Multi-functional Chitosan Polymeric Micelles for improving the oral bioavailability of Paclitaxel based on synergistic effect.

A novel multi-functional micelle delivery system was developed for enhancing the oral absorption of paclitaxel (PTX). The delivery carriers were constructed by modifying chitosan-stearic acid (CS-SA) micelles with L-carnitine (LC) and co-encapsulating quercetin (Que), and the PTX-loaded micelles were prepared by film-sonication dispersing technique. The as-prepared micelles showed homogeneous spherical shapes with a small particle size of 148.3 ± 1.7 nm, high drug loading of 7.05% and low critical micelle concentration (CMC) of 16.89 µg/ml. Compared to the in-house PTX formulation similar to the commercial injection Taxol™, the target PTX-loaded micelles had obvious sustained-release effects and exhibited an oral relative bioavailability of 168.08%. The cellular uptake studies of Caco-2 cells confirmed the micellar modification of LC and the co-loading of Que played important roles in promoting the absorption of drug loaded in micelles. The CYP3A4 enzyme test demonstrated the micelles had an inhibitory effect on the metabolic enzyme due to the presence of Que. These findings confirmed the potential of the multi-functional chitosan polymeric micelles based on synergistic effect as an effective oral delivery system.

Assessing the Oxidative Potential of Outdoor PM2.5 in Wintertime Fairbanks, Alaska.

The oxidative potential (OP) of outdoor PM2.5 in wintertime Fairbanks, Alaska, is investigated and compared to those in wintertime Atlanta and Los Angeles. Approximately 40 filter samples collected in January-February 2022 at a Fairbanks residential site were analyzed for OP utilizing dithiothreitol-depletion (OPDTT) and hydroxyl-generation (OPOH) assays. The study-average PM2.5 mass concentration was 12.8 µg/m3, with a 1 h average maximum of 89.0 µg/m3. Regression analysis, correlations with source tracers, and contrast between cold and warmer events indicated that OPDTT was mainly sensitive to copper, elemental carbon, and organic aerosol from residential wood burning, and OPOH to iron and organic aerosol from vehicles. Despite low photochemically-driven oxidation rates, the water-soluble fraction of OPDTT was unusually high at 77%, mainly from wood burning emissions. In contrast to other locations, the Fairbanks average PM2.5 mass concentration was higher than Atlanta and Los Angeles, whereas OPDTT in Fairbanks and Atlanta were similar, and Los Angeles had the highest OPDTT and OPOH. Site differences were observed in OP when normalized by both the volume of air sampled and the particle mass concentration, corresponding to exposure and the intrinsic health-related properties of PM2.5, respectively. The sensitivity of OP assays to specific aerosol components and sources can provide insights beyond the PM2.5 mass concentration when assessing air quality.

Indoor-Outdoor Oxidative Potential of PM2.5 in Wintertime Fairbanks, Alaska: Impact of Air Infiltration and Indoor Activities.

The indoor air quality of a residential home during winter in Fairbanks, Alaska, was investigated and contrasted with outdoor levels. Twenty-four-hour average indoor and outdoor filter samples were collected from January 17 to February 25, 2022, in a residential area with high outdoor PM2.5 concentrations. The oxidative potential of PM2.5 was determined using the dithiothreitol-depletion assay (OPDTT). For the unoccupied house, the background indoor-to-outdoor (I/O) ratio of mass-normalized OP (OPmDTT), a measure of the intrinsic health-relevant properties of the aerosol, was less than 1 (0.53 ± 0.37), implying a loss of aerosol toxicity as air was transported indoors. This may result from transport and volatility losses driven by the large gradients in temperature (average outdoor temperature of -19°C/average indoor temperature of 21 °C) or relative humidity (average outdoor RH of 78%/average indoor RH of 11%), or both. Various indoor activities, including pellet stove use, simple cooking experiments, incense burning, and mixtures of these activities, were conducted. The experiments produced PM2.5 with a highly variable OPmDTT. PM2.5 from cooking emissions had the lowest OP values, while pellet stove PM2.5 had the highest. Correlations between volume-normalized OPDTT (OPvDTT), relevant to exposure, and indoor PM2.5 mass concentration during experiments were much lower compared to those in outdoor environments. This suggests that mass concentration alone can be a poor indicator of possible adverse effects of various indoor emissions. These findings highlight the importance of considering both the quantity of particles and sources (chemical composition), as health metrics for indoor air quality.

