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With the focus on the insufficient origin-based cold storage in China, this study investigates the location and routing problem (LRP) of origin-based cold storage for fresh agricultural products. This study considers the loss of fresh agricultural products in different environments during transportation and presents a cold storage LRP model. To address this issue, a hybrid whale algorithm with heuristic rules is designed, and the effectiveness of the algorithm is verified by standard instances. Finally, taking Chenggu County as a practical case, the influence of cold storage capacity and farmers’ demand for refrigeration are analysed. Experimental results show that the proposed algorithm has a good effect in solving medium-scale LRP. As the storage capacity increases, the total cost of the system can be increased by 0.086%. As farmers’ demand for refrigeration increases, the total cost of the system can be increased by 34.034%. Farmers’ demand has a greater impact on the system’s total costs than the cold storage capacity. When optimizing the cold storage layout, changes in fresh agricultural product output in the next few years can be roughly predicted, and the most economical optimization scheme can be obtained.

The exclusion of sodium ions (Na + ) from the shoot tissue, termed shoot Na + exclusion, underlies a core mechanism of crop salt tolerance. Recent studies have shown that the HAK (High-Affinity K + Transporter) family Na + transporters play a key role in shoot Na + exclusion of various crops, however, it is unknown whether and how this type of transporter is post-transcriptionally regulated. Here, we show that two closely related SnRK2 kinases, designated as ZmSnRK2.9 and ZmSnRK2.10, promote shoot Na + exclusion and salt tolerance by activating the Na + transporter ZmHAK4 in maize. Under salt conditions, the kinase activity of ZmSnRK2.9 and ZmSnRK2.10 is activated, then they interact with and phosphorylate ZmHAK4 at Ser5, increasing the Na + transport activity of ZmHAK4, which in turn promotes salt tolerance by improving the exclusion of Na + from the shoot tissue. Furthermore, we show that a 20-bp deletion that occurred naturally in the ZmSnRK2.10 promoter decreases its transcript level, resulting in an increased shoot Na + content under salt conditions. Our findings support a breeding program that can utilize the favorable alleles of ZmHAK4 and ZmSnRK2.10 to enhance both the transcriptional and post-transcriptional activation of ZmHAK4, thus advancing the development of salt-tolerant maize. The authors demonstrated that maize SnRK2 kinases (ZmSnRK2.9/2.10) phosphorylate ZmHAK4, reducing shoot sodium and enhancing salt tolerance, and identified a favorable allele of ZmSnRK2.10 that provides a target for breeding salt-tolerant maize.

Understanding of the molecular mechanisms underlying age-associated cognitive impairments will not only contribute to our general knowledge about “aging” biology, but also provide insights for more effective strategies to prevent and improve the quality of life for both normal aging and pathological aging such as Alzheimer’s disease (AD). Here we first assessed and compared the performance of cognition and synaptic plasticity in young (3-5 month old) and aged c57BL/6J mice (19-21 months old). Findings from behavioral tests demonstrated that old mice, compared to young mice, displayed impairments in spatial learning/memory, recognition memory, and behavioral flexibility. Further, synaptic electrophysiology experiments on hippocampal slices revealed that early form of long-term potentiation (LTP, a synaptic model for memory formation) was inhibited in old mice. At the molecular level, biochemical assays on brain tissue showed dysregulation of signaling pathways controlling protein synthesis capacity including: up-regulation of AKT-mTORC1-p70S6K signaling, which is associated with translation of terminal oligopyrimidine (TOP) class of mRNAs that encode translational machinery; hyper-phosphorylation of mRNA translational elongation factor 2 (eEF2) and its upstream regulator AMP-activated protein kinase (AMPK), indicating repression of general protein synthesis. Moreover, young and old mice exhibited similar brain levels of translational initiation factor 2α (eIF2α) phosphorylation, which is known to be increased in AD and linked to the disease pathophysiology. Thus, our data provide evidence at the molecular level to highlight the similarity and difference between normal and pathological aging, which may contribute to future studies on diagnostic/prognostic biomarkers for aging-related dementia syndromes.

