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Comparative transcriptomics reveals a mixed basal, club, and hillock epithelial cell identity in castration-resistant prostate cancer
Inhibiting the androgen receptor (AR) is effective for treatment of advanced prostate cancers because of their AR-dependent luminal epithelial cell identity. Tumors progress during therapy to castration-resistant prostate cancer (CRPC) by restoring AR signaling and maintaining luminal identity or by converting through lineage plasticity to a neuroendocrine (NE) identity or double-negative CRPC (DNPC) lacking luminal or NE identities. Here, we show that DNPC cells express genes defining basal, club, and hillock epithelial cells from benign prostate. We identified KLF5 as a regulator of genes defining this mixed basal, club, and hillock cell identity in DNPC models. KLF5-mediated upregulation of RARG uncovered a DNPC sensitivity to growth inhibition by retinoic acid receptor agonists, which down-regulated KLF5 and up-regulated AR. These findings offer CRPC classifications based on prostate epithelial cell identities and nominate KLF5 and RARG as therapeutic targets for CRPC displaying a mixed basal, club, and hillock identity.
Artificial neural network controlled DSTATCOM for mitigating power quality concerns in solar PV and wind system
HflX-mediated drug resistance through ribosome splitting and rRNA disordering in mycobacteria
HflX is a highly conserved ribosome-associated GTPase implicated in rescuing stalled ribosomes and mediating antibiotic resistance in several bacteria, including macrolide-lincosamide antibiotic resistance in mycobacteria. Mycobacterial HflXs carry a distinct N-terminal extension (NTE) and a small insertion, as compared to their eubacterial homologs. Here, we present several high-resolution cryo-EM structures of mycobacterial HflX in complex with the 70S ribosome and its 50S subunit, with and without antibiotics. These structures reveal a distinct mechanism for HflX-mediated ribosome splitting and antibiotic resistance in mycobacteria. Our findings indicate that the NTE of mycobacterial HflX induces persistent disordering of multiple 23S rRNA helices, facilitating the dissociation of the 70S ribosome and generating an inactive pool of 50S subunits. During this process, HflX undergoes a large conformational change that stabilizes its NTE. Mycobacterial HflX also acts as an anti-association factor by binding to predissociated 50S subunits. Our structures show that a mycobacteria-specific insertion in HflX reaches far into the peptidyl transferase center (PTC), such that it would overlap with the ribosome-bound macrolide antibiotics. However, in the presence of antibiotics, this insertion retracts, adjusts around, and interacts with the antibiotic molecules. These results suggest that mycobacterial HflX is agnostic to antibiotic presence in the PTC. It mediates antibiotic resistance by splitting antibiotic-stalled 70S ribosomes and inactivating the resulting 50S subunits.
Research on the controller of an active vibration isolation unit for underwater crushing operations
Mec1-mediated Atg9 phosphorylation regulates the PAS recruitment of Atg9 vesicles upon energy stress
Mec1 plays an essential role in both the DNA damage response and glucose starvation–induced autophagy. We recently reported that Mec1 regulates glucose starvation–induced autophagy through its direct binding to Atg13. However, the role of Mec1’s kinase activity in autophagy remains unclear. In this study, we demonstrate that the kinase activity of Mec1 is required for glucose starvation–induced autophagy by regulating the phagophore assembly site (PAS) recruitment of Atg9 vesicles. Mechanistic and functional analyses identified Atg9 as a direct phosphorylation substrate of Mec1, with phosphorylation occurring at the S35, T203, and T243 sites. Mutations at these sites reduce the association of Atg9 with Atg17, Atg23, and Atg27, thereby impairing the PAS recruitment of Atg9 vesicles. Notably, we found that the Mec1–Atg13 binding is a prerequisite for the phosphorylation of Atg9 by Mec1. Furthermore, Mec1-mediated phosphorylation of Atg9 is also crucial for the PAS recruitment of Atg9 vesicles in response to DNA damage. We thus propose that Mec1’s kinase activity regulates the PAS recruitment of Atg9 vesicles by phosphorylating Atg9 in response to energy stress and DNA damage.
Publisher Correction: A meta-analysis of bulk RNA-seq datasets identifies potential biomarkers and repurposable therapeutics against Alzheimer’s disease
An ear for an ear, but only if you are a deomyinid
Bioinformatics analysis of coronary microvascular dysfunction in rats based on single-cell RNA sequencing
Abscisic acid signaling gates salt-induced responses of plant roots
Soil salinity presents a dual challenge for plants, involving both osmotic and ionic stress. In response, plants deploy distinct yet interconnected mechanisms to cope with these facets of salinity stress. In this investigation, we observed a substantial overlap in the salt (NaCl)-induced transcriptional responses of Arabidopsis roots with those triggered by osmotic stress or the plant stress hormone abscisic acid (ABA), as anticipated. Notably, a specific cluster of genes responded uniquely to sodium (Na + ) ions and are not regulated by the known monovalent cation sensing mechanism MOCA1 . Surprisingly, expression of sodium-induced genes exhibited a negative correlation with the ABA response and preceded the activation of genes induced by the osmotic stress component of salt. Elevated exogenous ABA levels resulted in the complete abolition of sodium-induced responses. Consistently, the ABA insensitive snrk2.2/2.3 double mutant displayed prolonged sodium-induced gene expression, coupled with increased root cell damage and root swelling under high salinity conditions. Moreover, ABA biosynthesis and signaling mutants were unable to redirect root growth to avoid high sodium concentrations and had increased sodium accumulation in the shoot. In summary, our findings unveil an unexpected and pivotal role for ABA signaling in mitigating cellular damage induced by salinity stress and modulating sodium-induced responses in plant roots.
