Frequent disturbances enhanced the resilience of past human populations.

The record of past human adaptations provides crucial lessons for guiding responses to crises in the future1-3. To date, there have been no systematic global comparisons of humans' ability to absorb and recover from disturbances through time4,5. Here we synthesized resilience across a broad sample of prehistoric population time-frequency data, spanning 30,000 years of human history. Cross-sectional and longitudinal analyses of population decline show that frequent disturbances enhance a population's capacity to resist and recover from later downturns. Land-use patterns are important mediators of the strength of this positive association: farming and herding societies are more vulnerable but also more resilient overall. The results show that important trade-offs exist when adopting new or alternative land-use strategies.

Case report: Response to Savolitinib/EGFR-TKI combination in NSCLC patients harboring concurrent primary MET amplification/overexpression and EGFR mutation.

Lung cancer is the leading cause of cancer death, accounting for one-third of all cancer deaths worldwide. The MET (c-MET) gene, as one of the therapeutic target spots of NSCLC, has become increasingly more important. MET amplification/overexpression was divided into primary (intrinsic) and secondary (acquired). Studies indicated that the combination of Osimertinib and Savolitinib was safe and showed promising antitumor effect in NSCLC patients with secondary MET amplification after EGFR mutations. However, NSCLC patients with primary MET amplification/overexpression and EGFR mutations are rare in clinics, and the efficacy of dual-target therapy combined with EGFR-TKI and Savolitinib for them has not been studied yet. Here, we reported two NSCLC patients with primary MET amplification/overexpression and EGFR mutation, who benefited from T+S therapy (the dual-target therapy of EGFR-TKI plus Savolitinib) and achieved a progression-free survival (PFS) of approximately 5 months. The two cases indicated that T+S therapy has an acceptable safety profile and encouraging antitumor efficacy in NSCLC patients harboring concurrent primary MET amplification/overexpression and EGFR mutation. Meanwhile, the observation stresses the importance of genetic testing, and the MET gene needs to be detected at first diagnosis for the best choice of targeted therapies.

A method for Porphyromonas gingivalis based on recombinase polymerase amplification and lateral flow strip technology.

OBJECTIVE: A practical visual detection method was established to detect Porphyromonas gingivalis (P. gingivalis) by employing a combination of recombinase polymerase amplification and lateral flow strips (RPA-LF) assay, designed for conducting point-of-care testing in clinical settings. METHODS: Primers and probes targeting the P. gingivalis pepO gene were designed. The RPA-LF assay was established by optimising reaction temperature and time, determining the limit of detection (LOD). The specificity of the method was determined by assessing its cross-reactivity with deoxyribonucleic acid from 23 pathogenic bacteria. Finally, the clinical samples from healthy controls (n = 30) and individuals with periodontitis (n = 31) were analysed. The results were compared with those obtained using real-time polymerase chain reaction (PCR). RESULTS: The optimal reaction temperature and time were 39 °C and 12 min. The method exhibited a LOD at 6.40 × 10-4 µg/mL and demonstrated high specificity and sensitivity during cross-reactivity assessment. The RPA-LF assay achieved a P. gingivalis detection rate of 84 % in individuals with periodontitis and 3 % in healthy controls. The results were consistent with those obtained through real-time PCR. CONCLUSION: An RPA-LF assay was developed for detecting P. gingivalis, characterised by its high sensitivity, high specificity, simple operational procedure, and rapid reaction time.

Transcriptome and Metabolomics Integrated Analysis Reveals MdMYB94 Associated with Esters Biosynthesis in Apple (Malus × domestica).

