Blap-6, a Novel Antifungal Peptide from the Chinese Medicinal Beetle Blaps rhynchopetera against Cryptococcus neoformans.

Cryptococcus neoformans (C. neoformans) is a pathogenic fungus that can cause life-threatening meningitis, particularly in individuals with compromised immune systems. The current standard treatment involves the combination of amphotericin B and azole drugs, but this regimen often leads to inevitable toxicity in patients. Therefore, there is an urgent need to develop new antifungal drugs with improved safety profiles. We screened antimicrobial peptides from the hemolymph transcriptome of Blaps rhynchopetera (B. rhynchopetera), a folk Chinese medicine. We found an antimicrobial peptide named blap-6 that exhibited potent activity against bacteria and fungi. Blap-6 is composed of 17 amino acids (KRCRFRIYRWGFPRRRF), and it has excellent antifungal activity against C. neoformans, with a minimum inhibitory concentration (MIC) of 0.81 µM. Blap-6 exhibits strong antifungal kinetic characteristics. Mechanistic studies revealed that blap-6 exerts its antifungal activity by penetrating and disrupting the integrity of the fungal cell membrane. In addition to its direct antifungal effect, blap-6 showed strong biofilm inhibition and scavenging activity. Notably, the peptide exhibited low hemolytic and cytotoxicity to human cells and may be a potential candidate antimicrobial drug for fungal infection caused by C. neoformans.

Regulating Tumor-Associated Macrophage Polarization by Cyclodextrin-Modified PLGA Nanoparticles Loaded with R848 for Treating Colon Cancer.

Purpose: This study aimed to develop a novel and feasible modification strategy to improve the solubility and antitumor activity of resiquimod (R848) by utilizing the supramolecular effect of 2-hydroxypropyl-beta-cyclodextrin (2-HP-ß-CD). Methods: R848-loaded PLGA nanoparticles modified with 2-HP-ß-CD (CD@R848@NPs) were synthesized using an enhanced emulsification solvent-evaporation technique. The nanoparticles were then characterized in vitro by several methods, such as scanning electron microscopy (SEM), differential scanning calorimetry (DSC), Fourier transform infrared (FTIR) spectroscopy, particle size analysis, and zeta potential analysis. Then, the nanoparticles were loaded with IR-780 dye and imaged using an in vivo imaging device to evaluate their biodistribution. Additionally, the antitumor efficacy and underlying mechanism of CD@R848@NPs in combination with an anti-TNFR2 antibody were investigated using an MC-38 colon adenocarcinoma model in vivo. Results: The average size of the CD@R848@NPs was 376 ± 30 nm, and the surface charge was 21 ± 1 mV. Through this design, the targeting ability of 2-HP-ß-CD can be leveraged and R848 is delivered to tumor-supporting M2-like macrophages in an efficient and specific manner. Moreover, we used an anti-TNFR2 antibody to reduce the proportion of Tregs. Compared with plain PLGA nanoparticles or R848, CD@R848@NPs increased penetration in tumor tissues, dramatically reprogrammed M1-like macrophages, removed tumors and prolonged patient survival. Conclusion: The new nanocapsule system is a promising strategy for targeting tumor, reprogramming tumor -associated macrophages, and enhancement immunotherapy.

Identification and Characterization of RK22, a Novel Antimicrobial Peptide from Hirudinaria manillensis against Methicillin Resistant Staphylococcus aureus.

Staphylococcus aureus (S. aureus) infections are a leading cause of morbidity and mortality, which are compounded by drug resistance. By manipulating the coagulation system, S. aureus gains a significant advantage over host defense mechanisms, with hypercoagulation induced by S. aureus potentially aggravating infectious diseases. Recently, we and other researchers identified that a higher level of LL-37, one endogenous antimicrobial peptide with a significant killing effect on S. aureus infection, resulted in thrombosis formation through the induction of platelet activation and potentiation of the coagulation factor enzymatic activity. In the current study, we identified a novel antimicrobial peptide (RK22) from the salivary gland transcriptome of Hirudinaria manillensis (H. manillensis) through bioinformatic analysis, and then synthesized it, which exhibited good antimicrobial activity against S. aureus, including a clinically resistant strain with a minimal inhibitory concentration (MIC) of 6.25 µg/mL. The RK22 peptide rapidly killed S. aureus by inhibiting biofilm formation and promoting biofilm eradication, with good plasma stability, negligible cytotoxicity, minimal hemolytic activity, and no significant promotion of the coagulation system. Notably, administration of RK22 significantly inhibited S. aureus infection and the clinically resistant strain in vivo. Thus, these findings highlight the potential of RK22 as an ideal treatment candidate against S. aureus infection.

