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Pancreatic ductal adenocarcinoma (PDA) is a lethal disease notoriously resistant to therapy1,2. This is mediated in part by a complex tumour microenvironment3, low vascularity4, and metabolic aberrations5,6. Although altered metabolism drives tumour progression, the spectrum of metabolites used as nutrients by PDA remains largely unknown. Here we identified uridine as a fuel for PDA in glucose-deprived conditions by assessing how more than 175 metabolites impacted metabolic activity in 21 pancreatic cell lines under nutrient restriction. Uridine utilization strongly correlated with the expression of uridine phosphorylase 1 (UPP1), which we demonstrate liberates uridine-derived ribose to fuel central carbon metabolism and thereby support redox balance, survival and proliferation in glucose-restricted PDA cells. In PDA, UPP1 is regulated by KRAS–MAPK signalling and is augmented by nutrient restriction. Consistently, tumours expressed high UPP1 compared with non-tumoural tissues, and UPP1 expression correlated with poor survival in cohorts of patients with PDA. Uridine is available in the tumour microenvironment, and we demonstrated that uridine-derived ribose is actively catabolized in tumours. Finally, UPP1 deletion restricted the ability of PDA cells to use uridine and blunted tumour growth in immunocompetent mouse models. Our data identify uridine utilization as an important compensatory metabolic process in nutrient-deprived PDA cells, suggesting a novel metabolic axis for PDA therapy.

Background Muscle mass development depends on increased protein synthesis and reduced degradation of muscle proteins. Muscle ring-finger protein-1 (MuRF1) plays a key role in controlling muscle atrophy. Its E3 ubiquitin ligase activity recognizes and degrades skeletal muscle proteins through the ubiquitin-proteasome system. The loss of Murf1 (the gene encoding MuRF1) in mice leads to the accumulation of skeletal muscle proteins and alleviation of muscle atrophy. However, the function of Murf1 in agricultural animals remains unclear. In this study, we bred F1 generation Murf1+/− and F2 generation Murf1−/− Duroc pigs from F0 Murf1−/− pigs to investigate the effect of Murf1 knockout on skeletal muscle development. Results The Murf1+/− pigs retained normal muscle growth and reproduction levels, and their lean meat percentage increased by 6% compared to that of the wild-type (WT) pigs. Furthermore, the meat color, pH, water-holding capacity, and tenderness of the Murf1+/− pigs were similar to those of the WT pigs. The drip loss rate and intramuscular fat decreased slightly in the Murf1+/− pigs. However, the cross-sectional area of the myofibers in the longissimus dorsi increased in adult Murf1+/− pigs. The skeletal muscle proteins MYBPC3 and actin, targeted by MuRF1, accumulated in the Murf1+/− and Murf1−/− pigs. Conclusions Our findings show that inhibiting muscle protein degradation in MuRF1-deficient Duroc pigs increases the size of their myofibers and percentage of lean meat without influencing their growth or pork quality. Our study demonstrates that Murf1 is a target gene for promoting skeletal muscle hypertrophy in pig breeding.

Chemoradiation-induced hearing loss (CRIHL) is one of the most devasting side effects for nasopharyngeal carcinoma (NPC) patients, which seriously affects survivors’ long-term quality of life. However, few studies have comprehensively characterized the risk factors for CRIHL. In this study, we found that age at diagnosis, tumor stage, and concurrent cisplatin dose were positively associated with chemoradiation-induced hearing loss. We performed a genome-wide association study (GWAS) in 777 NPC patients and identified rs1050851 (within the exon 2 of NFKBIA), a variant with a high deleteriousness score, to be significantly associated with hearing loss risk (HR = 5.46, 95% CI 2.93–10.18, P = 9.51 × 10–08). The risk genotype of rs1050851 was associated with higher NFKBIA expression, which was correlated with lower cellular tolerance to cisplatin. According to permutation-based enrichment analysis, the variants mapping to 149 hereditary deafness genes were significantly enriched among GWAS top signals, which indicated the genetic similarity between hereditary deafness and CRIHL. Pathway analysis suggested that synaptic signaling was involved in the development of CRIHL. Additionally, the risk score integrating genetic and clinical factors can predict the risk of hearing loss with a relatively good performance in the test set. Collectively, this study shed new light on the etiology of chemoradiation-induced hearing loss, which facilitates high-risk individuals’ identification for personalized prevention and treatment.