A lanthanide-rich kilonova in the aftermath of a long gamma-ray burst.

Observationally, kilonovae are astrophysical transients powered by the radioactive decay of nuclei heavier than iron, thought to be synthesized in the merger of two compact objects1-4. Over the first few days, the kilonova evolution is dominated by a large number of radioactive isotopes contributing to the heating rate2,5. On timescales of weeks to months, its behaviour is predicted to differ depending on the ejecta composition and the merger remnant6-8. Previous work has shown that the kilonova associated with gamma-ray burst 230307A is similar to kilonova AT2017gfo (ref. 9), and mid-infrared spectra revealed an emission line at 2.15 micrometres that was attributed to tellurium. Here we report a multi-wavelength analysis, including publicly available James Webb Space Telescope data9 and our own Hubble Space Telescope data, for the same gamma-ray burst. We model its evolution up to two months after the burst and show that, at these late times, the recession of the photospheric radius and the rapidly decaying bolometric luminosity (Lbol ∝ t-2.7±0.4, where t is time) support the recombination of lanthanide-rich ejecta as they cool.

CRM1 regulates androgen receptor stability and impacts DNA repair pathways in prostate cancer, independent of the androgen receptor.

Among the known nuclear exportins, CRM1 is the most studied prototype. Dysregulation of CRM1 occurs in many cancers, hence, understanding the role of CRM1 in cancer can help in developing synergistic therapeutics. The study investigates how CRM1 affects prostate cancer growth and survival. It examines the role of CRM1 in regulating androgen receptor (AR) and DNA repair in prostate cancer. Our findings reveal that CRM1 influences AR mRNA and protein stability, leading to a loss of AR protein upon CRM1 inhibition. Furthermore, it highlights the involvement of HSP90 alpha, a known AR chaperone, in the CRM1-dependent regulation of AR protein stability. The combination of CRM1 inhibition with an HSP90 inhibitor demonstrates potent effects on decreasing prostate cancer cell growth and survival. The study further explores the influence of CRM1 on DNA repair proteins and proposes a strategy of combining CRM1 inhibitors with DNA repair pathway inhibitors to decrease prostate cancer growth. Overall, the findings suggest that CRM1 plays a crucial role in prostate cancer growth, and a combination of inhibitors targeting CRM1 and DNA repair pathways could be a promising therapeutic strategy.

Schottky Barrier-Based Built-In Electric Field for Enhanced Tumor Photodynamic Therapy.

Photodynamic therapy's antitumor efficacy is hindered by the inefficient generation of reactive oxygen species (ROS) due to the photogenerated electron-hole pairs recombination of photosensitizers (PS). Therefore, there is an urgent need to develop efficient PSs with enhanced carrier dynamics. Herein, we designed Schottky junctions composed of cobalt tetroxide and palladium nanocubes (Co3O4@Pd) with a built-in electric field as effective PS. The built-in electric field enhanced photogenerated charge separation and migration, resulting in the generation of abundant electron-hole pairs and allowing effective production of ROS. Thanks to the built-in electric field, the photocurrent intensity and carrier lifetime of Co3O4@Pd were approximately 2 and 3 times those of Co3O4, respectively. Besides, the signal intensity of hydroxyl radical and singlet oxygen increased to 253.4% and 135.9%, respectively. Moreover, the localized surface plasmon resonance effect of Pd also enhanced the photothermal conversion efficiency of Co3O4@Pd to 40.50%. In vitro cellular level and in vivo xenograft model evaluations demonstrated that Co3O4@Pd could generate large amounts of ROS, trigger apoptosis, and inhibit tumor growth under near-infrared laser irradiation. Generally, this study reveals the contribution of the built-in electric field to improving photodynamic performance and provides new ideas for designing efficient inorganic PSs.

Machine learning based on functional and structural connectivity in mild cognitive impairment.

