TGN-020 ameliorates motor dysfunction post-spinal cord injury via enhancing astrocyte autophagy and mitigating inflammation by activating AQP4/PPAR-γ/mTOR pathway.

Spinal Cord Injury (SCI) is a severe condition that often leads to substantial neurological impairments. This study aimed to explore the role of Aquaporin-4 (AQP4) in regulating astrocyte autophagy and neuroinflammation post-SCI, as well as to evaluate the therapeutic potential of AQP4 inhibition using the specific inhibitor TGN-020. Using Western blot, CCK8 assays, immunofluorescence staining, histopathological assessments, and behavioral analyses, we investigated the effects of TGN-020 on SCI-induced alterations in autophagy, neuroinflammation, astrocyte proliferation, neuronal damage, and motor function recovery in both rat and astrocyte models. Our findings indicate that TGN-020 significantly enhances astrocyte autophagy, reduces neuroinflammation, thereby leading to mitigated astrocyte activation by suppressing AQP4 expression. These beneficial effects are associated with the activation of the peroxisome proliferator-activated receptor-γ/mammalian target of rapamycin (PPAR-γ/mTOR) signaling pathway. Notably, the introduction of the PPAR-γ specific inhibitor GW9662 abrogated the positive regulatory effects of TGN-020 on SCI-induced autophagy and neuroinflammation. Collectively, our in vivo and in vitro experiments demonstrate that TGN-020, by down-regulating AQP4, activates the PPAR-γ/mTOR pathway, ameliorates astrocyte autophagy, diminishes neuroinflammation, and ultimately enhances motor function recovery.

Moderate alternate wetting and drying irrigation enhances drought-resistance abilities by improving structural mesophyll conductance of water-saving and drought-resistant rice under severe drought.

Water-saving and drought-resistant rice (WDR) coupled with alternate wetting and drying irrigation (AWDI) possesses a high photosynthetic potential due to higher mesophyll conductance (gm) under drought conditions. However, the physiological and structural contributions to the gm of leaves and their mechanisms in WDR under AWDI are still unclear. In this study, WDR (Hanyou 73) and drought-sensitive rice (Huiliangyou 898) were selected as materials. Three irrigation patterns were established from transplanting to the heading stage, including conventional flooding irrigation (W1), moderate AWDI (W2), and severe AWDI (W3). A severe drought with a soil water potential of -50 kPa was applied for a week at the heading stage across all treatments and cultivars. The results revealed that severe drought reduced gas exchange parameters and gm but enhanced antioxidant enzyme activities and malondialdehyde content in the three treatments and both cultivars. The maximal photosynthetic rate (Amax) of HY73 in the W2 treatment was greater than that in the other combinations of cultivars and irrigation patterns. The contribution of leaf structure (54%) to gm (gm-S, structural gm) was higher than that of leaf physiology (46%) to gm (gm-P, physiological gm) in the W2 treatment of Hanyou 73. Additionally, gm-S was significantly and linearly positively correlated with gm under severe drought. Moreover, both the initial and apparent quantum efficiencies were significantly and positively with gm in rice plants (p < 0.05). These results suggest that the improvements in photosynthesis and yield in the WDR combined with moderate AWDI can mainly be attributed to the enhancement of gm-S under severe drought conditions. Quantum efficiency may be a potential factor in regulating photosynthesis by cooperating with the gm of rice plants under severe drought conditions.

Chinese expert consensus on management of antifungal-resistant dermatophytoses (2024 edition).

Antifungal-resistant dermatophytes (ARD) infection is a hotspot issue in clinical microbiology and the dermatology field. Trichophyton indotineae as the dominant species of dermatophyte with terbinafine-resistance or multidrug resistance, is easy to be missed detection clinically, which brings severe challenges to diagnosis and treatment. ARD infection cases have emerged in China, and it predicts a risk of transmission among human. Based on the existing medical evidence and research data, the Mycology Group of Combination of Traditional and Western Medicine Dermatology and Chinese Antifungal⁃Resistant Dermatophytoses Expert Consensus Group organized experts to make consensus on the management of the infection. Here, the consensus formulated diagnosis and treatment recommendations, to raise attention to dermatophytes drug resistance problem, and expect to provide reference information for the clinical diagnosis, treatment, prevention and control.

