Near-Infrared Light-Excited Quinolinium-Carbazole Small Molecule as Two-Photon Fluorescence Nucleic Acid Probe.

This article reports three new two-photon absorption (TPA) materials that are quinolinium-carbazole derivates. They are 3-(N-methyl-4-ethylquinolinium iodide)-9-ethylcarbazole (M4), 3-(N-methyl-4-ethylquinolinium iodide)-9-ethylcarbazole (H2), and 3-(N-methyl-4-ethylquinolinium iodide)-9-ethylcarbazole (H4). Their TPA cross-sections are 491, 515, and 512 GM, respectively. Under the excitation of near-infrared light, their fluorescence emission is about 650 nm. The compounds can stain nucleic acid DNA with the same level of nuclear localization as Hoechst 33342. Under continuous irradiation with a near-infrared laser, the three new compounds showed less fluorescence decay than DAPI, and the average fluorescence decay rates were 0.016%/s, 0.020%/s, and 0.023%/s. They are expected to become new two-photon fluorescent probes of nucleic acid DNA because of their excellent performance.

Case report and literature review: plexiform schwannoma in the penile and inguinal region in a child.

Penile schwannoma is an uncommonly seen peripheral nerve tumor, of which penile plexiform schwannomas (PS) is extremely rare that has only been reported in several adults. We present a case of penile PS with a similar lesion in inguinal region in a 9-year-old child, which appeared as painless masses and rapidly growing within one year. Penile ultrasonography suggested well-defined lesions with limited vascularity. Both masses presented with low-to-intermediated signal intensity and no definite enhancement in computed tomography. The lesions were completely resected with minimal intraoperative bleeding, and a diagnose of benign PS was confirmed based on H&E staining and positive S-100 expression in immunohistochemistry. There was no evidence of tumor recurrence or metastasis after 6 months of follow-up. Only 6 cases of penile schwannoma in children were recorded, of which 5 were malignant, and none was PS. The malignancy rate of penile schwannoma in children may be overestimated due to delayed diagnose of benign ones. A rapidly growing penile mass with a suspected metastatic lesion in inguinal region could be easily misdiagnosed as malignant. This case report and literature review is expected to assist clinicians in getting a comprehensive understanding of children penile schwannomas and choosing the best management strategy when faced with this rare condition.

Transcriptomic Signatures of Neuronally Derived Extracellular Vesicles Reveal the Presence of Olfactory Receptors in Clinical Samples from Traumatic Brain Injury Patients.

Traumatic brain injury (TBI) is defined as an injury to the brain by external forces which can lead to cellular damage and the disruption of normal central nervous system functions. The recently approved blood-based biomarkers GFAP and UCH-L1 can only detect injuries which are detectable on CT, and are not sensitive enough to diagnose milder injuries or concussion. Exosomes are small microvesicles which are released from the cell as a part of extracellular communication in normal as well as diseased states. The objective of this study was to identify the messenger RNA content of the exosomes released by injured neurons to identify new potential blood-based biomarkers for TBI. Human severe traumatic brain injury samples were used for this study. RNA was isolated from neuronal exosomes and total transcriptomic sequencing was performed. RNA sequencing data from neuronal exosomes isolated from serum showed mRNA transcripts of several neuronal genes. In particular, mRNAs of several olfactory receptor genes were present at elevated concentrations in the neuronal exosomes. Some of these genes were OR10A6, OR14A2, OR6F1, OR1B1, and OR1L1. RNA sequencing data from exosomes isolated from CSF showed a similar elevation of these olfactory receptors. We further validated the expression of these samples in serum samples of mild TBI patients, and a similar up-regulation of these olfactory receptors was observed. The data from these experiments suggest that damage to the neurons in the olfactory neuroepithelium as well as in the brain following a TBI may cause the release of mRNA from these receptors in the exosomes. Hence, olfactory receptors can be further explored as biomarkers for the diagnosis of TBI.

Halofantrine Hydrochloride Acts as an Antioxidant Ability Inhibitor That Enhances Oxidative Stress Damage to Candida albicans.

