ASD2023: towards the integrating landscapes of allosteric knowledgebase.

Allosteric regulation, induced by perturbations at an allosteric site topographically distinct from the orthosteric site, is one of the most direct and efficient ways to fine-tune macromolecular function. The Allosteric Database (ASD; accessible online at http://mdl.shsmu.edu.cn/ASD) has been systematically developed since 2009 to provide comprehensive information on allosteric regulation. In recent years, allostery has seen sustained growth and wide-ranging applications in life sciences, from basic research to new therapeutics development, while also elucidating emerging obstacles across allosteric research stages. To overcome these challenges and maintain high-quality data center services, novel features were curated in the ASD2023 update: (i) 66 589 potential allosteric sites, covering > 80% of the human proteome and constituting the human allosteric pocketome; (ii) 748 allosteric protein-protein interaction (PPI) modulators with clear mechanisms, aiding protein machine studies and PPI-targeted drug discovery; (iii) 'Allosteric Hit-to-Lead,' a pioneering dataset providing panoramic views from 87 well-defined allosteric hits to 6565 leads and (iv) 456 dualsteric modulators for exploring the simultaneous regulation of allosteric and orthosteric sites. Meanwhile, ASD2023 maintains a significant growth of foundational allosteric data. Based on these efforts, the allosteric knowledgebase is progressively evolving towards an integrated landscape, facilitating advancements in allosteric target identification, mechanistic exploration and drug discovery.

A2AR-mediated lymphangiogenesis via VEGFR2 signaling prevents salt-sensitive hypertension.

AIMS: Excess dietary sodium intake and retention lead to hypertension. Impaired dermal lymphangiogenesis and lymphatic dysfunction-mediated sodium and fluid imbalance are pathological mechanisms. The adenosine A2A receptor (A2AR) is expressed in lymphatic endothelial cells (LECs), while the roles and mechanisms of LEC-A2AR in skin lymphangiogenesis during salt-induced hypertension are not clear. METHODS AND RESULTS: The expression of LEC-A2AR correlated with lymphatic vessel density in both high-salt diet (HSD)-induced hypertensive mice and hypertensive patients. Lymphatic endothelial cell-specific A2AR knockout mice fed HSD exhibited 17 ± 2% increase in blood pressure and 17 ± 3% increase in Na+ content associated with decreased lymphatic density (-19 ± 2%) compared with HSD-WT mice. A2AR activation by agonist CGS21680 increased lymphatic capillary density and decreased blood pressure in HSD-WT mice. Furthermore, this A2AR agonist activated MSK1 directly to promote VEGFR2 activation and endocytosis independently of VEGF as assessed by phosphoprotein profiling and immunoprecipitation assays in LECs. VEGFR2 kinase activity inhibitor fruquintinib or VEGFR2 knockout in LECs but not VEGF-neutralizing antibody bevacizumab suppressed A2AR activation-mediated decrease in blood pressure. Immunostaining revealed phosphorylated VEGFR2 and MSK1 expression in the LECs were positively correlated with skin lymphatic vessel density and A2AR level in hypertensive patients. CONCLUSION: The study highlights a novel A2AR-mediated VEGF-independent activation of VEGFR2 signaling in dermal lymphangiogenesis and sodium balance, which might be a potential therapeutic target in salt-sensitive hypertension.

An Asymmetric Encryption-Based Key Distribution Method for Wireless Sensor Networks.

Wireless sensor networks are usually applied in hostile areas where nodes can easily be monitored and captured by an adversary. Designing a key distribution scheme with high security and reliability, low hardware requirements, and moderate communication load is crucial for wireless sensor networks. To address the above objectives, we propose a new key distribution scheme based on an ECC asymmetric encryption algorithm. The two-way authentication mechanism in the proposed scheme not only prevents illegal nodes from accessing the network, but also prevents fake base stations from communicating with the nodes. The complete key distribution and key update methods ensure the security of session keys in both static and dynamic environments. The new key distribution scheme provides a significant performance improvement compared to the classical key distribution schemes for wireless sensor networks without sacrificing reliability. Simulation results show that the proposed new scheme reduces the communication load and key storage capacity, has significant advantages in terms of secure connectivity and attack resistance, and is fully applicable to wireless sensor networks.

