Discovery, Characterization and Engineering of the Free l-Histidine C4-Prenyltransferase.

Prenylation of amino acids is a critical step for synthesizing building blocks of prenylated alkaloid family natural products, where the corresponding prenyltransferase that catalyzes prenylation on free l-histidine (l-His) has not yet been identified. Here, we first discovered and characterized a prenyltransferase FunA from the antifungal agent fungerin pathway that efficiently performs C4-dimethylallylation on l-His. Crystal structure-guided engineering of the prenyl-binding pocket of FunA, a single M181A mutation, successfully converted it into a C4-geranyltransferase. Furthermore, FunA and its variant FunA-M181A show broad substrate promiscuity toward substrates that vary in substituents of the imidazole ring. Our work furthers our knowledge of free amino acid prenyltransferase and expands the arsenal of alkylation biocatalysts for imidazole-containing small molecules.

Accumulated ß-catenin is associated with human atrial fibrosis and atrial fibrillation.

BACKGROUND: Atrial fibrillation (AF) is associated with increased risk of stroke and mortality. It has been reported that the process of atrial fibrosis was regulated by ß-catenin in rats with AF. However, pathophysiological mechanisms of this process in human with AF remain unclear. This study aims to investigate the possible mechanisms of ß-catenin in participating in the atrial fibrosis using human right atrial appendage (hRAA) tissues . METHODS: We compared the difference of ß-catenin expression in hRAA tissues between the patients with AF and sinus rhythm (SR). The possible function of ß-catenin in the development of AF was also explored in mice and primary cells. RESULTS: Firstly, the space between the membrane of the gap junctions of cardiomyocytes was wider in the AF group. Secondly, the expression of the gap junction function related proteins, Connexin40 and Connexin43, was decreased, while the expression of ß-catenin and its binding partner E-cadherin was increased in hRAA and cardiomyocytes of the AF group. Thirdly, ß-catenin colocalized with E-cadherin on the plasma membrane of cardiomyocytes in the SR group, while they were dissociated and accumulated intracellularly in the AF group. Furthermore, the expression of glycogen synthase kinase 3ß (GSK-3ß) and Adenomatous Polyposis Coli (APC), which participated in the degradation of ß-catenin, was decreased in hRAA tissues and cardiomyocytes of the AF group. Finally, the development of atrial fibrosis and AF were proved to be prevented after inhibiting ß-catenin expression in the AF model mice. CONCLUSIONS: Based on human atrial pathological and molecular analyses, our findings provided evidence that ß-catenin was associated with atrial fibrosis and AF progression.

Axo-axonic synaptic input drives homeostatic plasticity by tuning the axon initial segment structurally and functionally.

Homeostatic plasticity maintains the stability of functional brain networks. The axon initial segment (AIS), where action potentials start, undergoes dynamic adjustment to exert powerful control over neuronal firing properties in response to network activity changes. However, it is poorly understood whether this plasticity involves direct synaptic input to the AIS. Here, we show that changes of GABAergic synaptic input from chandelier cells (ChCs) drive homeostatic tuning of the AIS of principal neurons (PNs) in the prelimbic (PL) region, while those from parvalbumin-positive basket cells do not. This tuning is evident in AIS morphology, voltage-gated sodium channel expression, and PN excitability. Moreover, the impact of this homeostatic plasticity can be reflected in animal behavior. Social behavior, inversely linked to PL PN activity, shows time-dependent alterations tightly coupled to changes in AIS plasticity and PN excitability. Thus, AIS-originated homeostatic plasticity in PNs may counteract deficits elicited by imbalanced ChC presynaptic input at cellular and behavioral levels.

[Effects of Dexmedetomidine on the Recovery Quality of Donors Undergoing Pure Laparoscopic Donor Hepatectomy]. / å³ç¾Žæ‰˜å’ªå®šå¯¹è ¹è ”é•œä¾›è‚èŽ·å–æœ¯ä¾›è€ è‹é†’æœŸæ¢å¤è´¨é‡çš„å½±å“.