Toxicity and decomposition activity inhibition of VO2 micro/nanoparticles to white rot fungus Phanerochaete chrysosporium.

Vanadium dioxide (VO2) is an excellent phase transition material widely used in various applications, and thus inevitably enters the environment via different routes and encounters various organisms. Nonetheless, limited information is available on the environmental hazards of VO2. In this study, we investigated the impact of two commercial VO2 particles, nanosized S-VO2 and micro-sized M-VO2 on the white rot fungus Phanerochaete chrysosporium. The growth of P. chrysosporium is significantly affected by VO2 particles, with S-VO2 displaying a higher inhibitory effect on weight gain. In addition, VO2 at high concentrations inhibits the formation of fungal fibrous hyphae and disrupts the integrity of fungus cells as evidenced by the cell membrane damage and the loss of cytoplasm. Notably, at 200 µg/mL, S-VO2 completely alters the morphology of P. chrysosporium, while the M-VO2 treatment does not affect the mycelium formation of P. chrysosporium. Additionally, VO2 particles inhibit the laccase activity secreted by P. chrysosporium, and thus prevent the dye decoloration and sawdust decomposition by P. chrysosporium. The mechanism underlying this toxicity is related to the dissolution of VO2 and the oxidative stress induced by VO2. Overall, our findings suggest that VO2 nanoparticles pose significant environmental hazards and risks to white rot fungi.

Pumpless microfluidic sweat sensing yarn.

Textile sweat sensors possess immense potential for non-invasive health monitoring. Rapid in-situ sweat capture and prevention of its evaporation are crucial for accurate and stable real-time monitoring. Herein, we introduce a unidirectional, pump-free microfluidic sweat management system to tackle this challenge. A nanofiber sheath layer on micrometer-scale sensing filaments enables this pumpless microfluidic design. Utilizing the capillary effect of the nanofibers allows for the swift capture of sweat, while the differential configuration of the hydrophilic and hydrophobic properties of the sheath and core yarns prevents sweat evaporation. The Laplace pressure difference between the cross-scale fibers facilitates the management system to ultimately expulse sweat. This results in microfluidic control of sweat without the need for external forces, resulting in rapid (<5 s), sensitive (19.8 nA µM-1), and stable (with signal noise and drift suppression) sweat detection. This yarn sensor can be easily integrated into various fabrics, enabling the creation of health monitoring smart garments. The garments maintain good monitoring performance even after 20 washes. This work provides a solution for designing smart yarns for high-precision, stable, and non-invasive health monitoring.

Tailoring Single-Atom Coordination Environments in Carbon Nanofibers via Flash Heating for Highly Efficient Bifunctional Oxygen Electrocatalysis.

The rational design of carbon-supported transition metal single-atom catalysts necessitates precise atomic positioning within the precursor. However, structural collapse during pyrolysis can occlude single atoms, posing significant challenges in controlling both their utilization and coordination environment. Herein, we present a surface atom adsorption-flash heating (FH) strategy, which ensures that the pre-designed carbon nanofiber structure remains intact during heating, preventing unforeseen collapse effects and enabling the formation of metal atoms in nano-environments with either tetra-nitrogen or penta-nitrogen coordination at different flash heating temperatures. Theoretical calculations and in situ Raman spectroscopy reveal that penta-nitrogen coordinated cobalt atoms (Co-N5) promote a lower energy pathway for oxygen reduction and oxygen evolution reactions compared to the commonly formed Co-N4 sites. This strategy ensures that Co-N5 sites are fully exposed on the surface, achieving exceptionally high atomic utilization. The turnover frequency (65.33 s-1) is 47.4 times higher than that of 20% Pt/C under alkaline conditions. The porous, flexible carbon nanofibers significantly enhance zinc-air battery performance, with a high peak power density (273.8 mW cm-2), large specific capacity (784.2 mA h g-1), and long-term cycling stability over 600 h. Additionally, the flexible fiber-shaped zinc-air battery can power wearable devices, demonstrating significant potential in flexible electronics applications.

