 0.70). The circulatory neutrophil model may provide a mechanistic framework for predicting multi-organ neutrophil homeostasis and dynamics in response to therapeutic agents that target neutrophil dynamics and trafficking in different organs.

An interference screw made using a silk fibroin-based bulk material with high content of hydroxyapatite for anterior cruciate ligament reconstruction in a rabbit model.

Upgradation is still in need for the clinically applied interference screws in anterior cruciate ligament reconstruction for more reliable fixation. Silk fibroin bulk materials offer a promising opportunity for this application except lacking osteoinductivity to some extent. Here we report a novel silk-based bulk material with high content of hydroxyapatite-silk fibroin (HA-SF) hybrid particles, which is prepared via a dual-network hydrogel. This composite bulk material possesses a compression modulus of 3.2 GPa, comparable to that of the natural compact bone, and presents satisfactory cytocompatibility and osteoinductivity in vitro when combined with the HA-SF nanoparticles particularly. This composite bulk material shaped into interference screws exhibits remarkable biomechanical properties and significant new-bone ingrowth in the host bone tunnel in a rabbit anterior cruciate ligament reconstruction (ACLR) model at 4 weeks and 12 weeks post-operatively. Moreover, considering that this "hydrogel method" allows the material to be formed in a mold, avoiding complicated post fabrication, it is a potential candidate for clinical translation.

Temperature/pH Smart Nanofibers with Excellent Biocompatibility and Their Dual Interactions Stimulus-Responsive Mechanism.

Novel nanosized biomass-based pH- and temperature-responsive cellulose nanofibers (TOCNF-HPEI-IBAm) were designed and prepared by grafting hyperbranched polyethylenimine (HPEI) modified with isobutyramide (IBAm) groups (HPEI-IBAm) onto carboxylated cellulose nanofibers (TOCNFs). The as-prepared TOCNF-HPEI-IBAm possessed excellent biocompatibility and pH- and temperature-responsive properties. TOCNF-HPEI-IBAm showed a rapid wettability conversion from hydrophilic (WCA = 41.1°, WCA = 70.7°) to hydrophobic (WCA = 147.3°, WCA = 142.2°) in response to changes in pH and temperature from acidic conditions to alkaline conditions and from lower to higher temperatures. In addition, it possesses strong antibacterial activity against Escherichia coli and Listeria (Eb ≥ 97%). The amount of DOX loaded in TOCNF-HPEI-IBAm was 642.52 mg/g, and the maximum amount of DOX released was 39.30% at pH = 3.0 within 9 h. Furthermore, the dual interactions stimulus-responsive mechanism was revealed to be attributed to the expansion and collapse of the molecular chains of TOCNF-HPEI-IBAm in response to temperature and pH through mutual promotion and inhibition.

Cryo-EM structures of S-OPA1 reveal its interactions with membrane and changes upon nucleotide binding.

Mammalian mitochondrial inner membrane fusion is mediated by optic atrophy 1 (OPA1). Under physiological conditions, OPA1 undergoes proteolytic processing to form a membrane-anchored long isoform (L-OPA1) and a soluble short isoform (S-OPA1). A combination of L-OPA1 and S-OPA1 is essential for efficient membrane fusion; however, the relevant mechanism is not well understood. In this study, we investigate the cryo-electron microscopic structures of S-OPA1-coated liposomes in nucleotide-free and GTPγS-bound states. S-OPA1 exhibits a general dynamin-like structure and can assemble onto membranes in a helical array with a dimer building block. We reveal that hydrophobic residues in its extended membrane-binding domain are critical for its tubulation activity. The binding of GTPγS triggers a conformational change and results in a rearrangement of the helical lattice and tube expansion similar to that of S-Mgm1. These observations indicate that S-OPA1 adopts a dynamin-like power stroke membrane remodeling mechanism during mitochondrial inner membrane fusion.

Predicting Chemotherapy-Induced Neutropenia and Granulocyte Colony-Stimulating Factor Response Using Model-Based In Vitro to Clinical Translation.

