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PH5 is a petunia gene that encodes a plasma membrane H(+)-ATPase and determines the vacuolar pH. The citrate content of fruit cell vacuoles influences citrus organoleptic qualities. Although citrus could have PH5-like homologs that are involved in citrate accumulation, the details are still unknown. In this study, extensive data-mining with the PH5 sequence and PCR amplification confirmed that there are at least eight PH5-like genes (CsPH1-8) in the citrus genome. CsPHs have a molecular mass of approximately 100 kDa, and they have high similarity to PhPH5, AtAHA10 or AtAHA2 (from 64.6 to 80.9%). They contain 13-21 exons and 12-20 introns and were evenly distributed into four subgroups of the P3A-subfamily (CsPH1, CsPH2, and CsPH3 in Group I, CsPH4 and CsPH5 in Group II, CsPH6 in Group IV, and CsPH7 and CsPH8 in Group III together with PhPH5). A transcript analysis showed that CsPH1, 3, and 4 were predominantly expressed in mature leaves, whereas CsPH2 and 7 were predominantly expressed in roots, CsPH5 and 6 were predominantly expressed in flowers, and CsPH8 was predominantly expressed in fruit juice sacs (JS). Moreover, the CsPH transcript profiles differed between orange and pummelo, as well as between high-acid and low-acid cultivars. The low-acid orange \"Honganliu\" exhibits low transcript levels of CsPH3, CsPH4, CsPH5, and CsPH8, whereas the acid-free pummelo (AFP) has only a low transcript level of CsPH8. In addition, ABA injection increased the citrate content significantly, which was accompanied by the obvious induction of CsPH2, 6, 7, and 8 transcript levels. Taken together, we suggest that CsPH8 seems likely to regulate citrate accumulation in the citrus fruit vacuole.

The accumulation of soluble sugars in fleshy fruits largely determines their sweetness or taste. A spontaneous sweet orange mutant ‘Hong Anliu’ (HAL, Citrus sinensis ) accumulates low soluble sugar content in fruit juice sacs than its wild type, ‘Anliu’ (AL) orange; however, the cause of reduced sugar content in ‘HAL’ fruit remains unclear. In this study, sugar content and expression profiles of genes involved in sugar metabolism and transport were compared between ‘HAL’ and ‘AL’ fruit juice sacs. In both cultivars, fructose and glucose displayed the increasing trends with significantly lower contents in ‘HAL’ than ‘AL’ after 160 DAF; moreover, sucrose had a declining trend in ‘HAL’ and increasing trend in ‘AL’ with fruit development. On the other hand, transcript levels of VINV , CWINV1 , CWINV2 , SUS4 , SUS5 , SPS1 , SPS2 , VPP-1 , VPP-2 , and some sugar transporter genes were significantly decreased in ‘HAL’ compared with ‘AL’ after 100 DAF or 160 DAF. Interestingly, the transcript levels of SPS2 and SUT2 exhibited a similar trend as it was found for sucrose content in both cultivars. These results suggested that the low sugar accumulation in ‘HAL’ fruit JS is accompanied by the reduced sink strength, sucrose-synthesis ability, and vacuolar storage ability compared with ‘AL’; reduction of CWINVs , VINV , SPS2 , SUT2 , VPP-1 , and VPP-2 transcript levels possibly plays a key role in the low storage of soluble sugars in the vacuoles of mutant juice sacs.

Drought stress is one of the main limiting factors in apple (Malus domestica Borkh.) cultivation. Rootstock plays an important role in the drought tolerance of apple plants. ‘M.9-T337’ is a novel apple rootstock that was recently introduced and widely cultivated in China. In this study, we selected the new, widely promoted Chinese apple variety ‘Huashuo’ as the scion and grafted it onto ‘M.9-T337’ (HM9). Another combination, ‘Huashuo’/‘M.26’/Malus robusta Rehd. (HM26), served as the experimental control to analyse drought resistance in the two hybrids. We believe that this empirical approach is more representative than merely studying rootstock seedlings. After sustained drought stress for over 1 month, the leaf relative water content had decreased in both types of plants, but to a lesser extent in HM26 than in HM9. The SPAD values increased in both plants, but without significant difference. Drought stress reduced photosynthetic activity in both plants, and the net photosynthetic rate was higher in HM26 than in HM9. The observed changes in the chlorophyll fluorescence parameters indicated that drought had damaged the PSII activity centres of both plants, photosynthetic electron transfer was inhibited, and excessive excitation energy accumulated. However, compared to HM26, HM9 displayed lower maximal PSII quantum photochemical efficiency and potential PSII activity. Moreover, HM9 showed lower antioxidant enzyme activity than HM26 under drought stress. A membership function analysis confirmed that ‘M.9-T337’ was less drought resistant than ‘M.26’. Nevertheless, ‘M.9-T337’ could still recover after prolonged drought stress, indicating it also had good drought resistance.