Objective: To investigate the effects of intraoperative intravenous administration of dexmedetomidine (DEX) on the recovery quality of donors undergoing pure laparoscopic donor hepatectomy. Methods: A total of 56 liver donors who were going to undergo scheduled pure laparoscopic donor hepatectomy were enrolled and randomly assigned to two groups, a DEX group ( n=28) and a control group ( n=28). Donors in the DEX group received DEX infusion at a dose of 1 µg/kg over 15 minutes through a continuous pump, which was followed by DEX at 0.4 µg/(kg·h) until the disconnection of the portal branch. Donors in the control group were given an equal volume of 0.9% normal saline at the same infusion rate and over the same period of time as those of the dex infusion in the DEX group. The primary outcome was the incidence of emergence agitation (EA). The Aono's Four-point Scale (AFPS) score was used to assess EA. The secondary observation indicators included intraoperative anesthesia and surgery conditions, spontaneous respiration recovery time, recovery time, extubation time, scores for the Ramsay Sedation Scale, the incidence of chills, numeric rating scale (NRS) score for pain, and blood pressure and heart rate after extubation. Results: The incidence of EA was 10.7% and 39.3% in the DEX group and the control group, respectively, and the incidence of EA was significantly lower in the DEX group than that in the control group ( P=0.014). The APFS scores after extubation in the DEX group were lower than those in the control group (1 [1, 1] vs. 2 [1, 3], P=0.005). Compared to the control group, the dosages of intraoperative propofol and remifentanil were significantly reduced in the DEX group ( P<0.05). During the recovery period, the number of donors requiring additional boluses of analgesia, the blood pressure, and the heart rate were all lower in the DEX group than those in the control group ( P<0.05). No significant differences between the two groups were observed in the spontaneous respiration recovery time, recovery time, extubation time, the incidence of chills, NRS score, scores for the Ramsay Sedation Scale, and the length-of-stay in postanesthesia care unit (PACU) ( P>0.05). Conclusion: DEX can reduce the incidence of EA after pure laparoscopic donor hepatectomy and improve the quality of recovery without prolonging postoperative recovery time or extubation time.

Analysis of factors influencing the recurrence of diabetic foot ulcers.

OBJECTIVE: The aim of this study is to investigate the factors influencing the recurrence of diabetic foot ulcers (DFU) and provide guidance for reducing the recurrence rate. METHODS: A total of 211 patients diagnosed with DFU who were hospitalized and discharged from the hospital from October 2015 to January 2020 were included as the study cohort. Participants were divided into two groups according to whether the foot ulcer recurred during the 2-year follow-up period: a recurrence group (n = 84) and a non-recurrence group (n = 127). The following data were collected and analyzed for the two groups of patients: general information, foot information, laboratory indicators, diabetes comorbidities, and complications. RESULTS: (1) The overall recurrence rate of diabetic foot ulcers (DFU) within 2 years was 39.8%, indicating a high recurrence rate. (2) Significant differences were observed between the two patient groups in terms of BMI, HbA1c, TBIL, CRP, financial situation, foot deformity, first ulcer on the sole of the foot, previous amputation history, Wagner grade of the first ulcer, osteomyelitis, DFU duration (>60 days), lower limb vascular reconstruction, peripheral arterial disease (PAD), and diabetic peripheral neuropathy (DPN) (t = 2.455; Z = -1.988, -3.731, -3.618; χ2 = 7.88, 5.004, 3.906, 17.178, 16.237, 5.007, 24.642, 4.782, 29.334, 10.253). No significant differences were found for the other indicators. (3) Logistic regression analysis revealed that TBIL (OR = 0.886, p = 0.036) was a protective factor against ulcer recurrence. In contrast, PAD, previous amputation history, DPN, and the first ulcer on the sole of the foot (OR = 3.987, 6.758, 4.681, 2.405; p < 0.05 or p < 0.01) were identified as risk factors for ulcer recurrence. CONCLUSION: Early screening and preventive education targeting high-risk factors such as DPN, PAD and the initial ulcer location on the sole of the foot are essential to mitigate the high long-term recurrence rate of DFU. Furthermore, the protective role of TBIL in preventing ulcer recurrence underscores the importance of monitoring bilirubin levels as part of a comprehensive management strategy for DFU patients.