Characterization and genomic analysis of a Demerecviridae phage SP76 with lytic multiple-serotypes of Salmonella.

With the increase in antimicrobial resistance of Salmonella, phages have been paid more attention to as an alternative to antibiotics. In this study, a phage designated as SP76 was isolated from sewage. It can lyse several serotypes of Salmonella, including S. typhimurium (21/33), S. enteritidis (7/7), S. dublin (4/4), S. pullorum (2/2) and S. choleraesuis (1/2). SP76 showed a latent time of about 10 min, and maintained good lytic activity at a pH range of 3-10 and temperatures between 4 and 37 °C. Moreover, its optimal multiplicity of infection (MOI) was 0.0001. Based on the results of genomic sequence and analysis, SP76 was found to have a genome of 111,639 bp that encoded 166 predicted ORFs and belong to the Demerecviridae family, order Caudovirales. No virulence or lysogen formation gene clusters were identified in the SP76 genome. A pan-genome analysis based on 100 phages within the subfamily Markadamsvirinae indicated that SP76 had 23 core genes and 1199 accessory genes. We grouped the subfamily Markadamsvirinae and found that the main difference was in group III. In vitro bacteriostasis, experiments showed that the phage SP76 reduced planktonic bacteria by 1.52 log10 CFU/mL, and biofilms (24 h old) by 0.372 log10 CFU/mL, respectively. Thus, we isolated a safe and efficient phage that might be a good antibacterial agent.

Retinal safety evaluation of photoacoustic microscopy.

Photoacoustic microscopy (PAM) has significant potential as a promising diagnostic method for eye diseases and can provide anatomic and functional information of the retinal and choroidal vasculature. However, there are no FDA-approved PAM systems for ophthalmic imaging. In this study, a comprehensive safety evaluation was performed to evaluate the safety of PAM retinal imaging and whether PAM causes damage to retinal structure or function in rabbit eyes. 12 Dutch-Belted pigmented rabbits received photoacoustic imaging to 57% of the retinal surface area with a laser energy of 5% of the ANSI safety limit for five consecutive days and followed before imaging and 3 days, 1, 2, 3, and 4 weeks post imaging. Retinal morphologic analyses using slit lamp examination, fundus photography, red free, FA, FAF, ICGA, and OCT showed no retinal hemorrhage, edema, detachment, vascular abnormalities, or pigmentary abnormalities in the retina or choroid after PAM imaging. Full-field ERG analysis showed no significant difference in scotopic or photopic a- and b-wave amplitudes or implicit times between the control and experimental eyes over time (n = 6, P values > 0.05). Retinal ultrastructural evaluation using TEM showed normal structure of organelles and nuclei, and no significant loss of cells after PAM. TUNEL assay showed no evidence of cells apoptosis in retina. Retinal histopathology indicated that the architecture and thickness of the retinal layers was well preserved in all experimental eyes. A positive control at 500% of the ANSI limit demonstrated significant damage. The comprehensive retinal safety evaluation demonstrated no damage to retinal structure or function for 4 weeks after PAM imaging in rabbits.

Long-term multimodal imaging characterization of persistent retinal neovascularization using DL-alpha-aminoadipic acid in pigmented and white rabbits.

