A region-confined PROTAC nanoplatform for spatiotemporally tunable protein degradation and enhanced cancer therapy.

The antitumor performance of PROteolysis-TArgeting Chimeras (PROTACs) is limited by its insufficient tumor specificity and poor pharmacokinetics. These disadvantages are further compounded by tumor heterogeneity, especially the presence of cancer stem-like cells, which drive tumor growth and relapse. Herein, we design a region-confined PROTAC nanoplatform that integrates both reactive oxygen species (ROS)-activatable and hypoxia-responsive PROTAC prodrugs for the precise manipulation of bromodomain and extraterminal protein 4 expression and tumor eradication. These PROTAC nanoparticles selectively accumulate within and penetrate deep into tumors via response to matrix metalloproteinase-2. Photoactivity is then reactivated in response to the acidic intracellular milieu and the PROTAC is discharged due to the ROS generated via photodynamic therapy specifically within the normoxic microenvironment. Moreover, the latent hypoxia-responsive PROTAC prodrug is restored in hypoxic cancer stem-like cells overexpressing nitroreductase. Here, we show the ability of region-confined PROTAC nanoplatform to effectively degrade BRD4 in both normoxic and hypoxic environments, markedly hindering tumor progression in breast and head-neck tumor models.

2.09†µm high-gain, high-energy sub-nanosecond laser amplification system and its application to a millijoule-level mid-infrared ZnGeP2 optical parametric generator.

In this Letter, we report for the first time to our knowledge a 2 mJ-level 2.09 µm Ho:YAG regenerative amplifier (RA) seeded by the first-stage Ho-doped fiber (HDF) preamplifier of a gain-switched laser diode (GSLD). After the single-pass power amplifier (SPPA), the output of a 2.09 µm pulse laser with 1 kHz, 570 ps, and >10 mJ was achieved. The overall gain of the whole amplifier system was greater than 90 dB, providing a novel, stable, and reliable sub-nanosecond (sub-ns) pump source operating at a pulse repetition frequency (PRF) of 1 kHz for an optical parametric generator (OPG) based on ZnGeP2 (ZGP). Specifically, for the ZGP OPG structure, a maximum pulse energy of 1.82 mJ at 3-5 µm had been achieved with an injected pump pulse energy of 5.47 mJ, corresponding to a slope efficiency of 39.5% and an optical-to-optical conversion efficiency (OOCE) of 33.27%.

Narrowband mid-infrared optical parametric generator based on a type-II BaGa4Se7 crystal.

In this Letter, we first reported on a mid-infrared double-pass optical parametric generator (OPG) based on a single type-II phase-matching BaGa4Se7 (BGSe) crystal, pumped at 2.1 µm. The OPG achieved a maximum pulse energy of 55 µJ for generating narrowband mid-infrared laser pulses. The signal and idler lights exhibited center wavelengths of 4.04 and 4.33 µm, respectively, with bandwidths of 18.6 nm (11.4 cm-1) and 20.4 nm (10.9 cm-1). To improve the output performance, we utilized a cascaded scheme of type-I ZnGeP2 (ZGP) and type-II BGSe crystals. The spectral bandwidths of the signal and idler lights, nearing 4 µm, were narrower than 170 nm (90 cm-1), representing a significant improvement over the ZGP OPG. The cascaded OPG achieved a remarkable total optical-to-optical conversion efficiency (OOCE) of 14.9% and a maximum pulse energy of 0.329 mJ.

Unravelling tumour cell diversity and prognostic signatures in cutaneous melanoma through machine learning analysis.

Melanoma, a highly malignant tumour, presents significant challenges due to its cellular heterogeneity, yet research on this aspect in cutaneous melanoma remains limited. In this study, we utilized single-cell data from 92,521 cells to explore the tumour cell landscape. Through clustering analysis, we identified six distinct cell clusters and investigated their differentiation and metabolic heterogeneity using multi-omics approaches. Notably, cytotrace analysis and pseudotime trajectories revealed distinct stages of tumour cell differentiation, which have implications for patient survival. By leveraging markers from these clusters, we developed a tumour cell-specific machine learning model (TCM). This model not only predicts patient outcomes and responses to immunotherapy, but also distinguishes between genomically stable and unstable tumours and identifies inflamed ('hot') versus non-inflamed ('cold') tumours. Intriguingly, the TCM score showed a strong association with TOMM40, which we experimentally validated as an oncogene promoting tumour proliferation, invasion and migration. Overall, our findings introduce a novel biomarker score that aids in selecting melanoma patients for improved prognoses and targeted immunotherapy, thereby guiding clinical treatment decisions.

