A Homozygous Variant in NAA60 Is Associated with Primary Familial Brain Calcification.

BACKGROUND: Primary familial brain calcification (PFBC) is a monogenic disorder characterized by bilateral calcifications in the brain. The genetic basis remains unknown in over half of the PFBC patients, indicating the existence of additional novel causative genes. NAA60 was a recently reported novel causative gene for PFBC. OBJECTIVE: The aim was to identify the probable novel causative gene in an autosomal recessive inherited PFBC family. METHODS: We performed a comprehensive genetic study on a consanguineous Chinese family with 3 siblings diagnosed with PFBC. We evaluated the effect of the variant in a probable novel causative gene on the protein level using Western blot, immunofluorescence, and coimmunoprecipitation. Possible downstream pathogenic mechanisms were further explored in gene knockout (KO) cell lines and animal models. RESULTS: We identified a PFBC co-segregated homozygous variant of c.460_461del (p.D154Lfs*113) in NAA60. Functional assays showed that this variant disrupts NAA60 protein localization to Golgi and accelerated protein degradation. The mutant NAA60 protein alters its interaction with the PFBC-related proteins PiT2 and XPR1, affecting intracellular phosphate homeostasis. Further mass spectrometry analysis in NAA60 KO cell lines revealed decreased expression of multiple brain calcification-associated proteins, including reduced folate carrier (RFC), a folate metabolism-related protein. CONCLUSIONS: Our study replicated the identification of NAA60 as a novel causative gene for autosomal recessive PFBC, demonstrating our causative variant leads to NAA60 loss of function. The NAA60 loss of function disrupts not only PFBC-related proteins (eg, PiT2 and XPR1) but also a wide range of other brain calcification-associated membrane protein substrates (eg, RFC), and provided a novel probable pathogenic mechanism for PFBC. © 2024 International Parkinson and Movement Disorder Society.

Evaluation of phage-based decontamination in respiratory intensive care unit environments using ddPCR and 16S rRNA targeted sequencing techniques.

Background: Klebsiella pneumoniae is a major cause of hospital-acquired infections (HAIs), primarily spread through environmental contamination in hospitals. The effectiveness of current chemical disinfectants is waning due to emerging resistance, which poses environmental hazards and fosters new resistance in pathogens. Developing environmentally friendly and effective disinfectants against multidrug-resistant organisms is increasingly important. Methods: This study developed a bacteriophage cocktail targeting two common carbapenem-resistant Klebsiella pneumoniae (CRKP) strains, ST11 KL47 and ST11 KL64. The cocktail was used as an adjunctive disinfectant in a hospital's respiratory intensive care unit (RICU) via ultrasonic nebulization. Digital PCR was used to quantify CRKP levels post-intervention. The microbial community composition was analyzed via 16S rRNA sequencing to assess the intervention's impact on overall diversity. Results: The phage cocktail significantly reduced CRKP levels within the first 24 hours post-treatment. While a slight increase in pathogen levels was observed after 24 hours, they remained significantly lower than those treated with conventional disinfectants. 16S rRNA sequencing showed a decrease in the target pathogens' relative abundance, while overall species diversity remained stable, confirming that phages selectively target CRKP without disrupting ecological balance. Discussion: The findings highlight the efficacy and safety of phage-based biocleaners as a sustainable alternative to conventional disinfectants. Phages selectively reduce multidrug-resistant pathogens while preserving microbial diversity, making them a promising tool for infection control.

Morphine induces inflammatory responses via both TLR4 and cGAS-STING signaling pathways.