PURPOSE: Intravitreal (IVT) injection of DL-alpha-aminoadipic acid (AAA) is a new animal model for retinal neovascularization (RNV) reported in rabbits. This study performs longitudinal multimodal imaging for up to 1 year to evaluate DL-AAA RNV in both New Zealand white (NZW) rabbits and Dutch-Belted pigmented (DBP) rabbits. METHOD: Detailed characterization and quantification of this model were performed in these two strains in 32 eyes by optical coherence tomography (OCT), fundus photography, and fluorescein angiography (FA) for up to 16 weeks following DL-AAA administration in 32 eyes and up to 52 weeks in 5 eyes. H & E histology was also performed in these two strains 8 weeks after injection of DL-AAA. RESULT: RNV was successfully generated using 50 µL 80 mM DL-AAA solution for DBP rabbits and 80 µL 80 mM DL-AAA for NZW rabbits. The incidence of persistent vascular leakage is 100% (15/15) for DBP rabbits and 70.6% (12/17) for NZW rabbits at 16 weeks. Complications with NZW rabbits ultimately decreased the efficiency in NZW rabbits to 58.8% (10/17) of NZW rabbits getting persistent (to 16 weeks) vascular leakage without ocular complications as compared with 100% (15/15) in DBP rabbits. Five eyes (2 DBP and 3 NZW) were selected from those demonstrating RNV at 16 weeks and were monitored for up to 52 weeks. All 5 demonstrated persistent RNV to 52 weeks. Quantification of the mean leakage area (MLA) in DBP rabbits is more accurate than in NZW rabbits since the reduced contrast between the leakage and background in NZW rabbits makes it more challenging to quantify. CONCLUSION: DL-AAA can induce persistent and quantifiable RNV in both DBP and NZW rabbits. DBP rabbits have a higher success rate, lower required volume of DL-AAA, and more accurate method for quantification that could be more desirable.

Pulmonary fibrosis and cytokine release syndrome after hyperactivation with sintilimab.

WHAT IS KNOWN AND OBJECTIVE: Immunotherapy-related adverse events (irAEs) are common immunotherapy-associated diseases. Severe pulmonary fibrosis with hypercytokinaemia has not been reported with programmed cell death 1 (PD-1) inhibitors. We describe a case of sintilimab-induced pulmonary fibrosis with cytokine storm induced in a 50-year-old patient with colon cancer refractory to second-line systemic chemotherapy. CASE SUMMARY: Our patient developed hypercytokinaemia with elevated levels of interleukin (IL)-6 and IL-10 and pulmonary fibrosis, which differed from other irAEs. The patient benefited from a back-titrated regimen of methylprednisolone with the initial dosage of 2 mg/kg and anti-fibrotic effect of nintedanib and was successfully weaned from the ventilator. WHAT IS NEW AND CONCLUSION: This is the first report that a PD-1 inhibitor may have caused pulmonary fibrosis and a cytokine storm. This case indicates that the addition of nintedanib and glucocorticoid might possibly have potentially therapeutic effects of PD-1 induced pulmonary fibrosis and hypercytokinaemia.

High Resolution Multimodal Photoacoustic Microscopy and Optical Coherence Tomography Visualization of Choroidal Vascular Occlusion.

Photoacoustic microscopy is a novel, non-ionizing, non-invasive imaging technology that evaluates tissue absorption of short-pulsed light through the sound waves emitted by the tissue and has numerous biomedical applications. In this study, a custom-built multimodal imaging system, including photoacoustic microscopy (PAM) and optical coherence tomography (OCT), has been developed to evaluate choroidal vascular occlusion (CVO). CVO was performed on three living rabbits using laser photocoagulation. Longitudinal imaging of CVO was obtained using multiple imaging tools such as color fundus photography, fluorescein angiography, indocyanine green angiography (ICGA), OCT, and PAM. PAM images were acquired at different wavelengths, ranging from 532 to 700 nm. The results demonstrate that the CVO was clearly observed on PAM in both two dimensions (2D) and 3D with high resolution longitudinally over 28 days. In addition, the location and margin of the CVO were distinguished from the surrounding choroidal vasculature after the injection of ICG contrast agent. PAM imaging was achieved using a laser energy of approximately 80 nJ, which is about half of the American National Standards Institute safety limit. The proposed imaging technique may provide a potential tool for the evaluation of different chorioretinal vascular disease pathogeneses and other biological studies.

Growth/differentiation 5 promotes the differentiation of retinal stem cells into neurons via Atoh8.

Retinal diseases are characterized by the degeneration of retinal neural cells, and are the main cause of blindness. Although the development of stem cell including retinal stem cell therapies raises hope for retinal neuron replacement, currently, there is still no efficient method to regenerate retinal neurons. To realize the potential roles of the production of retinal neurons, neurotrophic factor direct the differentiation of retinal stem cells should be extensively identified. In this article, we characterized growth/differentiation 5 (GDF5), which caused the activation of Smad signaling, can induce neurogenesis and neurite outgrowth in retinal stem cell differentiation. Moreover, a bHLH transcription factor, Atoh8 modulates the effects stimulated by GDF5. These data suggested that GDF5 regulates neuron differentiation through mediating Atoh8 and help us to understand the pathophysiological function of GDF5 in retinal regeneration.