Volatile esters are major aromas contributing to the organoleptic quality of apple fruit. However, the molecular mechanisms underlying the regulation of volatile ester biosynthesis in apple remain elusive. This study investigated the volatile profiles and transcriptomes of 'Qinguan' (QG) apple fruit during development and/or postharvest storage. Although the constitution of volatiles varied widely between the peel and flesh, the volatile profiles of the peel and flesh of ripening QG fruit were dominated by volatile esters. WGCNA results suggested that 19 genes belonging to ester biosynthesis pathways and 11 hub transcription factor genes potentially participated in the biosynthesis and regulation of esters. To figure out key regulators of ester biosynthesis, correlation network analysis, dual-luciferase assays, and yeast one-hybrid assay were conducted and suggested that MdMYB94 trans-activated the MdAAT2 promoter and participated in the regulation of ester biosynthesis. This study provides a framework for understanding ester biosynthesis and regulation in apple.

MdIPT1, an adenylate isopentenyltransferase coding gene from Malus domestica, is involved in branching and flowering regulation.

Flowering and shoot branching are significant agricultural traits for apple tree breeding. Cytokinin metabolism and signaling pathways play a crucial role in plant development. However, little is known about cytokinin biosynthetic molecular mechanism and function involved in apple flowering and branching. In this study, an adenylate isopentenyl transferase coding gene MdIPT1, homologous to AtIPT3/AtIPT5 in Arabidopsis thaliana, was identified. MdIPT1 was highly expressed in apple floral and axillary buds and was dramatically up-regulated during floral induction and axillary bud outgrowth. The promoter of MdIPT1 showed high activity in multiple tissues and responded to different hormone treatments. The MdIPT1-overexpressing Arabidopsis showed a multi-branching and early-flowering phenotype, with elevated endogenous cytokinin levels and altered expression of genes related to branching and flower formation. Overexpression of MdIPT1 confers the growth vigor of transgenic apple callus on a CKs-deficient medium. Our findings suggest that MdIPT1 is a positive regulator involved in branching and flowering. The data presented herein provide extensive research results on MdIPT1 and will contribute to molecular breeding for new apple varieties.

The BELL1-like homeobox gene MdBLH14 from apple controls flowering and plant height via repression of MdGA20ox3.

Apple growth and yield are largely dependent on plant height and flowering characteristics. The BELL1-like homeobox (BLH) transcription factors regulate extensive plant biological processes. However, the BLH-mediated regulation of plant height and flowering in apple remains elusive. In the current study, 19 members of the MdBLH family were identified in the apple genome. Segmental duplication and purifying selection are the main reasons for the evolution of the MdBLH genes. A BLH1-like gene, MdBLH14, was isolated and functionally characterized. The MdBLH14 was preferentially expressed in flower buds, and downregulated during the floral induction period. The subcellular localization in tobacco leaves indicated that MdBLH14 is a nuclear protein. Overexpression of MdBLH14 in Arabidopsis led to a significant dwarfing and late-flowering phenotype by hindering active GA accumulation. Additionally, MdKNOX19, another member of the TALE superfamily, physically interacts with MdBLH14 and synergistically inhibits the expression of MdGA20ox3. This is the first report on the function of the MdBLH14 from apple, and its mechanism involving plant flower induction and growth. The data presented here provide a theoretical basis for genetically breeding new apple varieties.

Curcumol ß-cyclodextrin inclusion complex enhances radiosensitivity of esophageal cancer under hypoxic and normoxic condition.

PURPOSE: Radiotherapy is an indispensable treatment for esophageal cancer (EC), but radioresistance is not uncommon. Curcumol, as an active extract from traditional Chinese medicines, has been reported to have antitumor activity in various types of human tumor cells. However, its reversal of radioresistance has been rarely reported. MATERIALS AND METHODS: In the present study, curcumol was prepared as an inclusion complex with ß-cyclodextrin. EC cell lines were treated with radiation and curcumol ß-cyclodextrin inclusion complex (CßC), and the effect of radiosensitization of CßC was investigated in vitro and in vivo. The in vitro experiments included cell proliferation assay, clonogenic survival assay, apoptosis assay, cell cycle assay, and western blot assay. RESULTS: The in vitro data revealed that CßC and irradiation synergistically inhibited the proliferation, reduced the colony formation, promoted the apoptosis, increased the G2/M phase, inhibited DNA damage repair, and reversed the hypoxia-mediated radioresistance of EC cells to a greater extent than did CßC alone or irradiation alone. The sensitization enhancement ratios (SERs) were 1.39 for TE-1 and 1.48 for ECA109 under hypoxia. The SERs were 1.25 for TE-1 and 1.32 for ECA109 under normoxia. The in vivo data demonstrated that the combination of CßC and irradiation could inhibit tumor growth to the greatest extent compared with either monotherapy alone. The enhancement factor was 2.45. CONCLUSION: This study demonstrated that CßC could enhance radiosensitivity of EC cells under hypoxic and normoxic condition. Thus, CßC can be used as an effective radiosensitizer for EC.

