To evaluate diagnostic performance of metagenomic next-generation sequencing (mNGS) for Pneumocystis jirovecii pneumonia (PCP), in comparison with polymerase chain reaction (PCR), Gomori methenamine silver (GMS) staining and serum 1,3-β-d-Glucan (BG) assay.

Ultraviolet (UV) radiation can penetrate the basal layer of the skin and induce profound alterations in the underlying dermal tissues, including skin pigmentation, oxidative stress, photoaging, glycation, and skin cancer. Idebenone (IDB), an effective antioxidant that suppresses melanin biosynthesis and glycation, can protect the skin from UV-induced damage, accounting for its use in commercial anti-aging formulations. Ideally, IDB formulations should retain IDB inside the skin for a sufficient period, despite disturbances such as sweating or swimming. Herein, we present an IDB topical formulation based on Tris (tris(hydroxymethyl)-aminomethane)-modified bioadhesive nanoparticles (Tris-BNPs) and microneedle-assisted delivery. We found that Tris-BNPs loaded with IDB (IDB/Tris-BNPs) effectively reached the basal layer of the skin and were retained for at least 4 days with a slow and continuous drug release profile, unlike non-bioadhesive nanoparticles (NNPs) and bioadhesive nanoparticles (BNPs) of similar sizes (ranging from 120-142 nm) and zeta-potentials (above -20 mV), which experienced a significant reduction in concentration within 24 h. Notably, IDB/Tris-BNPs showed superior performance against UV-induced damage relative to IDB/NNPs and IDB/BNPs. This effect was demonstrated by lower levels of reactive oxygen species and advanced glycation end-products in skin tissues, as well as suppressed melanogenesis. Therefore, the proposed IDB delivery strategy provided long-term protective effects against UV-induced skin damage.

Great progress has been made in identifying positive regulators that activate adipocyte thermogenesis, but negative regulatory signaling of thermogenesis remains poorly understood. Here, we found that cardiotrophin-like cytokine factor 1 (CLCF1) signaling led to loss of brown fat identity, which impaired thermogenic capacity. CLCF1 levels decreased during thermogenic stimulation but were considerably increased in obesity. Adipocyte-specific CLCF1 transgenic (CLCF1-ATG) mice showed impaired energy expenditure and severe cold intolerance. Elevated CLCF1 triggered whitening of brown adipose tissue by suppressing mitochondrial biogenesis. Mechanistically, CLCF1 bound and activated ciliary neurotrophic factor receptor (CNTFR) and augmented signal transducer and activator of transcription 3 (STAT3) signaling. STAT3 transcriptionally inhibited both peroxisome proliferator-activated receptor-γ coactivator (PGC) 1α and 1β, which thereafter restrained mitochondrial biogenesis in adipocytes. Inhibition of CNTFR or STAT3 could diminish the inhibitory effects of CLCF1 on mitochondrial biogenesis and thermogenesis. As a result, CLCF1-TG mice were predisposed to develop metabolic dysfunction even without external metabolic stress. Our findings revealed a brake signal on nonshivering thermogenesis and suggested that targeting this pathway could be used to restore brown fat activity and systemic metabolic homeostasis in obesity.

Failure to achieve complete elimination of triple negative breast cancer (TNBC) stem cells after adjuvant therapy is associated with poor outcomes. Aldehyde dehydrogenase 1 (ALDH1) is a marker of breast cancer stem cells (BCSCs), and its enzymatic activity regulates tumor stemness. Identifying upstream targets to control ALDH+ cells may facilitate TNBC tumor suppression. Here, we show that KK-LC-1 determines the stemness of TNBC ALDH+ cells via binding with FAT1 and subsequently promoting its ubiquitination and degradation. This compromises the Hippo pathway and leads to nuclear translocation of YAP1 and ALDH1A1 transcription. These findings identify the KK-LC-1-FAT1-Hippo-ALDH1A1 pathway in TNBC ALDH+ cells as a therapeutic target. To reverse the malignancy due to KK-LC-1 expression, we employ a computational approach and discover Z839878730 (Z8) as an small-molecule inhibitor which may disrupt KK-LC-1 and FAT1 binding. We demonstrate that Z8 suppresses TNBC tumor growth via a mechanism that reactivates the Hippo pathway and decreases TNBC ALDH+ cell stemness and viability.

