Discovery of benzo[c]phenanthridine derivatives with potent activity against multidrug-resistant Mycobacterium tuberculosis.

Mycobacterium tuberculosis (Mtb), the pathogen responsible for tuberculosis (TB), is the leading cause of bacterial disease-related death worldwide. Current antibiotic regimens for the treatment of TB remain dated and suffer from long treatment times as well as the development of drug resistance. As such, the search for novel chemical modalities that have selective or potent anti-Mtb properties remains an urgent priority, particularly against multidrug-resistant (MDR) Mtb strains. Herein, we design and synthesize 35 novel benzo[c]phenanthridine derivatives (BPDs). The two most potent compounds, BPD-6 and BPD-9, accumulated within the bacterial cell and exhibited strong inhibitory activity (MIC90 ~2 to 10 µM) against multiple Mycobacterium strains while remaining inactive against a range of other Gram-negative and Gram-positive bacteria. BPD-6 and BPD-9 were also effective in reducing Mtb survival within infected macrophages, and BPD-9 reduced the burden of Mycobacterium bovis BCG in the lungs of infected mice. The two BPD compounds displayed comparable efficacy to rifampicin (RIF) against non-replicating Mtb (NR-Mtb). Importantly, BPD-6 and BPD-9 inhibited the growth of multiple MDR Mtb clinical isolates. Generation of BPD-9-resistant mutants identified the involvement of the Mmr efflux pump as an indirect resistance mechanism. The unique specificity of BPDs to Mycobacterium spp. and their efficacy against MDR Mtb isolates suggest a potential novel mechanism of action. The discovery of BPDs provides novel chemical scaffolds for anti-TB drug discovery.IMPORTANCEThe emergence of drug-resistant tuberculosis (TB) is a serious global health threat. There remains an urgent need to discover new antibiotics with unique mechanisms of action that are effective against drug-resistant Mycobacterium tuberculosis (Mtb). This study shows that novel semi-synthetic compounds can be derived from natural compounds to produce potent activity against Mtb. Importantly, the identified compounds have narrow spectrum activity against Mycobacterium species, including clinical multidrug-resistant (MDR) strains, are effective in infected macrophages and against non-replicating Mtb (NR-Mtb), and show anti-mycobacterial activity in mice. These new compounds provide promising chemical scaffolds to develop potent anti-Mtb drugs of the future.

Ligand-Enabled Pd-Catalyzed sp3 C-H Macrocyclization: Synthesis and Evaluation of Macrocyclic Sulfonamide for the Treatment of Parkinson's Disease.

The development of simplified synthetic strategy to create structurally and functionally diverse pseudo-natural macrocyclic molecules is highly appealing but poses a marked challenge. Inspired by natural scaffolds, herein, we describe a practical and concise ligand-enabled Pd(II)-catalyzed sp3 C-H alkylation, olefination and arylation macrocyclization, which could offer a novel set of pseudo-natural macrocyclic sulfonamides. Interestingly, the potential of ligand acceleration in C-H activation is also demonstrated by an unprecedented enantioselective sp3 C-H alkylation macrocyclization. Moreover, a combination of in silico screening and biological evaluation led to the identification of a novel spiro-grafted macrocyclic sulfonamide 2 a, which showed a promising efficacy for the treatment of Parkinson's disease (PD) in a mouse model through the activation of silent information regulator sirtuin 3 (SIRT3).

Small Molecule Targeting PPM1A Activates Autophagy for Mycobacterium tuberculosis Host-Directed Therapy.

Mycobacterium tuberculosis (Mtb), the infectious agent of tuberculosis (TB), causes over 1.5 million deaths globally every year. Host-directed therapies (HDT) for TB are desirable for their potential to shorten treatment and reduce the development of antibiotic resistance. Previously, we described a modular biomimetic strategy to identify SMIP-30, targeting PPM1A (IC50 = 1.19 µM), a metal-dependent phosphatase exploited by Mtb to survive intracellularly. SMIP-30 restricted the survival of Mtb in macrophages and lungs of infected mice. Herein, we redesigned SMIP-30 to create SMIP-031, which is a more potent inhibitor for PPM1A (IC50 = 180 nM). SMIP-031 efficiently increased the level of phosphorylation of S403-p62 and the expression of LC3B-II to activate autophagy, resulting in the dose-dependent clearance of Mtb in infected macrophages. SMIP-031 possesses a good pharmacokinetic profile and oral bioavailability (F = 74%). In vivo, SMIP-031 is well tolerated up to 50 mg/kg and significantly reduces the bacteria burden in the spleens of infected mice.