Real-time OCT guidance and multimodal imaging monitoring of subretinal injection induced choroidal neovascularization in rabbit eyes.

Choroidal neovascularization (CNV) is a major cause of vision loss that consists of abnormal growth of new blood vessels from the choroidal vasculature. High resolution in vivo imaging of animal models is essential to better elucidate and conduct research on CNV. This study evaluates a novel multimodal imaging platform combining optical coherence tomography (OCT) and photoacoustic microscopy (PAM). Using real-time OCT guidance subretinal injection to induce and multimodality imaging system to monitor CNV over time in rabbit eyes. The significance of our work lies in providing the optimal setting and conditions to make use of the OCT image guided system to improve the consistency and reproducibility of experimental results in subretinal injection induced CNV model in rabbits. For the first time, this study successfully demonstrated the dual-modality PAM-OCT system, without using exogenous contrast agents, can detect and visualize CNV in the rabbit eye with high resolution. This is promising system for diagnosing and monitoring CNV.

A specific electrochemiluminescence sensor for selective and ultra-sensitive mercury(ii) detection based on dithiothreitol functionalized copper nanocluster/carbon nitride nanocomposites.

Electrochemiluminescence (ECL) sensors are useful for the detection of heavy metal pollutants, in particular mercury(ii) ions, in water samples. We demonstrate the superior sensing performance of Hg2+ using a nanocomposite material based on carbon nitride nanosheets (CNNSs) and copper nanoclusters functionalized by dithiothreitol, which not only stabilizes the clusters, but also improves the sensitivity of Hg2+ detection. The ECL mechanism is related to the reaction of the nanocomposite with K2S2O8 in the electrochemical system, while the presence of Hg2+ leads to quenching of its excited state, and the suppression of the formation of anion-radicals. The Hg(ii) sensor presented here is cheap and fast, and shows high selectivity for the detection of Hg2+ on the background of other mono-, di-, and trivalent ions, with a linear range of 0.5-10 nM and the detection limit as low as 0.01 nM.

Spontaneous Crystallization of Perovskite Nanocrystals in Nonpolar Organic Solvents: A Versatile Approach for their Shape-Controlled Synthesis.

The growing demand for perovskite nanocrystals (NCs) for various applications has stimulated the development of facile synthetic methods. Perovskite NCs have often been synthesized by either ligand-assisted reprecipitation (LARP) at room temperature or by hot-injection at high temperatures and inert atmosphere. However, the use of polar solvents in LARP affects their stability. Herein, we report on the spontaneous crystallization of perovskite NCs in nonpolar organic media at ambient conditions by simple mixing of precursor-ligand complexes without application of any external stimuli. The shape of the NCs can be controlled from nanocubes to nanoplatelets by varying the ratio of monovalent (e.g. formamidinium+ (FA+ ) and Cs+ ) to divalent (Pb2+ ) cation-ligand complexes. The precursor-ligand complexes are stable for months, and thus perovskite NCs can be readily prepared prior to use. Moreover, we show that this versatile synthetic process is scalable and generally applicable for perovskite NCs of different compositions.

Revealing the Formation Mechanism of CsPbBr3 Perovskite Nanocrystals Produced via a Slowed-Down Microwave-Assisted Synthesis.

We developed a microwave-assisted slowed-down synthesis of CsPbBr3 perovskite nanocrystals, which retards the reaction and allows us to gather useful insights into the formation mechanism of these nanoparticles, by examining the intermediate stages of their growth. The trends in the decay of the emission intensity of CsPbBr3 nanocrystals under light exposure are well correlated with their stability against decomposition in TEM under electron beam. The results show the change of the crystal structure of CsPbBr3 nanocrystals from a deficient and easier to be destroyed lattice to a well crystallized one. Conversely the shift in the ease of degradation sheds light on the formation mechanism, indicating first the formation of a bromoplumbate ionic scaffold, with Cs-ion infilling lagging a little behind. Increasing the cation to halide ratio towards the stoichiometric level may account for the improved radiative recombination rates observed in the longer reaction time materials.