Signet-ring cell carcinoma (SRCC) has specific epidemiology and oncogenesis in gastric cancer, however, with no systematical investigation for prognostic genomic features. Here we report a systematic investigation conducted in 1868 Chinese gastric cancer patients indicating that signet-ring cells content was related to multiple clinical characteristics and treatment outcomes. We thus perform whole-genome sequencing on 32 pairs of SRC samples, and identify frequent CLDN18-ARHGAP26/6 fusion (25%). With 797 additional patients for validation, prevalence of CLDN18-ARHGAP26/6 fusion is noticed to be associated with signet-ring cell content, age at diagnosis, female/male ratio, and TNM stage. Importantly, patients with CLDN18-ARHGAP26/6 fusion have worse survival outcomes, and get no benefit from oxaliplatin/fluoropyrimidines-based chemotherapy, which is consistent with the fact of chemo-drug resistance acquired in CLDN18-ARHGAP26 introduced cell lines. Overall, this study provides insights into the clinical and genomic features of SRCC, and highlights the importance of frequent CLDN18-ARHGAP26/6 fusions in chemotherapy response for SRCC. Signet-ring cell carcinoma (SRCC) is a unique type of gastric cancer with no prognostic features. Here, the authors report a CLDN18-ARHGAP26/6 gene fusion in patients with a high signet-ring cell content, poor survival outcomes, and who experience no benefit from platinum/fluoropyrimidines-based chemotherapy.

Serum tyrosine levels increase during aging, neurocognitive, metabolic, and cardiovascular disorders. However, calorie restriction (CR) and sleep lower serum tyrosine levels. We previously showed that tyrosine inhibits tyrosyl-tRNA synthetase (TyrRS)-mediated activation of poly-ADP-ribose polymerase 1 (PARP1). Here, we show that histone serine-ADP-ribosylation is decreased in Alzheimer’s Disease (AD) brains, and increased tyrosine levels deplete TyrRS and cause neuronal DNA damage. However, dopamine and brain-derived neurotrophic factor (BDNF) increase TyrRS and histone serine-ADP-ribosylation. Furthermore, cis -resveratrol ( cis -RSV) that binds to TyrRS mimicking a ‘tyrosine-free’ conformation increases TyrRS, facilitates histone serine-ADP-ribosylation-dependent DNA repair, and provides neuroprotection in a TyrRS-dependent manner. Conversely, trans -RSV that binds to TyrRS mimicking a ‘tyrosine-like’ conformation decreases TyrRS, inhibits serine-ADP-ribosylation-dependent DNA repair, and induces neurodegeneration in rat cortical neurons. Our findings suggest that age-associated increase in serum tyrosine levels may effect neurocognitive and metabolic disorders and offer a plausible explanation for divergent results obtained in clinical trials using resveratrol. Here, the authors show that histone serine-ADP-ribosylation is decreased in Alzheimer’s disease brains and increased tyrosine levels deplete tyrosyl-tRNA synthetase levels and cause neuronal damage. Cis-resveratrol was shown to facilitate histone serine-ADP-ribosylation-dependent DNA repair and provides neuroprotection, while trans-resveratrol induces neurodegeneration in rat cortical neurons.

The 2019 coronavirus disease (COVID‐19) pandemic has become a global crisis. In the immunopathogenesis of COVID‐19, SARS‐CoV‐2 infection induces an excessive inflammatory response in patients, causing an inflammatory cytokine storm in severe cases. Cytokine storm leads to acute respiratory distress syndrome, pulmonary and other multiorgan failure, which is an important cause of COVID‐19 progression and even death. Among them, activation of inflammatory pathways is a major factor in generating cytokine storms and causing dysregulated immune responses, which is closely related to the severity of viral infection. Therefore, elucidation of the inflammatory signaling pathway of SARS‐CoV‐2 is important in providing otential therapeutic targets and treatment strategies against COVID‐19. Here, we discuss the major inflammatory pathways in the pathogenesis of COVID‐19, including induction, function, and downstream signaling, as well as existing and potential interventions targeting these cytokines or related signaling pathways. We believe that a comprehensive understanding of the regulatory pathways of COVID‐19 immune dysregulation and inflammation will help develop better clinical therapy strategies to effectively control inflammatory diseases, such as COVID‐19. The 2019 coronavirus disease (COVID‐19) pandemic has become a global crisis, with SARS‐CoV‐2 infection inducing excessive inflammation and cytokine storm. Cytokine storm leads to acute respiratory distress syndrome (ARDS) and multi‐organ failure, which are important causes of COVID‐19 progression and death. Therefore, elucidating the inflammatory pathways of COVID‐19 is crucial for the therapeutic strategy of COVID‐19.