Candida albicans, a prominent opportunistic pathogenic fungus in the human population, possesses the capacity to induce life-threatening invasive candidiasis in individuals with compromised immune systems despite the existence of antifungal medications. When faced with macrophages or neutrophils, C. albicans demonstrates its capability to endure oxidative stress through the utilization of antioxidant enzymes. Therefore, the enhancement of oxidative stress in innate immune cells against C. albicans presents a promising therapeutic approach for the treatment of invasive candidiasis. In this study, we conducted a comprehensive analysis of a library of drugs approved by the Food and Drug Administration (FDA). We discovered that halofantrine hydrochloride (HAL) can augment the antifungal properties of oxidative damage agents (plumbagin, menadione, and H2O2) by suppressing the response of C. albicans to reactive oxygen species (ROS). Furthermore, our investigation revealed that the inhibitory mechanism of HAL on the oxidative response is dependent on Cap1. In addition, the antifungal activity of HAL has been observed in the Galleria mellonella infection model. These findings provide evidence that targeting the oxidative stress response of C. albicans and augmenting the fungicidal capacity of oxidative damage agents hold promise as effective antifungal strategies.

Platelet-derived growth factor receptor ß-targeted positron emission tomography imaging for the noninvasive monitoring of liver fibrosis.

PURPOSE: Noninvasive quantifying activated hepatic stellate cells (aHSCs) by molecular imaging is helpful for assessing disease progression and therapeutic responses of liver fibrosis. Our purpose is to develop platelet-derived growth factor receptor ß (PDGFRß)-targeted radioactive tracer for assessing liver fibrosis by positron emission tomography (PET) imaging of aHSCs. METHODS: Comparative transcriptomics, immunofluorescence staining and flow cytometry were used to evaluate PDGFRß as biomarker for human aHSCs and determine the correlation of PDGFRß with the severity of liver fibrosis. The high affinity affibody for PDGFRß (ZPDGFRß) was labeled with gallium-68 (68Ga) for PET imaging of mice with carbon tetrachloride (CCl4)-induced liver fibrosis. Binding of the [68Ga]Ga-labeled ZPDGFRß ([68Ga]Ga-DOTA-ZPDGFRß) for aHSCs in human liver tissues was measured by autoradiography. RESULTS: PDGFRß overexpressed in aHSCs was highly correlated with the severity of liver fibrosis in patients and CCl4-treated mice. The 68Ga-labeled ZPDGFRß affibody ([68Ga]Ga-DOTA-ZPDGFRß) showed PDGFRß-dependent binding to aHSCs. According to the PET imaging, hepatic uptake of [68Ga]Ga-DOTA-ZPDGFRß increased with the accumulation of aHSCs and collagens in the fibrotic livers of mice. In contrast, hepatic uptake of [68Ga]Ga-DOTA-ZPDGFRß decreased with spontaneous recovery or treatment of liver fibrosis, indicating that the progression and therapeutic responses of liver fibrosis in mice could be visualized by PDGFRß-targeted PET imaging. [68Ga]Ga-DOTA-ZPDGFRß also bound human aHSCs and visualized fibrosis in patient-derived liver tissues. CONCLUSIONS: PDGFRß is a reliable biomarker for both human and mouse aHSCs. PDGFRß-targeted PET imaging could be used for noninvasive monitoring of liver fibrosis in mice and has great potential for clinical translation.

Anus preservation in low rectal adenocarcinoma based on MMR/MSI status (APRAM): a study protocol for a randomised, controlled, open-label, multicentre phase III trial.