OBJECTIVE: Alzheimer's disease (AD) is a chronic, degenerative neurological disorder characterized by progressive cognitive decline and mental behavioral abnormalities. Mild cognitive impairment (MCI) is regarded as a transitional stage in the progression from normal elderly individuals to patients with AD. While studies have identified abnormalities in brain connectivity in patients with MCI, including functional and structural connectivity, accurately identifying patients with MCI in clinical screening remains challenging. We hypothesized that utilizing machine learning (ML) based on both functional and structural connectivity could yield meaningful results in distinguishing between patients with MCI and normal elderly individuals, so as to provide valuable information for early diagnosis and precise evaluation of patients with MCI. METHODS: Following clinical criteria, we recruited 32 patients with MCI for the patient group, and 32 normal elderly individuals for the control group. All subjects underwent examinations for resting-state functional magnetic resonance imaging (rs-fMRI) and diffusion tensor imaging (DTI). Subsequently, significant functional and structural connectivity features were selected and combined with a support vector machine for classification of the patient and control groups. RESULTS: We observed significantly different functional connectivity in the frontal lobe and putamen between the MCI group and normal controls. The results based on functional connectivity features demonstrated a classification accuracy of 71.88% and an area under the curve (AUC) value of 0.78. In terms of structural connectivity, we found that decreased fractional anisotropy in patients with MCI was significantly associated with Montreal Cognitive Assessment scores, specifically in regions such as the precuneus and cingulate gyrus. The classification results using the structural connectivity feature yielded an accuracy of 92.19% and an AUC value of 0.99. Lastly, combining functional and structural connectivity features resulted in a classification accuracy and AUC value of 93.75% and 0.99, respectively. CONCLUSIONS: In this study, we demonstrated a high classification performance, underscoring the potential of both brain functional and structural connectivity in distinguishing patients with MCI from normal elderly individuals. Furthermore, the integration of functional connectivity and structural connectivity features indicated that utilizing rs-fMRI and DTI could enhance the accuracy and specificity of identifying patients with MCI compared with relying on a single neuroimaging technique.

An evaluation of the impact of China's green credit policy on different pathways using a CGE model.

The objective of the study was to quantitatively analyze the heterogeneous effects of different green credit implementation methods on energy, environmental, and economic systems by developing a computable general equilibrium model. The specific green credit implementation methods are divided into interest-penalty policy for energy-intensive industries and interest preferential policy for green industries. Various approaches to implementing green credit can lead to distinct impacts on energy consumption, environmental outcomes, and economic performance. Green credit policy experiments are carried out utilizing short-, medium-, and long-term scenarios to investigate how the consequences of green credit policies evolve. The findings demonstrate that (1) implementing a penalty interest policy for energy-intensive industries can have substantial short-term environmental effects, cutting total demand for fossil energy and lowering carbon dioxide emissions significantly. As the cycle progresses, this effect will progressively fade and have a negative economic impact. (2) The interest preferential policy for the green industry has a significant promoting effect on green technology, and its energy and environmental effects will be reflected in the long term, and the effect will continue to increase, which has a positive promoting effect on the economy. (3) There are significant differences in the policy effects brought about by the different implementation methods of green credit policies. Both policies can positively affect social energy and the environment, but the effect cycles are different. When two types of interest policies are implemented in the economy, the negative economic effect of the penalty interest policy is greater than the positive effect of the preferential interest policy, which harms the macroeconomy. These conclusions will provide theoretical and practical references for the government and banks to choose a better green credit implementation path.

Recent advances of hydrogels as smart dressings for diabetic wounds.

Chronic diabetic wounds have been an urgent clinical problem, and wound dressings play an important role in their management. Due to the design of traditional dressings, it is difficult to achieve adaptive adhesion and on-demand removal of complex diabetic wounds, real-time monitoring of wound status, and dynamic adjustment of drug release behavior according to the wound microenvironment. Smart hydrogels, as smart dressings, can respond to environmental stimuli and achieve more precise local treatment. Here, we review the latest progress of smart hydrogels in wound bandaging, dynamic monitoring, and drug delivery for treatment of diabetic wounds. It is worth noting that we have summarized the most important properties of smart hydrogels for diabetic wound healing. In addition, we discuss the unresolved challenges and future prospects in this field. We hope that this review will contribute to furthering progress on smart hydrogels as improved dressing for diabetic wound healing and practical clinical application.

Defensins: A novel weapon against Mycobacterium tuberculosis?