The past two decades of lunar exploration have seen the detection of substantial quantities of water on the Moon’s surface. It has been proposed that a hydrated layer exists at depth in lunar soils, buffering a water cycle on the Moon globally. However, a reservoir has yet to be identified for this hydrated layer. Here we report the abundance, hydrogen isotope composition and core-to-rim variations of water measured in impact glass beads extracted from lunar soils returned by the Chang’e-5 mission. The impact glass beads preserve hydration signatures and display water abundance profiles consistent with the inward diffusion of solar wind-derived water. Diffusion modelling estimates diffusion timescales of less than 15 years at a temperature of 360 K. Such short diffusion timescales suggest an efficient water recharge mechanism that could sustain the lunar surface water cycle. We estimate that the amount of water hosted by impact glass beads in lunar soils may reach up to 2.7 × 1014 kg. Our direct measurements of this surface reservoir of lunar water show that impact glass beads can store substantial quantities of solar wind-derived water on the Moon and suggest that impact glass may be water reservoirs on other airless bodies.

Gamma delta (γδ) T cells reside within human tissues including tumors, but their function in mediating antitumor responses to immune checkpoint inhibition is unknown. Here we show that kidney cancers are infiltrated by Vδ2− γδ T cells, with equivalent representation of Vδ1+ and Vδ1− cells, that are distinct from γδ T cells found in normal human tissues. These tumor-resident Vδ2− T cells can express the transcriptional program of exhausted αβ CD8+ T cells as well as canonical markers of terminal T-cell exhaustion including PD-1, TIGIT and TIM-3. Although Vδ2− γδ T cells have reduced IL-2 production, they retain expression of cytolytic effector molecules and co-stimulatory receptors such as 4-1BB. Exhausted Vδ2− γδ T cells are composed of three distinct populations that lack TCF7, are clonally expanded and express cytotoxic molecules and multiple Vδ2− T-cell receptors. Human tumor-derived Vδ2− γδ T cells maintain cytotoxic function and pro-inflammatory cytokine secretion in vitro. The transcriptional program of Vδ2− T cells in pretreatment tumor biopsies was used to predict subsequent clinical responses to PD-1 blockade in patients with cancer. Thus, Vδ2− γδ T cells within the tumor microenvironment can contribute to antitumor efficacy.

Purpose Currently, there are multiple active clinical trials involving poly(ADP-ribose) polymerase (PARP) inhibitors in the treatment of glioblastoma. The noninvasive quantification of baseline PARP expression using positron emission tomography (PET) may provide prognostic information and lead to more precise treatment. Due to the lack of brain-penetrant PARP imaging agents, the reliable and accurate in vivo quantification of PARP in the brain remains elusive. Herein, we report the synthesis of a brain-penetrant PARP PET tracer, (R)-2-(2-methyl-1-(methyl-11C)pyrrolidin-2-yl)-1H-benzo[d]imidazole-4-carboxamide ([11C]PyBic), and its preclinical evaluations in a syngeneic RG2 rat glioblastoma model and healthy nonhuman primates. Methods We synthesized [11C]PyBic using veliparib as the labeling precursor, performed dynamic PET scans on RG2 tumor-bearing rats and calculated the distribution volume ratio (DVR) using simplified reference region method 2 (SRTM2) with the contralateral nontumor brain region as the reference region. We performed biodistribution studies, western blot, and immunostaining studies to validate the in vivo PET quantification results. We characterized the brain kinetics and binding specificity of [11C]PyBic in nonhuman primates on FOCUS220 scanner and calculated the volume of distribution (VT), nondisplaceable volume of distribution (VND), and nondisplaceable binding potential (BPND) in selected brain regions. Results [11C]PyBic was synthesized efficiently in one step, with greater than 97% radiochemical and chemical purity and molar activity of 148 ± 85 MBq/nmol (n = 6). [11C]PyBic demonstrated PARP-specific binding in RG2 tumors, with 74% of tracer binding in tumors blocked by preinjected veliparib (i.v., 5 mg/kg). The in vivo PET imaging results were corroborated by ex vivo biodistribution, PARP1 immunohistochemistry and immunoblotting data. Furthermore, brain penetration of [11C]PyBic was confirmed by quantitative monkey brain PET, which showed high specific uptake (BPND > 3) and low nonspecific uptake (VND < 3 mL/cm3) in the monkey brain. Conclusion [11C]PyBic is the first brain-penetrant PARP PET tracer validated in a rat glioblastoma model and healthy nonhuman primates. The brain kinetics of [11C]PyBic are suitable for noninvasive quantification of available PARP binding in the brain, which posits [11C]PyBic to have broad applications in oncology and neuroimaging.