Radiation-induced mucositis: A retrospective study of dexamethasone-lidocaine-vitamin B12 mouth rinse versus compound chlorhexidine mouthwash in nasopharyngeal carcinoma.

Oral mucositis causes substantial morbidity during head and neck radiotherapy, especially nasopharyngeal carcinoma. During radiotherapy, patients develop severe oral mucositis, which leads to oral pain and difficulty in eating and interruption of radiotherapy, affects the treatment effect and increase the probability of recurrence. Although we have explored various methods to reduce the mucosal damage caused by radiotherapy, these methods still cannot reduce pain caused by mucositis clinically. Therefore, the use of Dexamethasone-Lidocaine-Vitamin B12 Mouth rinse (DLVBM) proved its role in reducing oral mucosal pain, reducing the weight loss of patients, and completing radiotherapy according to the course of treatment. 133 patients with nasopharyngeal carcinoma who received radiotherapy (a total dose of 70 Gy) in our hospital from January to December 2020-2021 were selected. 67 patients received DLVBM treatment for mucositis reaction, and 66 patients received Compound chlorhexidine mouthwash (CCM) to deal with mucositis. Symptoms related to oral mucosal pain score and body weight, mucosal healing time were analyzed retrospectively. We found that patients with the DLVBM group significantly reduced oral pain and reduced weight loss. However, there was no significant difference about the mucosal healing time between the DLVBM group and CCM group. DLVBM may be moderately more effective in preventing radiation-induced mucositis and mucositis-related pain, and their use may lead to less frequent RT course interruptions from mucositis.

The efficacy of mouthwashes on oral microorganisms and gingivitis in patients undergoing orthodontic treatment: a systematic review and meta-analysis.

BACKGROUND: Mouthwashes were convenient adjuncts to mechanical cleaning procedures. This review aimed to evaluate the efficacy of mouthwashes on oral microorganisms and gingivitis in orthodontic patients. METHODS: By April 16, 2022, multiple databases and grey literature were searched based on the PICOS strategy. Randomized controlled trials in orthodontic patients evaluating the efficacy of mouthwashes with at least one microbial parameter and/or plaque- and/or gingival inflammation-related index were included. Relevant data were extracted, and the risk of bias was evaluated using Cochrane's tool. Individual mean and standard deviation of the outcomes in mouthwashes and placebos/blank controls were pooled to estimate the weighted mean differences (WMDs) and 95% confidence intervals (95%CIs). Sensitivity analysis, and certainty of evidence were evaluated. RESULTS: Of 1684 articles, 32 studies satisfied the eligibility criteria, and nine were included for meta-analysis. Missing outcome data was the primary source of bias. Compared to blank controls, the short-term application of fluoride mouthwashes significantly reduced the colony counts of Mutans streptococci (MS), while the long-term application may not be effective. Compared to placebos or blank controls, Chlorhexidine mouthwashes significantly reduced the colony counts of multiple microorganisms in the short-term. Compared to placebos or blank controls, herbal mouthwashes showed the inhibitory effect of MS in the short-term, with some results lacking statistical significance. After meta-analysis, significant lower plaque- and gingival inflammation-related indexes were observed in the Chlorhexidine mouthwashes groups [Gingival Index: WMD = -0.45, 95%CI = -0.70 to -0.20 (placebos as control); WMD = -0.54, 95%CI = -0.96 to -0.13 (blank controls); Plaque Index: WMD = -0.70, 95%CI = -1.12 to -0.27 (blank controls)]. Significant lower gingival inflammation-related indexes were observed in the herbal mouthwashes groups [Gingival Index: WMD = -0.20, 95%CI = -0.32 to -0.09 (blank controls)]. CONCLUSIONS: The short-term application of fluoride mouthwashes may reduce the colony counts of cariogenic bacteria, but the long-term effect is not evident. Chlorhexidine may reduce the colony counts of multiple microorganisms in the short-term. Short-term application Chlorhexidine and herbal mouthwashes may effectively reduce plaque- and gingival inflammation-related indexes. However, the risk of bias, inconsistency, and imprecision in the included studies may reduce the certainty of the evidence.