Tuberculosis (TB) is a serious airborne communicable disease caused by organisms of the Mycobacterium tuberculosis (Mtb) complex. Although the standard treatment antimicrobials, including isoniazid, rifampicin, pyrazinamide, and ethambutol, have made great progress in the treatment of TB, problems including the rising incidence of multidrug-resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB), the severe toxicity and side effects of antimicrobials, and the low immunity of TB patients have become the bottlenecks of the current TB treatments. Therefore, both safe and effective new strategies to prevent and treat TB have become a top priority. As a subfamily of cationic antimicrobial peptides, defensins are rich in cysteine and play a vital role in resisting the invasion of microorganisms and regulating the immune response. Inspired by studies on the roles of defensins in host defence, we describe their research history and then review their structural features and antimicrobial mechanisms, specifically for fighting Mtb in detail. Finally, we discuss the clinical relevance, therapeutic potential, and potential challenges of defensins in anti-TB therapy. We further debate the possible solutions of the current application of defensins to provide new insights for eliminating Mtb.

Self-Cross-Linked Chitosan/Albumin-Bound Nanoparticle Hydrogel for Inhibition of Postsurgery Malignant Glioma Recurrence.

The development of chemoimmunotherapy with reduced systemic toxicity using local formulations is an effective strategy for combating tumor recurrence. Herein, we reported a localized hydrogel system for antitumor chemoimmunotherapy, formed by doxorubicin (DXR)-loaded bovine serum albumin (BSA) nanoparticles self-cross-linked with natural polysaccharide chitosan (CS). The drug-loaded hydrogel (DXR-CBGel) with antiswelling performance and prolonged drug-release profile was combined with antiprogrammed cell death protein 1 (aPD-1) as an in situ vaccine for treating glioblastoma multiforme (GBM) lesions. The antiswelling hydrogel system shows excellent biosafety for volume-sensitive GBM lesions. Both the albumin-bound formulation and the in situ gelation design facilitate the local retention and sustained release of DXR to generate long-term chemoimmunotherapy with reduced systemic toxicity. The chemotherapy-induced immunogenic cell death of DXR with the assistance of immunotherapeutic CS can trigger tumor-specific immune responses, which are further amplified by an immune checkpoint blockade to effectively inhibit cancer recurrence. The strategy of combining albumin-bound drug formulation and biocompatible polymer-based hydrogel for localized chemoimmunotherapy shows great potential against postsurgery glioblastoma recurrence.

The role of pyroptosis and gasdermin family in tumor progression and immune microenvironment.

Pyroptosis, an inflammatory programmed cell death, distinguishes itself from apoptosis and necroptosis and has drawn increasing attention. Recent studies have revealed a correlation between the expression levels of many pyroptosis-related genes and both tumorigenesis and progression. Despite advancements in cancer treatments such as surgery, radiotherapy, chemotherapy, and immunotherapy, the persistent hallmark of cancer enables malignant cells to elude cell death and develop resistance to therapy. Recent findings indicate that pyroptosis can overcome apoptosis resistance amplify treatment-induced tumor cell death. Moreover, pyroptosis triggers antitumor immunity by releasing pro-inflammatory cytokines, augmenting macrophage phagocytosis, and activating cytotoxic T cells and natural killer cells. Additionally, it transforms "cold" tumors into "hot" tumors, thereby enhancing the antitumor effects of various treatments. Consequently, pyroptosis is intricately linked to tumor development and holds promise as an effective strategy for boosting therapeutic efficacy. As the principal executive protein of pyroptosis, the gasdermin family plays a pivotal role in influencing pyroptosis-associated outcomes in tumors and can serve as a regulatory target. This review provides a comprehensive summary of the relationship between pyroptosis and gasdermin family members, discusses their roles in tumor progression and the tumor immune microenvironment, and analyses the underlying therapeutic strategies for tumor treatment based on pyroptotic cell death.

Machine Learning Models for Predicting Molecular Diffusion in Metal-Organic Frameworks Accounting for the Impact of Framework Flexibility.