Improving the prediction performance of leaf water content by coupling multi-source data with machine learning in rice (Oryza sativa L.).

BACKGROUND: Leaf water content (LWC) significantly affects rice growth and development. Real-time monitoring of rice leaf water status is essential to obtain high yield and water use efficiency of rice plants with precise irrigation regimes in rice fields. Hyperspectral remote sensing technology is widely used in monitoring crop water status because of its rapid, nondestructive, and real-time characteristics. Recently, multi-source data have been attempted to integrate into a monitored model of crop water status based on spectral indices. However, there are fewer studies using spectral index model coupled with multi-source data for monitoring LWC in rice plants. Therefore, 2-year field experiments were conducted with three irrigation regimes using four rice cultivars in this study. The multi-source data, including canopy ecological factors and physiological parameters, were incorporated into the vegetation index to accurately predict LWC in rice plants. RESULTS: The results presented that the model accuracy of rice LWC estimation after combining data from multiple sources improved by 6-44% compared to the accuracy of a single spectral index normalized difference index (ND). Additionally, the optimal prediction accuracy of rice LWC was produced using a machine algorithm of gradient boosted decision tree (GBDT) based on the combination of ND(1287,1673) and crop water stress index (CWSI) (R2 = 0.86, RMSE = 0.01). CONCLUSIONS: The machine learning estimation model constructed based on multi-source data fully utilizes the spectral information and considers the environmental changes in the crop canopy after introducing multi-source data parameters, thus improving the performance of spectral technology for monitoring rice LWC. The findings may be helpful to the water status diagnosis and accurate irrigation management of rice plants.

Comparative physiological and transcriptome analysis between potassium-deficiency tolerant and sensitive sweetpotato genotypes in response to potassium-deficiency stress.

BACKGROUND: Sweetpotato is a typical ''potassium (K+) favoring'' food crop, which root differentiation process needs a large supply of potassium fertilizer and determine the final root yield. To further understand the regulatory network of the response to low potassium stress, here we analyze physiological and biochemical characteristics, and investigated root transcriptional changes in two sweetpotato genotypes, namely, - K tolerant "Xu32" and - K susceptible"NZ1". RESULT: We found Xu32 had the higher capability of K+ absorption than NZ1 with better growth performance, higher net photosynthetic rate and higher chlorophyll contents under low potassium stress, and identified 889 differentially expressed genes (DEGs) in Xu32, 634 DEGs in NZ1, 256 common DEGs in both Xu32 and NZ1. The Gene Ontology (GO) term in molecular function enrichment analysis revealed that the DEGs under low K+ stress are predominately involved in catalytic activity, binding, transporter activity and antioxidant activity. Moreover, the more numbers of identified DEGs in Xu32 than that in NZ1 responded to K+-deficiency belong to the process of photosynthesis, carbohydrate metabolism, ion transport, hormone signaling, stress-related and antioxidant system may result in different ability to K+-deficiency tolerance. The unique genes in Xu32 may make a great contribution to enhance low K+ tolerance, and provide useful information for the molecular regulation mechanism of K+-deficiency tolerance in sweetpotato. CONCLUSIONS: The common and distinct expression pattern between the two sweetpotato genotypes illuminate a complex mechanism response to low potassium exist in sweetpotato. The study provides some candidate genes, which can be used in sweetpotato breeding program for improving low potassium stress tolerance.

How variable progenitor clones construct a largely invariant neocortex.

The neocortex contains a vast collection of diverse neurons organized into distinct layers. While nearly all neocortical neurons are generated by radial glial progenitors (RGPs), it remains largely unclear how a complex yet organized neocortex is constructed reliably and robustly. Here, we show that the division behavior and neuronal output of RGPs are highly constrained with patterned variabilities to support the reliable and robust construction of the mouse neocortex. The neurogenic process of RGPs can be well-approximated by a consistent Poisson-like process unfolding over time, producing deep to superficial layer neurons progressively. The exact neuronal outputs regarding layer occupation are variable; yet, this variability is constrained systematically to support all layer formation, largely reflecting the variable intermediate progenitor generation and RGP neurogenic entry and exit timing differences. Together, these results define the fundamental features of neocortical neurogenesis with a balanced reliability and variability for the construction of the complex neocortex.