Multisystem Langerhans Cell Histiocytosis following Treatment of Initially Presumed Atopic Dermatitis with Dupilumab: A Case Report of an Extremely Confusing Scenario.

Introduction: Atopic dermatitis (AD) is a common chronic, recurrent, and non-infectious inflammatory skin disease. Dupilumab is a human monoclonal antibody with clinical efficacy in severe AD and has a good safety profile. Case Presentation: We hereby describe a previously unreported case of multisystem Langerhans cell histiocytosis (MS-LCH) that is associated with a history of AD treatment using dupilumab. Conclusion: A single case of MS-LCH with a history of dupilumab treatment for AD was described for the first time. This case highlights that given its susceptibility to skin involvement, LCH needs to be considered as a differential diagnosis for skin lesions that are not improved by established therapies.

FOXP4-mediated induction of PTK7 activates the Wnt/ß-catenin pathway and promotes ovarian cancer development.

Ovarian cancer (OV) poses a significant challenge in clinical settings due to its difficulty in early diagnosis and treatment resistance. FOXP4, belonging to the FOXP subfamily, plays a pivotal role in various biological processes including cancer, cell cycle regulation, and embryonic development. However, the specific role and importance of FOXP4 in OV have remained unclear. Our research showed that FOXP4 is highly expressed in OV tissues, with its elevated levels correlating with poor prognosis. We further explored FOXP4's function through RNA sequencing and functional analysis in FOXP4-deficient cells, revealing its critical role in activating the Wnt signaling pathway. This activation exacerbates the malignant phenotype in OV. Mechanistically, FOXP4 directly induces the expression of protein tyrosine kinase 7 (PTK7), a Wnt-binding receptor tyrosine pseudokinase, which causes abnormal activation of the Wnt signaling pathway. Disrupting the FOXP4-Wnt feedback loop by inactivating the Wnt signaling pathway or reducing FOXP4 expression resulted in the reduction of the malignant phenotype of OV cells, while restoring PTK7 expression reversed this effect. In conclusion, our findings underscore the significance of the FOXP4-induced Wnt pathway activation in OV, suggesting the therapeutic potential of targeting this pathway in OV treatment.

CENPK orchestrates ovarian cancer progression via GOLPH3-Mediated activation of mTOR signaling.

Ovarian cancer stands as a formidable clinical challenge, with limited therapeutic options. This investigation delves into the intricate molecular mechanisms governing ovarian cancer progression and uncovers Centromere Protein K (CENPK) as a central figure in disease pathogenesis. Elevated CENPK levels within ovarian cancer tissues conspicuously align with adverse clinical outcomes, positioning CENPK as a promising prognostic biomarker. Deeper exploration reveals a direct transcriptional connection between CENPK and the E2F1 transcription factor and clearly establishes E2F1's role as the master regulator of CENPK expression in ovarian cancer. Our inquiry revealing a suppression of tumor-promoting signaling pathways, most notably the mTOR pathway, upon CENPK silencing. Intriguingly, CENPK renders ovarian cancer cells more responsive to the mTOR inhibitor rapamycin, introducing a promising avenue for therapeutic intervention. In summation, our study unravels the multifaceted role of CENPK in ovarian cancer progression. It emerges as a prognostic indicator, a pivotal mediator of cell proliferation and tumorigenicity, and a regulator of the mTOR pathway, shedding light on potential therapeutic avenues for this formidable disease.

CXXC5 drove inflammation and ovarian cancer proliferation via transcriptional activation of ZNF143 and EGR1.

