Astrocyte-mediated regulation of BLAWFS1 neurons alleviates risk-assessment deficits in DISC1-N mice.

Assessing and responding to threats is vital in everyday life. Unfortunately, many mental illnesses involve impaired risk assessment, affecting patients, families, and society. The brain processes behind these behaviors are not well understood. We developed a transgenic mouse model (disrupted-in-schizophrenia 1 [DISC1]-N) with a disrupted avoidance response in risky settings. Our study utilized single-nucleus RNA sequencing and path-clamp coupling with real-time RT-PCR to uncover a previously undescribed group of glutamatergic neurons in the basolateral amygdala (BLA) marked by Wolfram syndrome 1 (WFS1) expression, whose activity is modulated by adjacent astrocytes. These neurons in DISC1-N mice exhibited diminished firing ability and impaired communication with the astrocytes. Remarkably, optogenetic activation of these astrocytes reinstated neuronal excitability via D-serine acting on BLAWFS1 neurons' NMDA receptors, leading to improved risk-assessment behavior in the DISC1-N mice. Our findings point to BLA astrocytes as a promising target for treating risk-assessment dysfunctions in mental disorders.

Discovery of New Tricyclic Oxime Sampangine Derivatives as Potent Antifungal Agents for the Treatment of Cryptococcosis and Candidiasis.

Cryptococcus neoformans (C. neoformans) and Candida albicans (C. albicans) are classified as the critical priority groups among the pathogenic fungi, highlighting the urgent need for developing more effective antifungal therapies. On the basis of antifungal natural product sampangine, herein, a series of tricyclic oxime and oxime ether derivatives were designed. Among them, compound WZ-2 showed excellent inhibitory activity against C. neoformans (MIC80 = 0.016 µg/mL) and synergized with fluconazole to treat resistant C. albicans (FICI = 0.078). Interestingly, compound WZ-2 effectively inhibited virulence factors (e.g., capsule, biofilm, and yeast-to-hypha morphological transition), suggesting the potential to overcome drug resistance. In a mouse model of cryptococcal meningitis, compound WZ-2 (5 mg/kg) effectively reduced the brain C. neoformans H99 burden. Furthermore, compound WZ-2 alone and its combination with fluconazole also significantly reduced the kidney burden of the drug-resistant strain (0304103) and sensitive strain (SC5314) of C. albicans.

Divergent Selection in Low Recombination Regions Shapes the Genomic Islands in Two Incipient Shorebird Species.

Speciation in the face of gene flow is usually associated with a heterogeneous genomic landscape of divergence in nascent species pairs. However, multiple factors, such as divergent selection and local recombination rate variation, can influence the formation of these genomic islands. Examination of the genomic landscapes of species pairs that are still in the early stages of speciation provides an insight into this conundrum. In this study, population genomic analyses were undertaken using a wide range of sampling and whole-genome resequencing data from 96 unrelated individuals of Kentish plover (Charadrius alexandrinus) and white-faced plover (Charadrius dealbatus). We suggest that the two species exhibit varying levels of population admixture along the Chinese coast and on the Taiwan Island. Genome-wide analyses for introgression indicate that ancient introgression had occurred in Taiwan population, and gene flow is still ongoing in mainland coastal populations. Furthermore, we identified a few genomic regions with significant levels of interspecific differentiation and local recombination suppression, which contain several genes potentially associated with disease resistance, coloration, and regulation of plumage molting and thus may be relevant to the phenotypic and ecological divergence of the two nascent species. Overall, our findings suggest that divergent selection in low recombination regions may be a main force in shaping the genomic islands in two incipient shorebird species.

Efficacy of Warm Acupuncture Therapy Combined with Kegel Exercise on Postpartum Pelvic Floor Dysfunction in Women.