In the early stages of exploration, with only a limited amount of data available, it is difficult to evaluate a reservoir and optimize the sequence of the development plan. The score system is often used to rank the reservoir based on multidisciplinary factors that combine geology, production, and economics. However, current methods that are widely employed to classify the reservoir, such as analogy or single parameter, are qualitative or inaccurate, especially for carbonate gas reservoirs with complex geological conditions. In this study, we developed a score system using a data-driven approach to rank carbonate gas reservoirs in the Sichuan Basin. We developed two approaches, expert scoring and the random forest, to rank the quality of the reservoir, which agreed well with the field development plan. The expert scoring approach, which is highly dependent on the experience of experts in this area, is more suitable for reservoirs with limited data available, especially in the early exploration stage. The random forest model, which is more robust and able to reduce uncertainty from experience, is more suitable for developed areas with sufficient data. The developed score system can help rank new resource recovery and optimize the development plan in the Sichuan Basin.

Coronavirus disease 2019 (COVID-19) is currently a global pandemic. The pathogenesis of severe COVID-19 has been widely investigated, but it is still unclear. Human leukocyte antigen (HLA) plays a central role in immune response, and its variants might be related to COVID-19 progression and severity.To investigate the hypothesis that individual HLA variations could alter the course of COVID-19 and might be associated with the severity of COVID-19.In this study, we conducted an HLA targeted capture enrichment and sequencing of severe COVID-19 patients matched to mild cases. A total of 16 COVID-19 patients, confirmed by SARS-CoV-2 viral RNA polymerase-chain-reaction (PCR) test and chest computed tomography (CT) scan, were enrolled in this study. The HLA targeted capture enrichment and sequencing were conducted. HLA typing was performed by comparing contigs with IPD-IMGT/HLA Database.In this study, 139 four-digit resolution HLA alleles were acquired. The results showed that HLA-DRB3*01:01 allele was significantly associated with the severity of COVID-19 (odds ratio [OR] = 27.64, 95% confidence interval [CI] = 1.35-560.50, P = 0.0064). And HLA-K*01:01 might be a potential risk factor for COVID-19 severity (OR = 0.11, 95% CI = 0.017-0.66, P = 0.019), but HLA-K*01:02 might be a protective factor (OR = 7.50, 95% CI = 1.48-37.92, P = 0.019).Three non-classical HLA alleles, including HLA-DRB3*01:01, HLA-K*01:01, HLA-K*01:02 were identified to be associated with the severity of COVID-19 by comparing mild and severe patients. The current findings would be helpful for exploring the influence of HLA gene polymorphisms on the development and severity of COVID-19.