CXXC5, a zinc-finger protein, is known for its role in epigenetic regulation via binding to unmethylated CpG islands in gene promoters. As a transcription factor and epigenetic regulator, CXXC5 modulates various signaling processes and acts as a key coordinator. Altered expression or activity of CXXC5 has been linked to various pathological conditions, including tumorigenesis. Despite its known role in cancer, CXXC5's function and mechanism in ovarian cancer are unclear. We analyzed multiple public databases and found that CXXC5 is highly expressed in ovarian cancer, with high expression correlating with poor patient prognosis. We show that CXXC5 expression is regulated by oxygen concentration and is a direct target of HIF1A. CXXC5 is critical for maintaining the proliferative potential of ovarian cancer cells, with knockdown decreasing and overexpression increasing cell proliferation. Loss of CXXC5 led to inactivation of multiple inflammatory signaling pathways, while overexpression activated these pathways. Through in vitro and in vivo experiments, we confirmed ZNF143 and EGR1 as downstream transcription factors of CXXC5, mediating its proliferative potential in ovarian cancer. Our findings suggest that the CXXC5-ZNF143/EGR1 axis forms a network driving ovarian cell proliferation and tumorigenesis, and highlight CXXC5 as a potential therapeutic target for ovarian cancer treatment.

Spidroin-mimetic Engineered Protein Fibers with High Toughness and Minimized Batch-to-batch Variations through ß-sheets Co-assembly.

Synthetic spidroin fibers have not yet attained the same level of toughness and stability as natural spider silks due to the complexity of composition and hierarchical structure. Particularly, understanding the intricate interactions between spidroin components in spider fiber is still elusive. Herein, we report modular design and preparation of spidroin-mimetic fibers composed of a conservative C-terminus spidroin module, two different natural ß-sheets modules, and a non-spidroin random-coil module. The resulting fibers exhibit a toughness of ~200 MJ/m3, reaching the highest value among the reported artificial spider silks. The interactions between two components of recombinant spidroins facilitate the intermolecular co-assembly of ß-sheets, thereby enhancing the mechanical strength and reducing batch-to-batch variability in the dual-component spidroin fibers. Additionally, the dual-component spidroin fibers offer potential applications in implantable or even edible devices. Therefore, our work presents a generic strategy to develop high-performance protein fibers for diverse translations in different scenarios.

FBXO5-mediated RNF183 degradation prevents endoplasmic reticulum stress-induced apoptosis and promotes colon cancer progression.

Endoplasmic reticulum (ER) stress induces the unfolded protein response (UPR), and prolonged ER stress leads to cell apoptosis. Despite increasing research in this area, the underlying molecular mechanisms remain unclear. Here, we discover that ER stress upregulates the UPR signaling pathway while downregulating E2F target gene expression and inhibiting the G2/M phase transition. Prolonged ER stress decreases the mRNA levels of E2F2, which specifically regulates the expression of F-Box Protein 5(FBXO5), an F-box protein that functions as an inhibitor of the anaphase-promoting complex/cyclosome (APC/C) ubiquitin ligase complex. Depletion of FBXO5 results in increased ER stress-induced apoptosis and decreased expression of proteins related to PERK/IRE1α/ATF6 signaling. Overexpression of FBXO5 wild-type (not its ΔF-box mutant) alleviates apoptosis and the expression of the C/EBP Homologous Protein (CHOP)/ATF. Mechanistically, we find that FBXO5 directly binds to and promotes the ubiquitin-dependent degradation of RNF183, which acts as a ubiquitin E3 ligase in regulating ER stress-induced apoptosis. Reversal of the apoptosis defects caused by FBXO5 deficiency in colorectal cancer cells can be achieved by knocking down RNF183 in FBXO5-deficient cells. Functionally, we observed significant upregulation of FBXO5 in colon cancer tissues, and its silencing suppresses tumor occurrence in vivo. Therefore, our study highlights the critical role of the FBXO5/RNF183 axis in ER stress regulation and identifies a potential therapeutic target for colon cancer treatment.

Diagnosis of cutaneous primary nocardiosis in patients with normal immune function by metagenomic next-generation sequencing.