One of the long-standing enigmas for lunar tectonic-thermal evolution is the spatiotemporal association of contractional wrinkle ridges and basaltic volcanism in a compressional regime. Here, we show that most of the 30 investigated volcanic (eruptive) centers are linked to contractional wrinkle ridges developed above preexisting basin basement-involved ring/rim normal faults. Based on the tectonic patterns associated with the basin formation and mass loading and considering that during the subsequent compression the stress was not purely isotropic, we hypothesize that tectonic inversion produced not only thrust faults but also reactivated structures with strike-slip and even extensional components, thus providing a valid mechanism for magma transport through fault planes during ridge faulting and folding of basaltic layers. Our findings suggest that lunar syn-tectonic mare emplacement along reactivated inherited faults provides important records of basin-scale structure-involved volcanism, which is more complex than previously considered.

Evidence shows that some class I human leucocyte antigen (HLA) alleles are related to durable HIV controls. The T18A TCR, which has the alloreactivity between HLA-B∗42:01 and HLA-B∗81:01 and the cross-reactivity with different antigen mutants, can sustain long-term HIV controls. Here the structural basis of the T18A TCR binding to the immunodominant HIV epitope TL9 (TPQDLNTML180-188) presented by HLA-B∗42:01 was determined and compared to T18A TCR binding to the TL9 presented by the allo-HLA-B∗81:01. For differences between HLA-B∗42:01 and HLA-B∗81:01, the CDR1α and CDR3α loops adopt a small rearrangement to accommodate them. For different conformations of the TL9 presented by different HLA alleles, not like the conventional recognition of CDR3s to interact with peptide antigens, CDR3β of the T18A TCR shifts to avoid the peptide antigen but intensively recognizes the HLA only, which is different with other conventional TCR structures. Featured sequence pairs of CDR3β and HLA might account for this and were additionally found in multiple other diseases indicating the popularity of the unconventional recognition pattern which would give insights into the control of diseases with epitope mutating such as HIV.

Glucagon-like peptide-1 (GLP-1) is mainly secreted by preproglucagon neurons; it plays important roles in modulating neuronal activity and synaptic transmission through its receptors. In the present study, we investigated the effects of GLP-1 on parallel fiber-Purkinje cell (PF-PC) synaptic transmission in mouse cerebellar slices using whole-cell patch-clamp recording and pharmacology methods. In the presence of a γ-aminobutyric acid type A receptor antagonist, bath application of GLP-1 (100 nM) enhanced PF-PC synaptic transmission, with an increased amplitude of evoked excitatory postsynaptic synaptic currents (EPSCs) and a decreased paired-pulse ratio. The GLP-1-induced enhancement of evoked EPSCs was abolished by a selective GLP-1 receptor antagonist, exendin 9-39, as well as by the extracellular application of a specific protein kinase A (PKA) inhibitor, KT5720. In contrast, inhibiting postsynaptic PKA with a protein kinase inhibitor peptide-containing internal solution failed to block the GLP-1-induced enhancement of evoked EPSCs. In the presence of a mixture of gabazine (20 μM) and tetrodotoxin (1 μM), application GLP-1 significantly increased frequency, but not amplitude of miniature EPSCs via PKA signaling pathway. The GLP-1-induced increase in miniature EPSC frequency was blocked by both exendin 9-39 and KT5720. Together, our results indicate that GLP-1 receptor activation enhances glutamate release at PF-PC synapses via the PKA signaling pathway, resulting in enhanced PF-PC synaptic transmission in mice in vitro. These findings suggest that, in living animals, GLP-1 has a critical role in the modulation of cerebellar function by regulating excitatory synaptic transmission at PF-PC synapses.

RNA decay plays a crucial role in regulating mRNA abundance and gene expression. Modulation of RNA degradation is imperative to investigate an RNA's function. However, information regarding where and how RNA decay occurs remains scarce, partially because existing technologies fail to initiate RNA decay with the spatiotemporal precision or transcript specificity required to capture this stochastic and transient process. Here, we devised a general method that employs inducible tethering of regulatory protein factors to target RNAs and modulate their metabolism. Specifically, we established a Rapid Inducible Decay of RNA (RIDR) technology to degrade target mRNA within minutes. The fast and synchronous induction enabled direct visualization of mRNA decay dynamics in cells with spatiotemporal precision previously unattainable. When applying RIDR to endogenous ACTB mRNA, we observed rapid formation and disappearance of RNA granules, which coincided with pre-existing processing bodies (P-bodies). We measured the time-resolved RNA distribution in P-bodies and cytoplasm after induction, and compared different models of P-body function. We determined that mRNAs rapidly decayed in P-bodies upon induction. Additionally, we validated the functional role of P-bodies by knocking down specific a P-body constituent protein and RNA degradation enzyme. This study determined compartmentalized RNA decay kinetics for the first time. Together, RIDR provides a valuable and generalizable tool to study the spatial and temporal RNA metabolism in cells.