BACKGROUND: Opioid activation of the microglia or macrophage Toll-like receptor 4 (TLR4) and associated inflammatory cytokine release are implicated in opioid-induced hyperalgesia and tolerance. The cyclic GMP-AMP synthase/stimulator of interferon genes (cGAS-STING) signaling pathway, activated by double-stranded DNA including mitochondrial DNA (mtDNA), has emerged as another key mediator of inflammatory responses. This study tested the hypothesis that morphine induces immune inflammatory responses in microglia and macrophages involving TLR4 and cGAS-STING pathway. METHODS: BV2 microglia and Raw 264.7 (Raw) macrophage cells were exposed to morphine with and without a STING inhibitor (C176) for 6 h or TLR 4 inhibitor (TAK242) for 24 h. Western blotting and RT-qPCR analyses assessed TLR4, cGAS, STING, nuclear factor-kappa B (NF-κB), and pro-inflammatory cytokine expression. Morphine-induced mitochondria dysfunction was quantified by reactive oxygen species (ROS) release using MitoSOX, mtDNA release by immunofluorescence, and RT-qPCR. Polarization of BV2 and Raw cells was assessed by inducible nitric oxide (iNOS) and CD86 expression. The role of mtDNA on morphine-related inflammation was investigated by mtDNA depletion of the cells with ethidium bromide (EtBr) or cell transfection of mtDNA extracted from morphine-treated cells. RESULTS: Morphine significantly increased the expression of TLR4, cGAS, STING, p65 NF-κB, and cytokines (IL-6 and TNF-α) in BV2 and Raw cells. Morphine-induced mitochondrial dysfunction by increased ROS and mtDNA release; the increased iNOS and CD86 evidenced inflammatory M1-like phenotype polarization. TLR4 and STING inhibitors reduced morphine-induced cytokine release in both cell types. The transfection of mtDNA activated inflammatory signaling proteins, cytokine release, and polarization. Conversely, mtDNA depletion led to the reversal of these effects. CONCLUSION: Morphine activates the cGAS-STING pathway in macrophage cell types. Inhibition of the STING pathway can be an additional method to overcome immune cell inflammation-related morphine tolerance and opioid-induced hyperalgesia.

A deep learning-based cascade algorithm for pancreatic tumor segmentation.

Pancreatic tumors are small in size, diverse in shape, and have low contrast and high texture similarity with surrounding tissue. As a result, the segmentation model is easily confused by complex and changeable background information, leading to inaccurate positioning of small targets and false positives and false negatives. Therefore, we design a cascaded pancreatic tumor segmentation algorithm. In the first stage, we use a general multi-scale U-Net to segment the pancreas, and we exploit a multi-scale segmentation network based on non-local localization and focusing modules to segment pancreatic tumors in the second stage. The non-local localization module learns channel and spatial position information, searches for the approximate area where the pancreatic tumor is located from a global perspective, and obtains the initial segmentation results. The focusing module conducts context exploration based on foreground features (or background features), detects and removes false positive (or false negative) interference, and obtains more accurate segmentation results based on the initial segmentation. In addition, we design a new loss function to alleviate the insensitivity to small targets. Experimental results show that the proposed algorithm can more accurately locate pancreatic tumors of different sizes, and the Dice coefficient outperforms the existing state-of-the-art segmentation model. The code will be available at https://github.com/HeyJGJu/Pancreatic-Tumor-SEG.

Correlation-Embedded Transformer Tracking: A Single-Branch Framework.