BACKGROUND: Anus preservation has been a challenge in the treatment of patients with low rectal adenocarcinoma (within 5 cm from the anal verge) because it is difficult to spare the anus with its functioning sphincter complex under the safe margin of tumour resection. Patients with dMMR/MSI-H can achieve a favourable complete response (CR) rate by using a single immune checkpoint inhibitor. For patients with pMMR/MSS/MSI-L, intensified neoadjuvant three-drug chemotherapy may be the preferred option for anal preservation. In addition, the watch and wait (W&W) strategy has been proven safe and feasible for patients with rectal cancer who achieve a clinical complete response (cCR). Therefore, we initiated this clinical trial to explore the optimal neoadjuvant treatment pattern for patients with low locally advanced rectal cancer (LARC) with different MMR/MSI statuses, aiming to achieve a higher cCR rate with the W&W strategy and ultimately provide more patients with a chance of anus preservation. METHODS: This is a randomised, controlled, open-label, multicentre phase III trial. Patients with clinical stage T2-4 and/or N + tumours located within 5 cm from the anal verge are considered eligible. Based on the results of pathological biopsy, the patients are divided into two groups: dMMR/MSI-H and pMMR/MSS. Patients in the dMMR/MSI-H group will be randomly allocated in a 1:1 ratio to either arm A (monoimmunotherapy) or arm B (short-course radiotherapy followed by monoimmunotherapy). Patients in the pMMR/MSS group will be initially treated with long-term pelvic radiation with concurrent capecitabine combined with irinotecan. Two weeks after the completion of chemoradiotherapy (CRT), the patients will be randomly allocated in a 1:1 ratio to arm C (XELIRI six cycle regime) or arm D (FOLFIRINOX nine cycle regime). The irinotecan dose will be adjusted according to the UGT1A1-genotype. After treatment, a comprehensive assessment will be performed to determine whether a cCR has been achieved. If achieved, the W&W strategy will be adopted; otherwise, total mesorectal excision (TME) will be performed. The primary endpoint is cCR with the maintenance of 12 months at least, determined using digital rectal examination, endoscopy, and rectal MRI or PET/CT as a supplementary method. DISCUSSION: APRAM will explore the best anus preservation model for low LARC, combining the strategies of consolidation chemotherapy, immunotherapy, and short-course radiotherapy, and aims to preserve the anus of more patients using W&W. Our study provides an accurate individual treatment mode based on the MMR/MSI status for patients with low LARC, and more patients will receive the opportunity for anus preservation under our therapeutic strategy, which would transform into long-term benefits. TRIAL REGISTRATION: Clinicaltrials.gov NCT05669092 (Registered 28th Nov 2022).

Alteration of carbon and nitrogen allocation in winter wheat under elevated ozone.

Tropospheric ozone accelerates senescence and shortens grain filling, consequently affecting the remobilization and allocation efficiency of aboveground biomass and nutrients into grains in cereal crops. This study investigated carbon (C) and nitrogen (N) concentrations repeatedly in shoot biomass during the growth period and in grain after the harvest in eighteen wheat genotypes under control and ozone treatments in open-top chambers. Season-long ozone fumigation was conducted at an average ozone concentration of 70 ppb with three additional acute ozone episodes of around 150 ppb. Although there were no significant differences in straw C and N concentrations between the two treatments, the straw C:N ratio was significantly increased after long-term ozone fumigation, and the grain C:N ratio decreased under elevated ozone without significance. Grain N concentrations increased significantly under ozone stress, whereas N yield declined significantly due to grain yield losses induced by ozone. Moreover, different indicators of N use efficiency were significantly reduced with the exception of N utilization efficiency (NUtE), indicating that elevated ozone exposure reduced the N absorption from soil and allocation from vegetative to reproductive organs. The linear regression between straw C:N ratio and productivity indicated that straw C:N was not a suitable trait for predicting wheat productivity due to the low coefficient of determination (R2). Nitrogen harvest index (NHI) was not significantly affected by ozone stress among all genotypes. However, elevated ozone concentration changed the relationship between harvest index (HI) and NHI, and the reduced regression slope between them indicated that ozone exposure significantly affected the relationship of N and biomass allocation into wheat grains. The cultivar "Jenga" showed optimal ozone tolerance due to less yield reduction and higher NUE after ozone exposure. The genotypes with higher nutrient use efficiencies are promising to cope with ozone-induced changes in nitrogen partitioning.

A pyroptosis-related signature in colorectal cancer: exploring its prognostic value and immunological characteristics.

Background: The heterogeneity of colorectal cancer (CRC) is the main cause of the disparity of drug sensitivity and the variability of prognosis. Pyroptosis is closely associated with the development and prognosis of various tumors, including CRC. Dividing CRC into distinct subgroups based on pyroptosis is a worthwhile topic for improving the precision treatment and prognosis prediction of CRC. Methods: We classified patients into two clusters using the consensus clustering based on the pyroptosis-related genes (PRGs). Next, the prognostic signature was developed with LASSO regression analysis using the screened genes from differentially expressed genes (DEGs) by univariate and multivariate Cox analyses. According to the pyroptosis-related score (PR score) calculated with the signature, patients belonged to two groups with distinct prognosis. Moreover, we assessed the immune profile to explore the relationship between the signature and immunological characteristics. Two single cell sequencing databases were adopted for further exploration of tumor immune microenvironment (TME). In addition, we applied our own cohort and Drugbank to explore the correlation of the signature and clinical therapies. We also studied the expression of key genes by immunohistochemistry. Results: The signature performed well in predicting the prognosis of CRC as the high area under curve (AUC) value demonstrated. Patients with a higher PR score had poorer prognosis and higher expression of immune checkpoints but more abundant infiltration of immune cells. Combining with the indicator of therapeutic analysis, they might benefit more from immune checkpoint blockade (ICB) and neo-adjuvant chemoradiotherapy (nCRT). Conclusion: In conclusion, our study is based on genomics and transcriptomics to investigate the role of PRGs in CRC. We have established a prognostic signature and integrated single-cell data to study the relationship between the signature with the TME in CRC. Its clinical application in reliable prediction of prognosis and personalized treatment was validated by public and own sequencing cohort. It provided a new insight for the personalized treatment of CRC.