Blapstin, a Diapause-Specific Peptide-Like Peptide from the Chinese Medicinal Beetle Blaps rhynchopetera, Has Antifungal Function.

Drug resistance against bacteria and fungi has become common in recent years, and it is urgent to discover novel antimicrobial peptides to manage this problem. Many antimicrobial peptides from insects have been reported to have antifungal activity and are candidate molecules in the treatment of human diseases. In the present study, we characterized an antifungal peptide named blapstin that was isolated from the Chinese medicinal beetle Blaps rhynchopetera used in folk medicine. The complete coding sequence was cloned from the cDNA library prepared from the midgut of B. rhynchopetera. It is a 41-amino-acid diapause-specific peptide (DSP)-like peptide stabilized by three disulfide bridges and shows antifungal activity against Candida albicans and Trichophyton rubrum with MICs of 7 µM and 5.3 µM, respectively. The C. albicans and T. rubrum treated with blapstin showed irregular and shrunken cell membranes. In addition, blapstin inhibited the activity of C. albicans biofilm and showed little hemolytic or toxic activity on human cells and it is highly expressed in the fat body, followed by the hemolymph, midgut, muscle, and defensive glands. These results indicate that blapstin may help insects fight against fungi and showed a potential application in the development of antifungal reagents. IMPORTANCE Candida albicans is one of the conditional pathogenic fungi causing severe nosocomial infections. Trichophyton rubrum and other skin fungi are the main pathogens of superficial cutaneous fungal diseases, especially in children and the elderly. At present, antibiotics such as amphotericin B, ketoconazole, and fluconazole are the main drugs for the clinical treatment of C. albicans and T. rubrum infections. However, these drugs have certain acute toxicity. Long-term use can increase kidney damage and other side effects. Therefore, obtaining broad-spectrum antifungal drugs with high efficiency and low toxicity for the treatment of C. albicans and T. rubrum infections is a top priority. Blapstin is an antifungal peptide which shows activity against C. albicans and T. rubrum. The discovery of blapstin provides a novel clue for our understanding of the innate immunity of Blaps rhynchopetera and provides a template for designing antifungal drugs.

A novel iron molybdate photocatalyst with heterojunction-like band gap structure for organic pollutant degradation by activation of persulfate under simulated sunlight irradiation.

Advanced oxidation processes (AOPs) applied to wastewater treatment have become increasingly well developed and the ability of a single technology to remove difficult organic pollutants is limited. One of the main limiting factors is the insufficient variety and quantity of active species generated during the reaction process and catalyst failure. The coupling of the two methods is a practical and effective approach. In this study, different types of semiconductor persulfate (PS) activators, iron molybdate nanoparticles (I-FeMoO4, II-FeMoO4, and III-FeMoO4), were synthesized by simple solvothermal and calcination methods and applied to photo-assisted activation of PS systems. In addition, the relationship between the intrinsic physicochemical and optoelectronic properties of FeMoO4 and the catalytic degradation performance was revealed by a series of characterization tools, and the dominant catalysts were screened. At an unadjusted pH of 4.86, 0.6 g L-1 of PS and 0.4 g L-1 of I-FeMoO4 could achieve efficient degradation of several difficult organic dye contaminants (rhodamine b (Rh B), methylene blue (MB), malachite green (MG), methyl orange (MO), and tartrazine (TTZ)) and other antibiotic contaminants (sulfamethoxazole (SMX), tetracycline (TC), norfloxacin (NOR), and carbamazepine (CBZ)) within 5-60 min. Possible degradation mechanisms in the I-FeMoO4/PS/Light reaction system were suggested by radical trapping experiments and electron paramagnetic resonance (EPR) tests. Recovery tests demonstrated that I-FeMoO4 has good recoverable stability and did not cause secondary pollution. Finally, our study provided a new perspective on the application of coupled wastewater treatment technologies in the practical treatment of organic wastewater.