Predictive Value of Amplitude-Integrated Electroencephalogram Combined with General Movements for Neurodevelopmental Outcomes in Neonates with Severe Hyperbilirubinemia.

Objective: To investigate the predictive value of amplitude-integrated electroencephalogram (aEEG) combined with general movements (GMs) for neurodevelopmental outcomes in neonates with severe hyperbilirubinemia. Methods: A total of 115 infants with severe hyperbilirubinemia admitted to our hospital from December 2021 to February 2024 were enrolled. All the subjects were tested using aEEG, GMs, cranial magnetic resonance imaging (MRI), or auditory brainstem response (ABR), and followed up for 12 months to evaluate the neurodevelopmental outcomes. Results: Among the 100 children who received follow-up, 19 had adverse neurodevelopmental outcomes. They had significantly higher levels of total serum bilirubin (P < .05) than those with positive neurodevelopmental outcomes. The examination results of abnormalities in aEEG, GMs, ABR, aEEG + GMs, aEEG + ABR, and MRI + ABR are all correlated with adverse neurodevelopmental outcomes (P < .05). Logistic regression analysis indicated that abnormal aEEG, GMs, and ABR were predictors of adverse neurodevelopmental outcomes. The aEEG + GMs method significantly outperformed the individual use of aEEG or GMs in terms of sensitivity, specificity, positive predictive value, and negative predictive value. Conclusion: The aEEG + GMs technique can predict the neurodevelopmental outcomes of neonates with severe hyperbilirubinemia and outperforms the individual use of aEEG or GMs in terms of sensitivity, specificity, positive predictive value, and negative predictive value. As a result, the combined technique merits broader clinical use.

Modular Biomimetic Strategy Enables Discovery and SAR Exploration of Oxime Macrocycles as Influenza A Virus (H1N1) Inhibitors.

Although vaccination remains the prevalent prophylactic means for controlling Influenza A virus (IAV) infections, novel structural antivirus small-molecule drugs with new mechanisms of action for treating IAV are highly desirable. Herein, we describe a modular biomimetic strategy to expeditiously achieve a new class of macrocycles featuring oxime, which might target the hemagglutinin (HA)-mediated IAV entry into the host cells. SAR analysis revealed that the size and linker of the macrocycles play an important role in improving potency. Particularly, as a 14-membered macrocyclic oxime, 37 exhibited potent inhibitory activity against IAV H1N1 with an EC50 value of 23 nM and low cytotoxicity, which alleviated cytopathic effects and protected cell survival obviously after H1N1 infection. Furthermore, 37 showed significant synergistic activity with neuraminidase inhibitor oseltamivir in vitro.

Dual network composite hydrogels with robust antibacterial and antifouling capabilities for efficient wound healing.

Wound dressings play a critical role in the wound healing process; however, conventional dressings often address singular functions, lacking versatility in meeting diverse wound healing requirements. Herein, dual-network, multifunctional hydrogels (PSA/CS-GA) have been designed and synthesized through a one-pot approach. The in vitro and in vivo experiments demonstrate that the optimized hydrogels have exceptional antifouling properties, potent antibacterial effects and rapid hemostatic capabilities. Notably, in a full-thickness rat wound model, the hydrogel group displays a remarkable wound healing rate exceeding 95% on day 10, surpassing both the control group and the commercial 3M group. Furthermore, the hydrogels exert an anti-inflammatory effect by reducing inflammatory factors interleukin 6 (IL-6) and tumor necrosis factor-α (TNF-α), enhance the release of the vascular endothelial growth factor (VEGF) to promote blood vessel proliferation, and augment collagen deposition in the wound, thus effectively accelerating wound healing in vivo. These innovative hydrogels present a novel and highly effective approach to wound healing.

How long can pulmonary resection surgery be performed after SARS-CoV-2 infection? A multicenter retrospective study.