INTRODUCTION AND HYPOTHESIS: The objective was to observe the clinical efficacy of warm acupuncture combined with Kegel exercise in treating postpartum pelvic floor dysfunction in women. METHODS: A total of 70 primiparous women with postpartum pelvic floor muscle (PFM) injury were randomly divided into a combination group (n = 35, receiving warm acupuncture at Zhibian (BL54) acupoint and Kegel exercise) and a sham control group (n = 35, receiving sham warm acupuncture and Kegel exercise). Both groups were treated three times a week for 4 consecutive weeks. The recovery of PFM strength and changes in Urethral Rotation Angle (URA), Bladder Neck Descent (BND), and Retrovesical Angle (RVA) in pelvic floor ultrasound reports, the scores of pelvic floor dysfunction-related questionnaires, and the efficacy of urinary incontinence treatment of the two groups were compared before and after treatment. RESULTS: After treatment, the recovery rates of type I and II PFM strength, pelvic floor ultrasound parameters, pelvic floor dysfunction-related scale scores, and urinary incontinence treatment efficacy in the combination group were significantly better than those in the sham control group (p < 0.05). CONCLUSION: Warm acupuncture combined with Kegel exercise can significantly improve PFM strength and promote the recovery of postpartum pelvic floor function in women.

Discovery of Pyrazolone Carbothioamide Derivatives as Inhibitors of the Pdr1-KIX Interaction for Combinational Treatment of Azole-Resistant Candidiasis.

Candida glabrata has emerged as an important opportunistic pathogen of invasive candidiasis due to increasing drug resistance. Targeting Pdr1-KIX interactions with small molecules represents a potential strategy for treating drug-resistant candidiasis. However, effective Pdr1-KIX inhibitors are rather limited, hindering the validation of target druggability. Here, new Pdr1-KIX inhibitors were designed and assayed. Particularly, compound B8 possessed a new chemical scaffold and exhibited potent KIX binding affinity, leading to enhanced synergistic efficacy with fluconazole to treat resistant C. glabrata infection (FICI = 0.28). Compound B8 acted by inhibiting the efflux pump and down-regulating resistance-associated genes through blocking the Pdr1-KIX interaction. Compound B8 exhibited excellent in vitro and in vivo antifungal potency in combination with fluconazole against azole-resistant C. glabrata. It also had direct antifungal effect to treat C. glabrata infection, suggesting new mechanisms of action independent of Pdr1-KIX inhibition. Therefore, compound B8 represents a promising lead compound for antifungal drug development.

Controlling antifungal activity with light: Optical regulation of fungal ergosterol biosynthetic pathway with photo-responsive CYP51 inhibitors.

Invasive fungal infections (IFIs) have been associated with high mortality, highlighting the urgent need for developing novel antifungal strategies. Herein the first light-responsive antifungal agents were designed by optical control of fungal ergosterol biosynthesis pathway with photocaged triazole lanosterol 14α-demethylase (CYP51) inhibitors. The photocaged triazoles completely shielded the CYP51 inhibition. The content of ergosterol in fungi before photoactivation and after photoactivation was 4.4% and 83.7%, respectively. Importantly, the shielded antifungal activity (MIC80 ≥ 64 µg/mL) could be efficiently recovered (MIC80 = 0.5-8 µg/mL) by light irradiation. The new chemical tools enable optical control of fungal growth arrest, morphological conversion and biofilm formation. The ability for high-precision antifungal treatment was validated by in vivo models. The light-activated compound A1 was comparable to fluconazole in prolonging survival in Galleria mellonella larvae with a median survival of 14 days and reducing fungal burden in the mouse skin infection model. Overall, this study paves the way for precise regulation of antifungal therapy with improved efficacy and safety.

Anion-induced robust ferroelectricity in sulfurized pseudo-rhombohedral epitaxial BiFeO3 thin films via polarization rotation.

Polarization rotation caused by various strains, such as substrate and/or chemical strain, is essential to control the electronic structure and properties of ferroelectric materials. This study proposes anion-induced polarization rotation with chemical strain, which effectively improves ferroelectricity. A method for the sulfurization of BiFeO3 thin films by introducing sulfur anions is presented. The sulfurized films exhibited substantial enhancement in room-temperature ferroelectric polarization through polarization rotation and distortion, with a 170% increase in the remnant polarization from 58 to 100.7 µC cm-2. According to first-principles calculations and the results of X-ray absorption spectroscopy and high-angle annular dark-field scanning transmission electron microscopy, this enhancement arose from the introduction of S atoms driving the re-distribution of the lone-pair electrons of Bi, resulting in the rotation of the polarization state from the [001] direction to the [110] or [111] one. The presented method of anion-driven polarization rotation might enable the improvement of the properties of oxide materials.