Role of endogenous insulin gene enhancer protein ISL-1 in angiogenesis.

OBJECTIVE: To elucidate the role of insulin gene enhancer protein ISL-1 (Islet-1) in angiogenesis and regulation of vascular endothelial growth factor (VEGF) expression in vitro and in vivo. METHODS: siRNA targeting Islet-1 was transfected to human umbilical vein endothelial cell lines (HUVECs). The expression of Islet-1 and VEGF in the cultured cells was measured using real-time PCR and immunoblotting. 3-[4,5-dimethylthiazol-2-yl]-2,5- diphenyltetrazolium bromide; thiazolyl blue (MTT) assay was used to analyze the proliferation of HUVECs affected by Islet-1. Wound healing and Transwell assays were conducted to assess the motility of HUVECs. The formation of capillary-like structures was examined using growth factor-reduced Matrigel. siRNA targeting Islet-1 was intravitreally injected into the murine model of oxygen-induced retinopathy (OIR). Retinal neovascularization was evaluated with angiography using fluorescein-labeled dextran and then quantified histologically. Real-time PCR and immunoblotting were used to determine whether local Islet-1 silencing affected the expression of Islet-1 and VEGF in murine retinas. RESULTS: The expression of Islet-1 and VEGF in HUVECs was knocked down by siRNA. Reduced endogenous Islet-1 levels in cultured cells greatly inhibited the proliferation, migration, and tube formation in HUVECs in vitro. Retinal neovascularization following injection of Islet-1 siRNA was significantly reduced compared with that of the contralateral control eye. Histological analysis indicated that the neovascular nuclei protruding into the vitreous cavity were decreased. Furthermore, the Islet-1 and VEGF expression levels were downregulated in murine retinas treated with siRNA against Islet-1. CONCLUSIONS: Reducing the expression of endogenous Islet-1 inhibits proliferation, migration, and tube formation in vascular endothelial cells in vitro and suppresses retinal angiogenesis in vivo. Endogenous Islet-1 regulates angiogenesis via VEGF.

Bacillus-shape design of polymer based drug delivery systems with janus-faced function for synergistic targeted drug delivery and more effective cancer therapy.

The particle shape of the drug delivery systems had a strong impact on their in vitro and in vivo performance, but there was limited availability of techniques to produce the specific shaped drug carriers. In this article, the novel methotrexate (MTX) decorated MPEG-PLA nanobacillus (MPEG-PLA-MTX NB) was prepared by the self-assembly technique followed by the extrusion through SPG membrane with high N2 pressure for targeted drug delivery, in which Janus-like MTX was not only used as a specific anticancer drug but could also be served as a tumor-targeting ligand. The MPEG-PLA-MTX NBs demonstrated much higher in vitro and in vivo targeting efficiency compared to the MPEG-PLA-MTX nanospheres (MPEG-PLA-MTX NSs) and MPEG-PLA nanospheres (MPEG-PLA NSs). In addition, the MPEG-PLA-MTX NBs also displayed much more excellent in vitro and in vivo antitumor activity than the MPEG-PLA-MTX NSs and free MTX injection. To our knowledge, this work provided the first example of the integration of the shape design (which mediated an early phase tumor accumulation and a late-phase cell internalization) and Janus-faced function (which mediated an early phase active targeting effect and a late-phase anticancer effect) on the basis of nanoscaled drug delivery systems. The highly convergent and cooperative drug delivery strategy opens the door to more drug delivery systems with new shapes and functions for cancer therapy.

Mitomycin C-soybean phosphatidylcholine complex-loaded self-assembled PEG-lipid-PLA hybrid nanoparticles for targeted drug delivery and dual-controlled drug release.