Developing robust and discriminative appearance models has been a long-standing research challenge in visual object tracking. In the prevalent Siamese-based paradigm, the features extracted by the Siamese-like networks are often insufficient to model the tracked targets and distractor objects, thereby hindering them from being robust and discriminative simultaneously. While most Siamese trackers focus on designing robust correlation operations, we propose a novel single-branch tracking framework inspired by the transformer. Unlike the Siamese-like feature extraction, our tracker deeply embeds cross-image feature correlation in multiple layers of the feature network. By extensively matching the features of the two images through multiple layers, it can suppress non-target features, resulting in target-aware feature extraction. The output features can be directly used to predict target locations without additional correlation steps. Thus, we reformulate the two-branch Siamese tracking as a conceptually simple, fully transformer-based Single-Branch Tracking pipeline, dubbed SBT. After conducting an in-depth analysis of the SBT baseline, we summarize many effective design principles and propose an improved tracker dubbed SuperSBT. SuperSBT adopts a hierarchical architecture with a local modeling layer to enhance shallow-level features. A unified relation modeling is proposed to remove complex handcrafted layer pattern designs. SuperSBT is further improved by masked image modeling pre-training, integrating temporal modeling, and equipping with dedicated prediction heads. Thus, SuperSBT outperforms the SBT baseline by 4.7%,3.0%, and 4.5% AUC scores in LaSOT, TrackingNet, and GOT-10K. Notably, SuperSBT greatly raises the speed of SBT from 37 FPS to 81 FPS. Extensive experiments show that our method achieves superior results on eight VOT benchmarks. Code is available at https://github.com/phiphiphi31/SBT.

Mesenchymal stem cell-derived extracellular vesicles mitigate neuronal damage from intracerebral hemorrhage by modulating ferroptosis.

BACKGROUND: Hemorrhagic stroke is a devastating cerebrovascular event with a high rate of early mortality and long-term disability. The therapeutic potential of mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) for neurological conditions, such as intracerebral hemorrhage (ICH), has garnered considerable interest, has garnered considerable interest, though their mechanisms of action remain poorly understood. METHODS: EVs were isolated from human umbilical cord MSCs, and SPECT/CT was used to track the 99mTc-labeled EVs in a mouse model of ICH. A series of comprehensive evaluations, including magnetic resonance imaging (MRI), histological study, RNA sequencing (RNA-Seq), or miRNA microarray, were performed to investigate the therapeutic action and mechanisms of MSC-EVs in both cellular and animal models of ICH. RESULTS: Our findings show that intravenous injection of MSC-EVs exhibits a marked affinity for the ICH-affected brain regions and cortical neurons. EV infusion alleviates the pathological changes observed in MRI due to ICH and reduces damage to ipsilateral cortical neurons. RNA-Seq analysis reveals that EV treatment modulates key pathways involved in the neuronal system and metal ion transport in mice subjected to ICH. These data were supported by the attenuation of neuronal ferroptosis in neurons treated with Hemin and in ICH mice following EV therapy. Additionally, miRNA microarray analysis depicted the EV-miRNAs targeting genes associated with ferroptosis, and miR-214-3p was identified as a regulator of neuronal ferroptosis in the ICH cellular model. CONCLUSIONS: MSC-EVs offer neuroprotective effects against ICH-induced neuronal damage by modulating ferroptosis highlighting their therapeutic potential for combating neuronal ferroptosis in brain disorders.

Gut microbiota as a residual risk factor causally influencing cardiac structure and function: Mendelian randomization analysis and biological annotation.

Background: The gut microbiota (GM) is widely acknowledged to have a significant impact on cardiovascular health and may act as a residual risk factor affecting cardiac structure and function. However, the causal relationship between GM and cardiac structure and function remains unclear. Objective: This study aims to employ a two-sample Mendelian randomization (MR) approach to investigate the causal association between GM and cardiac structure and function. Methods: Data on 119 GM genera were sourced from a genome-wide association study (GWAS) meta-analysis (13,266 European participants) conducted by the MiBioGen consortium, while data on 16 parameters of cardiac structure and function were obtained from the UK Biobank's GWAS of cardiac magnetic resonance imaging (up to 41,135 European participants). Inverse variance weighted (IVW), MR-Egger, and weighted median (WM) methods were utilized for causal association assessments, with sensitivity analyses conducted to reinforce the findings. Finally, biological annotation was performed on the GWAS data of GM and cardiac phenotypes with causal associations to explore potential mechanisms. Results: The MR analysis, predominantly based on the IVW model, revealed 93 causal associations between the genetically predicted abundance of 44 GM genera and 16 cardiac structure and function parameters. These associations maintained consistent directions in MR-Egger and WM models, with no evidence of pleiotropy detected. Biological annotations suggest that GM may influence cardiac structure and function through pathways involved in myocardial cell development, cardiac contractility, and apoptosis. Conclusion: The MR analysis supports a causal association between certain abundances of genetically predicted GM and cardiac structure and function, suggesting that GM could be a residual risk factor impacting cardiac phenotypes.