Efficacy and safety of different radiotherapy doses in neoadjuvant chemoradiotherapy in patients with locally advanced rectal cancer: A retrospective study.

Background: This study aims to compare the efficacy and safety of neoadjuvant chemoradiotherapy (nCRT) with different radiotherapy doses (45Gy and 50.4Gy) in patients with locally advanced rectal cancer (LARC). Methods: Herein, 120 patients with LARC were retrospectively enrolled between January 2016 and June 2021. All patients underwent two courses of induction chemotherapy (XELOX), chemoradiotherapy, and total mesorectum excision (TME). A total of 72 patients received a radiotherapy dose of 50.4 Gy, while 48 patients received a dose of 45 Gy. Surgery was then performed within 5-12 weeks following nCRT. Results: There was no statistically significant difference between the baseline characteristics of the two groups. The rate of good pathological response in the 50.4Gy group was 59.72% (43/72), while in the 45Gy group achieved 64.58% (31/48) (P>0.05). The disease control rate (DCR) in the 50.4Gy group was 88.89% (64/72), compared to 89.58% (43/48) in the 45Gy group (P>0.05). The incidence of adverse reactions for radioactive proctitis, myelosuppression, and intestinal obstruction or perforation differed significantly between the two groups (P<0.05). The anal retention rate in the 50.4Gy group was significantly higher in contrast to the 45Gy group (P<0.05). Conclusions: Patients receiving a radiotherapy dose of 50.4Gy have a better anal retention rate but also a higher incidence of adverse events such as radioactive proctitis, myelosuppression, and intestinal obstruction or perforation, and a comparable prognosis to patients treated with a radiotherapy dose of 45Gy.

Regulation of secretory pathway kinase or kinase-like proteins in human cancers.

Secretory pathway kinase or kinase-like proteins (SPKKPs) are effective in the lumen of the endoplasmic reticulum (ER), Golgi apparatus (GA), and extracellular space. These proteins are involved in secretory signaling pathways and are distinctive from typical protein kinases. Various reports have shown that SPKKPs regulate the tumorigenesis and progression of human cancer via the phosphorylation of various substrates, which is essential in physiological and pathological processes. Emerging evidence has revealed that the expression of SPKKPs in human cancers is regulated by multiple factors. This review summarizes the current understanding of the contribution of SPKKPs in tumorigenesis and the progression of immunity. With the epidemic trend of immunotherapy, targeting SPKKPs may be a novel approach to anticancer therapy. This study briefly discusses the recent advances regarding SPKKPs.

The Relationship Between Periodontal Disease and Breast Cancer: From Basic Mechanism to Clinical Management and Prevention.

PURPOSE: Periodontal disease is potentially related to certain kinds of cancer. This review aimed to summarize the relationship between periodontal disease and breast cancer, providing some strategies for the clinical treatment and periodontal health care of breast cancer patients. MATERIALS AND METHODS: Systematic reviews, randomised controlled trials, prospective and retrospective clinical studies, case series and reports were collected using search terms entered into the PubMed, Google Scholar and JSTOR databases. RESULTS: Research has provided some evidence that periodontal disease is related to the occurrence and development of breast cancer. Periodontal disease and breast cancer have some common pathogenic factors. Periodontal disease may affect the initiation and development of breast cancer involving microorganisms and inflammation. Periodontal health is affected by radiotherapy, chemotherapy, and endocrine therapy for breast cancer. CONCLUSIONS: Periodontal therapy for breast cancer patients should be performed differently according to the stage of cancer treatment. Adjuvant endocrine treatment (e.g. bisphosphonates) has a great impact on oral treatment. Periodontal therapy contributes to the primary prevention of breast cancer. Periodontal health care of breast cancer patients is worthy of clinician attention.

