Prognostic and immunological implications of heterogeneous cell death patterns in prostate cancer.

BACKGROUND: Prostate cancer is one of the most common cancers in men with a significant proportion of patients developing biochemical recurrence (BCR) after treatment. Programmed cell death (PCD) mechanisms are known to play critical roles in tumor progression and can potentially serve as prognostic and therapeutic biomarkers in PCa. This study aimed to develop a prognostic signature for BCR in PCa using PCD-related genes. MATERIALS AND METHODS: We conducted an analysis of 19 different modes of PCD to develop a comprehensive model. Bulk transcriptomic, single-cell transcriptomic, genomic, and clinical data were collected from multiple cohorts, including TCGA-PRAD, GSE58812, METABRIC, GSE21653, and GSE193337. We analyzed the expression and mutations of the 19 PCD modes and constructed, evaluated, and validated the model. RESULTS: Ten PCD modes were found to be associated with BCR in PCa, with specific PCD patterns exhibited by various cell components within the tumor microenvironment. Through Lasso Cox regression analysis, we established a Programmed Cell Death Index (PCDI) utilizing an 11-gene signature. High PCDI values were validated in five independent datasets and were found to be associated with an increased risk of BCR in PCa patients. Notably, older age and advanced T and N staging were associated with higher PCDI values. By combining PCDI with T staging, we constructed a nomogram with enhanced predictive performance. Additionally, high PCDI values were significantly correlated with decreased drug sensitivity, including drugs such as Docetaxel and Methotrexate. Patients with lower PCDI values demonstrated higher immunophenoscores (IPS), suggesting a potentially higher response rate to immune therapy. Furthermore, PCDI was associated with immune checkpoint genes and key components of the tumor microenvironment, including macrophages, T cells, and NK cells. Finally, clinical specimens validated the differential expression of PCDI-related PCDRGs at both the gene and protein levels. CONCLUSION: In conclusion, we developed a novel PCD-based prognostic feature that successfully predicted BCR in PCa patients and provided insights into drug sensitivity and potential response to immune therapy. These findings have significant clinical implications for the treatment of PCa.

Mutations in VWA8 cause autosomal-dominant retinitis pigmentosa via aberrant mitophagy activation.

BACKGROUND: Although retinitis pigmentosa (RP) is the most common type of hereditary retinal dystrophy, approximately 25%-45% of cases remain without a molecular diagnosis. von Willebrand factor A domain containing 8 (VWA8) encodes a mitochondrial matrix-targeted protein; its molecular function and pathogenic mechanism in RP remain unexplained. METHODS: Family members of patients with RP underwent ophthalmic examinations, and peripheral blood samples were collected for exome sequencing, ophthalmic targeted sequencing panel and Sanger sequencing. The importance of VWA8 in retinal development was demonstrated by a zebrafish knockdown model and cellular and molecular analysis. RESULTS: This study recruited a Chinese family of 24 individuals with autosomal-dominant RP and conducted detailed ophthalmic examinations. Exome sequencing analysis of six patients revealed heterozygous variants in VWA8, namely, the missense variant c.3070G>A (p.Gly1024Arg) and nonsense c.4558C>T (p.Arg1520Ter). Furthermore, VWA8 expression was significantly decreased both at the mRNA and protein levels. The phenotypes of zebrafish with VWA8 knockdown are similar to those of clinical individuals harbouring VWA8 variants. Moreover, VWA8 defects led to severe mitochondrial damage, resulting in excessive mitophagy and the activation of apoptosis. CONCLUSIONS: VWA8 plays a significant role in retinal development and visual function. This finding may provide new insights into RP pathogenesis and potential genes for molecular diagnosis and targeted therapy.

Polystyrene nanoplastics exposure causes erectile dysfunction in rats.

Polystyrene nanoplastics (PS-NPs), emerging and increasingly pervasive environmental contaminants, have the potential to cause persistent harm to organisms. Although previous reports have documented local accumulation and adverse effects in a variety of major organs after PS-NPs exposure, the impact of PS-NPs exposure on erectile function remains unexplored. Herein, we established a rat model of oral exposure to 100 nm PS-NPs for 28 days. To determine the best dose range of PS-NPs, we designed both low-dose and high-dose PS-NPs groups, which correspond to the minimum and maximum human intake doses, respectively. The findings indicated that PS-NPs could accumulate within the corpus cavernosum and high dose but not low dose of PS-NPs triggered erectile dysfunction. Moreover, the toxicological effects of PS-NPs on erectile function include fibrosis in the corpus cavernous, endothelial dysfunction, reduction in testosterone levels, elevated oxidative stress and apoptosis. Overall, this study revealed that PS-NPs exposure can cause erectile dysfunction via multiple ways, which provided new insights into the toxicity of PS-NPs.