Role of gene signature regulation in tumor immune microenvironment on the mechanism of uveal melanoma metastasis.

BACKGROUND: Uveal melanoma (UM) is a rare but deadly cancer. The main cause of death from UM is liver metastasis. Though the metastasis mechanism remains unclear, it is closely related to the immune microenvironment and gene expression. OBJECTIVE: This study aimed to identify the prognostic genes in primary and metastatic UM and their relationship with the immune microenvironment. METHODS: Primary and metastatic UM data from the GEO database included GSE22138 and GSE44295 datasets. Kaplan-Meier analysis, Cox regression models, and ROC analysis were applied to screen genes in GSE22138. TIMER2.0 was employed to analyze the immune microenvironment from gene expression. Prognostic immune gene correlation was tested by Spearman. The results were validated in the independent dataset of cohort GSE44295. RESULTS: Metastasis and primary differential gene analysis showed 107 significantly different genes associated with prognosis, and 11 of them were immune-related. ROC analysis demonstrated that our signature was predictive for UM prognosis (AUC > 0.8). Neutrophil and myeloid dendritic cells were closely associated with metastasis with scores that significantly divided patients into high-risk and low-risk groups (log-rank p< 0.05). Of these 11 genes, FABP5 and SHC4 were significantly associated with neutrophils in metastatic tumors, while ROBO1 expression was significantly correlated with myeloid dendritic cells in the primary tumors. CONCLUSIONS: The present study constructed an 11-gene signature and established a model for risk stratification and prediction of overall survival in metastatic UM. Since FABP5 and SHC4 are related to neutrophil infiltration in metastatic UM, FABP5 and neutrophil regulation might be crucial in metastatic UM.

The substrate stiffness at physiological range significantly modulates vascular cell behavior.

Changes in the stiffness of the cellular microenvironment are involved in many pathological processes of blood vessels. Substrate stiffness has been shown to have extensive effects on vascular endothelial cells (VECs) and vascular smooth muscle cells (VSMCs). However, the material stiffness of most previously reported in-vitro models is ranging from ~100 kPa to the magnitude of MPa, which does not match the mechanical properties of natural vascular tissue (10-100 kPa). Herein, we constructed hydrogel substrates with the stiffness of 18-86 kPa to explore the effect of physiological stiffness on vascular cells. Our findings show that, with the increase of stiffness at the physiological range, the cell adhesion and proliferation behaviors of VECs and VSMCs are significantly enhanced. On the soft substrate, VECs express more nitric oxide (NO), and VSMCs tend to maintain a healthy contraction phenotype. More importantly, we find that the number of differentially expressed genes in cells cultured between 18 kPa and 86 kPa substrates (560 in VECs, 243 in VSMCs) is significantly higher than that between 86 kPa and 333 kPa (137 in VECs, 172 in VSMCs), indicating that a small increase in stiffness within the physiological range have a higher impact on vascular cell behaviors. Overall, our results expanded the exploration of how stiffness affects the behavior of vascular cells at the physiological range.

Physical Activity Improves Cognition and Activities of Daily Living in Adults with Alzheimer's Disease: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

OBJECTIVE: The purpose of this meta-analysis was to examine the effects of physical activity (PA) on cognition and activities of daily living in adults with Alzheimer's Disease (AD). METHODS: Six electronic databases (MEDLINE, CINAHL, PsycArticles, SPORTDiscus, EMBASE and CNKI) were used to search for potential studies from inception until October 2021. Randomized controlled trials (RCTs) investigating the effect of physical activity (PA) on cognition and activities of daily living in AD patients compared to a control condition were included. The effect sizes were synthesized using a random effects model with a 95% confidence interval (CI). RESULTS: Sixteen articles including 945 participants (aged 70 to 88 years, 34.6% male) met the inclusion criteria. The pooled effect sizes demonstrated that PA intervention was associated with significant improvements in global cognition (Standard Mean Difference (SMD) = 0.41, 95% CI [0.24, 0.58], p < 0.01) and activities of daily living (SMD = 0.56, 95% CI [0.32, 0.79], p < 0.01) in AD patients. Subgroup analyses suggested that PA for 3-4 times per week for 30-45 min for more than 12 weeks had a relatively strong effect on improving global cognition in AD patients. The sensitivity analysis showed robust results. CONCLUSIONS: The findings from the current meta-analysis suggested that AD patients can improve their global cognition and Activities of Daily Living (ADL) through engaging in aerobic and mixed exercise (aerobic and anaerobic exercise).