Background: Living donor liver transplantation (LDLT) has become a widely accepted alternative to deceased donor liver transplantation (DDLT). Nevertheless, the available meta-analyses shed light on a perplexing issue regarding which transplant is better. Therefore, we performed an umbrella review to summarize and evaluate the evidence from current meta-analyses. Methods: Two independent reviewers conducted a search of PubMed, Embase, Web of Science, and the Cochrane Database of Systematic Reviews from inception to 1 June 2024. The methodological quality of each included meta-analysis was evaluated using AMSTAR2 (A Measurement Tool to Assess Systematic Reviews). Results: The search identified 10 meta-analyses from 486 individual articles, including cohort studies and observational studies. Regrettably, the quality of these meta-analyses ranged from critically low to moderate. Receipt of LDLT offers a survival advantage to the patients with HCC compared with DDLT but with a higher complication rate. However, high-quality studies are required in the future to validate our assertions owing to the low certainty of the evidence. Conclusions: Despite the complication risks, LDLT remains a cost-effective option without compromising patient and graft survival, especially for HCC patients. Extensive, well-designed studies are essential to validate these conclusions.

Alternative splicing (AS) is a crucial post-transcriptional regulatory mechanism that is frequently disrupted in cancer, leading to the generation of tumor-specific splice variants. These aberrant splicing events, often driven by mutations in splice sites or splicing factors (SFs), produce abnormal mRNA transcripts and protein isoforms that contribute to tumor initiation, progression, and immune evasion. Recent advancements in cancer immunotherapy have positioned AS-derived neoantigens as a novel and promising class of tumor-specific targets. These neoepitopes significantly expand the pool of immunogenic antigens for mRNA vaccines and adoptive cell transfer therapies, triggering robust and targeted anti-tumor immune responses. This review offers a comprehensive overview of the molecular mechanisms driving the generation of AS-derived neoantigens, their tumorigenic and immunological properties, and the antigen processing and presentation pathways involved. Additionally, we discuss emerging therapeutic strategies that exploit these neoantigens, such as splicing modulation and personalized immunotherapies, while also addressing current challenges and future prospects for translating AS-derived neoantigens into precision cancer immunotherapy.

Glutamate decarboxylase (GAD, EC 4.1.1.15) has been suggested to be a key, regulatory point in the biosynthesis of γ-aminobutyrate (GABA) and in the utilization of citric acid through GABA shunt pathway. In this study we discovered two GAD genes, named as CsGAD1 and CsGAD2, in citrus genome database and then successfully cloned. Both CsGAD1 and CsGAD2 have a putative pyridoxal 5-phosphate binding domain in the middle region and a putative calmodulin-binding domain at the carboxyl terminus. Gene structure analysis showed that much difference exists in the size of exons and introns or in cis-regulatory elements in promoter region between the two GAD genes. Gene expression indicated that CsGAD1 transcript was predominantly expressed in flower and CsGAD2 transcript was predominantly expressed in fruit juice sacs; in the ripening fruit, CsGAD1 transcript level was at least 2-time higher than CsGAD2 transcript level. Moreover, CsGAD1 transcript level was increased significantly along with the increase of GAD activity and accompanied by a significant decrease of titratable acid (TA), suggesting that it is CsGAD1 rather than CsGAD2 plays a role in the citric acid utilization during fruit ripening. In addition, injection of abscisic acid and foliar spray of K₂SO₄ significantly increased the TA content of Satsuma mandarin, and significantly decreased GAD activity as well as CsGAD1 transcript, further suggesting the important role of CsGAD1 in the citrate utilization of citrus fruit.

‘Hong Anliu’ (HAL, Citrus sinensis cv. Hong Anliu) is a bud mutant of ‘Anliu’ (AL), characterized by a comprehensive metabolite alteration, such as lower accumulation of citrate, high accumulation of lycopene and soluble sugars in fruit juice sacs. Due to carboxylic acid metabolism connects other metabolite biosynthesis and/or catabolism networks, we therefore focused analyzing citrate accumulation-related gene expression profiles and/or enzyme activities, along with metabolic fingerprinting between ‘HAL’ and ‘AL’. Compared with ‘AL’, the transcript levels of citrate biosynthesis- and utilization-related genes and/or the activities of their respective enzymes such as citrate synthase, cytosol aconitase and ATP-citrate lyase were significantly higher in ‘HAL’. Nevertheless, the mitochondrial aconitase activity, the gene transcript levels of proton pumps, including vacuolar H + -ATPase, vacuolar H + -PPase, and the juice sac-predominant p-type proton pump gene ( CsPH8 ) were significantly lower in ‘HAL’. These results implied that ‘HAL’ has higher abilities for citrate biosynthesis and utilization, but lower ability for the citrate uptake into vacuole compared with ‘AL’. Combined with the metabolites-analyzing results, a model was then established and suggested that the reduction in proton pump activity is the key factor for the low citrate accumulation and the comprehensive metabolite alterations as well in ‘HAL’.