Molecular diffusion in MOFs plays an important role in determining whether equilibrium can be reached in adsorption-based chemical separations and is a key driving force in membrane-based separations. Molecular dynamics (MD) simulations have shown that in some cases inclusion of framework flexibility in MOF changes predicted molecular diffusivities by orders of magnitude relative to more efficient MD simulations using rigid structures. Despite this, all previous efforts to predict molecular diffusion in MOFs in a high-throughput way have relied on MD data from rigid structures. We use a diverse data set of MD simulations in flexible and rigid MOFs to develop a classification model that reliably predicts whether framework flexibility has a strong impact on molecular diffusion in a given MOF/molecule pair. We then combine this approach with previous high-throughput MD simulations to develop a reliable model that efficiently predicts molecular diffusivities in cases in which framework flexibility can be neglected. The use of this approach is illustrated by making predictions of molecular diffusivities in ∼70,000 MOF/molecule pairs for molecules relevant to gas separations.

Fluorinated Cell-Penetrating Peptide for Co-Delivering siHIF-1α and Sorafenib to Enhance In Vitro Anti-Tumor Efficacy.

Antiangiogenic therapy with sorafenib (SF) alone is ineffective in eradicating tumors, and its long-term application can exacerbate tumor hypoxia, which in turn restricts SF's therapeutic efficacy. Here, a redox-responsive fluorinated peptide (DEN-TAT-PFC) consisting of dendritic poly-lysine, cell-penetrating peptide TAT, and perfluorocarbon was designed and synthesized to co-load siRNA-targeting hypoxia-inducible factors (siHIF-1α) and SF. The unique architecture of the peptide and fluorinated modifications enhanced the siRNA delivery efficiency, including increased siRNA binding, GSH-responsive release, cellular uptake, endosomal escape, and serum resistance. Simultaneously, the DEN-TAT-PFC/SF/siHIF-1α co-delivery system achieved efficient knockdown of HIF-1α at mRNA and protein levels, thus alleviating hypoxia and further substantially reducing VEGF expression. Additionally, the excellent oxygen-carrying ability of DEN-TAT-PFC may facilitate relief of the hypoxic microenvironment. As a result of these synergistic effects, DEN-TAT-PFC/SF/siHIF-1α exhibited considerable anti-tumor cell proliferation and anti-angiogenesis effects. Therefore, DEN-TAT-PFC can be a versatile platform for fabricating fluorine-containing drugs/siRNA complex nano-systems.

A Novel Smartphone App for Self-Monitoring of Neonatal Jaundice Among Postpartum Mothers: Qualitative Research Study.

Background: Neonatal jaundice (NNJ) or hyperbilirubinemia is a ubiquitous condition in newborn infants. Currently, the transcutaneous bilirubinometer is used to screen for NNJ in health care facilities, where neonates need to be physically present (ie, a centralized model of care for NNJ screening). Mobile health (mHealth) apps present a low-cost, home-based, and noninvasive system that could facilitate self-monitoring of NNJ and could allow mothers the convenience of screening for NNJ remotely. However, end users' acceptability of such mHealth apps is of fundamental importance before the incorporation of such apps into clinical practice. Objective: The study aimed to explore the perception of postpartum mothers toward self-monitoring of NNJ using a novel mHealth app. Methods: Mothers attending video consultations for early postpartum care at 2 Singapore primary care clinics watched an instructional video for a hyperbilirubinemia-screening mHealth app (HSMA). An independent researcher used a semistructured topic guide to conduct in-depth interviews with 25 mothers, assessing their views on HSMAs. All interviews were audio recorded, transcribed verbatim, and checked for accuracy before data analysis. Two researchers independently analyzed the transcripts via thematic analysis. Data were managed using NVivo qualitative data management software. Results: The identified themes were grouped under perceived usability and utility. Mothers valued the convenience and utility of HSMAs for remote monitoring of NNJ. They appreciated the objectivity the app readings provided compared to visual inspection. However, they perceived that the app's applicability would be restricted to severe jaundice, were concerned about its accuracy and restriction to the English language, and lacked confidence in using it. Nevertheless, they were willing to use it once its accuracy was proven and when they received adequate guidance from health care professionals. They also suggested including an action plan for the measured readings and clinical signs within the app. Mothers proposed pairing teleconsultations with HSMAs to boost their confidence and enhance adoption. Conclusions: Mothers were receptive to using HSMAs but had concerns. Multiple languages, proof of accuracy, and resources to guide users should be incorporated into the app in the next phase to increase its successful adoption. Complementing such apps with a teleconsultation service presents a plausible and pragmatic NNJ care delivery model in general practice.