Macrogenomic and Metabolomic Analyses Reveal Mechanisms of Gut Microbiota and Microbial Metabolites in Diarrhea of Weaned Piglets.

Recent studies have shown a correlation between piglet diarrhea and the gut microbiota. However, the precise mechanism by which intestinal microorganisms and their metabolites influence diarrhea in weaned piglets remains unclear. This study explored differences in the gut microbiota and associated metabolites between healthy and diarrheic-weaned piglets using macrogenomic and metabolomic analyses. The histomorphological results showed that diarrheic piglets had shorter jejunal and ileal villi, some of which were shed, compared to healthy piglets. Substantial differences in gut microbial diversity and metabolites were also observed, with Bacteroidaceae bacterium and Caudoviricetes being the main differential organisms that were strongly correlated with host status. Microbial functions, mainly the metabolism of carbohydrates, glycans, lipids, and amino acids, as well as related enzyme activities, were substantially different. The major differential metabolites were carnosine, pantothenic acid (vitamin B5), pyridoxal, methylimidazoleacetic acid, indole-3-acetaldehyde, and 5-hydroxyindoleacetic acid. These metabolites were enriched in beta-alanine, histidine, tryptophan, and vitamin B6 metabolism, and in the pantothenate and CoA biosynthesis pathways. Combined macrogenomic and metabolomic analyses revealed that carnosine, vitamin B5, and pyridoxal were negatively correlated with Caudoviricetes; methylimidazoleacetic acid, indole-3-acetaldehyde, and 5-hydroxyindoleacetic acid were positively correlated with Caudoviricetes. Whereas carnosine and vitamin B5 were positively correlated with Bacteroidaceae bacterium, 5-hydroxyindoleacetic acid was negatively correlated. The decreased abundance of Bacteroidaceae bacterium and the increased abundance of Caudoviricetes and related metabolites likely contribute to post-weaning diarrhea in piglets. Therefore, the abundance of Bacteroidaceae bacterium and Caudoviricetes can likely serve as potential markers for identifying and preventing diarrhea in post-weaning piglets.

Optimized equalization based on MAP detection for C-band bandwidth-limited IM/DD systems.

Entangled dynamic and deterministic inter-symbol interferences (ISIs) induced by complicated channel impairments, limit the transmission capacity of intensity modulation and direct detection (IM/DD) systems. This Letter proposes a colored noise-suppressed channel shortening filter (CNS-CSF)-enabled maximum a posteriori (MAP) estimation (CNS-CSF-MAP) scheme to disentangle and mitigate deterministic and dynamic ISIs, where the CNS-CSF is deployed to perform the optimized dynamic ISI equalization with equalization-enhanced noise suppression, and the subsequent MAP algorithm is used to eliminate the residual deterministic ISI. The performance of the CNS-CSF-MAP scheme is evaluated and demonstrated in a C-band 61-Gb/s 100-km optical on-off keying (OOK) IM/DD system. The experimental results show that the proposed CNS-CSF-MAP scheme reaches the 20% and 7% forward error correction (FEC) thresholds at received optical powers (ROPs) of -6.6 dBm and -4 dBm, achieving 0.5- and 1.5-dB gains over a conventional post-filter-enabled MAP (PF-MAP) scheme.

Lumican promotes calcific aortic valve disease through H3 histone lactylation.