KDM1A/LSD1 inhibition enhances chemotherapy response in ovarian cancer.

Ovarian cancer (OCa) is the deadliest of all gynecological cancers. The standard treatment for OCa is platinum-based chemotherapy, such as carboplatin or cisplatin in combination with paclitaxel. Most patients are initially responsive to these treatments; however, nearly 90% will develop recurrence and inevitably succumb to chemotherapy-resistant disease. Recent studies have revealed that the epigenetic modifier lysine-specific histone demethylase 1A (KDM1A/LSD1) is highly overexpressed in OCa. However, the role of KDM1A in chemoresistance and whether its inhibition enhances chemotherapy response in OCa remains uncertain. Analysis of TCGA datasets revealed that KDM1A expression is high in patients who poorly respond to chemotherapy. Western blot analysis show that treatment with chemotherapy drugs cisplatin, carboplatin, and paclitaxel increased KDM1A expression in OCa cells. KDM1A knockdown (KD) or treatment with KDM1A inhibitors NCD38 and SP2509 sensitized established and patient-derived OCa cells to chemotherapy drugs in reducing cell viability and clonogenic survival and inducing apoptosis. Moreover, knockdown of KDM1A sensitized carboplatin-resistant A2780-CP70 cells to carboplatin treatment and paclitaxel-resistant SKOV3-TR cells to paclitaxel. RNA-seq analysis revealed that a combination of KDM1A-KD and cisplatin treatment resulted in the downregulation of genes related to epithelial-mesenchymal transition (EMT). Interestingly, cisplatin treatment increased a subset of NF-κB pathway genes, and KDM1A-KD or KDM1A inhibition reversed this effect. Importantly, KDM1A-KD, in combination with cisplatin, significantly reduced tumor growth compared to a single treatment in an orthotopic intrabursal OCa xenograft model. Collectively, these findings suggest that combination of KDM1A inhibitors with chemotherapy could be a promising therapeutic approach for the treatment of OCa.

Thermoelectric Properties Regulated by Quantum Size Effects in Quasi-One-Dimensional γ-Graphdiyne Nanoribbons.

Using density functional theory combined with the first principles calculation method of non-equilibrium Green's function (NEGF-DFT), we studied the thermoelectric (TE) characteristics of one-dimensional γ-graphdiyne nanoribbons (γ-GDYNRs). The study found that the thermal conductivity of γ-GDYNRs has obvious anisotropy. At the same temperature and geometrical size, the lattice thermal conductivity of zigzag-edged γ-graphdiyne nanoribbons (γ-ZGDYNRs) is much lower than that of armchair-edged γ-graphdiyne nanoribbons (γ-AGDYNRs). We disclose the underlying mechanism for this intrinsic orientation. That is, γ-AGDYNRs have more phonon dispersion over the entire frequency range. Furthermore, the orientation dependence increases when the width of the γ-GDYNRs decreases. These excellent TE properties allow armchair-edged γ-graphdiyne nanoribbons with a planar width of 1.639 nm (γ-Z(2)GDYNRs) to have a higher power factor and lower thermal conductivity, ultimately resulting in a significantly higher TE conversion rate than other γ-GDYNR structures.

Degenerative and regenerative peripheral processes are associated with persistent painful chemotherapy-induced neuropathies in males and females.

This study investigated the time course of gene expression changes during the progression of persistent painful neuropathy caused by paclitaxel (PTX) in male and female mouse hindpaws and dorsal root ganglia (DRG). Bulk RNA-seq was used to examine these gene expression changes at 1, 16, and 31 days post-last PTX. At these time points, differentially expressed genes (DEGs) were predominantly related to the reduction or increase in epithelial, skin, bone, and muscle development and to angiogenesis, myelination, axonogenesis, and neurogenesis. These processes are accompanied by the regulation of DEGs related to the cytoskeleton, extracellular matrix organization, and cellular energy production. This gene plasticity during the progression of persistent painful neuropathy could be interpreted as a biological process linked to tissue regeneration/degeneration. In contrast, gene plasticity related to immune processes was minimal at 1-31 days after PTX. It was also noted that despite similarities in biological processes and pain chronicity between males and females, specific DEGs differed dramatically according to sex. The main conclusions of this study are that gene expression plasticity in hindpaw and DRG during PTX neuropathy progression similar to tissue regeneration and degeneration, minimally affects immune system processes and is heavily sex-dependent at the individual gene level.