Target- and prodrug-based design for fungal diseases and cancer-associated fungal infections.

Invasive fungal infections (IFIs) are emerging as a serious threat to public health and are associated with high incidence and mortality. IFIs also represent a frequent complication in patients with cancer who are undergoing chemotherapy. However, effective and safe antifungal agents remain limited, and the development of severe drug resistance further undermines the efficacy of antifungal therapy. Therefore, there is an urgent need for novel antifungal agents to treat life-threatening fungal diseases, especially those with new mode of action, favorable pharmacokinetic profiles, and anti-resistance activity. In this review, we summarize new antifungal targets and target-based inhibitor design, with a focus on their antifungal activity, selectivity, and mechanism. We also illustrate the prodrug design strategy used to improve the physicochemical and pharmacokinetic profiles of antifungal agents. Dual-targeting antifungal agents offer a new strategy for the treatment of resistant infections and cancer-associated fungal infections.

Discovery of BRD4-HDAC Dual Inhibitors with Improved Fungal Selectivity and Potent Synergistic Antifungal Activity against Fluconazole-Resistant Candida albicans.

Over the past several decades, invasive fungal infections, especially candidiasis, have caused dramatic morbidity and mortality due to ineffective antifungal drugs and severe drug resistance. Herein, new BRD4-histone deacetylase (HDAC) inhibitors were designed to restore the susceptibility of Candida albicans (C. albicans) to fluconazole (FLC). Interestingly, several compounds showed excellent selectivity against fungal HDACs. In particular, compound B2 showed excellent synergistic effect with FLC against resistant C. albicans (FICI = 0.063) with high selectivity against fungal HDACs (SI = 1653) and low cytotoxicity. Compound B2 effectively synergized with FLC and prevented biofilm formation and morphological transition in resistant C. albicans, potentiating the antifungal activity of FLC in vivo and significantly reducing kidney fungal loads. Thus, this drug combination is promising in the treatment of resistant C. albicans infections.

Discovery of a new chemical scaffold for the treatment of superbug Candida auris infections.

Candida auris has emerged as a serious threat of public health and caused global epidemic due to multi-drug resistance, remarkable transmissibility and high mortality. To tackle the challenging super fungus, novel benzoanilide antifungal agents were discovered by an integrated strategy of phenotypic screen, hit optimization, antifungal assays and mechanism exploration. The most promising compound A1 showed potent in vitro and in vivo efficacy against Candida auris infection. Mechanism investigation revealed that compound A1 blocked the biosynthesis of virulence factors and fungal cell walls through the inhibition of glycosylphosphatidylinositol (GPI) and GPI-anchored proteins. Thus, compound A1 represents a promising lead compound to combat drug-resistant candidiasis.

MicroRNA-128 suppresses tau phosphorylation and reduces amyloid-beta accumulation by inhibiting the expression of GSK3ß, APPBP2, and mTOR in Alzheimer's disease.

INTRODUCTION AND AIMS: Alzheimer's disease (AD) is characterized by the abnormal accumulation of hyperphosphorylated tau proteins and amyloid-beta (Aß) peptides. Recent studies have shown that many microRNAs (miRNAs) are dysregulated in AD, and modulation of these miRNAs can influence the development of tau and Aß pathology. The brain-specific miRNA miR-128, encoded by MIR128-1 and MIR128-2, is important for brain development and dysregulated in AD. In this study, the role of miR-128 in tau and Aß pathology as well as the regulatory mechanism underlying its dysregulation were investigated. METHODS: The effect of miR-128 on tau phosphorylation and Aß accumulation was examined in AD cellular models through miR-128 overexpression and inhibition. The therapeutic potential of miR-128 in AD mouse model was assessed by comparing phenotypes of 5XFAD mice administered with miR-128-expressing AAVs with 5XFAD mice administered with control AAVs. Phenotypes examined included behavior, plaque load, and protein expression. The regulatory factor of miR-128 transcription was identified through luciferase reporter assay and validated by siRNA knockdown and ChIP analysis. RESULTS: Both gain-of-function and loss-of-function studies in AD cellular models reveal that miR-128 represses tau phosphorylation and Aß secretion. Subsequent investigations show that miR-128 directly inhibits the expression of tau phosphorylation kinase GSK3ß and Aß modulators APPBP2 and mTOR. Upregulation of miR-128 in the hippocampus of 5XFAD mice ameliorates learning and memory impairments, decreases plaque deposition, and enhances autophagic flux. We further demonstrated that C/EBPα transactivates MIR128-1 transcription, while both C/EBPα and miR-128 expression are inhibited by Aß. CONCLUSION: Our findings suggest that miR-128 suppresses AD pathogenesis, and could be a promising therapeutic target for AD. We also find a possible mechanism underlying the dysregulation of miR-128 in AD, in which Aß reduces miR-128 expression by inhibiting C/EBPα.