Community ecological succession of endophytic fungi associates with medicinal compound accumulation in Sophora alopecuroides.

Endophytic fungi of medicinal plants are symbiotic with the host and play an important role in determining metabolites. To understand the relationship between the accumulation of Sophora alopecuroides' medicinal bioactive compounds and the ecological succession of endophytic fungi, here we collected samples from S. alopecuroides at four developmental stages (adult, flowering, podding, and mature) and different organs (roots, stems, leaves, and seeds) at the mature stage. We then used high-performance liquid chromatography-mass spectrometry and high-throughput sequencing on the internal transcribed spacer region to identify the medicinal compounds and endophytic fungal communities in each sample. The endophytic fungal community characteristics and accumulation of medicinally bioactive compounds of S. alopecuroides varied with the host's developmental stages and organs, with the highest total alkaloids content of 111.9 mg/g at the mature stage. Membership analysis and network connection analysis showed a total of 15 core endophytic fungi in different developmental stages and 16 core endophytic fungi in different organs at the mature stage. The unclassified Ascomycota, Aspergillus, and Alternaria were significantly and positively correlated with the medicinal compounds of S. alopecuroides at the mature stage (r > 0.6 or r < -0.6; P < 0.05). In this study, we identified key endophytic fungal resources that affect the content of medicinally bioactive compounds in S. alopecuroides. This discovery could lay the foundation for enhancing the yield of medicinally bioactive compounds in S. alopecuroides and the development and application of functional endophytic fungi.IMPORTANCESophora alopecuroides is a traditional Chinese herbal medicine. The major medicinal chemicals are considered to be quinolizidine alkaloids. Quinolizidine alkaloids have been widely used for the treatment of tumors, dysentery, and enteritis. Previous studies have found that endophytic fungi in S. alopecuroides can promote the accumulation of host quinolizidine alkaloids. However, the relationship between the accumulation of S. alopecuroides' medicinal bioactive compounds and the ecological succession of endophytic fungi remains unclear. In this study, we screened the key endophytic fungal resources affecting the content of medicinally bioactive compounds and laid the foundation for subsequent research on the mechanism by which endophytic fungi promote the accumulation of medicinally bioactive compounds in S. alopecuroides.

Transcriptional response of wolfberry to infestation with the endophytic Fusarium nematophilum strain NQ8GII4.

Fusarium nematophilum NQ8GII4 is an endophytic fungus isolated from the root of healthy wolfberry (Lycium barbarum). Previous studies have reported that NQ8GII4 could dwell in wolfberry roots and enhance the defense responses in wolfberry against root rot, which is caused by F. oxysporum. To further elucidate the molecular mechanism of wolfberry disease resistance induced by NQ8GII4, in the present study, we adopted RNA sequencing analysis to profile the transcriptome of wolfberry response to NQ8GII4 infestation over a time course of 3 and 7 days post-inoculation (dpi). Gene ontology (GO) enrichment analysis revealed that DEGs were enriched related to biological regulation, response to stimulus, signaling, detoxification, immune system process, transporter activity, electron carrier activity, transcription factor activity, nucleic acid binding transcription factor, and antioxidant activity. Through Kyoto encyclopedia of genes and genomes (KEGG) analysis, it was found that many of these DEGs were enriched in pathways related to plant-pathogen interactions, hormone signal transduction, and phenylpropanoid biosynthesis pathway in wolfberry. This suggests that innate immunity, phytohormone signaling, and numerous phenylpropanoid compounds, which comprise a complex defense network in wolfberry. Chloroplast 50S ribosomal proteins (50S RP) were consistently located at the core position of the response in wolfberry following infestation with NQ8GII4 analyzed by protein-protein interaction (PPI) network. This study elucidated the molecular mechanism underlying the interaction between NQ8GII4 and wolfberry, clarified the wolfberry immune response network to endophytic fungi infestation, identified candidate resistance genes in wolfberry, and provided a fundamental date for subsequent work.

Plasticity of mesophyll cell density and cell wall thickness and composition play a pivotal role in regulating plant growth and photosynthesis under shading in rapeseed.