Differential Expression of Amanitin Biosynthetic Genes and Novel Cyclic Peptides in Amanita molliuscula.

Amanita molliuscula is a basal species of lethal Amanita and intrigues the field because it does not produce discernable α-amanitin when inspected by High Performance Liquid Chromatography (HPLC), which sets it apart from all known amanitin-producing (lethal) Amanita species. In order to study the underlining genetic basis of the phenotype, we sequenced this species through PacBio and Illumina RNA-Seq platforms. In total, 17 genes of the "MSDIN" family (named after the first five amino acid residues of the precursor peptides) were found in the genome and 11 of them were expressed at the transcription level. The expression pattern was not even but in a differential fashion: two of the MSDINs were highly expressed (FPKM value > 100), while the majority were expressed at low levels (FPKM value < 1). Prolyl oligopeptidease B (POPB) is the key enzyme in the amanitin biosynthetic pathway, and high expression of this enzyme was also discovered (FPKM value > 100). The two MSDINs with highest transcription further translated into two novel cyclic peptides, the structure of which is distinctive from all known cyclic peptides. The result illustrates the correlation between the expression and the final peptide products. In contrast to previous HPLC result, the genome of A. molliuscula harbors α-amanitin genes (three copies), but the product was in trace amount indicated by MS. Overall, transcription of MSDINs encoding major toxins (α-amanitin, ß-amanitin, phallacidin and phalloidin) were low, showing that these toxins were not actively synthesized at the stage. Collectively, our results indicate that the amanitin biosynthetic pathway is highly active at the mature fruiting body stage in A. molliuscula, and due to the differential expression of MSDIN genes, the pathway produces only a few cyclic peptides at the time.

Novel Cyclic Peptides from Lethal Amanita Mushrooms through a Genome-Guided Approach.

Most species in the genus Amanita are ectomycorrhizal fungi comprising both edible and poisonous mushrooms. Some species produce potent cyclic peptide toxins, such as α-amanitin, which places them among the deadliest organisms known to mankind. These toxins and related cyclic peptides are encoded by genes of the "MSDIN" family (named after the first five amino acid residues of the precursor peptides), and it is largely unknown to what extent these genes are expressed in the basidiocarps. In the present study, Amanita rimosa and Amanita exitialis were sequenced through the PacBio and Illumina techniques. Together with our two previously sequenced genomes, Amanita subjunquillea and Amanita pallidorosea, in total, 46 previously unknown MSDIN genes were discovered. The expression of over 80% of the MSDIN genes was demonstrated in A. subjunquillea. Through a combination of genomics and mass spectrometry, 12 MSDIN genes were shown to produce novel cyclic peptides. To further confirm the results, three of the cyclic peptides were chemically synthesized. The tandem mass spectrometry (MS/MS) spectra of the natural and the synthetic peptides shared a majority of the fragment ions, demonstrating an identical structure between each peptide pair. Collectively, the results suggested that the genome-guided approach is reliable for identifying novel cyclic peptides in Amanita species and that there is a large peptide reservoir in these mushrooms.

The Effects of Tai Chi on Markers of Atherosclerosis, Lower-limb Physical Function, and Cognitive Ability in Adults Aged Over 60: A Randomized Controlled Trial.

Objective: The purpose of this study was to investigate the effects of Tai Chi (TC) on arterial stiffness, physical function of lower-limb, and cognitive ability in adults aged over 60. Methods: This study was a prospective and randomized 12-week intervention trial with three repeated measurements (baseline, 6, and 12 weeks). Sixty healthy adults who met the inclusion criteria were randomly allocated into three training conditions (TC-24, TC-42, and TC-56) matched by gender, with 20 participants (10 males, 10 females) in each of the three groups. We measured the following health outcomes, including markers of atherosclerosis, physical function (leg power, and static and dynamic balance) of lower-limb, and cognitive ability. Results: When all three TC groups (p < 0.05) have showed significant improvements on these outcomes but overall cognitive ability at 6 or 12 weeks training period, TC-56 appears to have superior effects on arterial stiffness and static/dynamic balance in the present study. Conclusions: Study results of the present study add to growing body of evidence regarding therapeutic TC for health promotion and disease prevention in aging population. Future studies should further determine whether TC-42 and TC-56 are beneficial for other non-Chinese populations, with rigorous research design and follow-up assessment.