Multiple Copies of Mobile Tigecycline Resistance Efflux Pump Gene Cluster tmexC2D2.2-toprJ2 Identified in Chromosome of Aeromonas spp.

The appearance and prevalence of novel plasmid-encoded tigecycline resistance efflux pump gene clusters tmexC1D1-toprJ1 and tmexC2D2-toprJ2 in Enterobacteriaceae have raised a threat to public health. Here, another tigecycline resistance gene cluster, tmexC2D2.2-toprJ2, was identified in two Aeromonas isolates recovered from fish meat and vegetables. Cloning confirmed the expression of tmexC2D2.2-toprJ2 mediated the resistance to tigecycline and decreased susceptibility to tetracyclines and cephalosporins in both Escherichia coli and Aeromonas. In an Aeromonas veronii strain, four copies of tmexC2D2.2-toprJ2 were located on the chromosome. Further analysis revealed that tmexC2D2.2-toprJ2 has been detected in the chromosomes of A. veronii, Aeromonas hydrophila, and Aeromonas caviae with one to four copies due to the insertion of a potential integrative transferable unit. The occurrence of multiple copies of chromosomal tmexC2D2.2-toprJ2 may act as a sink for this tigecycline resistance gene cluster, which requires continuous monitoring. IMPORTANCE Tigecycline is regarded as one of the few effective drugs against multidrug-resistant bacterial infection. However, mobile tigecycline resistance efflux pump gene clusters such as tmexC1D1-toprJ1 and its variants have been identified in both animal- and human-origin Enterobacteriaceae. In this study, we first found another efflux pump gene cluster, tmexC2D2.2-toprJ2, in the Aeromonas chromosome. This gene cluster could mediate tigecycline resistance and decrease susceptibility to tetracyclines and cephalosporins in the Aeromonas host strain. Meanwhile, tmexC2D2.2-toprJ2 was detected with multiple copies in Aeromonas spp. This multidrug resistance efflux pump gene cluster with multiple copy numbers might stably exist in Aeromonas and serve as a reservoir for tmexCD2-toprJ2, facilitating its persistent presence and spread.

Small molecules for combating multidrug-resistant superbug Candida auris infections.

Candida auris is emerging as a major global threat to human health. C. auris infections are associated with high mortality due to intrinsic multi-drug resistance. Currently, therapeutic options for the treatment of C. auris infections are rather limited. We aim to provide a comprehensive review of current strategies, drug candidates, and lead compounds in the discovery and development of novel therapeutic agents against C. auris. The drug resistance profiles and mechanisms are briefly summarized. The structures and activities of clinical candidates, drug combinations, antifungal chemosensitizers, repositioned drugs, new targets, and new types of compounds will be illustrated in detail, and perspectives for guiding future research will be provided. We hope that this review will be helpful to prompting the drug development process to combat this fungal pathogen.

The Central Nervous Mechanism of Stress-Promoting Cancer Progression.

Evidence shows that stress can promote the occurrence and development of tumors. In recent years, many studies have shown that stress-related hormones or peripheral neurotransmitters can promote the proliferation, survival, and angiogenesis of tumor cells and impair the body's immune response, causing tumor cells to escape the "surveillance" of the immune system. However, the perception of stress occurs in the central nervous system (CNS) and the role of the central nervous system in tumor progression is still unclear, as are the underlying mechanisms. This review summarizes what is known of stress-related CNS-network activation during the stress response and the influence of the CNS on tumors and discusses available adjuvant treatment methods for cancer patients with negative emotional states, such as anxiety and depression.