BACKGROUND AND AIMS: Plasticity of leaf growth and photosynthesis is an important strategy of plants to adapt to shading stress; however, their strategy of leaf development to achieve a simultaneous increase in leaf area and photosynthesis under shading remains unknown. METHODS: In the present study, a pot experiment was conducted using three rapeseed genotypes of Huayouza 50 (HYZ50), Zhongshuang 11 (ZS11) and Huayouza 62 (HYZ62), and the responses of plant growth, leaf morphoanatomical traits, cell wall composition and photosynthesis to shading were investigated. KEY RESULTS: Shading significantly increased leaf area per plant (LAplant) in all genotypes, but the increase in HYZ62 was greater than that in HYZ50 and ZS11. The greater increment of LAplant in HYZ62 was related to the larger decrease in leaf mass per area (LMA) and leaf density (LD), which were in turn related to less densely packed mesophyll cells and thinner cell walls (Tcw). Moreover, shading significantly increased photosynthesis in HYZ62 but significantly decreased it in HYZ50. The enhanced photosynthesis in HYZ62 was related to increased mesophyll conductance (gm) due primarily to thinner cell walls. CONCLUSIONS: The data presented indicate that the different plasticity of mesophyll cell density, cell wall thickness and cell wall composition in response to shading can dramatically affect leaf growth and photosynthesis.

Exploration and Practice of the "One Combination, Two Highlights, Three Combinations, Four in One" Innovative Talents Training Mode in Forensic Medicine.

Talent is one of the basic and strategic supports for building a modern socialist country in all aspects. Since the 1980s, the establishment of forensic medicine major and the cultivation of innovative talents in forensic medicine have become hot topics in higher education in forensic medicine. Over the past 43 years, the forensic medicine team of Shanxi Medical University has adhered to the joint education of public security and colleges, and made collaborative innovation, forming a training mode of "One Combination, Two Highlights, Three Combinations, Four in One" for innovative talents in forensic medicine. It has carried out "5+3/X" integrated reform, and formed a relatively complete talent training innovation mode and management system in teaching, scientific research, identification, major, discipline, team, platform and cultural construction. It has made a historic contribution to China's higher forensic education, accumulated valuable experience for the construction of first-class major and first-class discipline of forensic medicine, and provided strong support for the construction of the national new forensic talent training system. The popularization of this training mode is conducive to the rapid and sustainable development of forensic science, and provides more excellent forensic talents for national building, regional social development and the discipline construction of forensic science.

The Role of IAA in Regulating Root Architecture of Sweetpotato (Ipomoea batatas [L.] Lam) in Response to Potassium Deficiency Stress.

Plants can adapt to the spatial heterogeneity of soil nutrients by changing the morphology and architecture of the root system. Here, we explored the role of auxin in the response of sweetpotato roots to potassium (K+) deficiency stress. Two sweetpotato cultivars, Xushu 32 (low-K-tolerant) and Ningzishu 1 (low-K-sensitive), were cultured in low K+ (0.1 mmol L-1, LK) and normal K+ (10 mmol L-1, CK) nutrient solutions. Compared with CK, LK reduced the dry mass, K+ content, and K+ accumulation in the two cultivars, but the losses of Xushu 32 were smaller than those of Ningzishu 1. LK also affected root growth, mainly impairing the length, surface area, forks number, and crossings number. However, Xushu 32 had significantly higher lateral root length, density, and surface area than Ningzishu 1, closely related to the roots' higher indole-3-acetic acid (IAA) content. According to the qPCR results, Xushu 32 synthesized more IAA (via IbYUC8 and IbTAR2) in leaves but transported and accumulated in roots through polar transport (via IbPIN1, IbPIN3, and IbAUX1). It was also associated with the upregulation of auxin signaling pathway genes (IbIAA4 and IbIAA8) in roots. These results imply that IAA participates in the formation of lateral roots and the change in root architecture during the tolerance to low K+ stress of sweetpotato, thus improving the absorption of K+ and the formation of biomass.

Reduction of photosynthesis under P deficiency is mainly caused by the decreased CO2 diffusional capacities in wheat (Triticum aestivum L.).