BACKGROUND: No studies to date have focused on the timing of pulmonary resection in patients with previous severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. In the present study, the authors analyzed the surgical outcomes and evaluated the optimal time point of pulmonary resection surgery following SARS-CoV-2 infection. MATERIALS AND METHODS: In this multicenter retrospective cohort study, patients were divided into different groups according to the time interval between SARS-CoV-2 diagnosis and pulmonary resection. The primary outcome measure was postoperative complications within 30 days after surgery, which was investigated to determine the optimal time point of pulmonary resection. Logistic regression models were used to calculate the risk factors for postoperative complications. RESULTS: In total, 400 patients were enrolled, and the postoperative pathologic examination of 322 (80.5%) patients showed lung cancer. As the interval between SARS-CoV-2 infection and pulmonary resection increased, the incidence of complications gradually decreased in each group. The incidence of grade ≥II complications was higher in the ≤2-week and 2-week to 4-week groups than in the 4-week to 6-week, 6-week to 8-week and >8-week groups [3 (21.4%), 17 (20.2%), 10 (10.6%), 13 (7.9%), and 3 (6.5%), respectively] ( P <0.05). Multiclassification regression analysis showed that the risk of grade ≥II complications in the ≤2-week and 2-week to 4-week groups was significantly higher than that in the >8-week group [odds ratio (95% CI), 3.937 (1.072-14.459), P =0.039 and 3.069 (1.232-6.863), P =0.015]. The logistic regression analysis suggested that underlying disease, persistent SARS-CoV-2 symptoms, and surgical timing (≤4 weeks) were independent risk factors for complications of pulmonary resection after SARS-CoV-2 infection. CONCLUSION: Pulmonary resection should be delayed for at least 4 weeks following SARS-CoV-2 infection to reduce the risk of postoperative complications.

Integrated Transcriptomic and Metabolomics Analyses Reveal Molecular Responses to Cold Stress in Coconut (Cocos nucifera L.) Seedlings.

Coconut is an important tropical and subtropical fruit and oil crop severely affected by cold temperature, limiting its distribution and application. Thus, studying its low-temperature reaction mechanism is required to expand its cultivation range. We used growth morphology and physiological analyses to characterize the response of coconuts to 10, 20, and 30 d of low temperatures, combined with transcriptome and metabolome analysis. Low-temperature treatment significantly reduced the plant height and dry weight of coconut seedlings. The contents of soil and plant analyzer development (SPAD), soluble sugar (SS), soluble protein (SP), proline (Pro), and malondialdehyde (MDA) in leaves were significantly increased, along with the activities of superoxide dismutase (SOD), peroxidase (POD), and catalase (CAT), and the endogenous hormones abscisic acid (ABA), auxin (IAA), zeatin (ZR), and gibberellin (GA) contents. A large number of differentially expressed genes (DEGs) (9968) were detected under low-temperature conditions. Most DEGs were involved in mitogen-activated protein kinase (MAPK) signaling pathway-plant, plant hormone signal transduction, plant-pathogen interaction, biosynthesis of amino acids, amino sugar and nucleotide sugar metabolism, carbon metabolism, starch and sucrose metabolism, purine metabolism, and phenylpropanoid biosynthesis pathways. Transcription factors (TFs), including WRKY, AP2/ERF, HSF, bZIP, MYB, and bHLH families, were induced to significantly differentially express under cold stress. In addition, most genes associated with major cold-tolerance pathways, such as the ICE-CBF-COR, MAPK signaling, and endogenous hormones and their signaling pathways, were significantly up-regulated. Under low temperatures, a total of 205 differentially accumulated metabolites (DAMs) were enriched; 206 DAMs were in positive-ion mode and 97 in negative-ion mode, mainly including phenylpropanoids and polyketides, lipids and lipid-like molecules, benzenoids, organoheterocyclic compounds, organic oxygen compounds, organic acids and derivatives, nucleosides, nucleotides, and analogues. Comprehensive metabolome and transcriptome analysis revealed that the related genes and metabolites were mainly enriched in amino acid, flavonoid, carbohydrate, lipid, and nucleotide metabolism pathways under cold stress. Together, the results of this study provide important insights into the response of coconuts to cold stress, which will reveal the underlying molecular mechanisms and help in coconut screening and breeding.

Organ preservation strategies after neoadjuvant chemoimmunotherapy in resectable non-small cell lung cancer: a multicenter retrospective cohort study.