The Research Progress of Magnesium Alloy Building Formwork.

Building formwork is a kind of temporary supporting structure consumable material used in the construction field. In recent years, building formwork has gradually developed to become lighter, more environmentally friendly, and have higher performance. This sets higher requirements for the materials used to make building formwork. There is an urgent need to find a lighter and more durable material for building formwork. Magnesium alloys possess the advantages of low density, high alkali resistance, and high strength. As a building formwork material, it can reduce the weight of formwork and improve its durability. Therefore, a magnesium alloy is considered a material with high potential for building formwork. Currently, magnesium alloy building formwork has attracted the attention of many companies and research and development institutions, with preliminary research applications and good feedback on usage effects. It is highly possible to obtain the opportunity to put it into market application. However, to be applied on a large scale, there are still some important problems that need to be solved. These problems fall into three main areas, including the relatively low processing efficiency of magnesium alloy materials, the unstable price of magnesium alloys, and the fact that the formwork is easily corroded during storage. Firstly, at present, the main processing methods for magnesium alloy building formwork are casting and extrusion, and the production efficiency of both methods needs to be improved. Secondly, high-performance magnesium alloy materials are usually more expensive, which is not conducive to the large-scale application of the formwork. The price of magnesium alloys has fluctuated greatly in recent years, which increases the difficulty of promoting magnesium alloy building formwork. Thirdly, in the atmosphere, the oxide film on the surface of the magnesium alloy cannot play an effective role in corrosion resistance. So, surface treatment is necessary for magnesium alloy building formwork. Among the various surface treatment methods for magnesium alloys, the chemical conversion method has the advantages of being easy to operate, cost-effective, and having good corrosion resistance. It may be a very suitable protective method for large-scale applications of magnesium alloy building formwork and possesses excellent potential for application. The future of magnesium alloy building formwork will focus on new low-cost materials, high-efficiency processing technology, and low-cost green anti-corrosion technology. With in-depth research and the maturation of technology, magnesium alloy formwork is expected to play a more important role in the construction industry.

Dysregulated expression of miR-140 and miR-122 compromised microglial chemotaxis and led to reduced restriction of AD pathology.

BACKGROUND: Deposition of amyloid ß, which is produced by amyloidogenic cleavage of APP by ß- and γ-secretase, is one of the primary hallmarks of AD pathology. APP can also be processed by α- and γ-secretase sequentially, to generate sAPPα, which has been shown to be neuroprotective by promoting neurite outgrowth and neuronal survival, etc. METHODS: The global expression profiles of miRNA in blood plasma samples taken from 11 AD patients as well as from 14 age and sex matched cognitively normal volunteers were analyzed using miRNA-seq. Then, overexpressed miR-140 and miR-122 both in vivo and in vitro, and knock-down of the endogenous expression of miR-140 and miR-122 in vitro. Used a combination of techniques, including molecular biology, immunohistochemistry, to detect the impact of miRNAs on AD pathology. RESULTS: In this study, we identified that two miRNAs, miR-140-3p and miR-122-5p, both targeting ADAM10, the main α-secretase in CNS, were upregulated in the blood plasma of AD patients. Overexpression of these two miRNAs in mouse brains induced cognitive decline in wild type C57BL/6J mice as well as exacerbated dyscognition in APP/PS1 mice. Although significant changes in APP and total Aß were not detected, significantly downregulated ADAM10 and its non-amyloidogenic product, sAPPα, were observed in the mouse brains overexpressing miR-140/miR-122. Immunohistology analysis revealed increased neurite dystrophy that correlated with the reduced microglial chemotaxis in the hippocampi of these mice, independent of the other two ADAM10 substrates (neuronal CX3CL1 and microglial TREM2) that were involved in regulating the microglial immunoactivity. Further in vitro analysis demonstrated that both the reduced neuritic outgrowth of mouse embryonic neuronal cells overexpressing miR-140/miR-122 and the reduced Aß phagocytosis in microglia cells co-cultured with HT22 cells overexpressing miR-140/miR-122 could be rescued by overexpressing the specific inhibitory sequence of miR-140/miR-122 TuD as well as by addition of sAPPα, rendering these miRNAs as potential therapeutic targets. CONCLUSIONS: Our results suggested that neuroprotective sAPPα was a key player in the neuropathological progression induced by dysregulated expression of miR-140 and miR-122. Targeting these miRNAs might serve as a promising therapeutic strategy in AD treatment.