Interaction of AcMADS68 with transcription factors regulates anthocyanin biosynthesis in red-fleshed kiwifruit.

In red-fleshed kiwifruit, anthocyanin pigmentation is a crucial commercial trait. The MYB-bHLH-WD40 (MBW) complex and other transcription factors regulate its accumulation. Herein, a new SEP gene, AcMADS68, was identified as a regulatory candidate for anthocyanin biosynthesis in the kiwifruit by transcriptome data and bioinformatic analyses. AcMADS68 alone could not induce the accumulation of anthocyanin both in Actinidia arguta fruit and tobacco leaves. However, in combination with AcMYBF110, AcMYB123, and AcbHLH1, AcMADS68 co-overexpression increased anthocyanin biosynthesis, whereas its silencing reduced anthocyanin accumulation. The results of the dual-luciferase reporter, firefly luciferase complementation, yeast two-hybrid and co-immunoprecipitation assays showed that AcMADS68 could interact with both AcMYBF110 and AcMYB123 but not with AcbHLH1, thereby co-regulating anthocyanin biosynthesis by promoting the activation of the target genes, including AcANS, AcF3GT1, and AcGST1. Moreover, AcMADS68 also could activate the promoter of AcbHLH1 surported by dual-luciferase reporter and yeast one-hybrid assays, thereby further amplifying the regulation signals from the MBW complex, thus resulting in enhanced anthocyanin accumulation in the kiwifruit. These findings may facilitate better elucidation of various regulatory mechanisms underlying anthocyanin accumulation and contribute to the quality enhancement of red-fleshed kiwifruit.

The Efficacy and Safety of Oral Irrigator on the Control of Dental Plaque and Gingivitis: A Randomized, Single-Blind, Parallel-Group Clinical Trial.

BACKGROUND: To evaluate the efficacy and safety of oral irrigator (OI) in controlling dental plaque and gingivitis. METHODS: Ninety participants diagnosed with gingivitis were randomly assigned to two groups, given a toothbrush combined with OI (WaterPik®) (test) or a toothbrush alone (control). The Turesky-Modified Quigley-Hein Plaque Index (T-QH), Modified Gingival Index (MGI), Bleeding Index (BI), and percentage of sites with bleeding on probing (BOP%) were evaluated at baseline, 4 weeks, 8 weeks, and 12 weeks. The full analysis set (FAS) and per-protocol set (PPS) were analyzed. Adverse events were recorded through electronic diaries and examinations. RESULTS: Of the 90 participants, the efficacy was assessed in the following numbers (FAS/PPS): test (45/33) and control (43/38). Compared with the control, MGI, BI, and BOP% were significantly lower in the test group after 4 weeks (4 weeks: p = 0.017, p = 0.001, and p = 0.001, respectively; 8 weeks and 12 weeks: p < 0.001 for all, FAS); T-QH was significantly lower after 8 weeks (8 weeks: p = 0.033; 12 weeks: p = 0.006, FAS). Transient gingival bleeding may be associated with OI. Self-reported pain and dentin hypersensitivity symptoms were similar between groups. CONCLUSIONS: As adjuncts to toothbrushing, OI demonstrated significantly better efficacy in controlling dental plaque and gingival inflammation with no substantial safety hazards.

Cytokinin-responsive MdTCP17 interacts with MdWOX11 to repress adventitious root primordium formation in apple rootstocks.