BACKGROUND AND AIMS: Valve interstitial cells (VICs) undergo a transition to intermediate state cells before ultimately transforming into the osteogenic cell population, which is a pivotal cellular process in calcific aortic valve disease (CAVD). Herein, this study successfully delineated the stages of VIC osteogenic transformation and elucidated a novel key regulatory role of lumican (LUM) in this process. METHODS: Single-cell RNA-sequencing (scRNA-seq) from nine human aortic valves was used to characterize the pathological switch process and identify key regulatory factors. The in vitro, ex vivo, in vivo, and double knockout mice were constructed to further unravel the calcification-promoting effect of LUM. Moreover, the multi-omic approaches were employed to analyse the molecular mechanism of LUM in CAVD. RESULTS: ScRNA-seq successfully delineated the process of VIC pathological transformation and highlighted the significance of LUM as a novel molecule in this process. The pro-calcification role of LUM is confirmed on the in vitro, ex vivo, in vivo level, and ApoE-/-//LUM-/- double knockout mice. The LUM induces osteogenesis in VICs via activation of inflammatory pathways and augmentation of cellular glycolysis, resulting in the accumulation of lactate. Subsequent investigation has unveiled a novel LUM driving histone modification, lactylation, which plays a role in facilitating valve calcification. More importantly, this study has identified two specific sites of histone lactylation, namely, H3K14la and H3K9la, which have been found to facilitate the process of calcification. The confirmation of these modification sites' association with the expression of calcific genes Runx2 and BMP2 has been achieved through ChIP-PCR analysis. CONCLUSIONS: The study presents novel findings, being the first to establish the involvement of lumican in mediating H3 histone lactylation, thus facilitating the development of aortic valve calcification. Consequently, lumican would be a promising therapeutic target for intervention in the treatment of CAVD.

[Authenticity discrimination for Galli Gigerii Endothelium Corneum based on UPLC-MS/MS and peptidomics].

Peptidomics was employed to systematically analyze the characteristic peptides in Galli Gigerii Endothelium Corneum and its adulterants and establish a method for distinguishing Galli Gigerii Endothelium Corneum from its adulterants, including the gizzard membranes from ducks, geese, and pigeons. UPLC-Q-Exactive Orbitrap-MS was combined with multivariate statistical analysis to analyze the peptides in Galli Gigerii Endothelium Corneum and its adulterants. The structures of peptides were identified by pNovo combined with manual recognition of spectra, and synthetic peptide standards were used for validation. LC-MS/MS was used to optimize the sample pre-processing conditions, including the extraction procedure, extraction time, extraction solvents, and solvent volumes, for the characteristic peptide LESY in Galli Gigerii Endothelium Corneum. Multiple reaction monitoring(MRM) in the ESI~+ mode with m/z 511.24→269.11 and 511.24→243.13 as detection ions was employed for qualitative and quantitative analyses. The established UPLC-MS/MS method demonstrated good specificity, stability, and durability. The content of LESY in 16 batches of Galli Gigerii Endothelium Corneum samples ranged from 55.03 to 113.36 µg·g~(-1). Additionally, a qualitative detection method for the common peptide RDPVLVSR in adulterants was established with m/z 471.28→785.45 and 471.28→670.41 as the detection ions. This study established a convenient, rapid, and accurate detection method for the characteristic peptides in Galli Gigerii Endothelium Corneum and its adulterants. The method possesses good specificity, stability, and durability, providing a valuable reference for the identification and quality control of Galli Gigerii Endothelium Corneum and other traditional Chinese medicines derived from animal sources.

Neoadjuvant therapy of sequential TACE, camrelizumab, and apatinib for single huge hepatocellular carcinoma (NEO-START): study protocol for a randomized controlled trial.