Retraction Notice to: Overexpression of MicroRNA-340-5p Inhibits Pulmonary Arterial Hypertension Induced by APE by Downregulating IL-1ß and IL-6.

[This retracts the article DOI: 10.1016/j.omtn.2020.05.022.].

Characteristics of Mulberry Leaf Powder Enriched With γ-Aminobutyric Acid and Its Antioxidant Capacity as a Potential Functional Food Ingredient.

To improve the functional properties of mulberry leaves, γ-aminobutyric acid (GABA) enrichment treatments were applied. The results showed that the combined treatment of sodium glutamate immersion, cold shock, and anoxic significantly increased the GABA content. HPLC analysis displayed that the quantity of some active phenolics was significantly increased after the treatment. The GABA-enriched mulberry leaf powders were subsequently prepared, and it was found that as the particle size decreased, their water and oil holding capacity and their swelling power decreased, while the angle of repose increased. The dissolution rate of GABA and total phenolics increased as the particle size decreased. Optical observations and SEM results revealed that the fiber structures of the particles were gradually destroyed as the particle size decreased. Further, FTIR analysis showed that the active compounds in the powders were not destroyed. M400 and M140 powder showed the maximum DPPH radical scavenging ability and AGEs inhibition capacity, respectively. Additionally, adding the powders effectively alleviated the staling of bread without any significant effect on taste.

Abnormal Antennal Olfactory Sensilla Phenotypes Involved in Olfactory Deficit in Bactrocera correcta (Diptera: Tephritidae).

The guava fruit fly, Bactrocera correcta, is one of the most destructive pests in the genus Bactrocera and detects environmental odorants mainly through antennal olfactory sensilla phenotypes with nanopores. However, it is unclear whether there are naturally occurring abnormal antennal olfactory sensilla phenotypes that affect olfaction. Here, we found that there were abnormal bulges besides nanopores on the surface of trichoid and basiconic olfactory sensilla in the antennal flagellum of long-term laboratory rearing colony (LTC), and that nanopore number in these olfactory sensilla was also remarkably reduced. Notably, the electroantennogram (EAG) responses of LTC insects to methyl eugenol or ß-caryophyllene were inhibited, and their behavioral responses elicited by the same odorants were also impaired. These results revealed naturally occurring abnormal antennal olfactory sensilla phenotypes which were involved in olfactory deficit in B. correcta, providing a platform to further study nanopore-targeted pest control technologies in the future.

Discovery of Novel Sertraline Derivatives as Potent Anti-Cryptococcus Agents.

Treatment of life-threatening cryptococcal meningitis (CM) is highly challenging due to the limited efficacy of the available antifungal drugs. Antidepressant sertraline (SER) has been proposed to be a potential antifungal agent for CM. However, clinical studies indicated that SER failed to achieve the expected therapeutic effects. Herein, novel SER derivatives were designed by scaffold hopping, and they showed improved anticryptococcal activity both in vitro and in vivo. In particular, compound D16 was identified as a promising anti-CM agent with a new antifungal mode of action. It acted by blocking the biosynthesis of ergosterol through the inhibition of Δ5,6-desaturase. This study provides a new target and a drug-like candidate for CM treatment.

Exogenous GABA improves the antioxidant and anti-aging ability of silkworm (Bombyx mori).

Silkworm (Bombyx mori) was used to explore the anti-aging ability of Gamma-aminobutyric acid (GABA) and its potential mechanism. 0.086∼8.6 mM GABA solutions were sprayed on mulberry leaves to raise silkworms. The results showed that GABA increased the fecundity of adult silkworms. And in the larva silkworms on the 3th day of the 5th instar, GABA significantly reduced the trehalose content in the hemolymph, the triglycerides and glycogen levels in the fat body, while sharply increased the NAD+/NADH level in the fat body. GABA significantly increased the GSH content and activities of SOD and CAT, while reduced the level of MDA. Furthermore, GABA reduced the mRNA expression of BmRpd3, Bmchico and BmAkh2, while increased the mRNA expression of BmAMPK. In summary, GABA has anti-aging potential by playing roles in energy homeostasis, reducing carbohydrate and lipid level, increasing anti-oxidative capacity, and regulating mRNA expression of longevity-related genes.