The effects of bitter melon (Momordica charantia) on anthropometric indices in adults: A systematic review and meta-analysis of randomized controlled trials.

There is controversial data on the impacts of bitter melon (Momordica charantia) supplementations on anthropometric indices. Thus, we aimed to clarify this role of bitter melon through a systematic review, and meta-analysis of the trials. All clinical trials conducted on the impact of bitter melon on anthropometric indices were published until August 2023 in PubMed, Web of Sciences, Scopus, Embase, and Cochrane Library web databases included. Overall, 10 studies with 448 individuals were included in the meta-analysis. Meta-analysis of 10 trials with 448 participants revealed no significant reductions in body weight (BW) (WMD: 0.04 Kg; 95 %CI: -0.16-0.25; P =0.651), body mass index (BMI) (WMD: -0.18 kg/m2; 95 %CI: -0.43-0.07; P =0.171), waist circumference (WC) (WMD: -0.95 cm; 95 % CI: -3.05-1.16; p =0.372), and percentage of body fat (PBF) (WMD: -0.99; 95 % CI: -2.33-0.35; p =0.141) following bitter melon supplementation. There was no significant impact of bitter melon supplementation on BW, BMI, WC, and PBF. More large-scale and high-quality RCTs are necessary to confirm these results.

Towards mixed physical node reservoir computing: light-emitting synaptic reservoir system with dual photoelectric output.

Memristor-based physical reservoir computing holds significant potential for efficiently processing complex spatiotemporal data, which is crucial for advancing artificial intelligence. However, owing to the single physical node mapping characteristic of traditional memristor reservoir computing, it inevitably induces high repeatability of eigenvalues to a certain extent and significantly limits the efficiency and performance of memristor-based reservoir computing for complex tasks. Hence, this work firstly reports an artificial light-emitting synaptic (LES) device with dual photoelectric output for reservoir computing, and a reservoir system with mixed physical nodes is proposed. The system effectively transforms the input signal into two eigenvalue outputs using a mixed physical node reservoir comprising distinct physical quantities, namely optical output with nonlinear optical effects and electrical output with memory characteristics. Unlike previously reported memristor-based reservoir systems, which pursue rich reservoir states in one physical dimension, our mixed physical node reservoir system can obtain reservoir states in two physical dimensions with one input without increasing the number and types of devices. The recognition rate of the artificial light-emitting synaptic reservoir system can achieve 97.22% in MNIST recognition. Furthermore, the recognition task of multichannel images can be realized through the nonlinear mapping of the photoelectric dual reservoir, resulting in a recognition accuracy of 99.25%. The mixed physical node reservoir computing proposed in this work is promising for implementing the development of photoelectric mixed neural networks and material-algorithm collaborative design.

A photothermal surface modified with polyelectrolyte multilayers for gene transfection and cell harvest.