BACKGROUND: The high recurrence rate after liver resection emphasizes the urgent need for neoadjuvant therapy in hepatocellular carcinoma (HCC) to enhance the overall prognosis for patients. Immune checkpoint inhibitors, camrelizumab combined with an anti-angiogenic tyrosine kinase inhibitor (TKI) apatinib, have emerged as a first-line treatment option for patients with unresectable HCC, yet its neoadjuvant application in combination with transarterial chemoembolization (TACE) in HCC remains unexplored. Therefore, this study aims to investigate the efficacy and safety of sequential TACE, camrelizumab, and apatinib as a neoadjuvant therapy for single, huge HCC. METHODS: This multi-center, open-label randomized phase 3 trial will be conducted at 7 tertiary hospitals. Patients with single huge (≥ 10 cm in diameter), resectable HCC will be randomly assigned in a 1:1 ratio to arm of surgery alone or arm of neoadjuvant therapy followed by surgery. In the neoadjuvant therapy group, patients will receive TACE within 1 week after randomization, followed by camrelizumab (200 mg q2w, 4 cycles), along with apatinib (250 mg qd, 2 months). Patients will receive liver resection after neoadjuvant therapy unless the disease is assessed as progressive. The primary outcome is recurrence-free survival (RFS) at 1 year. The planned sample size of 60 patients will be calculated to permit the accumulation of sufficient RFS events in 1 year to achieve 80% power for the RFS primary endpoint. DISCUSSION: Synergistic effects provided by multimodality therapy of locoregional treatment, TKI, and anti-programmed cell death 1 inhibitor significantly improved overall survival for patients with unresectable HCC. Our trial will investigate the efficacy and safety of the triple combination of TACE, camrelizumab, and apatinib as a neoadjuvant strategy for huge, resectable HCC. TRIAL REGISTRATION: www.chitr.org.cn ChiCTR2300078086. Registered on November 28, 2023. Start recruitment: 1st January 2024. Expected completion of recruitment: 15th June 2025.

The role of CD8+ T-cells in colorectal cancer immunotherapy.

Immunotherapy has been an advanced and effective approach to treating various types of solid tumors in recent years, and the most successful strategy is immune checkpoint inhibitors (ICIs), which have shown beneficial effects in patients with colorectal cancer (CRC). Drug resistance to ICIs is usually associated with CD8+ T-cells targeting tumor antigens; thus, CD8+ T-cells play an important role in immunotherapy. Unfortunately, Under continuous antigen stimulation, tumor microenvironment(TME), hypoxia and other problems it leads to insufficient infiltration of CD8+ T-cells, low efficacy and mechanism exhaustion, which have become obstacles to immunotherapy. Thus, this article describes the relationship between CRC and the immune system, focuses on the process of CD8+ T-cells production, activation, transport, killing, and exhaustion, and expounds on related mechanisms leading to CD8+ T-cells exhaustion. Finally, this article summarizes the latest strategies and methods in recent years, focusing on improving the infiltration, efficacy, and exhaustion of CD8+ T-cells, which may help to overcome the barriers to immunotherapy.

Reg2 treatment is protective but the induced Reg2 autoantibody is destructive to the islets in NOD mice.

Regenerating family protein 2 (Reg2) is a trophic factor which stimulates ß-cell replication and resists islet destruction. However, Reg2 also serves as an islet autoantigen, which makes it complicated to judge the effectiveness in treating diabetes. How Reg2 treatment behaves in non-obese diabetic (NOD) mice is to be investigated. NOD mice were treated with recombinant Reg2 protein, Complete Freund's adjuvant (CFA) + PBS and CFA+Reg2 vaccinations, CFA+PBS- and CFA+Reg2-immunized antisera, and single chain variable fragment (scFv)-Reg2 and mIgG2a-Reg2 antibodies. Glycemic level, bodyweight, serum Reg2 antibody titer, glucose tolerance, and insulin secretion were determined. Islet morphological characteristics, insulitis, cell apoptosis, islet cell components, and T cell infiltration were analyzed by histological examinations. The autoantigenicity of constructed Reg2C and Reg2X fragments was determined in healthy BALB/c mice, and the bioactivity in stimulating cell proliferation and survival was assessed in insulinoma MIN6 cells. Reg2 administration alleviated diabetes in NOD mice with improved glucose tolerance and insulin secretion but elevated serum Reg2 autoantibodies. Histomorphometry showed reduced inflammatory area, TUNEL signal and CD8 + T cell infiltration, and increased ß-cell proportion in support of the islet-protective effect of Reg2 treatment. CFA+PBS and CFA+Reg2 immunizations prevented diabetic onset and alleviated insulitis while injections of the antisera offered mild protections. Antibody treatments accelerated diabetic onset without increasing the overall incidence. Reg2C fragment depletes antigenicity, but reserves protective activity in streptozotocin (STZ)-treated MIN6 cells. In conclusion, Reg2 treatment alleviates type 1 diabetes (T1D) by preserving islet ß-cells, but induces Reg2 autoantibody production which poses a potential risk of accelerating diabetic progression.