Phosphorus is one of the most important essential mineral elements for plant growth and development. It has been widely recognized that phosphorus deficiency can lead to the significant declines in leaf photosynthetic rate and leaf area. However, the internal mechanism associated with the leaf anatomical traits has not been well understood. In present study, a hydroponic experiment was conducted to study the effect of phosphorus deficiency on leaf growth and photosynthesis in Jimai 22 (JM22, Triticum aestivum L.) and Suk Landarace 26 (SL26, Triticum aestivum L.). With the decrease in phosphorus concentration, leaf photosynthetic rate and leaf area in SL26 and JM22 all decreased significantly, but the decrease in leaf area occurred earlier than that in leaf photosynthetic rate. The thresholds of phosphorus concentration to maintain a high photosynthesis were 145.5 and 138.7 mg m-2, respectively, in SL26 and JM22; and they were 197.5 and 212.0 mg m-2, respectively, for leaf growth. The decrease in leaf photosynthetic rate under low P conditions was mainly caused by the lowered stomatal conductance and mesophyll conductance, and to a less extent by the decrease in biochemical capacities. The decrease in stomatal conductance was attributed to the smaller vascular bundle area, xylem conduits area and the lower leaf hydraulic conductance. However, the reduction in mesophyll conductance was not related to either the cell wall thickness or the development of chloroplast.

Accelerating superluminal laser focus generated by a long-focal-depth mirror with high numerical aperture.

The long-focal-depth mirror is a novel reflective element proposed in recent years. Due to the advantages of negligible dependence on wavelength and high damage threshold, it is suitable to focus ultra-short laser pulses with broadband spectra and high intensity with a focal depth of centimeter scale. To the best of our knowledge, the focusing properties of this mirror has been only studied under low numerical aperture (NA). In this paper, we extend it to the case of high NA and it is proved that an accelerating superluminal laser focus can be always generated by this extension, in which the degree of acceleration increases with the increase of NA. And the velocity of laser focus increases approximately linearly from c to 1.6c for NA = 0.707. Due to its properties of tight focusing, the Richards-Wolf integrals have been used to study the intensity distribution of each polarization component for different kinds of incident light. And these are linearly polarized light, radially polarized light, azimuthally polarized light, linearly polarized light with spiral phase, and linearly polarized light with ultrashort pulses. From comparisons of numerical results, the intensity distributions are obviously different for different kind of incident light, and accelerating superluminal laser focus with special structure (such as the hollow conical beam) can be produced under appropriate condition. We believe this study can expand the fields of application for the long-focal-depth mirror.

Effects of phosphorus application on yield, quality and phosphorus use efficiency of edible sweetpotato: A case study of Xushu 32.

To explore the appropriate amount of phosphorus (P) fertilizer and improve economic yield and P use efficiency of edible sweetpotato, we took Xushu 32 as an example and compared the effects of different P application rates on yield, quality, P accumulation and P use efficiency of edible sweetpotato based on a two-year field experiment (soil available P content was 31.70 mg·kg-1) from 2018 to 2019. There were five P application levels (P2O5), including 0 (P0), 25 (P25), 50 (P50), 75 (P75) and 100 kg·hm-2(P100). The results showed that, 1) compared with P0, P application significantly increased the yield of fresh sweetpotao and commodity potato, with the effects being the stongest under P75 treatment, followed by P50 treatment. However, there was no significant difference between the two treatments. 2) P application significantly increased the contents of starch and reducing sugar in storage root. The contents of soluble sugar and protein increased significantly under P50 treatment. 3) Du-ring the growth period of 90 to 120 d, P fertilizer supply significantly increased P accumulation and dry matter accumulation of sweetpotato. 4) The apparent P use efficiency (APUE) decreased with increasing P application rates, while P agronomic efficiency (PAE) increased first and then decreased with the increases of P application rates, which was significantly higher under P50 than other treatments. Taking into account the yield, quality, economic yield and P utilization rate of edible sweetpotato, the optimal dosage of P2O5 is 50 kg·hm-2 under the experimental conditions.

Clonal Dissemination of Antifungal-Resistant Candida haemulonii, China.