Adventitious root (AR) formation plays an important role in vegetatively propagated plants. Cytokinin (CK) inhibits AR formation, but the molecular mechanisms driving this process remain unknown. In this study, we confirmed that CK content is related to AR formation and further revealed that a high auxin/CK ratio was beneficial to AR formation in apple (Malus domestica). A correlation between expression of CK-responsive TEOSINTE BRANCHED1, CYCLOIDEA, and PCF17 (MdTCP17) and AR formation in response to CK was identified, and overexpression of MdTCP17 in transgenic apple inhibited AR formation. Yeast two-hybrid, bimolecular fluorescence complementation, and co-immunoprecipitation assays revealed an interaction between MdTCP17 and WUSCHEL-RELATED HOMEOBOX11 (MdWOX11), and a significant correlation between the expression of MdWOX11 and AR ability. Overexpression of MdWOX11 promoted AR primordium formation in apple, while interference of MdWOX11 inhibited AR primordium production. Moreover, a positive correlation was found between MdWOX11 and LATERAL ORGAN BOUNDARIES DOMAIN29 (MdLBD29) expression, and yeast one-hybrid, dual luciferase reporter, and ChIP-qPCR assays verified the binding of MdWOX11 to the MdLBD29 promoter with a WOX-box element in the binding sequence. Furthermore, MdTCP17 reduced the binding of MdWOX11 and MdLBD29 promoters, and coexpression of MdTCP17 and MdWOX11 reduced MdLBD29 expression. Together, these results explain the function and molecular mechanism of MdTCP17-mediated CK inhibition of AR primordium formation, which could be used to improve apple rootstocks genetically.

Circ_0000011 promotes cerebral ischemia/reperfusion injury via miR-27a-3p-dependent regulation of NRIP1.

BACKGROUND: Cerebral ischemia/reperfusion (I/R) can result in brain function impairments. Circular RNAs (circRNAs) have emerged as vital regulators in cerebral I/R injury. However, the functions of mmu_circ_0000011 in cerebral I/R injury are still unclear. Thus, in this study, we aimed to explore the effect of mmu_circ_0000011 on cerebral I/R injury. METHODS: Oxygen-glucose deprivation and reperfusion (OGD/R)-induced HT-22 cells were used to mimic the condition of cerebral I/R injury in vitro. Cell Counting Kit-8 (CCK-8) assay, lactate dehydrogenase (LDH) assay, 5'-ethynyl-2'-deoxyuridine (EdU) assay and flow cytometry analysis were utilized to assess cell viability, LDH release, proliferation and apoptosis, respectively. qRT-PCR and western blot were performed to determined the levels of circ_0000011, miR-27a-3p and NRIP1. Dual-luciferase reporter assay and RNA pull-down assay were utilized to analyze the targeting relation of circ_0000011, miR-27a-3p and NRIP1. RESULTS: OGD/R treatment inhibited HT-22 cell viability and promoted LDH release, cell apoptosis and inflammation. Circ_0000011 level was increased in OGD/R-induced HT-22 cells. Silencing of circ_0000011 promoted cell proliferation and inhibited LDH release, apoptosis and inflammation in OGD/R-treated HT-22 cells. For mechanism analysis, circ_0000011 was demonstrated to sponge miR-27a-3p, which directly targeted NRIP1. MiR-27a-3p inhibition or NRIP1 overexpression ameliorated the impacts of circ_0000011 silencing on cell proliferation, LDH release, apoptosis and inflammation in OGD/R-treated HT-22 cells. CONCLUSIONS: Circ_0000011 promotes OGD/R-induced HT-22 cell impairments by elevating NRIP1 through sponging miR-27a-3p.

Double-Edged Sword Effect of Pyroptosis: The Role of Caspase-1/-4/-5/-11 in Different Levels of Apical Periodontitis.