ATP-citrate lyase (ACL, EC4.1.3.8) catalyzes citrate to oxaloacetate and acetyl-CoA in the cell cytosol, and has important roles in normal plant growth and in the biosynthesis of some secondary metabolites. We identified three ACL genes, CitACLα1, CitACLα2, and CitACLβ1, in the citrus genome database. Both CitACLα1 and CitACLα2 encode putative ACL α subunits with 82.5 % amino acid identity, whereas CitACLβ1 encodes a putative ACL β subunit. Gene structure analysis showed that CitACLα1 and CitACLα2 had 12 exons and 11 introns, and CitACLβ1 had 16 exons and 15 introns. CitACLα1 and CitACLβ1 were predominantly expressed in flower, and CitACLα2 was predominantly expressed in stem and fibrous roots. As fruits ripen, the transcript levels of CitACLα1, CitACLβ1, and/or CitACLα2 in cultivars ‘Niuher’ and ‘Owari’ increased, accompanied by significant decreases in citrate content, while their transcript levels decreased significantly in ‘Egan No. 1’ and ‘Iyokan’, although citrate content also decreased. In ‘HB pummelo’, in which acid content increased as fruit ripened, and in acid-free pummelo, transcript levels of CitACLα2, CitACLβ1, and/or CitACLα1 increased. Moreover, mild drought stress and ABA treatment significantly increased citrate contents in fruits. Transcript levels of the three genes were significantly reduced by mild drought stress, and the transcript level of only CitACLβ1 was significantly reduced by ABA treatment. Taken together, these data indicate that the effects of ACL on citrate use during fruit ripening depends on the cultivar, and the reduction in ACL gene expression may be attributed to citrate increases under mild drought stress or ABA treatment.

The sucrose transporter (SUT) plays a major role in the transport of sucrose apoplastically. An extensive mining of the data confirmed that at least three SUT genes (CitSUT1, CitSUT2, and CitSUT3) were found in the databases of the three currently available citrus genomes. The exon and intron sizes varied among the three CitSUT genes, and the similarities among the genes were 40–50 %. The phylogenetic analysis revealed that the CitSUT1, CitSUT2, and CitSUT3 were distributed into groups SUT I, SUT II, and SUT III, respectively. The analysis of the spatiotemporal expression of the genes showed that the CitSUT1, CitSUT2, and CitSUT3 were predominantly expressed in the stamens, young leaves, and fruits [juice sacs (JS) and/or segment membrane (SM)], respectively. Moreover, in addition to the significant increase in sucrose levels from 114 days after anthesis (DAA) to 160 DAA, the transcript levels of CitSUT1 and CitSUT3 increased significantly in the JS and decreased significantly in the SM, whereas the CitSUT2 transcript levels decreased significantly either in the JS or in the SM. Additionally, treatment with ABA increased the accumulations of sucrose and fructose in fruits, which were accompanied by the induction of the CitSUT2 transcripts in fruits (JS and SM) and the CitSUT3 transcripts in the SM and the reduction of the CitSUT1 and CitSUT3 transcript levels in the JS. Thus, the CitSUT1 and CitSUT3 might play important roles in the transport of sucrose into the fruit JS during normal fruit development; the transcript alterations of the CitSUT2 and CitSUT3 under the ABA treatment might contribute to the increased accumulation of sucrose.

ObjectiveTo investigate the effect of Chinese medicine (CM) on survival of patients with stage II and III colorectal cancer (CRC).MethodsA total of 295 patients who received chemotherapy were assigned to Group 1. The other 171 patients received the same chemotherapy treatment combined with the usage of CM Jianpi Jiedu Formula (健脾解毒方, JPJD) for more than 3 months (Group 2). Patients' survival time, relapse and metastasis, and cause of death were observed. Cox proportional hazard regression models were established for the analysis of the effect of independent factors on the survival prognosis of patients with CRC.ResultsThe survival rate of patients in Group 2 was higher than that of Group 1 (P<0.05). Compared with Group 1, the mean survival time was prolonged by 5.594 months and the median survival time was prolonged by 6 months in Group 2 (P=0.004). Cox regression analysis indicated that CM combined with chemotherapy provided signifificant protective effect, as observed with the improvements in the survival rates of CRC patients (P<0.01).ConclusionCM can improve the survival rate in patients with stage II and III CRC.