Synthesis and antifungal evaluation of novel triazole derivatives bearing a pyrazole-methoxyl moiety.

Life-threatening invasive fungal infections pose a serious threat to human health. A series of novel triazole derivatives bearing a pyrazole-methoxyl moiety were designed and synthesized in an effort to obtain antifungals with potent, broad-spectrum activity that are less susceptible to resistance. Most of these compounds exhibited moderate to excellent in vitro antifungal activities against Candida albicans SC5314 and 10,231, Cryptococcus neoformans 32,609, Candida glabrata 537 and Candida parapsilosis 22,019 with minimum inhibitory concentration (MIC) values of ≤0.125 µg/mL to 0.5 µg/mL. Use of recombinant Saccharomyces cerevisiae strains showed compounds 7 and 10 overcame the overexpression and resistant-related mutations in ERG11 of S. cerevisae and several pathogenic Candida spp. Despite being substrates of the C. albicans and Candida auris Cdr1 drug efflux pumps, compounds 7 and 10 showed moderate potency against five fluconazole (FCZ)-resistant fungi with MIC values from 2.0 µg/mL to 16.0 µg/mL. Growth kinetics confirmed compounds 7 and 10 had much stronger fungistatic activity than FCZ. For C. albicans, compounds 7 and 10 inhibited the yeast-to-hyphae transition, biofilm formation and destroyed mature biofilm more effectively than FCZ. Preliminary mechanism of action studies showed compounds 7 and 10 blocked the ergosterol biosynthesis pathway at Erg11, ultimately leading to cell membrane disruption. Further investigation of these novel triazole derivatives is also warranted by their predicted ADMET properties and low cytotoxicity.

A Clinical Bacterial Dataset for Deep Learning in Microbiological Rapid On-Site Evaluation.

Microbiological Rapid On-Site Evaluation (M-ROSE) is based on smear staining and microscopic observation, providing critical references for the diagnosis and treatment of pulmonary infectious disease. Automatic identification of pathogens is the key to improving the quality and speed of M-ROSE. Recent advancements in deep learning have yielded numerous identification algorithms and datasets. However, most studies focus on artificially cultured bacteria and lack clinical data and algorithms. Therefore, we collected Gram-stained bacteria images from lower respiratory tract specimens of patients with lung infections in Chinese PLA General Hospital obtained by M-ROSE from 2018 to 2022 and desensitized images to produce 1705 images (4,912 × 3,684 pixels). A total of 4,833 cocci and 6,991 bacilli were manually labelled and differentiated into negative and positive. In addition, we applied the detection and segmentation networks for benchmark testing. Data and benchmark algorithms we provided that may benefit the study of automated bacterial identification in clinical specimens.

Unveiling the link between ACR TI-RADS grading and Bethesda score of thyroid nodules in diabetic patients: A comprehensive analysis.