Unexpected Inhibitory Effect of Octenidine Dihydrochloride on Candida albicans Filamentation by Impairing Ergosterol Biosynthesis and Disrupting Cell Membrane Integrity.

Candida albicans filamentation plays a significant role in developing both mucosal and invasive candidiasis, making it a crucial virulence factor. Consequently, exploring and identifying inhibitors that impede fungal hyphal formation presents an intriguing approach toward antifungal strategies. In line with this anti-filamentation strategy, we conducted a comprehensive screening of a library of FDA-approved drugs to identify compounds that possess inhibitory properties against hyphal growth. The compound octenidine dihydrochloride (OCT) exhibits potent inhibition of hyphal growth in C. albicans across different hyphae-inducing media at concentrations below or equal to 3.125 µM. This remarkable inhibitory effect extends to biofilm formation and the disruption of mature biofilm. The mechanism underlying OCT's inhibition of hyphal growth is likely attributed to its capacity to impede ergosterol biosynthesis and induce the generation of reactive oxygen species (ROS), compromising the integrity of the cell membrane. Furthermore, it has been observed that OCT demonstrates protective attributes against invasive candidiasis in Galleria mellonella larvae through its proficient eradication of C. albicans colonization in infected G. mellonella larvae by impeding hyphal formation. Although additional investigation is required to mitigate the toxicity of OCT in mammals, it possesses considerable promise as a potent filamentation inhibitor against invasive candidiasis.

Understanding fluconazole tolerance in Candida albicans: implications for effective treatment of candidiasis and combating invasive fungal infections.

OBJECTIVES: Fluconazole (FLC) tolerant phenotypes in Candida species contribute to persistent candidemia and the emergence of FLC resistance. Therefore, making FLC fungicidal and eliminating FLC tolerance are important for treating invasive fungal diseases (IFDs) caused by Candida species. However, the mechanisms of FLC tolerance in Candida species remain to be fully explored. METHODS: This review discusses the high incidence of FLC tolerance in Candida species and the importance of successfully clearing FLC tolerance in treating candidiasis. We further define and characterize FLC tolerance in C. albicans. RESULTS: This review identifies global factors affecting FLC tolerance and suggest that FLC tolerance is a strategy of C. albicans response to FLC damage whose mechanism differs from FLC resistance. CONCLUSIONS: This review highlights the significance of the cell membrane and cell wall integrity in FLC tolerance, guiding approaches to combat IFDs caused by Candida species..

Attention mechanism based multi-sequence MRI fusion improves prediction of response to neoadjuvant chemoradiotherapy in locally advanced rectal cancer.

BACKGROUND: Accurate prediction of response to neoadjuvant chemoradiotherapy (nCRT) is very important for treatment plan decision in locally advanced rectal cancer (LARC). The aim of this study was to investigate whether self-attention mechanism based multi-sequence fusion strategy applied to multiparametric magnetic resonance imaging (MRI) based deep learning or hand-crafted radiomics model construction can improve prediction of response to nCRT in LARC. METHODS: This retrospective analysis enrolled 422 consecutive patients with LARC who received nCRT before surgery at two hospitals. All patients underwent multiparametric MRI scans with three imaging sequences. Tumor regression grade (TRG) was used to assess the response of nCRT based on the resected specimen. Patients were separated into 2 groups: poor responders (TRG 2, 3) versus good responders (TRG 0, 1). A self-attention mechanism, namely channel attention, was applied to fuse the three sequence information for deep learning and radiomics models construction. For comparison, other two models without channel attention were also constructed. All models were developed in the same hospital and validated in the other hospital. RESULTS: The deep learning model with channel attention mechanism achieved area under the curves (AUCs) of 0.898 in the internal validation cohort and 0.873 in the external validation cohort, which was the best performed model in all cohorts. More importantly, both the deep learning and radiomics model that applied channel attention mechanism performed better than those without channel attention mechanism. CONCLUSIONS: The self-attention mechanism based multi-sequence fusion strategy can improve prediction of response to nCRT in LARC.