BACKGROUND: Neoadjuvant chemoimmunotherapy has shown a good therapeutic effect on non-small cell lung cancer (NSCLC), which also opens up the possibility of applying organ preservation strategies. This study investigated the feasibility of modified surgery after potent neoadjuvant chemoimmunotherapy in central type NSCLC. METHODS: In this multicenter retrospective cohort study, patients with central type NSCLC who received 2-4 cycles of neoadjuvant chemoimmunotherapy between January 2019 and June 2022 at Air Force Medical University Tangdu Hospital and Peking University People's Hospital were eligible. Patients were divided into modified and nonmodified groups according to the extent of surgery, after which, the safety and long-term prognosis of surgery were investigated. RESULTS: A total of 84 patients were enrolled. Of 36 (42.9%) patients who underwent modified surgery, 21 patients underwent lobectomy, 12 patients underwent lobectomy with bronchoplasty, 2 patients underwent sleeve lobectomy, and 1 patient underwent bilobectomy. The modification rate for the initially estimated pneumonectomy, sleeve lobectomy, and bilobectomy was 48.6, 44.8, and 30%, respectively. Grades II-V postoperative complications were found in 5 (13.9%) patients in the modified group and 17 (35.4%) patients in the nonmodified group (relative risk, 0.393; 95% CI, 0.016-0.963; P =0.026). No significant difference was observed regarding the surgical approach, operative duration, blood loss, or R0 resection rate. The 2-year local recurrence rate was 3.7% (95% CI, 0.004-0.175) and 5.2% (95% CI, 0.012-0.168) in the modified group and nonmodified group, respectively. The 1-year PFS rate of modified and nonmodified groups was 97.1% (95% CI, 83.7-99.8) and 86.9% (95% CI, 73.4-94.4), respectively, while 2-year PFS were 89.8% (95% CI, 74.1-96.9) and 71.8% (95% CI, 56.7-83.4), respectively. CONCLUSION: Applying organ preservation strategies, that is, undergoing modified surgery after neoadjuvant chemoimmunotherapy, is feasible for selected central type NSCLC patients with favorable safety and long-term survival.

Integrated transcriptomic and metabolomic analyses reveal key metabolic pathways in response to potassium deficiency in coconut (Cocos nucifera L.) seedlings.

Potassium ions (K+) are important for plant growth and crop yield. However, the effects of K+ deficiency on the biomass of coconut seedlings and the mechanism by which K+ deficiency regulates plant growth remain largely unknown. Therefore, in this study, we compared the physiological, transcriptome, and metabolite profiles of coconut seedling leaves under K+-deficient and K+-sufficient conditions using pot hydroponic experiments, RNA-sequencing, and metabolomics technologies. K+ deficiency stress significantly reduced the plant height, biomass, and soil and plant analyzer development value, as well as K content, soluble protein, crude fat, and soluble sugar contents of coconut seedlings. Under K+ deficiency, the leaf malondialdehyde content of coconut seedlings were significantly increased, whereas the proline (Pro) content was significantly reduced. Superoxide dismutase, peroxidase, and catalase activities were significantly reduced. The contents of endogenous hormones such as auxin, gibberellin, and zeatin were significantly decreased, whereas abscisic acid content was significantly increased. RNA-sequencing revealed that compared to the control, there were 1003 differentially expressed genes (DEGs) in the leaves of coconut seedlings under K+ deficiency. Gene Ontology analysis revealed that these DEGs were mainly related to "integral component of membrane," "plasma membrane," "nucleus", "transcription factor activity," "sequence-specific DNA binding," and "protein kinase activity." Kyoto Encyclopedia of Genes and Genomes pathway analysis indicated that the DEGs were mainly involved in "MAPK signaling pathway-plant," "plant hormone signal transduction," "starch and sucrose metabolism," "plant-pathogen interaction," "ABC transporters," and "glycerophospholipid metabolism." Metabolomic analysis showed that metabolites related to fatty acids, lipidol, amines, organic acids, amino acids, and flavonoids were generally down-regulated in coconut seedlings under K+ deficiency, whereas metabolites related to phenolic acids, nucleic acids, sugars, and alkaloids were mostly up-regulated. Therefore, coconut seedlings respond to K+ deficiency stress by regulating signal transduction pathways, primary and secondary metabolism, and plant-pathogen interaction. These results confirm the importance of K+ for coconut production, and provide a more in-depth understanding of the response of coconut seedlings to K+ deficiency and a basis for improving K+ utilization efficiency in coconut trees.