This study aimed to screen, design, and evaluate an optimal nanoemulsion formulation for Aucklandiae Radix extraction (ARE). A simple lattice design (SLD) method was used to determine the preparation process of Aucklandiae Radix extract-nanoemulsions (ARE-NEs). After optimization, the average particle size of ARE-NEs was 14.1 ± 1.1 nm, polydispersity index was 0.2376, and pH was 6.92. In vitro penetration tests verified that the permeability ratios of costunolide (CE), dehydrocostus lactone (DE), and ARE-NEs were approximately 6.33 times and 8.20 times higher, respectively, than those of the control group. The results of the pharmacokinetic study indicated that after topical administration, the content of the index components of ARE-NEs increased in vivo, with a longer release time and higher bioavailability in vivo than in vitro. The index components were CE and DE, respectively. In addition, a skin irritation test was conducted on normal and skin-damaged rabbits, aided by HE staining and scanning electron microscopy, to reveal the transdermal mechanism of ARE-NEs and proved that NEs are safe for topical application. ARE-NEs energetically developed the properties of skin and penetration through the transdermal route, which were secure when applied via the transdermal delivery system .

Fibroblast growth factors (FGFs) are key factors affecting diabetic wound healing. However, the FGF family's expression patterns in skin and wounds influenced by both diabetes and sex are still unknown.In this study, normal and Streptozotocin (STZ)-induced type 1 diabetic C57BL/6J male and female mice were used to study the FGF family's expression in non-wound skin and wounds. We found that the expression patterns of Fgfs were affected by sex in both normal and diabetic animals during wound healing. In normal control mice, sex difference had a limited effect on basal skin Fgf expressions. However, it significantly influenced Fgf expressions in wounds. Type 1 diabetes reduced basal and wound-induced skin Fgf expressions. Female mice had far lower wound-induced skin Fgf expressions in diabetic mice. In addition, sex differently influenced Fibroblast growth factors receptor (Fgfr) expression patterns of non-wound skin and wounds in both normal and diabetic mice. Moreover, female mice had a lower relative level of Fibronectin leucine-rich repeat transmembrane protein 2 (FLRT2) - a FGFR activation marker gene - in wound and blood plasma. Correspondingly, the wound areas of female animals were larger than that of male animals in the early stage of wound healing (less than 3-day injury).Our research shows that the FGF family have different expression patterns in normal and diabetic wound healing in mice of different sex. Additionally, we also provide the signatures of individual FGFs in diabetic wound healing, which deserve further investigation.

SNHG4 is a lncRNA that was previously reported to promote colorectal cancer (CRC) progression via molecular sponge mechanism. Bioinformatic analysis suggested SNHG4 might scaffold TAF15 protein-RNF14 mRNA interaction. We aimed to investigate the mechanisms of potential SNHG4/TAF15/RNF14 axis in promoting CRC malignant phenotypes. Protein-RNA interaction was determined using RNA immunoprecipitation, pull-down and fluorescence in situ hybridization (FISH) combined immunofluorescence assays. Cell apoptosis rates were quantified using flow cytometry. CCK-8 and colony formation were adopted to determine cell proliferation. Wound healing and transwell assays were employed to assess cell migration and invasion, respectively. Xenograft tumor model was applied to assess the effects of SNHG4 on CRC tumorigenesis in vivo. SNHG4, TAF15 and RNF14 were up-regulated in CRC tissues. SNHG4 overexpression promoted cell proliferation, migration, invasion, and Wnt/β-catenin pathway activation in vitro, as well as tumor growth in vivo. The inhibited malignant phenotypes caused by SNHG4 knockdown were impeded by TAF15 or RNF14 overexpression. Mechanistically, SNHG4 recruited TAF15 protein and thus promoted the interaction between TAF15 protein and RNF14 mRNA, leading to the increased RNF14 mRNA stability. This in turn facilitated the Wnt/β-catenin signal transduction. SNHG4 enhanced RNF14 mRNA stability and activated the Wnt/β-catenin pathway to promote the progression of colorectal cancer by recruiting TAF15 protein.