Effects and Mechanisms of Non-Thermal Plasma-Mediated ROS and Its Applications in Animal Husbandry and Biomedicine.

Non-thermal plasma (NTP) is an ionized gas composed of neutral and charged reactive species, electric fields, and ultraviolet radiation. NTP presents a relatively low discharge temperature because it is characterized by the fact that the temperature values of ions and neutral particles are much lower than that of electrons. Reactive species (atoms, radicals, ions, electrons) are produced in NTP and delivered to biological objects induce a set of biochemical processes in cells or tissues. NTP can mediate reactive oxygen species (ROS) levels in an intensity- and time-dependent manner. ROS homeostasis plays an important role in animal health. Relatively low or physiological levels of ROS mediated by NTP promote cell proliferation and differentiation, while high or excessive levels of ROS mediated by NTP cause oxidative stress damage and even cell death. NTP treatment under appropriate conditions not only produces moderate levels of exogenous ROS directly and stimulates intracellular ROS generation, but also can regulate intracellular ROS levels indirectly, which affect the redox state in different cells and tissues of animals. However, the treatment condition of NTP need to be optimized and the potential mechanism of NTP-mediated ROS in different biological targets is still unclear. Over the past ten decades, interest in the application of NTP technology in biology and medical sciences has been rapidly growing. There is significant optimism that NTP can be developed for a wide range of applications such as wound healing, oral treatment, cancer therapy, and biomedical materials because of its safety, non-toxicity, and high efficiency. Moreover, the combined application of NTP with other methods is currently a hot research topic because of more effective effects on sterilization and anti-cancer abilities. Interestingly, NTP technology has presented great application potential in the animal husbandry field in recent years. However, the wide applications of NTP are related to different and complicated mechanisms, and whether NTP-mediated ROS play a critical role in its application need to be clarified. Therefore, this review mainly summarizes the effects of ROS on animal health, the mechanisms of NTP-mediated ROS levels through antioxidant clearance and ROS generation, and the potential applications of NTP-mediated ROS in animal growth and breeding, animal health, animal-derived food safety, and biomedical fields including would healing, oral treatment, cancer therapy, and biomaterials. This will provide a theoretical basis for promoting the healthy development of animal husbandry and the prevention and treatment of diseases in both animals and human beings.

Research on a Time Difference Processing Method for RTD-Fluxgate Data Based on the Combination of the Mahalanobis Distance and Group Covariance.

During the measurement of magnetic fields, Residence Time Difference (RTD)-fluxgate sensors suffer from abnormal time difference jumps due to the random interference of magnetic core noise and environmental noise, which results in gross errors. This situation restricts the improvement of sensor accuracy and stability. In order to solve the above problems efficiently, a time difference gross error processing method based on the combination of the Mahalanobis distance (MD) and group covariance is presented in this paper, and the processing effects of different methods are compared and analyzed. The results of the simulation and experiment indicate that the proposed method is more advantageous in identifying the gross error in time difference. The signal-to-noise ratio for the time difference is improved by about 34 times, while the fluctuation of the Negative Magnetic Saturation Time (NMST) ΔTNMST is reduced by 95.402%, which significantly reduces the fluctuation of time difference and effectively improves the accuracy and stability of the sensor.

Analysis of Airway Thickening and Serum Cytokines in COPD Patients with Frequent Exacerbations: A Heart of the Matter.