Adapting crop production to climate change and air pollution at different scales.

Air pollution and climate change are tightly interconnected and jointly affect field crop production and agroecosystem health. Although our understanding of the individual and combined impacts of air pollution and climate change factors is improving, the adaptation of crop production to concurrent air pollution and climate change remains challenging to resolve. Here we evaluate recent advances in the adaptation of crop production to climate change and air pollution at the plant, field and ecosystem scales. The main approaches at the plant level include the integration of genetic variation, molecular breeding and phenotyping. Field-level techniques include optimizing cultivation practices, promoting mixed cropping and diversification, and applying technologies such as antiozonants, nanotechnology and robot-assisted farming. Plant- and field-level techniques would be further facilitated by enhancing soil resilience, incorporating precision agriculture and modifying the hydrology and microclimate of agricultural landscapes at the ecosystem level. Strategies and opportunities for crop production under climate change and air pollution are discussed.

Effect of Noise and Music on Neurotransmitters in the Amygdala: The Role Auditory Stimuli Play in Emotion Regulation.

Stress caused by noise is becoming widespread globally. Noise may lead to deafness, endocrine disorders, neurological diseases, and a decline in mental health. The mechanism behind noise-induced neurodevelopmental abnormalities is unclear, but apoptosis and pro-inflammatory signals may play an important role. In this study, weaned piglets were used as a model to explore noise-induced neurodevelopmental abnormalities. We hypothesized that long-term noise exposure would induce anxiety and cause acute stress, exhibited by alterations in neurotransmission in the amygdala. A total of 72 hybrid piglets (Large White × Duroc × Min Pig) were randomly divided into three groups, including noise (exposed to mechanical noise, 80-85 dB), control (blank, exposed to natural background sound, <40 dB), and music (positive control, exposed to Mozart K.448, 60-70 dB) groups. The piglets were exposed to 6 h of auditory noise daily (10:00-16:00) for 28 days. Compared with the control group, piglets exposed to noise showed more aggressive behavior. The expression of Caspase3, Caspase9, Bax, NF-κB (p56), TLR4, MYD88, I κ B α, IL-1 ß, TNF-α, and IL-12RB2 was significantly upregulated in the amygdala, while the expression of Nrf2, HO-1, CAT, and SOD was downregulated in piglets in the noise group. Cell death occurred, and numerous inflammatory cells accumulated in the amygdala of piglets in the noise group. Targeted metabolomics showed that the content of inhibitory neurotransmitter GABA was higher in the amygdala of piglets in the noise group. Compared with the noise group, piglets in the music group displayed more positive emotion-related behaviors. Compared with the noise group, the expression of genes related to apoptosis, inflammation, and oxidative damage was lower in the music group. Cells of the amygdala in the music group were also of normal morphology. Our results show that noise-induced stress causes apoptosis and neuroinflammation in the amygdala and induces anxiety during the early neonatal neural development of piglets. In contrast, to some extent, music alleviates noise-induced anxiety.

Genetic polymorphisms in genes regulating cell death and prognosis of patients with rectal cancer receiving postoperative chemoradiotherapy.

OBJECTIVE: The identification of biomarkers for predicting chemoradiotherapy efficacy is essential to optimize personalized treatment. This study determined the effects of genetic variations in genes involved in apoptosis, pyroptosis, and ferroptosis on the prognosis of patients with locally advanced rectal cancer receiving postoperative chemoradiotherapy (CRT). METHODS: The Sequenom MassARRAY was used to detect 217 genetic variations in 40 genes from 300 patients with rectal cancer who received postoperative CRT. The associations between genetic variations and overall survival (OS) were evaluated using hazard ratios (HRs) and 95% confidence intervals (CIs) computed using a Cox proportional regression model. Functional experiments were performed to determine the functions of the arachidonate 5-lipoxygenase (ALOX5) gene and the ALOX5 rs702365 variant. RESULTS: We detected 16 genetic polymorphisms in CASP3, CASP7, TRAILR2, GSDME, CASP4, HO-1, ALOX5, GPX4, and NRF2 that were significantly associated with OS in the additive model (P < 0.05). There was a substantial cumulative effect of three genetic polymorphisms (CASP4 rs571407, ALOX5 rs2242332, and HO-1 rs17883419) on OS. Genetic variations in the CASP4 and ALOX5 gene haplotypes were associated with a higher OS. We demonstrated, for the first time, that rs702365 [G] > [C] represses ALOX5 transcription and corollary experiments suggested that ALOX5 may promote colon cancer cell growth by mediating an inflammatory response. CONCLUSIONS: Polymorphisms in genes regulating cell death may play essential roles in the prognosis of patients with rectal cancer who are treated with postoperative CRT and may serve as potential genetic biomarkers for individualized treatment.