This study aimed to explores the factors influencing thyroid nodules (TNs) in individuals with type 2 diabetes mellitus (T2DM) and evaluates the consistency between different American College of Radiology Thyroid Imaging Reporting and Data System (ACR TI-RADS) grades and Bethesda scores. Total of 642 T2DM patients were divided into TN group (245) and control group (397) based on the presence or absence of TNs. TN patients were further categorized into ACR TI-RADS classification (TR) 1 to 4 and TR5 subgroups. Diabetes-related clinical and biochemical parameters were collected, and differences were analyzed using univariate analysis. Logistic regression analysis was utilized to pinpoint independent influencing factors for TN occurrence and different TN classifications. Consequently, age, body mass index (BMI), fasting plasma glucose level (FBGL), low density lipoprotein cholesterol (LDL-C), diabetic progression, and family history of TNs emerged as independent risk factors for TN development in T2DM patients. Additionally, glycosylated hemoglobin (HbA1c), nodule diameter, and family history of TNs were identified as independent risk factors for TR5 TN development in T2DM patients. All TR1 to 2 nodules had a Bethesda score of 2 and all showed benign pathological findings. In 97.10% of cases (67/69), nodules classified as TR3 exhibited a Bethesda score of 2, with all pathological results indicating benign findings, aligning with the Bethesda score. In addition, the concordance between TR4 nodules and Bethesda score was only 78.57% (88/112). In conclusion, TNs and their malignancy in T2DM patients are significantly linked to blood glucose and lipid metabolism indexes. TR3 classification in T2DM patients poses a low malignancy risk, suggesting caution when conducting fine needle aspiration cytology (FNAC) testing.

Novel antibody-antibiotic conjugate using KRM-1657 as payload eliminates intracellular MRSA in vitro and in vivo.

Staphylococcus aureus is considered to be an extracellular pathogen. However, survival of S.aureus within host cells may cause long-term colonization and clinical failure. Current treatments have poor efficacy in clearing intracellular bacteria. Antibody-antibiotic conjugates (AACs) is a novel strategy for eliminating intracellular bacteria. Herein, we use KRM-1657 as payload of AAC for the first time, and we conjugate it with anti S. aureus antibody via a dipeptide linker (Valine-Alanine) to obtain a novel AAC (ASAK-22). The ASAK-22 exhibits good in vitro pharmacokinetic properties and inhibitory activity against intracellular MRSA, with 100 µg/mL of ASAK-22 capable of eliminating intracellular MRSA to the detection limit. Furthermore, the in vivo results demonstrate that a single administration of ASAK-22 significantly reduces the bacterial burden in the bacteremia model, which is superior to the vancomycin treatment.

Prognostication of colorectal cancer liver metastasis by CE-based radiomics and machine learning.

The liver is the most common organ for the formation of colorectal cancer metastasis. Non-invasive prognostication of colorectal cancer liver metastasis (CRLM) may better inform clinicians for decision-making. Contrast-enhanced computed tomography images of 180 CRLM cases were included in the final analyses. Radiomics features, including shape, first-order, wavelet, and texture, were extracted with Pyradiomics, followed by feature engineering by penalized Cox regression. Radiomics signatures were constructed for disease-free survival (DFS) by both elastic net (EN) and random survival forest (RSF) algorithms. The prognostic potential of the radiomics signatures was demonstrated by Kaplan-Meier curves and multivariate Cox regression. 11 radiomics features were selected for prognostic modelling for the EN algorithm, with 835 features for the RSF algorithm. Survival heatmap indicates a negative correlation between EN or RSF risk scores and DFS. Radiomics signature by EN algorithm successfully separates DFS of high-risk and low-risk cases in the training dataset (log-rank test: p < 0.01, hazard ratio: 1.45 (1.07-1.96), p < 0.01) and test dataset (hazard ratio: 1.89 (1.17-3.04), p < 0.05). RSF algorithm shows a better prognostic implication potential for DFS in the training dataset (log-rank test: p < 0.001, hazard ratio: 2.54 (1.80-3.61), p < 0.0001) and test dataset (log-rank test: p < 0.05, hazard ratio: 1.84 (1.15-2.96), p < 0.05). Radiomics features have the potential for the prediction of DFS in CRLM cases.