Modular Biomimetic Strategy Enabled Discovery of Simplified Pseudo-Natural Macrocyclic P-Glycoprotein Inhibitors Capable of Overcoming Multidrug Resistance.

Natural macrocycles have shown impressive activity to overcome P-glycoprotein (P-gp)-mediated multidrug resistance (MDR). However, the total synthesis and structural modification of natural macrocycles are challenging, which would hamper the deeper investigations of their structure-activity relationship (SAR) and drug likeness. Herein, we describe a modular biomimetic strategy to expeditiously achieve a new class of macrocycles featuring polysubstituted 1,3-diene, which efficiently inhibited P-gp and reversed MDR in cancer cells. The SAR analysis revealed that the size and linker of the macrocycles are important structural characteristics to restore activity. Particularly, 32 containing a naphthyl group and (d)-Phe moiety has higher potency with an excellent reversal fold than verapamil at a concentration of 5 µM, which induces conformational change of P-gp and inhibits its function instead of altering P-gp expression. Furthermore, 23 and 32 were identified to be attractive leads, which possess a good pharmacokinetic profile and antitumor activity in a KBV200 xenograft mouse model.

Rhodium(III)-Catalyzed C-H/O2 Dual Activation and Macrocyclization: Synthesis and Evaluation of Pyrido[2,1-a]isoindole Grafted Macrocyclic Inhibitors for Influenza H1N1.

The development of environment-friendly, step economic couplings to generate structurally diverse macrocyclic compounds is highly desirable but poses a marked challenge. Inspired by the C-H oxidation mechanism of cytochromes P450, an unprecedented and practical RhIII -catalyzed acylmethylation macrocyclization via C-H/O2 dual activation has been developed by us. The process of macrocyclization is facilitated by a synergic coordination from pyridine and ester group. Interestingly, the reaction mode derives from a three-component coupling which differs from established olefination and alkylation paths. Density functional theory (DFT) calculations and control experiments revealed the mechanism of this unique C-H/O2 dual activation. The newly achieved acylmethylation macrocyclic products and their derivatives showed a potent anti-H1N1 bioactivity, which may provide an opportunity for the discovery of novel anti-H1N1 macrocyclic leading compounds.

3D Printing and Performance Study of Porous Artificial Bone Based on HA-ZrO2-PVA Composites.

An ideal artificial bone implant should have similar mechanical properties and biocompatibility to natural bone, as well as an internal structure that facilitates stomatal penetration. In this work, 3D printing was used to fabricate and investigate artificial bone composites based on HA-ZrO2-PVA. The composites were proportionally configured using zirconia (ZrO2), hydroxyapatite (HA) and polyvinyl alcohol (PVA), where the ZrO2 played a toughening role and PVA solution served as a binder. In order to obtain the optimal 3D printing process parameters for the composites, a theoretical model of the extrusion process of the composites was first established, followed by the optimization of various parameters including the spray head internal diameter, extrusion pressure, extrusion speed, and extrusion line width. The results showed that, at the optimum parameters of a spray head diameter of 0.2 mm, extrusion pressure values ranging from 1-3 bar, a line spacing of 0.8-1.5 mm, and a spray head displacement range of 8-10 mm/s, a better structure of biological bone scaffolds could be obtained. The mechanical tests performed on the scaffolds showed that the elastic modulus of the artificial bone scaffolds reached about 174 MPa, which fulfilled the biomechanical requirements of human bone. According to scanning electron microscope observation of the scaffold sample, the porosity of the scaffold sample was close to 65%, which can well promote the growth of chondrocytes and angiogenesis. In addition, c5.18 chondrocytes were used to verify the biocompatibility of the composite materials, and the cell proliferation was increased by 100% when compared with that of the control group. The results showed that the composite has good biocompatibility.

Activation of the human chemokine receptor CX3CR1 regulated by cholesterol.

As the only member of the CX3C chemokine receptor subfamily, CX3CR1 binds to its sole endogenous ligand CX3CL1, which shows notable potential as a therapeutic target in atherosclerosis, cancer, and neuropathy. However, the drug development of CX3CR1 is hampered partially by the lack of structural information. Here, we present two cryo-electron microscopy structures of CX3CR1-Gi1 complexes in ligand-free and CX3CL1-bound states at 2.8- and 3.4-Å resolution, respectively. Together with functional data, the structures reveal the key factors that govern the recognition of CX3CL1 by both CX3CR1 and US28. A much smaller conformational change of helix VI upon activation than previously solved class A GPCR-Gi complex structures is observed in CX3CR1, which may correlate with three cholesterol molecules that play essential roles in conformation stabilization and signaling transduction. Thus, our data deepen the understanding of cholesterol modulation in GPCR (G protein-coupled receptor) signaling and provide insights into the diversity of G protein coupling.