Gene transfection, which involves introducing nucleic acids into cells, is a pivotal technology in the life sciences and medical fields, particularly in gene therapy. Surface-mediated transfection, primarily targeting cells adhering to surfaces, shows promise for enhancing cell transfection by localizing and presenting surface-bound nucleic acids directly to the cells. However, optimizing endocytosis for efficient delivery remains a persistent challenge. Additionally, ensuring efficient and non-traumatic cell harvest capability is crucial for applications such as ex vivo cell-based therapy. To address these challenges, we developed a photothermal platform with enzymatic degradation capability for efficient gene transfection and cell harvest. This platform is based on carbon nanotubes (CNTs) doped with poly(dimethylsiloxane) and modified with polyelectrolyte multilayers (PEMs) containing hyaluronic acid and quaternized chitosan, allowing for substantial loading of poly(ethyleneimine)/plasmid DNA (pDNA) complexes through electrostatic interactions. Upon irradiation of near-infrared laser, the photothermal properties of CNTs enable high transfection efficiency by delivering pDNA into attached cells via a membrane disruption mechanism. The engineered cells can be harvested by treating with a non-toxic hyaluronidase solution to degrade PEMs, thus maintaining good viability for further applications. This platform has demonstrated remarkable efficacy across various cell lines (including Hep-G2 cells, Ramos cells and primary T cells), achieving a transfection efficiency exceeding 95 %, cell viability exceeding 90 %, and release efficiency surpassing 95 %, highlighting its potential for engineering living cells.

Allosterically activating SHP2 by oleanolic acid inhibits STAT3-Th17 axis for ameliorating colitis.

Src homology 2 domain-containing tyrosine phosphatase 2 (SHP2) is an essential tyrosine phosphatase that is pivotal in regulating various cellular signaling pathways such as cell growth, differentiation, and survival. The activation of SHP2 has been shown to have a therapeutic effect in colitis and Parkinson's disease. Thus, the identification of SHP2 activators and a complete understanding of their mechanism is required. We used a two-step screening assay to determine a novel allosteric activator of SHP2 that stabilizes it in an open conformation. Oleanolic acid was identified as a suitable candidate. By binding to R362, K364, and K366 in the active center of the PTP domain, oleanolic acid maintained the active open state of SHP2, which facilitated the binding between SHP2 and its substrate. This oleanolic acid-activated SHP2 hindered Th17 differentiation by disturbing the interaction between STAT3 and IL-6Rα and inhibiting the activation of STAT3. Furthermore, via the activation of SHP2 and subsequent attenuation of the STAT3-Th17 axis, oleanolic acid effectively mitigated colitis in mice. This protective effect was abrogated by SHP2 knockout or administration of the SHP2 inhibitor SHP099. These findings underscore the potential of oleanolic acid as a promising therapeutic agent for treating inflammatory bowel diseases.

Disruption of recombination machinery alters the mutational landscape in plant organellar genomes.

Land plant organellar genomes have extremely low rates of point mutation yet also experience high rates of recombination and genome instability. Characterizing the molecular machinery responsible for these patterns is critical for understanding the evolution of these genomes. While much progress has been made towards understanding recombination activity in land plant organellar genomes, the relationship between recombination pathways and point mutation rates remains uncertain. The organellar targeted mutS homolog MSH1 has previously been shown to suppress point mutations as well as non-allelic recombination between short repeats in Arabidopsis thaliana. We therefore implemented high-fidelity Duplex Sequencing to test if other genes that function in recombination and maintenance of genome stability also affect point mutation rates. We found small to moderate increases in the frequency of single nucleotide variants (SNVs) and indels in mitochondrial and/or plastid genomes of A. thaliana mutant lines lacking radA, recA1, or recA3. In contrast, osb2 and why2 mutants did not exhibit an increase in point mutations compared to wild type (WT) controls. In addition, we analyzed the distribution of SNVs in previously generated Duplex Sequencing data from A. thaliana organellar genomes and found unexpected strand asymmetries and large effects of flanking nucleotides on mutation rates in WT plants and msh1 mutants. Finally, using long-read Oxford Nanopore sequencing, we characterized structural variants in organellar genomes of the mutant lines and show that different short repeat sequences become recombinationally active in different mutant backgrounds. Together, these complementary sequencing approaches shed light on how recombination may impact the extraordinarily low point mutation rates in plant organellar genomes.

Dispersal limitation and environmental filtering effects: The taxonomic and functional beta diversity of ground beetles along the altitudinal gradient in Chinese warm-temperature forests.