The study was to investigate the effect of canonical and noncanonical pyroptosis in apical periodontitis. Proteins' profiles of human apical periodontitis tissue were analyzed by label-free proteomics. Immunofluorescence was used to detect proteins related to pyroptosis in human apical periodontitis tissues and experimental apical periodontitis models. A dual experimental apical periodontitis model with both smaller (mandible) and larger (maxilla) bone lesions was established. THP-1-derived macrophages were stimulated with P. gingivalis lipopolysaccharide in vitro with or without the caspase-1/-4/-5 inhibitor Ac-FTDL-CMK. Propidium iodide staining, lactic dehydrogenase release and Western blot were applied to evaluate cell death and the protein expression. Caspase-1/-4/-5 were expressed in human apical periodontitis tissues. Caspase-1/-11 were involved in bone loss in experimental apical periodontitis. Caspase-1/-11 inhibitors reduced bone loss in larger lesions (maxilla) but accelerated bone loss in smaller lesions (mandible). Caspase-1/-4/-5 inhibitors also showed double-edged sword effects on propidium iodide staining and lactic dehydrogenase release in vitro. The expression of cleaved-caspase-1/-4/-5, mature interluekin-1ß and gasdermin D N-terminal domain increased in THP-1-derived macrophages after lipopolysaccharide stimulation but decreased after treatment with Ac-FTDL-CMK. Pyroptosis contributed to apical periodontitis and excited a double-edged sword effect in inducing bone loss in vivo and cell death in vitro.

Molecular profiling identifies distinct subtypes across TP53 mutant tumors.

Tumor protein 53 mutation (TP53mut) is one of the most important driver events facilitating tumorigenesis, which could induce a series of chain reactions to promote tumor malignant transformation. However, the malignancy progression patterns under TP53 mutation remain less known. Clarifying the molecular landscapes of TP53mut tumors will help us understand the process of tumor development and aid precise treatment. Here, we distilled genetic and epigenetic features altered in TP53mut cancers for cluster-of-clusters analysis. Using integrated classification, we derived 5 different subtypes of TP53mut patients. These subtypes have distinct features in genomic alteration, clinical relevance, microenvironment dysregulation, and potential therapeutics. Among the 5 subtypes, COCA3 was identified as the subtype with worst prognosis, causing an immunosuppressive microenvironment and immunotherapeutic resistance. Further drug efficacy research highlighted olaparib as the most promising therapeutic agents for COCA3 tumors. Importantly, the therapeutic efficacy of olaparib in COCA3 and immunotherapy in non-COCA3 tumors was validated via in vivo experimentation. Our study explored the important molecular events and developed a subtype classification system with distinct targeted therapy strategies for different subtypes of TP53mut tumors. These multiomics classification systems provide a valuable resource that significantly expands the knowledge of TP53mut tumors and may eventually benefit in clinical practice.

Identification and expression analysis of the lipid phosphate phosphatases gene family reveal their involvement in abiotic stress response in kiwifruit.

Lipid phosphate phosphatases (LPPs) are a key enzyme in the production and degradation of phosphatidic acid (PA), which plays an important role in plant growth, development, stress resistance and plant hormone response. Thus far, little is known about the LPP family genes in kiwifruit (Actinidia spp.). According to this study, 7 members in the AcLPP family were identified from the whole genome of kiwifruit, the subcellular localization predictions were mainly on the plasma membrane. Chromosomal localization analysis showed that the AcLPP genes were unevenly distributed on 5 chromosomes, it was determined to have undergone strong purifying selection pressure. There were 5 duplicate gene pairs and all underwent segmental duplication events. The LPP genes of kiwifruit were conserved when compared with other plants, especially in terms of evolutionary relationships, conserved motifs, protein sequences, and gene structures. Cis-regulatory elements mainly included hormone response elements and abiotic response elements. Functional annotation of GO revealed that AcLPP genes were closely related to phosphatase/hydrolase activity, phosphorus metabolism and dephosphorylation. AcLPP genes family were predicted to be targets of miRNA. Transcript level analysis revealed that the AcLPP family played diverse functions in different tissues and during growth, development, and postharvest storage stages. qPCR analysis showed that the members of AcLPP gene family might be regulated by ETH, ABA, GA3, and IAA hormone signals. The family members were regulated by the stress of salt stress, osmotic stress, cold stress, and heat stress. These results would provide a basis and reference for studying the agricultural characteristics of kiwifruit and improving its stress resistance.