Lung Nodule Segmentation and Recognition Algorithm Based on Multiposition U-Net.

Lung nodules are the main lesions of the lung, and conditions of the lung can be directly displayed through CT images. Due to the limited pixel number of lung nodules in the lung, doctors have the risk of missed detection and false detection in the detection process. In order to reduce doctors' work intensity and assist doctors to make accurate diagnosis, a lung nodule segmentation and recognition algorithm is proposed by simulating doctors' diagnosis process with computer intelligent methods. Firstly, the attention mechanism model is established to focus on the region of lung parenchyma. Then, a pyramid network of bidirectional enhancement features is established from multiple body positions to extract lung nodules. Finally, the morphological and imaging features of lung nodules are calculated, and then, the signs of lung nodules can be identified. The experiments show that the algorithm conforms to the doctor's diagnosis process, focuses the region of interest step by step, and achieves good results in lung nodule segmentation and recognition.

A selective PPM1A inhibitor activates autophagy to restrict the survival of Mycobacterium tuberculosis.

Metal-dependent protein phosphatases (PPMs) have essential roles in a variety of cellular processes, including inflammation, proliferation, differentiation, and stress responses, which are intensively investigated in cancer and metabolic diseases. Targeting PPMs to modulate host immunity in response to pathogens is an ambitious proposition. The feasibility of such a strategy is unproven because development of inhibitors against PPMs is challenging and suffers from poor selectivity. Combining a biomimetic modularization strategy with function-oriented synthesis, we design, synthesize and screen more than 500 pseudo-natural products, resulting in the discovery of a potent, selective, and non-cytotoxic small molecule inhibitor for PPM1A, SMIP-30. Inhibition of PPM1A with SMIP-30 or its genetic ablation (ΔPPM1A) activated autophagy through a mechanism dependent on phosphorylation of p62-SQSTM1, which restricted the intracellular survival of Mycobacterium tuberculosis in macrophages and in the lungs of infected mice. SMIP-30 provides proof of concept that PPMs are druggable and promising targets for the development of host-directed therapies against tuberculosis.

CFD-Based Flow Channel Optimization and Performance Prediction for a Conical Axial Maglev Blood Pump.

Ventricular assist devices or total artificial hearts can be used to save patients with heart failure when there are no donors available for heart transplantation. Blood pumps are integral parts of such devices, but traditional axial flow blood pumps have several shortcomings. In particular, they cause hemolysis and thrombosis due to the mechanical contact and wear of the bearings, and they cause blood stagnation due to the separation of the front and rear guide wheel hubs and the impeller hub. By contrast, the implantable axial flow, maglev blood pump has the characteristics of no mechanical contact, no lubrication, low temperature rise, low hemolysis, and less thrombosis. Extensive studies of axial flow, maglev blood pumps have shown that these pumps can function in laminar flow, transitional flow, and turbulent flow, and the working state and performance of such pumps are determined by their support mechanisms and flow channel. Computational fluid dynamics (CFD) is an effective tool for understanding the physical and mechanical characteristics of the blood pump by accurately and effectively revealing the internal flow field, pressure-flow curve, and shear force distribution of the blood pump. In this study, magnetic levitation supports were used to reduce damages to the blood and increase the service life of the blood pump, and a conical impeller hub was used to reduce the speed, volume, and power consumption of the blood pump, thereby facilitating implantation. CFD numerical simulation was then carried out to optimize the structural parameters of the conical axial maglev blood pump, predict the hemolysis performance of the blood pump, and match the flow channel and impeller structure. An extracorporeal circulation simulation platform was designed to test whether the hydraulic characteristics of the blood pump met the physiological requirements. The results showed that the total pressure distribution in the blood pump was reasonable after optimization, with a uniform pressure gradient, and the hemolysis performance was improved.

Platelets and High-Altitude Exposure: A Meta-Analysis.