Nocardia primarily affects immunocompromised individuals, and Infection with Nocardia is uncommon and primary cutaneous nocardiosis caused by percutaneous inoculation is even rarer. Primary cutaneous nocardiosis remains a diagnostic challenge and should be considered in the differential diagnosis for any superficial cutaneous infection that arises in patients with normal immune function. We report a case that was diagnosed with primary cutaneous Nocardia by metagenomic next-generation sequencing technology.

Simultaneous determination of five compounds of fried Radix Paeoniae Alba extract in beagle dogs plasma by Ultra Performance Liquid Chromatography Tandem Mass Spectrometry and its application in a pharmacokinetic study.

In this present study, we developed a reliable and simple ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) assay for the simultaneous quantification of paeoniflorin, albiflorin, oxypaeoniflorin, benzoylpaeoniflorin and isomaltopaeoniflorin in beagle dog plasma. We also analyzed the pharmacokinetics of those components after oral administration of fried Radix Paeoniae Alba (FRPA) in beagle dogs. Plasma samples were processed by protein precipitation with methanol. Chromatographic separation was performed with a Waters HSS-T3 C18 column (100 × 2.1 mm, 1.8 µm, kept at 40°C) using multiple reaction monitoring mode. A gradient elution procedure was used with solvent A (0.02% formic acid-water) and solvent B (0.02% formic acid-acetonitrile) as mobile phases. Method validation was performed as US Food and Drug Administration guidelines, and the results met the acceptance criteria. The method we establish in this experiment was successfully applied to the pharmacokinetic study after oral administration of FRPA extract to beagle dogs.

Effect of Gushen shetuo decoction in improving motor and non-motor symptoms and the expression of PERK, ATF4 and CHOP in patients with Parkinson's disease.

This study aims to observe the therapeutic effect of Gushen Shetuo decoction on Parkinson's disease (PD), so as to provide reference for clinical practice. In order to demonstrate the clinical value of Gushen Shetuo Decoction, we selected 80 patients with PD for the study. Among them, 38 patients received the Gushen Shetuo decoction (research group), and 42 patients received Levodopa and Benserazide Hydrochloride Tablets (control group). There was no difference in Non-Motor Symptoms Scale (NMSS) scores between the research group and the control group (P>0. 05). However, the scores of motor complications in Movement Disorder Society-sponsored revision of the Parkinson's Disease Rating Scale (MDS-UPDRS) and those of Drooling Severity and Frequency Scale (DSFS) in the research group were lower than those in the control group (P<0. 05). Subsequently, we established PD model rats, and after Gushen Shetuo Decoction gavage treatment, we found that rats in the intervention group had increased mobility (P<0. 05), as well as notably improved pathological damage of substantia nigra and striatum. Also, the expression of PERK, ATF4 and CHOP in the brain tissues of rats in the intervention group was lower than those in the control group (P<0. 05). These results confirm that Gushen Shetuo decoction effectively improved the drooling of patients with PD and showed high safety.

Protein fibers with self-recoverable mechanical properties via dynamic imine chemistry.

The manipulation of internal interactions at the molecular level within biological fibers is of particular importance but challenging, severely limiting their tunability in macroscopic performances and applications. It thus becomes imperative to explore new approaches to enhance biological fibers' stability and environmental tolerance and to impart them with diverse functionalities, such as mechanical recoverability and stimulus-triggered responses. Herein, we develop a dynamic imine fiber chemistry (DIFC) approach to engineer molecular interactions to fabricate strong and tough protein fibers with recoverability and actuating behaviors. The resulting DIF fibers exhibit extraordinary mechanical performances, outperforming many recombinant silks and synthetic polymer fibers. Remarkably, impaired DIF fibers caused by fatigue or strong acid treatment are quickly recovered in water directed by the DIFC strategy. Reproducible mechanical performance is thus observed. The DIF fibers also exhibit exotic mechanical stability at extreme temperatures (e.g., -196 °C and 150 °C). When triggered by humidity, the DIFC endows the protein fibers with diverse actuation behaviors, such as self-folding, self-stretching, and self-contracting. Therefore, the established DIFC represents an alternative strategy to strengthen biological fibers and may pave the way for their high-tech applications.