Beta diversity patterns along environmental gradients and underlying mechanisms constitute key research inquiries in biogeography. However, ecological processes often also influence the functional traits of biological communities, making the assessment of functional ß-diversity crucial. Ground beetles (Coleoptera: Carabidae) are one of the most species-rich groups in the insect community, displaying strong habitat specificity and morphological differences. In this study, we explored the patterns of taxonomic and functional beta diversity in ground beetle communities along the altitudinal gradient of warm-temperature forests. By partitioning beta diversity into turnover and nestedness components, we evaluated their relationship with spatial distance. Our findings indicate a decline in species and functional trait similarity with increasing elevation and geographic distance. Further analysis attributed both types of beta diversity in carabids to a combination of dispersal limitation and environmental filtering, with elevation and geographic distance emerging as significant factors. Interestingly, forest-type variations were found to have no impact on the beta diversity of these communities. Our study reveals the impact of environmental filtering and dispersal limitation on both taxonomic and functional beta-diversity, shedding light on carabid community assembly in localized warm-temperature forest areas in eastern China.

Impact of prostate MRI image quality on diagnostic performance for clinically significant prostate cancer (csPCa).

OBJECTIVES: With the widespread clinical application of prostate magnetic resonance imaging (MRI), there has been an increasing demand for lesion detection and accurate diagnosis in prostate MR, which relies heavily on satisfactory image quality. Focusing on the primary sequences involved in Prostate Imaging Reporting and Data System (PI-RADS), this study have evaluated common quality issues in clinical practice (such as signal-to-noise ratio (SNR), artifacts, boundaries, and enhancement). The aim of the study was to determine the impact of image quality on clinically significant prostate cancer (csPCa) detection, positive predictive value (PPV) and radiologist's diagnosis in different sequences and prostate zones. METHODS: This retrospective study included 306 patients who underwent prostate MRI with definitive pathological reports from February 2021 to December 2022. All histopathological specimens were evaluated according to the recommendations of the International Society of Urological Pathology (ISUP). An ISUP Grade Group ≥ 2 was considered as csPCa. Three radiologists from different centers respectively performed a binary classification assessment of image quality in the following ten aspects: (1) T2WI in the axial plane: SNR, prostate boundary conditions, the presence of artifacts; (2) T2WI in the sagittal or coronal plane: prostate boundary conditions; (3) DWI: SNR, delineation between the peripheral and transition zone, the presence of artifacts, the matching of DWI and T2WI images; (4) DCE: the evaluation of obturator artery enhancement, the evaluation of dynamic contrast enhancement. Fleiss' Kappa was used to determine the inter-reader agreement. Wilson's 95% confidence interval (95% CI) was used to calculate PPV. Chi-square test was used to calculate statistical significance. A p-value < 0.05 was considered statistically significant. RESULTS: High-quality images had a higher csPCa detection rate (56.5% to 64.3%) in axial T2WI, DWI, and DCE, with significant statistical differences in SNR in axial T2WI (p 0.002), the presence of artifacts in axial T2WI (p 0.044), the presence of artifacts in DWI (p < 0.001), and the matching of DWI and T2WI images (p < 0.001). High-quality images had a higher PPV (72.5% to 78.8%) and showed significant statistical significance in axial T2WI, DWI, and DCE. Additionally, we found that PI-RADS 3 (24.0% to 52.9%) contained more low-quality images compared to PI-RADS 4-5 (20.6% to 39.3%), with significant statistical differences in the prostate boundary conditions in axial T2WI (p 0.048) and the presence of artifacts in DWI (p 0.001). Regarding the relationship between csPCa detection and image quality in different prostate zones, this study found that significant statistical differences were only observed between high- (63.5% to 75.7%) and low-quality (30.0% to 50.0%) images in the peripheral zone (PZ). CONCLUSION: Prostate MRI quality may have an impact on the diagnostic performance. The poorer image quality is associated with lower csPCa detection rates and PPV, which can lead to an increase in radiologist's ambiguous diagnosis (PI-RADS 3), especially for the lesions located at PZ.

Energy competition remodels the metabolic glucose landscape of psoriatic epidermal cells.