Fabrication of CsxFA1-xPbI3 Mixed-Cation Perovskites via Gas-Phase-Assisted Compositional Modulation for Efficient and Stable Photovoltaic Devices.

Over the past few years, significant attention has been focused on HC(NH2)2PbI3 (FAPbI3) perovskite due to its reduced band gap and enhanced thermal stability compared with the most studied CH3NH3PbI3 (MAPbI3). However, FAPbI3 is sensitive to moisture and also encounters a serious structural phase-transition from photoactive α-phase to photoinactive δ-phase. Herein, we first develop a novel FAI gas-phase-assisted mixed-cation compositional modulation method to fabricate CsxFA1-xPbI3 perovskite solar cells (PSCs), and realize the structural stabilization of α-phase FAPbI3 with the incorporation of smaller inorganic Cs+ ions. Through the setting of different Cs+ contents (x = 0, 0.05, 0.10, 0.15, 0.20, 0.25, 0.30, 0.50) along with a moderate FAI vapor deposition process, a series of CsxFA1-xPbI3 films with consistent compositions are fabricated, which perfectly resolves the main blocking problems of the conventional solution approach, such as difficulty in compositional control and rough film morphology. Meanwhile, we find that the Cs+ amount is crucial for generating phase-pure CsxFA1-xPbI3 (0 < x < 0.30) while higher contents result in phase segregation. Consequently, the optimum amount of Cs+ (x = 0.15) is verified, and Cs0.15FA0.85PbI3 shows the smallest unit cell volume and good moisture-resistant feature. Correspondingly, the highest power conversion efficiency (PCE) of 14.45% based on Cs0.15FA0.85PbI3 PSCs is successfully achieved in this work.

Phase-Defined van der Waals Schottky Junctions with Significantly Enhanced Thermoelectric Properties.

We demonstrate a van der Waals Schottky junction defined by crystalline phases of multilayer In2Se3. Besides ideal diode behaviors and the gate-tunable current rectification, the thermoelectric power is significantly enhanced in these junctions by more than three orders of magnitude compared with single-phase multilayer In2Se3, with the thermoelectric figure-of-merit approaching ∼1 at room temperature. Our results suggest that these significantly improved thermoelectric properties are not due to the 2D quantum confinement effects but instead are a consequence of the Schottky barrier at the junction interface, which leads to hot carrier transport and shifts the balance between thermally and field-driven currents. This "bulk" effect extends the advantages of van der Waals materials beyond the few-layer limit. Adopting such an approach of using energy barriers between van der Waals materials, where the interface states are minimal, is expected to enhance the thermoelectric performance in other 2D materials as well.

Solvent Engineering for Ambient-Air-Processed, Phase-Stable CsPbI3 in Perovskite Solar Cells.

Inorganic CsPbI3 perovskite solar cells (PSCs) owning comparable photovoltaic performance and enhanced thermal stability compared to organic-inorganic hybrid perovskites have attracted enormous interest in the past year. However, it is still a challenge to stabilize the desired black α-CsPbI3 perovskites in ambient air for photovoltaic applications. Herein, sequential solvent engineering including the addition of hydroiodic acid (HI) and subsequent isopropanol (IPA) treatment for fabricating stable and working CsPbI3 PSCs is developed, and a novel low-temperature phase-transition route from new intermediate Cs4PbI6 to stable α-CsPbI3 is also released for the first time. As such, the as-prepared PSCs give a relatively high power conversion efficiency (PCE) of 4.13% (reverse scan), and the steady-state power output of 1.88% is confirmed for the selected cell with an initial PCE of 3.13%. To the best of our knowledge, this is the first demonstration of fabricating CsPbI3 inorganic PSCs under fully open-air conditions.

A novel transformation route from PbS to CH3NH3PbI3 for fabricating curved and large-area perovskite films.

We present a new transformation route from PbS to CH3NH3PbI3 for the facile preparation of perovskites with all kinds of shapes via vapor-assisted chemical bath deposition (VACBD). As such, curved and large-area CH3NH3PbI3 films with high quality are successfully achieved, which are suitable for the manufacturing scale-up of perovskite solar cells.