Optimal Strategies of Quantum Metrology with a Strict Hierarchy.

One of the main quests in quantum metrology is to attain the ultimate precision limit with given resources, where the resources are not only of the number of queries, but more importantly of the allowed strategies. With the same number of queries, the restrictions on the strategies constrain the achievable precision. In this Letter, we establish a systematic framework to identify the ultimate precision limit of different families of strategies, including the parallel, the sequential, and the indefinite-causal-order strategies, and provide an efficient algorithm that determines an optimal strategy within the family of strategies under consideration. With our framework, we show there exists a strict hierarchy of the precision limits for different families of strategies.

Association of the NLR, BNP, PCT, CRP, and D-D with the Severity of Community-Acquired Pneumonia in Older Adults.

BACKGROUND: This study aimed to investigate the value of the neutrophil-to-lymphocyte ratio (NLR), B-type natriuretic peptide (BNP), and D-dimer (D-D) in predicting pneumonia severity in older adults with community-acquired pneumonia (CAP). METHODS: The retrospective study included older adults with CAP at the General Hospital of Northern Theater Command from January 2017 to December 2019. Patient demographic information and clinical characteristics were collected. Logistic multivariable analysis was used to analyze the factors associated with CAP severity. Receiver operating curve (ROC) analysis was used to evaluate the value of each biomarker in severity prediction. RESULTS: A total of 158 patients were included: 85 with mild-moderate CAP and 73 with severe CAP. The multivariable logistic analysis showed that CRP (OR = 1.011; 95% CI: 1.011 - 1.022; p = 0.039), BNP (OR = 1.003; 95% CI: 1.001 - 1.004; p = 0.001), D-D (OR = 1.289; 95% CI: 1.031 - 1.611; p = 0.026), and NLR (OR = 1.111; 95% CI: 1.011 - 1.222; p = 0.030) were independent factors associated with pneumonia severity. ROC analysis demonstrated the value of each biomarker in pneumonia severity prediction: CRP (AUC = 0.791, 95% CI: 0.720 - 0.861), BNP (AUC = 0.803, 95% CI: 0.649 - 0.806), D-D (AUC = 0.727, 95% CI: 0.734 - 0.872), and NLR (AUC = 0.817, 95% CI: 0.751 - 0.883). The positive and negative predictive values were 0.68 and 0.81 for CRP, 0.79 and 0.75 for BNP, 0.62 and 0.80 for D-D, and 0.80 and 0.76 for NLR. CONCLUSIONS: CRP, BNP, D-D, and NLR might be helpful independent factors in predicting pneumonia severity in older adults with CAP.

Poly(A) binding KPAF4/5 complex stabilizes kinetoplast mRNAs in Trypanosoma brucei.

In Trypanosoma brucei, mitochondrial pre-mRNAs undergo 3'-5' exonucleolytic processing, 3' adenylation and uridylation, 5' pyrophosphate removal, and, often, U-insertion/deletion editing. The 3' modifications are modulated by pentatricopeptide repeat (PPR) Kinetoplast Polyadenylation Factors (KPAFs). We have shown that KPAF3 binding to the 3' region stabilizes properly trimmed transcripts and stimulates their A-tailing by KPAP1 poly(A) polymerase. Conversely, poly(A) binding KPAF4 shields the nascent A-tail from uridylation and decay thereby protecting pre-mRNA upon KPAF3 displacement by editing. While editing concludes in the 5' region, KPAF1/2 dimer induces A/U-tailing to activate translation. Remarkably, 5' end recognition and pyrophosphate hydrolysis by the PPsome complex also contribute to mRNA stabilization. Here, we demonstrate that KPAF4 functions as a heterodimer with KPAF5, a protein lacking discernable motifs. We show that KPAF5 stabilizes KPAF4 to enable poly(A) tail recognition, which likely leads to mRNA stabilization during the editing process and impedes spontaneous translational activation of partially-edited transcripts. Thus, KPAF4/5 represents a poly(A) binding element of the mitochondrial polyadenylation complex. We present evidence that RNA editing substrate binding complex bridges the 5' end-bound PPsome and 3' end-bound polyadenylation complexes. This interaction may enable mRNA circularization, an apparently critical element of mitochondrial mRNA stability and quality control.

Comparison of fluoxetine with other selective serotonin reuptake inhibitors in the treatment of premature ejaculation: A systematic review and meta-analysis.