Most present drug-phospholipid delivery systems were based on a water-insoluble drug-phospholipid complex but rarely water-soluble drug-phospholipid complex. Mitomycin C (MMC) is a water-soluble anticancer drug extensively used in first-line chemotherapy but is limited by its poor aqueous stability in vitro, rapid elimination from the body, and lack of target specificity. In this article, we report the MMC-soybean phosphatidylcholine complex-loaded PEG-lipid-PLA hybrid nanoparticles (NPs) with Folate (FA) functionalization (FA-PEG-PE-PLA NPs@MMC-SPC) for targeted drug delivery and dual-controlled drug release. FA-PEG-PE-PLA NPs@MMC-SPC comprise a hydrophobic core (PLA) loaded with MMC-SPC, an amphiphilic lipid interface layer (PE), a hydrophilic shell (PEG), and a targeting ligand (FA) on the surface, with a spherical shape, a nanoscaled particle size, and high drug encapsulation efficiency of almost 95%. The advantage of the new drug delivery systems is the early phase controlled drug release by the drug-phospholipid complex and the late-phase controlled drug release by the pH-sensitive polymer-lipid hybrid NPs. In vitro cytotoxicity and hemolysis assays demonstrated that the drug carriers were cytocompatible and hemocompatible. The pharmacokinetics study in rats showed that FA-PEG-PE-PLA NPs@MMC-SPC significantly prolonged the blood circulation time compared to that of the free MMC. More importantly, FA-PEG-PE-PLA NPs@MMC-SPC presented the enhanced cell uptake/cytotoxicity in vitro and superior tumor accumulation/therapeutic efficacy in vivo while reducing the systemic toxicity. A significant accumulation of MMC in the nuclei as the site of MMC action achieved in FA-PEG-PE-PLA NPs@MMC-SPC made them ideal for MMC drug delivery. This study may provide an effective strategy for the design and development of the water-soluble drug-phospholipid complex-based targeted drug delivery and sustained/controlled drug release.

[Construction and verification of a nomogram of factors influencing the risk of death in patient with sepsis-associated thrombocytopenia].

OBJECTIVE: To construct a nomogram prediction model for predicting the risk of death in patients with sepsis-associated thrombocytopenia (SAT) in intensive care unit (ICU) for early indentification and active intervention. METHODS: Clinical data of SAT patients admitted to ICU of the First Affiliated Hospital of Nanjing Medical University from December 2019 to August 2021 were retrospectively collected, including demographic data, laboratory indicators, etc. According to the prognosis at 28 days, the patients were divided into the death group and the survival group, and the differences of clinical variables between the two groups were compared. Multivariate Logistic regression analysis was performed to analyze the independent risk factors influencing mortality of patients within 28 days, then a nomogram predictive model was constructed and its performance was verified with internal data. Receiver operator characteristic curve (ROC curve) was used to evaluate the diagnostic effectiveness of the nomogram model, and the clinical applicability of this model was evaluated by clinical decision curve analysis (DCA). RESULTS: A total of 275 patients were included, with 95 deaths at 28 days and a 28-day mortality of 34.5%. Compared with the survival group, acute physiology and chronic health evaluation II (APACHE II), sequential organ failure assessment (SOFA), lactic acid (Lac), platelet distribution width (PDW) on day 5 of ICU admission, blood urea nitrogen (BUN), total bilirubin (TBIL), aspartate aminotransferase (AST), C-reactive protein (CRP) of patients in the death group were higher, activated partial thromboplastin time (APTT) and prothrombin time (PT) were longer, platelet count (PLT) on day 3 and day 5 of ICU admission, direct bilirubin (DBIL), fibrinogen (FIB) were lower, the history of chronic lung disease, mixed site infection, lung infection, bloodstream infection, Gram-negative bacterial infection and fungal infection accounted for a higher proportion, the history of diabetes mellitus, urinary tract infection and no pathogenic microorganisms cultured accounted for a lower proportion, and the proportion of the use of vasoactive drugs, mechanical ventilation (MV), continuous renal replacement therapy (CRRT), bleeding events and platelet transfusion were higher. Multivariate Logistic regression analysis showed that APACHE II score at the day of ICU admission [odds ratio (OR) = 1.417, 95% confidence interval (95%CI) was 1.153-1.743, P = 0.001], chronic lung disease (OR = 72.271, 95%CI was 4.475-1 167.126, P = 0.003), PLT on day 5 of ICU admission (OR = 0.954, 95%CI was 0.922-0.987, P = 0.007), vasoactive drug (OR = 622.943, 95%CI was 10.060-38 575.340, P = 0.002), MV (OR = 91.818, 95%CI was 3.973-2 121.966, P = 0.005) were independent risk factors of mortality in SAT patients. The above independent risk factors were used to build a nomogram prediction model, and the area under the curve (AUC), sensitivity and specificity were 0.979, 94.7% and 91.7%, respectively, suggesting that the model had good discrimination. The Hosmer-Lemeshow goodness of fit test showed a good calibration with P > 0.05. At the same time, DCA showed that the nomogram model had good clinical applicability. CONCLUSIONS: Patients with SAT has a higher risk of death. The nomogram model based on APACHE II score at the day of ICU admission, chronic lung disease, PLT on day 5 of ICU admission, the use of vasoactive drug and MV has good clinical significance for the prediction of 28-day mortality, and the discrimination and calibration are good, however, further verification is needed.