Despite potential impact on the graft vs. leukemia (GVL) effect, immunotherapy targeting CTLA-4 and/or PD-1 has not been successfully combined with bone marrow transplant (BMT) because it exacerbates graft vs. host disease (GVHD). Here, using models of GVHD and leukemia, we demonstrate that targeting hypoxia-inducible factor 1α (HIF1α) via pharmacological or genetic approaches reduces GVHD by inducing PDL1 expression on host tissue while selectively inhibiting PDL1 in leukemia cells to enhance the GVL effect. More importantly, combination of HIF1α inhibition with anti-CTLA-4 antibodies allows simultaneous inhibition of both PDL1 and CTLA-4 checkpoints to achieve better outcomes in models of mouse and human BMT-leukemia settings. These findings provide an approach to enhance the curative effect of BMT for leukemia and broaden the impact of cancer immunotherapy.

As one of the most widely used nanomaterials, CeO2 nanoparticles (NPs) might be released into the aquatic environment. In this paper, the interaction of CeO2 NPs and Ce3+ ions (0~10 mg/L) with duckweed (Lemna minor L.) was investigated. CeO2 NPs significantly inhibited the root elongation of duckweed at concentrations higher than 0.1 mg/L, while the inhibition threshold of Ce3+ ions was 0.02 mg/L. At high doses, both reduced photosynthetic pigment contents led to cell death and induced stomatal deformation, but the toxicity of Ce3+ ions was greater than that of CeO2 NPs at the same concentration. According to the in situ distribution of Ce in plant tissues by μ-XRF, the intensity of Ce signal was in the order of root > old frond > new frond, suggesting that roots play a major role in the uptake of Ce. The result of XANES showed that 27.6% of Ce(IV) was reduced to Ce(III) in duckweed treated with CeO2 NPs. We speculated that the toxicity of CeO2 NPs to duckweed was mainly due to its high sensitivity to the released Ce3+ ions. To our knowledge, this is the first study on the toxicity of CeO2 NPs to an aquatic higher plant.

The gut mycobiome of patients with lung adenocarcinoma (LUAD) remains unexplored. This study aimed to characterize the gut mycobiome in patients with LUAD and evaluate the potential of gut fungi as non-invasive biomarkers for early diagnosis.

Mild normobaric hypoxia (NH) and modest exercise have multiple beneficial effects on health, but the changes in physiological function induced by NH and/or exercise remain unclear. The purpose of this investigation was to examine the specific effects of NH and/or exercise on cardiac function and myocardial structure and behavior including sleep-activity and negative geotaxis in aged Drosophila. We also assessed the survival rate of flies after hypoxia and/or exercise. One-thousand wild-type w1118 virgin female flies were randomly divided into four groups and treated with NH and/or exercise from ages 3-6 weeks. We found that exercise remarkably delayed the decline of actin and myosin and the age-related changes in cardiac structure, improved abnormal cardiac contraction, and enhanced the cardiac pumping force by inducing cardiac hypertrophy and delaying deterioration of cardiac contractility and diastolic compliance, and improved abnormal heart contraction. NH also increased the content of actin and myosin, but induced a decrease in heart diameter and heart rate, as well as an increase in the number of mitochondria and deeper sleep, which may be the manifestation of energy saving under long-term hypoxia. Both NH and exercise improved sleep quality and climbing ability of aged flies, as well as extended the maximum life span, which shows the benefits of hypoxia and exercise. Finally, the superposition of NH and exercise did not impart any obvious physiological and behavior improvement. Therefore, it is necessary to further explore the appropriate combination of hypoxia and exercise.

The transmembrane receptor Kremen2 has been reported to participate in the tumorigenesis and metastasis of gastric cancer. However, the role of Kremen2 in non-small cell lung cancer (NSCLC) and the underlying mechanism remain unclear. This study aimed to explore the biological function and regulatory mechanism of Kremen2 in NSCLC.

The recurrence of papillary thyroid carcinoma (PTC) is not unusual and associated with risk of death. This study is aimed to construct a nomogram that combines clinicopathological characteristics and ultrasound radiomics signatures to predict the recurrence in PTC.