Molecular superglue-mediated higher-order assembly of TRAIL variants with superior apoptosis induction and antitumor activity.

Prompting higher-order death receptor (DR) clustering by increasing the valency of DR agonist is efficient to induce apoptosis of tumor cells. As an attractive DR agonist with superior biosafety, the trimeric tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) exerts limited antitumor effect in patients, which is predominantly attributed to its low DR clustering ability and short serum half-life. Previous antibody scaffolds-based engineering strategies to increase the valency and/or prolong the serum half-life of TRAIL improve apoptosis induction, however, often produce large proteins with poor tumor penetration. Covalent protein ligation mediated by small molecular superglues such as SpyTag/SpyCatcher might be a novel strategy to assemble higher-order TRAIL variants. Upon fusion to TRAIL promotor, SpyTag/SpyCatcher molecular superglue preferentially ligated two trimeric TRAIL to produce a hexameric TRAIL variant, HexaTR, exhibiting a significantly increased apoptosis induction. In addition, an albumin-binding HexaTR, ABD-HexaTR, with a prolonged serum half-life by binding to endogenous albumin was also produced using the same strategy. Compared to the trimeric TRAIL, the hexameric HexaTR and ABD-HexaTR showed 20-50 times greater in vivo antitumor effect, resulting in eradication of several types of large (150-300 mm3) tumor xenografts. Combination with bortezomib carried by liposome further improved the antitumor effects of the hexavalent HexaTR and ABD-HexaTR in refractory cancer. Our results indicate that the superglue-mediated higher-order assembly is promising to improve the DR clustering and proapoptotic signaling of TRAIL, showing great advantages in constructing the next generation of DR agonists for cancer therapy.

Bargaining power of new-energy enterprises in China's credit-financing market.

The new-energy industry, which is a key area for coping with climate change, faces serious credit-financing difficulties. This study used a bilateral stochastic frontier model to measure the bargaining power of new-energy companies in China's credit-financing market. We then examined the main factors affecting the bargaining power of new-energy enterprises by comparing the results of the firms in different groups, including corporate-related factors, government policies, and financial development levels. The results showed that the bargaining power of both banks and enterprises had an important influence on the final financing price. In the bargaining process, new-energy companies were at a disadvantage, and financing prices were 17.2% higher than fair prices. The nature of state-owned enterprises hinders the improvement of the bargaining power of new-energy enterprises. Technology competence and relationships with banks are useful ways for new-energy enterprises to improve their bargaining power. In solving the financing difficulties in the credit market of new-energy enterprises, government subsidies are usually ineffective, while improving the financial development level is effective.

P-induced bottom-up growth of Fe-doped Ni12P5 nanorod arrays for urea oxidation reaction.

Synthesis of regular morphology catalysts with self-growing substrates is one of the effective methods to solve the problem of easy shedding of heterogeneous catalysts. In this study, Fe-doped Ni12P5 nanorods were prepared by depositing 1,1' -bis (diphenylphosphine) ferrocene (DPPF) on N-doped C/NF. The bottom-up growth of the nanorod is ascribed to the preferential adsorption of DPPF with a P site to NF that is surface-doped with the solid-solving C, and the length of nanorods can reach tens of microns and has good robustness. The N-doped carbon-constrained rod-shaped Fe-doped Ni12P5 catalyst (Fe-Ni12P5/NdC/NF-800) that grows on NF has excellent catalytic performance for the urea oxidation reaction. In addition, the current density can be maintained as high as 100 mA cm-2 and the current attenuation is weak for 12 h, and the rod shape remains good. This work provides a new idea for synthesizing self-growing catalysts with regular morphology to improve the performance of heterogeneous catalysts.

A Small Molecule Inhibitor of Erg251 Makes Fluconazole Fungicidal by Inhibiting the Synthesis of the 14α-Methylsterols.