Osmotically Rupturing Phagosomes in Macrophages Using PNIPAM Microparticles.

The rupture of macrophage phagosomes has been implicated in various human diseases and plays a critical role in immunity. However, the mechanisms underlying this process are complex and not yet fully understood. This study describes the development of a robust engineering method for rupturing phagosomes based on a well-defined mechanism. The method utilizes microfabricated microparticles composed of uncrosslinked linear poly(N-isopropylacrylamide) (PNIPAM) as phagocytic objects. These microparticles are internalized into phagosomes at 37 °C. By exposing the cells to a cold shock at 0 °C, the vast majority of the microparticle-containing phagosomes rupture. The percentage of phagosomal rupture decreases with the increase of the cold-shock temperature. The osmotic pressure in the phagosomes and the tension in the phagosomal membrane are calculated using the Flory-Huggins theory and the Young-Laplace equation. The modeling results indicate that the osmotic pressure generated by dissolved microparticles is probably responsible for phagosomal rupture, are consistent with the experimentally observed dependence of phagosomal rupture on the cold-shock temperature, and suggest the existence of a cellular mechanism for resisting phagosomal rupture. Moreover, the effects of various factors including hypotonic shock, chloroquine, tetrandrine, colchicine, and l-leucyl-l-leucine O-methyl ester (LLOMe) on phagosomal rupture have been studied with this method. The results further support that the osmotic pressure generated by the dissolved microparticles causes phagosomal rupture and demonstrated usefulness of this method for studying phagosomal rupture. This method can be further developed, ultimately leading to a deeper understanding of phagosomal rupture.

Parallel beam splitting and controlling system based on cascaded acousto-optic modulators.

In recent years, ultrashort pulse lasers (lasers) have been already widely used for providing excellent laser machining quality for the electronics industry, replication tools, and other applications. However, the major drawback of this processing is low efficiency, especially for a large number of laser ablation demands. In this paper, a beam-splitting approach based on cascaded acousto-optic modulators (AOMs) is proposed and analyzed in detail. The cascaded AOMs can split a laser beam into several beamlets with the same propagation direction. These beamlets can be switched on and off individually, and the beam pitch can be changed independently. At the same time, the experimental setup of three cascaded AOM beam splittings is built up to verify the capability of the high-speed control (switching rate:1 MHz), high-energy utilization rate (>96% at three AOMs), and high-energy splitting uniformity (nonuniformity: 3.3%). This scalable approach enables the processing of arbitrary surface structures with high quality and efficiency.

Dermoscopy in Mycobacterium marinum infection and its correlation with clinical and histopathological features: a prospective observational study.

BACKGROUND: Mycobacterium marinum is a nontuberculous mycobacterium and a conditional pathogen to humans, which can be inoculated directly and cause chronic skin granulomas. Dermoscopy has been applied to other granulomatous skin diseases, but not to M. marinum infection. AIM: To explore the dermoscopic features of M. marinum infection, and its correlation with clinical and histopathological features. METHODS: In total, 27 lesions from 27 patients (19 women, 8 men, age range 28-71 years) diagnosed with M. marinum infection were identified by clinical examination, histopathological results, PCR sequencing and mycobacterial culture in the dermatology outpatient department of our hospital from March 2020 to February 2022. The dermoscopy images and pathological characteristics were analysed. RESULTS: Lesions were located on the hands, forearms and upper arms. The following dermoscopic features were observed: yellowish-orange structureless areas (85·2%), white striped structures (59·3%), follicular plugs (29·6%), yellowish oval clods (14·8%) and reddish or pinkish areas (14·8%). Vessel structures were visible in all cases: long hairpin vessels (81·5%), corkscrew vessels (25·9%), comma-shaped vessels (22·2%) and linear vessels (22·2%). CONCLUSION: Yellowish-orange structureless areas, white striped structures and long hairpin vessels are the most common dermoscopic features of M. marinum infection. Thus, dermoscopy could be used as a noninvasive auxiliary diagnostic method to provide a diagnostic basis for this disease.