Candida haemulonii, a relative of C. auris, frequently shows antifungal resistance and is transmissible. However, molecular tools for genotyping and investigating outbreaks are not yet established. We performed genome-based population analysis on 94 C. haemulonii strains, including 58 isolates from China and 36 other published strains. Phylogenetic analysis revealed that C. haemulonii can be divided into 4 clades. Clade 1 comprised strains from China and other global strains; clades 2-4 contained only isolates from China, were more recently evolved, and showed higher antifungal resistance. Four regional epidemic clusters (A, B, C, and D) were identified in China, each comprising ≥5 cases (largest intracluster pairwise single-nucleotide polymorphism differences <50 bp). Cluster A was identified in 2 hospitals located in the same city, suggesting potential intracity transmissions. Cluster D was resistant to 3 classes of antifungals. The emergence of more resistant phylogenetic clades and regional dissemination of antifungal-resistant C. haemulonii warrants further monitoring.

Potency of olorofim (F901318) compared to contemporary antifungal agents against clinical Aspergillus fumigatus isolates, and review of azole resistance phenotype and genotype epidemiology in China.

Triazole resistance in A. fumigatus is an increasing worldwide problem that causes major challenges in the management of aspergillosis. New antifungal drugs are needed with novel targets, that are effective in triazole-resistant infection. In this study, we retrospectively evaluated potency of the novel drug olorofim compared to contemporary antifungal agents against 111 clinical A. fumigatus isolates collected from Huashan Hospital, Shanghai, China, using EUCAST methodology, and reviewed the literature on triazole resistant A. fumigatus published between 1966 and 2020 in China. Olorofim was active in vitro against all tested A. fumigatus isolates with MIC90 of 0.031mg/L (range 0.008-0.062 mg/L). For 4 triazole-resistant A. fumigatus (TRAF) isolates, the olorofim MIC ranged between 0.016-0.062mg/L. The reported rates of TRAF in China is 2.5% - 5.56% for clinical isolates, and 0-1.4% for environmental isolates.TR34/L98H/S297T/F495I is the predominant resistance mechanism, followed by TR34/L98H. Non TR-mediated TRAF isolates, mostly harboring a cyp51A single point mutation, showed greater genetic diversity than TR-mediated resistant isolates. Resistance due toTR34/L98H and TR34/L98H/S297T/F495I mutations among TRAF isolates might have evolved from separate local isolates in China. Continuous isolation of TRAF in China underscores the need for systematic resistance surveillance as well as the need for novel drug targets such as olorofim.

miR­222-3p reduces neuronal cell apoptosis and alleviates spinal cord injury by inhibiting Bbc3 and Bim.

Spinal cord injury (SCI) is a severe traumatic event, but without any established effective treatment because of the irreversible neuronal death. Here, we investigated the role of miR-222-3p in neuronal apoptosis following SCI. Rat SCI models and neuron hypoxia models were accordingly established. The Bbc3, Bim, Bcl-2, Bax, cleaved-caspase 3, cleaved-caspase 9, Cytochrome c, and miR-222-3p expression levels were examined by Western blotting and real-time reverse transcription polymerase chain reaction (RT-qPCR). The possible association between miR-222-3p and Bbc3/Bim was analyzed by dual-luciferase assay. The neuron viability was assessed by Cell Counting Kit-8 assay and Nissl's staining. Live cell staining was performed to detect the mitochondrial membrane potential and neuronal apoptosis. Rat locomotor function was assessed using the Basso-Beattie-Bresnahan scores. Cytochrome c was outflowed from the mitochondria after SCI or hypoxia treatment, and Bbc3, Bim, Bax, cleaved-caspase 9, and cleaved-caspase 3 were significantly upregulated, while Bcl-2 and miR-222-3p were decreased remarkably. Meanwhile, neuronal cell viability was significantly inhibited. Treatment of miR-222-3p significantly suppressed the Cytochrome c efflux and neuronal apoptosis and improved neuronal cell viability and motor function in SCI rats. Moreover, we found that Bbc3 and Bim were the direct targets of miR-222-3p. Overall, our data suggest that miR-222-3p could alleviate the mitochondrial pathway-mediated apoptosis and motor dysfunction in rats after SCI by targeting Bbc3 and Bim.