The ability to predict the incidence of chemotherapy-induced neutropenia in early drug development can inform risk monitoring and mitigation strategies, as well as decisions on advancing compounds to clinical trials. In this report, a physiological model of granulopoiesis that incorporates the drug's mechanism of action on cell cycle proliferation of bone marrow progenitor cells was extended to include the action of the cytotoxic agents paclitaxel, carboplatin, doxorubicin, and gemcitabine. In vitro bone marrow studies were conducted with each compound, and results were used to determine the model's drug effect parameters. Population simulations were performed to predict the absolute neutrophil count (ANC) and incidence of neutropenia for each compound, which were compared to results reported in the literature. In addition, using the single agent in vitro study results, the model was able to predict ANC time course in response to paclitaxel plus carboplatin in combination, which compared favorably to the results reported in a phase 1 clinical trial of 46 patients (r2 = 0.70). Model simulations were used to compare the relative risk (RR) of neutropenia in patients with high baseline ANCs for five chemotherapeutic regimens: doxorubicin (RR = 0.59), paclitaxel plus carboplatin combination (RR = 0.079), carboplatin (RR = 0.047), paclitaxel (RR = 0.031), and gemcitabine (RR = 0.013). Finally, the model was applied to quantify the reduced incidence of neutropenia with coadministration of pegfilgrastim or filgrastim, for both paclitaxel and the combination of paclitaxel plus carboplatin. The model provides a framework for predicting clinical neutropenia using in vitro bone marrow studies of anticancer agents that may guide drug development decisions.

Curvature induction and membrane remodeling by FAM134B reticulon homology domain assist selective ER-phagy.

FAM134B/RETREG1 is a selective ER-phagy receptor that regulates the size and shape of the endoplasmic reticulum. The structure of its reticulon-homology domain (RHD), an element shared with other ER-shaping proteins, and the mechanism of membrane shaping remain poorly understood. Using molecular modeling and molecular dynamics (MD) simulations, we assemble a structural model for the RHD of FAM134B. Through MD simulations of FAM134B in flat and curved membranes, we relate the dynamic RHD structure with its two wedge-shaped transmembrane helical hairpins and two amphipathic helices to FAM134B functions in membrane-curvature induction and curvature-mediated protein sorting. FAM134B clustering, as expected to occur in autophagic puncta, amplifies the membrane-shaping effects. Electron microscopy of in vitro liposome remodeling experiments support the membrane remodeling functions of the different RHD structural elements. Disruption of the RHD structure affects selective autophagy flux and leads to disease states.

Machine Learning Algorithms for Risk Prediction of Severe Hand-Foot-Mouth Disease in Children.

The identification of indicators for severe HFMD is critical for early prevention and control of the disease. With this goal in mind, 185 severe and 345 mild HFMD cases were assessed. Patient demographics, clinical features, MRI findings, and laboratory test results were collected. Gradient boosting tree (GBT) was then used to determine the relative importance (RI) and interaction effects of the variables. Results indicated that elevated white blood cell (WBC) count > 15 × 109/L (RI: 49.47, p < 0.001) was the top predictor of severe HFMD, followed by spinal cord involvement (RI: 26.62, p < 0.001), spinal nerve roots involvement (RI: 10.34, p < 0.001), hyperglycemia (RI: 3.40, p < 0.001), and brain or spinal meninges involvement (RI: 2.45, p = 0.003). Interactions between elevated WBC count and hyperglycemia (H statistic: 0.231, 95% CI: 0-0.262, p = 0.031), between spinal cord involvement and duration of fever ≥3 days (H statistic: 0.291, 95% CI: 0.035-0.326, p = 0.035), and between brainstem involvement and body temperature (H statistic: 0.313, 95% CI: 0-0.273, p = 0.017) were observed. Therefore, GBT is capable to identify the predictors for severe HFMD and their interaction effects, outperforming conventional regression methods.