Rationale: Skin cells actively metabolize nutrients to ensure cell proliferation and differentiation. Psoriasis is an immune-disorder-related skin disease with hyperproliferation in epidermal keratinocytes and is increasingly recognized to be associated with metabolic disturbance. However, the metabolic adaptations and underlying mechanisms of epidermal hyperproliferation in psoriatic skin remain largely unknown. Here, we explored the role of metabolic competition in epidermal cell proliferation and differentiation in psoriatic skin. Methods: Bulk- and single-cell RNA-sequencing, spatial transcriptomics, and glucose uptake experiments were used to analyze the metabolic differences in epidermal cells in psoriasis. Functional validation in vivo and in vitro was done using imiquimod-like mouse models and inflammatory organoid models. Results: We observed the highly proliferative basal cells in psoriasis act as the winners of the metabolic competition to uptake glucose from suprabasal cells. Using single-cell metabolic analysis, we found that the "winner cells" promote OXPHOS pathway upregulation by COX7B and lead to increased ROS through glucose metabolism, thereby promoting the hyperproliferation of basal cells in psoriasis. Also, to prevent toxic damage from ROS, basal cells activate the glutathione metabolic pathway to increase their antioxidant capacity to assist in psoriasis progression. We further found that COX7B promotes psoriasis development by modulating the activity of the PPAR signaling pathway by bulk RNA-seq analysis. We also observed glucose starvation and high expression of SLC7A11 that causes suprabasal cell disulfide stress and affects the actin cytoskeleton, leading to immature differentiation of suprabasal cells in psoriatic skin. Conclusion: Our study demonstrates the essential role of cellular metabolic competition for skin tissue homeostasis.

On-chip photonic convolution by phase-change in-memory computing cells with quasi-continuous tuning.

Matrix multiplication acceleration by on-chip photonic integrated circuits (PICs) is emerging as one of the attractive and promising solutions, offering outstanding benefits in speed and bandwidth as compared to non-photonic approaches. Incorporating nonvolatile phase-change materials into PICs or devices enables optical storage and computing, surpassing their electrical counterparts. In this paper, we propose a design of on-chip photonic convolution for optical in-memory computing by integrating the phase change chalcogenide of Ge2Sb2Se4Te1 (GSST) into an asymmetric directional coupler for constructions of an in-memory computing cell, marrying the advantages of both the large bandwidth of Mach-Zehnder interferometers (MZIs) and the small size of micro-ring resonators (MRRs). Through quasi-continuous electro-thermal tuning of the GSST-integrated in-memory computing cells, numerical calculations about the optical and electro-thermal behaviors during GSST phase transition confirm the tunability of the programmable elements stored in the in-memory computing cells within [-1, 1]. For proof-of-concept verification, we apply the proposed optical convolutional kernel to a typical image edge detection application. As evidenced by the evaluation results, the prototype achieves the same accuracy as the convolution kernel implemented on a common digital computer, demonstrating the feasibility of the proposed scheme for on-chip photonic convolution and optical in-memory computing.

The Role and Treatment Strategies of Ammonia-Related Metabolism in Tumor Microenvironment.

Tumor cells achieve their adaptability through various metabolic reprogramming processes. Among them, ammonia, as a traditional metabolic waste, plays an increasingly important role in the tumor microenvironment along with its associated metabolites. Other cells in the microenvironment can also reshape the immune status of the microenvironment by regulating ammonia-related metabolism, and targeting this metabolic aspect has emerged as a potential strategy for tumor treatment. In this study, we have systematically reviewed the source and destination of ammonia in tumor cells, as well as the links between ammonia and other biological processes. We have also analyzed the ammonia-related metabolic regulation of other cells (including T cells, macrophages, dendritic cells, natural killer cells, myeloid-derived suppressor cells, and stromal cells) in the tumor microenvironment, and summarized the tumor treatment methods that target this metabolism. Through ammonia-related metabolic reprogramming, tumor cells obtain the energy they need for rapid growth and proliferation. Multiple immune cells and stromal cells in the microenvironment also interact with each other through this metabolic regulation, ultimately leading to immune suppression. Despite the heterogeneity of tumors and the complexity of cellular functions, further research into therapeutic interventions targeting ammonia-related metabolism is warranted. This review has focused on the role and regulation of ammonia-related metabolism in tumor cells and other cells in the microenvironment, and highlighted the efficacy and prospects of targeted ammonia-related metabolism therapy.