The primary goal of this systematic review and meta-analysis was to compare the efficacy and safety of fluoxetine with other oral pharmaceuticals in the treatment of premature ejaculation (PE). We searched through databases including CNKI, PubMed, EMBASE and Cochrane to find research published up to 31 March 2022. PROSPERO was used to pre-register this meta-analysis (registration number CRD42022315459). Two separate writers extracted relevant details from all of the papers included in the study. To analyse the quality of literature publishing, we used the Cochrane risk of bias tool. The severity of premature ejaculation was determined using intravaginal ejaculatory latency time (IELT), and the effectiveness and safety of pharmacological interventions were determined using standardized mean difference (SMD) and risk ratio (RR) values with matching 95% confidence level intervals (95% CIs). Our meta-analysis includes a total of ten trials to investigate into the differences in treatment efficacy and safety between fluoxetine and other medicines. The findings revealed that fluoxetine was more effective than placebo in treating PE, whereas sertraline and paroxetine were more effective than fluoxetine (p < 0.05). The side effects of the medications were not significantly different, and they were all acceptable. The results of the sensitivity analysis were unaffected by the removal of any of the articles. There was no evidence of bias in the media. This meta-analysis examined the differences in efficacy and safety between fluoxetine and other oral medications and can be used by clinicians in the treatment of PE.

Toward High-Contrast Atomic Force Microscopy-Tip-Enhanced Raman Spectroscopy Imaging: Nanoantenna-Mediated Remote-Excitation on Sharp-Tip Silver Nanowire Probes.

The tip-enhanced Raman spectroscopy (TERS) imaging technique is designed to provide correlated morphological and chemical information with a nanoscale spatial resolution by utilizing the plasmonic resonance supported by metallic nanostructures at the tip apex of a scanning probe. However, limited by the scattering cross sections of these nanostructures, only a small fraction of the incident light can be coupled to the plasmonic resonance to generate Raman signals. The uncoupled light then directly excites background spectra with a diffraction-limited resolution, which becomes the background noise that often blurs the TERS image. Here, we demonstrate how this problem can be solved by physically separating the light excitation region from the Raman signal generation region on the scanning probe. The remote-excitation TERS (RE-TERS) probe, which can be fabricated with a facile, robust and reproducible method, utilizes silver nanoparticles as nanoantennas to mediate the coupling of free-space excitation light to propagating surface plasmon polaritons (SPPs) in a sharp-tip silver nanowire to excite Raman signals remotely. With this RE-TERS probe, a 10 nm spatial resolution was demonstrated on a single-walled carbon nanotube sample, and the strain distribution in a monolayer molybdenum disulfide (MoS2) was mapped.

Capillary-Force-Assisted Clean-Stamp Transfer of Two-Dimensional Materials.

A simple and clean method of transferring two-dimensional (2D) materials plays a critical role in the fabrication of 2D electronics, particularly the heterostructure devices based on the artificial vertical stacking of various 2D crystals. Currently, clean transfer techniques rely on sacrificial layers or bulky crystal flakes (e.g., hexagonal boron nitride) to pick up the 2D materials. Here, we develop a capillary-force-assisted clean-stamp technique that uses a thin layer of evaporative liquid (e.g., water) as an instant glue to increase the adhesion energy between 2D crystals and polydimethylsiloxane (PDMS) for the pick-up step. After the liquid evaporates, the adhesion energy decreases, and the 2D crystal can be released. The thin liquid layer is condensed to the PDMS surface from its vapor phase, which ensures the low contamination level on the 2D materials and largely remains their chemical and electrical properties. Using this method, we prepared graphene-based transistors with low charge-neutral concentration (3 × 1010 cm-2) and high carrier mobility (up to 48 820 cm2 V-1 s-1 at room temperature) and heterostructure optoelectronics with high operation speed. Finally, a capillary-force model is developed to explain the experiment.

Synthesis and assembly of Hepatitis B virus envelope protein-derived particles in Escherichia coli.

Hepatitis B virus (HBV) envelope particles have been synthesized in eukaryotic cells (e.g., mammalian cells, insect cells, and yeast cells) as an HB vaccine immunogen and drug delivery system (DDS) nanocarrier. Many researchers had made attempts to synthesize the particles in Escherichia coli for minimize the cost and time for producing HBV envelope particles, but the protein was too deleterious to be synthesized in E. coli. In this study, we generated deletion mutants of HBV envelope L protein (389 amino acid residues (aa)) containing three transmembrane domains (TM1, TM2, TM3). The ΔNC mutant spanning from TM2 to N-terminal half of TM3 (from 237 aa to 335 aa) was found as a shortest form showing spontaneous particle formation. After the N-terminal end of ΔNC mutant was optimized by the N-end rule for E. coli expression, the modified ΔNC mutant (mΔNC) was efficiently expressed as particles in E. coli. The molecular mass of mΔNC particle was approx. 670 kDa, and the diameter was 28.5 ± 6.2 nm (mean ± SD, N = 61). The particle could react with anti-HBV envelope S protein antibody, indicating the particles exhibited S antigenic domain outside as well as HBV envelope particles. Taken together, the E. coli-derived mΔNC particles could be used as a substitute of eukaryotic cell-derived HBV envelope particles for versatile applications.