Assessment of heavy metals and microbial loads in Nile tilapia (Oreochromis niloticus) from different farms and rivers
Synergistic anion–π interactions in peptidomimetic polyethers
Anion–π interactions are crucial in various biological processes, such as enzyme catalysis and ion transport. Despite their significance, the exploitation of anion–π interactions in synthetic polymer systems remains underexplored. This study investigates anion–π interactions using chemically well-defined peptidomimetics guided by the composition of mussel foot proteins. Specifically, polyether-based polymers were designed utilizing two functional epoxide monomers—catechol acetonide glycidyl ether and 4,4-dimethyl-2-oxazoline glycidyl ether—to mimic the key amino acids 3,4-dihydroxyphenylalanine and aspartic acid, respectively. A surface forces apparatus was employed to study the anion–π interaction between the polymers, considering the effects of relative monomer composition and pH conditions. The maximum cohesion energy of 15.0 mJ/m 2 was observed at an equimolar monomer composition at pH 7. Incorporating a phenyl group instead of the catechol group and introducing competing anions confirmed the dominant role of anion–π interactions. This study highlights the significance of anion–π interactions, posing a high potential in the design and synthesis of functional materials.
Rapid antimicrobial susceptibility testing using carbon screen printed electrodes in a microfluidic device
Profile of Bik-Kwoon Tye
Visual perception of wind hazards using cycloidal scanning LiDAR system
QnAs with Jeremy J. Michalek and Corey D. Harper
ANGPTL3 regulates the peroxisomal translocation of SmarcAL1 in response to cell growth states
CO <sub>2</sub> potentiates echinocandin efficacy during invasive candidiasis therapy via dephosphorylation of Hsp90 by Ptc2 in condensates
Carbon dioxide is a signaling cue critical for fungal pathogenesis. Ptc2, a type 2C protein phosphatase (PP2C), serves as a conserved CO 2 sensor in fungi. By combining phosphoproteomic and biochemical assays, we identified Hsp90 as a direct target of Ptc2 at host CO 2 concentrations and Ssb1 as a Ptc2 target protein regardless of CO 2 levels in Candida albicans , the most prevalent human fungal pathogen. Ptc2 forms reversible condensates at elevated CO 2 , which enables the recruitment of Hsp90, but not Ssb1, to condensates, allowing efficient dephosphorylation. This process confers an enhanced susceptibility to caspofungin in vitro and during in vivo infection therapy. Importantly, we demonstrate this phenomenon in non-albicans Candida species. Sequential passages of C. albicans in mice with caspofungin treatment readily induce in vivo drug tolerance, causing therapeutic failure. These evolved strains display increased resistance to caspofungin under host concentrations of CO 2 but remain susceptible in air. Collectively, our study reveals a profound impact of host concentrations of CO 2 on antifungal drug susceptibility and connects this phenotype to therapeutic outcomes and highlights condensate formation as an efficient means that enables selective recruitment of substrates for certain signaling events.
Quality control of hospitals and its effect on hospitalized fatality rate of COVID-19
Rapid restoration of potent neutralization activity against the latest Omicron variant JN.1 via AI rational design and antibody engineering
The rapid evolution of the viral genome has led to the continual generation of new variants of SARS-CoV-2. Developing antibody drugs with broad-spectrum and high efficiency is a long-term task. It is promising but challenging to develop therapeutic neutralizing antibodies (nAbs) through in vitro evolution based on antigen–antibody binding interactions. From an early B cell antibody repertoire, we isolated antibody 8G3 that retains its nonregressive neutralizing activity against Omicron BA.1 and various other strains in vitro. 8G3 protected ACE2 transgenic mice from BA.1 and WA1/2020 virus infection without adverse clinical manifestations and completely cleared viral load in the lungs. Similar to most IGHV3–53 antibodies, the binding sites of 8G3 and ACE2 largely overlap, enabling competition with ACE2 for binding to RBD. By comprehensively considering the binding free energy changes of the antigen–antibody complexes, the biological environment of their interactions, and the evolutionary direction of the antibodies, we were able to select 50 mutants. Among them, 11 were validated by experiments showing better neutralizing activities. Further, a combination of four mutations were identified in 8G3 that increased its neutralization potency against JN.1, the latest Omicron mutant, by approximately 1,500-fold, and one of the mutations led to an improvement in activity against multiple variants to a certain extent. Together, we established a procedure of rapid selection of neutralizing antibodies with potent SARS-CoV-2 neutralization activity. Our results provide a reference for engineering neutralizing antibodies against future SARS-CoV-2 variants and even other pandemic viruses.