Background: Differences in lung function for Chronic Obstructive Pulmonary Disease (COPD) cause bias in the findings when identifying frequent exacerbator phenotype-related causes. The aim of this study was to determine whether computed tomographic (CT) biomarkers and circulating inflammatory biomarkers were associated with the COPD frequent exacerbator phenotype after eliminating the differences in lung function between a frequent exacerbator (FE) group and a non-frequent exacerbator (NFE) group. Methods: A total of 212 patients with stable COPD were divided into a FE group (n=106) and a NFE group (n=106) according to their exacerbation history. These patients were assessed by spirometry, quantitative CT measurements and blood sample measurements during their stable phase. Univariate and multivariate logistic regression were used to assess the association between airway thickening or serum cytokines and the COPD frequent exacerbator phenotype. Receiver operating characteristic (ROC) curves were calculated for Pi10, WA%, IL-1ß and IL-4 to identify frequent exacerbators. Results: Compared with NFE group, FE group had a greater inner perimeter wall thickness of a 10 mm diameter bronchiole (Pi10), a greater airway wall area percentage (WA%) and higher concentrations of IL-1ß and IL-4 (p<0.001). After adjusting for sex, age, BMI, FEV1%pred and smoking pack-years, Pi10, WA%, IL-ß and IL-4 were independently associated with a frequent exacerbator phenotype (p<0.001). Additionally, there was an increase in the odds ratio of the frequent exacerbator phenotype with increasing Pi10, WA%, IL-4, and IL-1ß (p for trend <0.001). The ROC curve demonstrated that IL-1ß had a significantly larger calculated area under the curve (p < 0.05) than Pi10, WA% and IL-4. Conclusion: Pi10, WA%, IL-4, and IL-1ß were independently associated with the frequent exacerbator phenotype among patients with stable COPD, suggesting that chronic airway and systemic inflammation contribute to the frequent exacerbator phenotype. Trial Registration: This trial was registered in Chinese Clinical Trial Registry (https://www.chictr.org.cn). Its registration number is ChiCTR2000038700, and date of registration is September 29, 2020.

Soil-root interface hydraulic conductance determines responses of photosynthesis to drought in rice and wheat.

Rice (Oryza sativa) production consumes a huge amount of fresh water, and improvement of drought tolerance in rice is important to conserve water resources and minimize yield loss under drought. However, processes to improve drought tolerance in rice have not been fully explored, and a comparative study between rice and wheat (Triticum aestivum) is an effective method to understand the mechanisms determining drought tolerance capacity. In the present study, we applied short-term drought stress to Shanyou 63 rice and Yannong 19 wheat to create a range of water potentials and investigated the responses of gas exchange, plant hydraulic conductance, and root morphological and anatomical traits to soil drought. We found that photosynthesis in rice was more sensitive to drought stress than that in wheat, which was related to differences in the decline of stomatal conductance and plant hydraulic conductance (Kplant). The decline of Kplant under drought was mainly driven by the decrease of soil-root interface hydraulic conductance (Ki) because Ki was more sensitive to drought than root and shoot hydraulic conductance and the soil-root interface contributed to >40% of whole-plant hydraulic resistance in both crops. Root shrinkage in response to drought was more severe in rice than that in wheat, which explains the larger depression of Ki and Kplant under drought stress in rice. We concluded that the decline of Ki drives the depression of Kplant and photosynthesis in both crops, and the plasticity of root morphology and anatomy is important in determining drought tolerance capacity.

Selectivity Mechanism of Pyrrolopyridone Analogues Targeting Bromodomain 2 of Bromodomain-Containing Protein 4 from Molecular Dynamics Simulations.

Bromodomain and extra-terminal domain (BET) proteins play an important role in epigenetic regulation and are linked to several diseases; therefore, they are interesting targets. BET has two bromodomains: bromodomain 1 (BD1) and BD2. Selective targeting of BD1 or BD2 may produce different activities and greater effects than pan-BD inhibitors. However, the selective mechanism of the specific core must be studied at the atomic level. This study determined the effectiveness of pyrrolopyridone analogues to selectively inhibit BD2 using a pan-BD inhibitor (ABBV-075) and a selective-BD2 inhibitor (ABBV-744). Molecular dynamics simulations and calculations of binding free energies were used to systematically study the selectivity of BD2 inhibition by the pyrrolopyridone analogues. Overall, the pyrrolopyridone analogue inhibitors targeting BD2 interacted mainly with the following amino acid pairs between bromodomain-containing protein 4 (BRD4)-BD1 and BRD4-BD2 complexes: I146/V439, N140/N433, D144/H437, P82/P375, V87/V380, D88/D381, and Y139/Y432. The pyrrolopyridone analogues targeting BRD4-BD2 were divided into five regions based on selectivity mechanism. These results suggest that the R3 and R5 regions of pyrrolopyridone analogues can be modified to improve the selectivity between BRD4-BD1 and BRD4-BD2. The selectivity of BD2 inhibition by pyrrolopyridone analogues can be used to design novel BD2 inhibitors based on a pyrrolopyridone core.