Background The leading cause of end-stage renal disease (ESRD) is diabetic nephropathy (DN). Podocyte damage is an early event in the development of DN. Currently, there is no effective treatment strategy that can slow the progression of DN or reverse its onset. The role of mesenchymal stem cells (MSCs) transplantation in diabetes and its complications has been extensively studied, and diabetic nephropathy has been a major focus. Irbesartan exerts reno-protective effects independent of lowering blood pressure, can reduce the incidence of proteinuria in rats, and is widely used clinically. However, it remains undetermined whether the combined utilization of the angiotensin II receptor antagonist irbesartan and MSCs could enhance efficacy in addressing DN. Methods A commonly used method for modeling type 2 diabetic nephropathy (T2DN) was established using a high-fat diet and a single low-dose injection of STZ (35 mg/kg). The animals were divided into the following 5 groups: (1) the control group (CON), (2) the diabetic nephropathy group (DN), (3) the mesenchymal stem cells treatment group (MSCs), (4) the irbesartan treatment group (Irb), and (5) the combined administration group (MSC + Irb). MSCs (2 × 10 6 cells/rat) were injected every 10 days through the tail vein for a total of three injections; irbesartan (30 mg/kg/d) was administered by gavage. Additionally, the safety and homing of mesenchymal stem cells were verified using positron emission tomography (PET) imaging. Results The combination treatment significantly reduced the UACR, kidney index, IGPTT, HOMA-IR, BUN, serum creatine, and related inflammatory factor levels and significantly improved renal function parameters and the expression of proteins related to glomerular podocyte injury in rats. Moreover, MSCs can homing target to damaged kidneys. Conclusions Compared to the administration of MSCs or irbesartan alone, the combination of MSCs and irbesartan exerted better protective effects on glomerular podocyte injury, providing new ideas for the clinical application of mesenchymal stem cells.

Background Ovarian cancer (OvCA) exhibits a distinctive tendency toward peritoneal metastasis, a pathological process that greatly affects disease progression and postoperative recurrence. Understanding the biological mechanisms underlying this metastatic cascade is critical for improving prognosis and developing targeted therapeutic strategies. This study investigated the functional role of TROP2 in extracellular vesicles (EVs) from ovarian cancer ascites, and revealed how TROP2 induces mesothelial-mesenchymal transition (MMT) through EV-mediated intercellular communication. This process remodeled the mesothelial microenvironment into a pro-metastatic environment that enables peritoneal dissemination. Methods EVs were isolated from ascites and cell culture supernatants through differential centrifugation combined with ultracentrifugation. After incubation with mesothelial cells, Western blot analysis, migration assays, and adhesion assays were performed to assess the induction of mesenchymal phenotype. Through proteomic profiling analysis of ascitic EVs, the differential protein TROP2 was identified and subsequently verificated clinical samples. TROP2 expression was modified through lentiviral transfection, and an orthotopic xenograft mouse model of ovarian cancer was established to evaluate tumor growth and metastasis through in vivo bioluminescence live imaging. Results EVs secreted by ovarian cancer cells induced phenotypic changes in mesenchymal cells and enhanced their adhesion to cancer cells. Proteomic analysis identified TROP2 as a differentially expressed protein in ascitic EVs. Phenotypic experiments indicated that EVs from ovarian cancer deliver TROP2 to peritoneal mesothelial cells, where it induces MMT and promotes peritoneal colonization in vitro. In the orthotopic mouse model of ovarian cancer, injection of TROP2-enriched EVs promoted peritoneal metastasis. Mechanistic investigations revealed that TROP2 induced the MMT process in mesothelial cells through activating the TNF-α/NF-κB pathway. Furthermore, treatment with quinazoline (QNZ), the TNF-α/NF-κB pathway inhibitor effectively reversed the TROP2 induced mesenchymal phenotype in mesothelial cells. Conclusion This study is the first to identify the pivotal role of TROP2 from ascitic EV in promoting metastatic dissemination by activating the TNF-α/NF-κB signaling axis. By remodeling the peritoneal microenvironment, TROP2 facilitates metastatic spread. These findings provide novel molecular insights into the mechanism of ovarian cancer peritoneal metastasis and offer significant implications for clinical translation.