Wang, Yuliang, Xuewen Huang, Weibo Yang, and Qingxian Zeng. Platelets and high-altitude exposure: a meta-analysis. High Alt Med Biol. 23:43-56, 2022. Background: How high-altitude hypoxia influences platelets is controversial. We attempted to quantify the impact of high-altitude exposure on platelets through meta-analysis. Methods: We systematically searched electronic databases (PubMed, Embase, Web of Science, VIP, Wanfang, and CNKI) and identified articles reporting an association between platelet count (PC) or platelet indices (platelet distribution width, mean platelet volume [MPV], and plateletcrit) and high-altitude exposure. The mean and standard deviation were extracted, and the standard mean difference (SMD) was estimated using random-effects models. Stata 15.3 was used to analyze statistical data. Results: Thirty-two studies were ultimately included. For acute high-altitude hypoxia (1-14 days), no significant difference was detected, even in patients with acute mountain disease. For the chronic high-altitude hypoxia (≥1 month) group, a significant decrease in PC (SMD [95% confidence interval, CI] = -0.34 [-0.63 to -0.04]) and increase in MPV (SMD [95% CI] = 1.55 [0.60 to 2.49]) were detected compared with those in the control group. Subgroup analysis showed that the tendency was more obvious in the group with longer exposure (≥1 year). Moreover, the PC of the chronic mountain sickness group was less compared with the healthy altitude control group (SMD [95% CI] = -1.82 [-2.74 to -0.91]). Conclusion: A reduced PC and an increased MPV are associated with chronic exposure to high-altitude hypoxia. Moreover, acute high-altitude exposure has no significant influence on platelets.

Effects of grazing on vegetation diversity and soil multifunctionality in coconut plantations.

Grazing is the main way of utilizing understory vegetation in the tropics. However, the effects of grazing on vegetation diversity and soil functions in coconut plantations remain unclear. Therefore, this study was conducted in a young coconut plantation that was grazed by geese in Wenchang, China. We identified four grazing intensities according to the aboveground biomass, namely, no grazing (CK), light grazing (LG), moderate grazing (MG), and heavy grazing (HG). In April 2022, we used the quadrat method to investigate the composition and traits of vegetation, collected and analyzed 0-40-cm soil samples in each grazing intensity. The results showed that grazing changed the composition of understory species. The predominant species changed from Bidens pilosa to Praxelis clematidea + Paspalum thunbergii and then to P. clematidea with increasing grazing intensity. The richness, Shannon-Wiener index, evenness, modified functional attribute diversity (MFAD), functional divergence (Fdiv), and functional evenness (Feve) of CK were 4.5, 1.0, 0.29, 0.20, 0.84, and 0.80, respectively. Taxonomic diversity did not respond to LG, but responded significantly to MG and HG. Compared with CK, MG and HG increased richness by 96% and 200%, respectively, and Shannon-Wiener index increased by 40% and 98%, respectively. HG increased evenness by 95%. For functional diversity, MG and HG increased MFAD by 164% and 560%, respectively, but Fdiv and Feve did not respond to grazing intensity. The carbon (C) functioning, nitrogen (N) functioning, phosphorus (P) functioning, and multifunctionality in the 0-10-cm topsoil of CK were -0.03, 0.37, -0.06, 0.20, and 0.14, respectively. Grazing increased C functioning, P functioning, and multifunctionality in the 0-10-cm topsoil but decreased N functioning. Multiple linear regression showed that the taxonomic diversity and functional diversity could be used to estimate soil functions, but these vary among soil layers. In general, MG and HG can increase vegetation diversity and soil function. It may be possible to promote even distribution of geese by adding water sources or zoning grazing. Furthermore, quantitative grazing experiments are needed to determine the efficient use pattern of the understory in coconut plantations in tropics.

Rh-Catalyzed cascade C-H activation/C-C cleavage/cyclization of carboxylic acids with cyclopropanols.

Merging both C-H and C-C activation in a tandem process is a marked challenge. A novel Rh(iii)-catalyzed C-H activation/ring opening C-C cleavage/cyclization of carboxylic acids with cyclopropanols was developed for the synthesis of 3-substituted phthalides and α,ß-butenolides. This reaction displays excellent functional group tolerance with respect to both carboxylic acids and cyclopropanols and features relatively mild conditions. Remarkably, the utility of this method was highlighted by the rapid construction of bioactive compounds bearing a 3-substituted phthalide framework via late-stage functionalization.