Fluconazole (FLC) is widely used to prevent and treat invasive fungal infections. However, FLC is a fungistatic agent, allowing clinical FLC-susceptible isolates to tolerate FLC. Making FLC fungicidal in combination with adjuvants is a promising strategy to avoid FLC resistance and eliminate the persistence and recurrence of fungal infections. Here, we identify a new small molecule compound, CZ66, that can make FLC fungicidal. The mechanism of action of CZ66 is targeting the C-4 sterol methyl oxidase, encoded by the ERG251 gene, resulting in decreased content of sterols with the 14α-methyl group and ultimately eliminating FLC tolerance of Candida albicans. CZ66 most likely interacts with Erg251 through residues Glu195, Gly206, and Arg241. Establishing Erg251 as a synergistic lethal target protein of FLC should direct research to identify specific small molecule inhibitors of 14α-methylsterol synthesis and open the way to abolishing fungal FLC tolerance. IMPORTANCE Fluconazole (FLC) tolerance increases the frequency of acquired FLC resistance, and a high FLC tolerance level is associated with persistent candidemia. Multiple functional proteins, such as calcineurin, heat shock protein 90 (Hsp90), and ADP ribosylation factor, are essential for the survival of C. albicans exposed to FLC, but how these factors increase the fungicidal activity of FLC remains to be determined. In this study, we found that 14α-methylsterols replace ergosterol to allow C. albicans to survive FLC, but Erg251 inactivated by CZ66 results in loss of 14α-methylsterol synthesis and cell death of C. albicans treated with FLC. Establishing Erg251 as a synergistic lethal target protein of FLC should direct research to identify specific small molecule inhibitors of 14α-methylsterol synthesis and open the way to abolishing fungal FLC tolerance.

P-Induced Permeation of Nickel into WO3 Octahedra to Form a Synergistic Catalyst for Urea Oxidation.

Small-molecule induction can lead to the oriented migration of metal elements, which affords functional materials with synergistic components. In this study, phosphating nickel foam (NF)-supported octahedral WO3 with phosphine affords P-WO3 /NF electrocatalyst. Ni is found to form Ni-P bonds that migrate from NF to WO3 under the induction of P, resulting in the complex oxides W1.3 Ni0.24 O4 and Ni2 P2 O7 in the particle interior and nickel phosphide on the octahedral grain surface. The catalytic activity of P-WO3 /NF in the urea oxidation reaction (UOR) is improved by synergistic action of the components in the synthesized hybrid particles. A current density of 10 mA cm-2 can be reached at a potential of 1.305 V, the double layer capacitance of the catalyst is significantly increased, and the electron transfer impedance in catalytic UOR is reduced. This work demonstrates that small-molecule induction is suitable for constructing co-catalysts with complex components in a simple protocol, which provides a new route for the design of highly efficient urea oxidation electrocatalysts.

A trimeric immunoglobin G-binding domain outperforms recombinant protein G and protein L as a ligand for fragment antigen-binding purification.

Fragment antigen-binding (Fab) has several advantages in the treatment and diagnosis of some diseases. The lack of highly efficient affinity chromatography platform creates a purification bottleneck for the downstream processing of Fab-based products, which raises the urgent need for a novel immunoglobin G (IgG)-binding domain (IgBD) with both high affinity and broad specificity for Fab. SpGC3FabRR (designated CFab) was previously identified as a Fab-selective IgBD, which triggered our interest in evaluating the potential of CFab for Fab purification. However, we found that monomeric CFab showed weak Fab-binding. To increase its affinity, a self-trimerizing domain (tri) was fused to CFab to produce CFab-tri. It was found that CFab-tri existed as a trimer and showed promising binding to Fab derived from IgG of humans, rhesus monkeys, mice, rats, and rabbits. Affinity chromatography demonstrated that the recovery rates of Fab derived from IgG of humans, rats, mice, and rabbits by CFab-tri-HP column were 2- to 5-fold of those by protein G-HP column. Human Fab was effectively purified by both protein L- and CFab-tri-HP column. However, unlike CFab-tri-HP column, protein L-HP column was inefficient for purification of Fab derived from IgG of rats, mice, and rabbits. Notably, rat Fab spiked into the extract of Escherichia coli (E. coli) was effectively recovered by CFab-tri-HP column. These results indicate that CFab-tri outperforms protein G and protein L as a ligand for Fab purification, and CFab-tri-based affinity chromatography might be developed as a novel platform for Fab purification.