Background Directly discharging livestock and poultry slaughter blood without proper treatment can cause severe ecological damage. Exploring the use of microorganisms to break down waste blood into smaller molecules such as peptides and amino acids, as well as investigating the possibility of transforming these small molecules into water-soluble fertilizers containing amino acids, holds significant research value in the comprehensive utilization of livestock and poultry blood. Results In this study, a single strain of Bacillus pumilus NWMCC0302, which has effectively degraded bovine blood, was isolated from abattoir blood sludge using casein agar plates and Columbia blood agar plates. The degradation test was carried out using bovine raw blood as a nitrogen source in the medium, and the results showed that the strain degraded 53.83% of bovine blood under optimal degradation conditions. The whole genome sequencing of Bacillus pumilus NWMCC0302 was conducted using the second-generation DNBSEQ platform and the third-generation PacBio platform, employing high-throughput sequencing technology. The size of the strain's entire genome was determined to be 3 868 814 bp with a G-C content of 41.63%. The total gene length accounted for 88.98% of the genome length at 3 442 341 bp and encoded 4 113 genes. The strain contained 79 tRNAs, 24 rRNAs, 7 sRNAs, and 296 repetitive sequences. The gene data obtained from sequencing were also functionally annotated using the COG, KEGG, and VFDB databases. In the COG database, 310 genes were involved in amino acid transport and metabolism, including 10 catabolic proteins related to COGs. In the KEGG database, were 201 genes involved in amino acid metabolism pathways, including 8 genes in nitrogen metabolism pathways and 2 genes in oxidative pathways. The VFDB database contains two lysostaphin genes and one serine protease-hydrolyzed ClpP gene. Conclusions In summary, Bacillus pumilus NWMCC0302 was screened for its efficient ability to degrade bovine blood. Additionally, the genetic information of Bacillus pumilus NWMCC0302 was revealed at the genetic level, providing a feasible experimental method for applying this strain to the degradation of blood from slaughtered livestock and poultry. Moreover, it is a potential functional strain for producing amino acid-containing water-soluble fertilisers.

Background Apoptosis signal-regulating kinase 1-interacting protein 1 (AIP1) participates in inflammatory neovascularization induction. NADPH oxidase 4 (NOX4) produces reactive oxygen species (ROS), leading to an imbalance in nucleotide-binding oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3) and NLR family pyrin domain containing 6 (NLRP6) expression. The mechanisms of AIP1, NOX4, ROS and inflammasomes in corneal neovascularization were studied herein. Methods C57BL/6 and AIP1-knockout mice were used in this study. The alkali burn procedure was performed on the right eye. Adenovirus encoding AIP1 plus green fluorescence protein (GFP) (Ad-AIP1-GFP) or GFP alone was injected into the right anterior chamber, GLX351322 was applied as a NOX4 inhibitor, and then corneal neovascularization was scored. The expression of related genes was measured by quantitative real-time polymerase chain reaction, western blotting and immunofluorescence staining. 2′,7′-Dichlorofluorescin diacetate staining was used to determine the ROS levels. Results The expression of AIP1 was decreased, while that of cleaved interleukin-1β (clv-IL-1β) and vascular endothelial growth factor A (VEGFa) was increased after alkali burn injury. NOX4 expression was increased, the imbalance in NLRP3/NLRP6 was exacerbated, and corneal neovascularization was increased significantly in AIP1-knockout mice compared with those in C57BL/6 mice after alkali burns. These effects were reversed by AIP1 overexpression. NLRP3/NLRP6 expression was imbalanced after alkali burns. GLX351322 reversed the imbalance in NLRP3/NLRP6 by reducing the ROS levels. This treatment also reduced the expression of clv-IL-1β and VEGFa, suppressing neovascularization. Conclusions AIP1 and NOX4 can regulate corneal inflammation and neovascularization after alkali burn injury. Based on the pathogenesis of corneal neovascularization, these findings are expected to provide new therapeutic strategies for patients. Plain English summary Corneal alkali burn injury is a common type of ocular injury that is difficult to treat in the clinic. The cornea is a clear and avascular tissue. Corneal neovascularization after alkali burn injury is a serious complication; it not only seriously affects the patient’s vision but also is the main reason for failed corneal transplantation. Corneal neovascularization affects approximately 1.4 million patients a year. We show for the first time that AIP1 and NOX4 can regulate corneal inflammation and neovascularization after alkali burns. The expression of AIP1 was decreased, while that of clv-IL-1β and VEGFa was increased after alkali burns. We tried to elucidate the specific molecular mechanisms by which AIP1 regulates corneal neovascularization. NOX4 activation was due to decreased AIP1 expression in murine corneas with alkali burns. NOX4 expression was increased, the imbalance in NLRP3/NLRP6 was exacerbated, and corneal neovascularization was increased significantly in AIP1-knockout mice compared with those in C57BL/6 mice after alkali burns. These effects were reversed by AIP1 overexpression. Additionally, NLRP3/NLRP6 expression was unbalanced, with NLRP3 activation and NLRP6 suppression in the corneal alkali burn murine model. Eye drops containing GLX351322, a NOX4 inhibitor, reversed the imbalance in NLRP3/NLRP6 by reducing ROS expression. This treatment also reduced the expression of clv-IL-1β and VEGFa, reducing neovascularization. Therefore, we provide new gene therapeutic strategies for patients. With the development of neovascularization therapy, we believe that in addition to corneal transplantation, new drug or gene therapies can achieve better results. 4JfT1-9DioSts9dbj1op36 Video Abstract