Gene-editing technology shows great potential in glioblastoma (GBM) therapy. Due to the complexity of GBM pathogenesis, a single gene-editing-based therapy is unlikely to be successful; therefore, a multi-gene knockout strategy is preferred for effective GBM inhibition. Here, a non-invasive, biodegradable brain-targeted CRISPR/Cas12a nanocapsule is used that simultaneously targeted dual oncogenes, EGFR and PLK1, for effective GBM therapy. This cargo nanoencapsulation technology enables the CRISPR/Cas12a system to achieve extended blood half-life, efficient blood-brain barrier (BBB) penetration, active tumor targeting, and selective release. In U87MG cells, the combinatorial gene editing system resulted in 61% and 33% knockout of EGFR and PLK1, respectively. Following systemic administration, the CRISPR/Cas12a system demonstrated promising brain tumor accumulation that led to extensive EGFR and PLK1 gene editing in both U87MG and patient-derived GSC xenograft mouse models with negligible off-target gene editing detected through NGS. Additionally, CRISPR/Cas12a nanocapsules that concurrently targeted the EGFR and PLK1 oncogenes showed superior tumor growth suppression and significantly improved the median survival time relative to nanocapsules containing single oncogene knockouts, signifying the potency of the multi-oncogene targeting strategy. The findings indicate that utilization of the CRISPR/Cas12a combinatorial gene editing technique presents a practical option for gene therapy in GBM.

Glucocorticoid-induced glaucoma (GIG) is a prevalent complication associated with glucocorticoids (GCs), resulting in irreversible blindness. GIG is characterized by the abnormal deposition of extracellular matrix (ECM) in the trabecular meshwork (TM), elevation of intraocular pressure (IOP), and loss of retinal ganglion cells (RGCs). The objective of this study is to investigate the effects of nicotinamide riboside (NR) on TM in GIG.

Currently, conventional dimethoxymethane synthesis methods are environmentally unfriendly. Here, we report a photo-redox catalysis system to generate dimethoxymethane using a silver and tungsten co-modified blue titanium dioxide catalyst (Ag.W-BTO) by coupling CO2 reduction and CH3OH oxidation under mild conditions. The Ag.W-BTO structure and its electron and hole transfer are comprehensively investigated by combining advanced characterizations and theoretical studies. Strikingly, Ag.W-BTO achieve a record photocatalytic activity of 5702.49 µmol g-1 with 92.08% dimethoxymethane selectivity in 9 h of ultraviolet-visible irradiation without sacrificial agents. Systematic isotope labeling experiments, in-situ diffuse reflectance infrared Fourier-transform analysis, and theoretical calculations reveal that the Ag and W species respectively catalyze CO2 conversion to *CH2O and CH3OH oxidation to *CH3O. Subsequently, an asymmetric carbon-oxygen coupling process between these two crucial intermediates produces dimethoxymethane. This work presents a CO2 photocatalytic reduction system for multi-carbon production to meet the objectives of sustainable economic development and carbon neutrality.

Asparagus officinalis (ASP) has antioxidation, anti-inflammatory, antiaging, and immune system-enhancing effects. We explored the preventive and therapeutic consequences of ASP on the brain damage elicited by fluorosis through network pharmacology and in vivo experimental validation. We ascertained the pharmaceutically active ingredients and drug targets of ASP from the Traditional Chinese Medicine Systems Pharmacology database, predicted the disease targets of fluorosis-induced brain injury using GeneCards and Online Mendelian Inheritance in Man databases, obtained target protein-protein interaction networks in the Search Tool for the Retrieval of Interacting Genes/Proteins database, used Cytoscape to obtain key targets and active ingredients, and conducted enrichment analyses of key targets in the Database for Annotation, Visualization and Integrated Discovery. Enrichment analyses showed that "mitogen-activated protein kinase" (MAPK), "phosphoinositide 3-kinase/protein kinase B" (PI3K-Akt), "nuclear factor-kappa B" (NF-κB), and the "neurotrophin signaling pathway" were the most enriched biological processes and signaling pathways. ASP could alleviate fluorosis-based injury, improve brain-tissue damage, increase urinary fluoride content, and improve oxidation levels and inflammatory-factor levels in the body. ASP could also reduce dental fluorosis, bone damage, fluoride concentrations in blood and bone, and accumulation of lipid peroxide. Upon ASP treatment, expression of silent information regulator (SIRT)1, brain-derived neurotrophic factor (BDNF), tropomyosin receptor kinase B (TrkB), MAPK, NF-κB, PI3K, Akt, and B-cell lymphoma-2 in rat brain tissue increased gradually, whereas that of Bax, caspase-3, and p53 decreased gradually. We demonstrated that ASP could regulate the brain damage caused by fluorosis through the SIRT1/BDNF/TrkB signaling pathway, and reported the possible part played by ASP in preventing and treating fluorosis.

Myocardial ischemia reperfusion injury (MIRI), the tissue damage which is caused by the returning of blood supply to tissue after a period of ischemia, greatly reduces the therapeutic effect of treatment of myocardial infarction. But the underlying functional mechanisms of MIRI are still unclear.

Radiomics is increasingly utilized to distinguish pulmonary nodules between lung adenocarcinoma (LUAD) and tuberculosis (TB). However, it remains unclear whether different segmentation criteria, such as the inclusion or exclusion of the cavity region within nodules, affect the results.