Electrical Doping of Metal Halide Perovskites by Co-Evaporation and Application in PN Junctions.

Electrical doping of semiconductors is a revolutionary development that enabled many electronic and optoelectronic technologies. While doping of many inorganic and organic semiconductors is well-established, controlled electrical doping of metal halide perovskites (MHPs) is yet to be demonstrated. In this work, efficient n- and p-type electrical doping of MHPs by co-evaporating the perovskite precursors alongside organic dopant molecules is achieved. It is demonstrated that the Fermi level can be shifted by up to 500 meV toward the conduction band and by up to 400 meV toward the valence band by n- and p-doping, respectively, which increases the conductivity of the films. The doped layers are employed in PN and NP diodes, showing opposing trends in rectification. Demonstrating controlled electrical doping by a scalable, industrially relevant deposition method opens the route to developing perovskite devices beyond solar cells, such as thermoelectrics or complementary logic.

ALKBH5-mediated m6A modification of IL-11 drives macrophage-to-myofibroblast transition and pathological cardiac fibrosis in mice.

Cardiac macrophage contributes to the development of cardiac fibrosis, but factors that regulate cardiac macrophages transition and activation during this process remains elusive. Here we show, by single-cell transcriptomics, lineage tracing and parabiosis, that cardiac macrophages from circulating monocytes preferentially commit to macrophage-to-myofibroblast transition (MMT) under angiotensin II (Ang II)-induced hypertension, with accompanying increased expression of the RNA N6-methyladenosine demethylases, ALKBH5. Meanwhile, macrophage-specific knockout of ALKBH5 inhibits Ang II-induced MMT, and subsequently ameliorates cardiac fibrosis and dysfunction. Mechanistically, RNA immunoprecipitation sequencing identifies interlukin-11 (IL-11) mRNA as a target for ALKBH5-mediated m6A demethylation, leading to increased IL-11 mRNA stability and protein levels. By contrast, overexpression of IL11 in circulating macrophages reverses the phenotype in ALKBH5-deficient mice and macrophage. Lastly, targeted delivery of ALKBH5 or IL-11 receptor α (IL11RA1) siRNA to monocytes/macrophages attenuates MMT and cardiac fibrosis under hypertensive stress. Our results thus suggest that the ALKBH5/IL-11/IL11RA1/MMT axis alters cardiac macrophage and contributes to hypertensive cardiac fibrosis and dysfunction in mice, and thereby identify potential targets for cardiac fibrosis therapy in patients.

Convolutional neural network based on photoplethysmography signals for sleep apnea syndrome detection.

Introduction: The current method of monitoring sleep disorders is complex, time-consuming, and uncomfortable, although it can provide scientifc guidance to ensure worldwide sleep quality. This study aims to seek a comfortable and convenient method for identifying sleep apnea syndrome. Methods: In this work, a one-dimensional convolutional neural network model was established. To classify this condition, the model was trained with the photoplethysmographic (PPG) signals of 20 healthy people and 39 sleep apnea syndrome (SAS) patients, and the influence of noise on the model was tested by anti-interference experiments. Results and Discussion: The results showed that the accuracy of the model for SAS classifcation exceeds 90%, and it has some antiinterference ability. This paper provides a SAS detection method based on PPG signals, which is helpful for portable wearable detection.