Control of the innate immune response by the mevalonate pathway.

Deficiency in mevalonate kinase (MVK) causes systemic inflammation. However, the molecular mechanisms linking the mevalonate pathway to inflammation remain obscure. Geranylgeranyl pyrophosphate, a non-sterol intermediate of the mevalonate pathway, is the substrate for protein geranylgeranylation, a protein post-translational modification that is catalyzed by protein geranylgeranyl transferase I (GGTase I). Pyrin is an innate immune sensor that forms an active inflammasome in response to bacterial toxins. Mutations in MEFV (encoding human PYRIN) result in autoinflammatory familial Mediterranean fever syndrome. We found that protein geranylgeranylation enabled Toll-like receptor (TLR)-induced activation of phosphatidylinositol-3-OH kinase (PI(3)K) by promoting the interaction between the small GTPase Kras and the PI(3)K catalytic subunit p110δ. Macrophages that were deficient in GGTase I or p110δ exhibited constitutive release of interleukin 1ß that was dependent on MEFV but independent of the NLRP3, AIM2 and NLRC4 inflammasomes. In the absence of protein geranylgeranylation, compromised PI(3)K activity allows an unchecked TLR-induced inflammatory responses and constitutive activation of the Pyrin inflammasome.

Interfacial solvation-structure regulation for stable Li metal anode by a desolvation coating technique.

Rechargeable lithium (Li) metal batteries face challenges in achieving stable cycling due to the instability of the solid electrolyte interphase (SEI). The Li-ion solvation structure and its desolvation process are crucial for the formation of a stable SEI on Li metal anodes and improving Li plating/stripping kinetics. This research introduces an interfacial desolvation coating technique to actively modulate the Li-ion solvation structure at the Li metal interface and regulate the participation of the electrolyte solvent in SEI formation. Through experimental investigations conducted using a carbonate electrolyte with limited compatibility to Li metal, the optimized desolvation coating layer, composed of 12-crown-4 ether-modified silica materials, selectively displaces strongly coordinating solvents while simultaneously enriching weakly coordinating fluorinated solvents at the Li metal/electrolyte interface. This selective desolvation and enrichment effect reduce solvent participation to SEI and thus facilitate the formation of a LiF-dominant SEI with greatly reduced organic species on the Li metal surface, as conclusively verified through various characterization techniques including XPS, quantitative NMR, operando NMR, cryo-TEM, EELS, and EDS. The interfacial desolvation coating technique enables excellent rate cycling stability (i.e., 1C) of the Li metal anode and prolonged cycling life of the Li||LiCoO2 pouch cell in the conventional carbonate electrolyte (E/C 2.6 g/Ah), with 80% capacity retention after 333 cycles.

Preclinical testing of CT1113, a novel USP28 inhibitor, for the treatment of T-cell acute lymphoblastic leukaemia.

T-cell acute lymphoblastic leukaemia (T-ALL) is a highly aggressive and heterogeneous lymphoid malignancy with poor prognosis in adult patients. Aberrant activation of the NOTCH1 signalling pathway is involved in the pathogenesis of over 60% of T-ALL cases. Ubiquitin-specific protease 28 (USP28) is a deubiquitinase known to regulate the stability of NOTCH1. Here, we report that genetic depletion of USP28 or using CT1113, a potent small molecule targeting USP28, can strongly destabilize NOTCH1 and inhibit the growth of T-ALL cells. Moreover, we show that USP28 also regulates the stability of sterol regulatory element binding protein 1 (SREBP1), which has been reported to mediate increased lipogenesis in tumour cells. As the most critical transcription factor involved in regulating lipogenesis, SREBP1 plays an important role in the metabolism of T-ALL. Therefore, USP28 may be a potential therapeutic target, and CT1113 may be a promising novel drug for T-ALL with or without mutant NOTCH1.

Promoting Lymphangiogenesis and Lymphatic Growth and Remodeling to Treat Cardiovascular and Metabolic Diseases.

Lymphatic vessels are low-pressure, blind-ended tubular structures that play a crucial role in the maintenance of tissue fluid homeostasis, immune cell trafficking, and dietary lipid uptake and transport. Emerging research has indicated that the promotion of lymphatic vascular growth, remodeling, and function can reduce inflammation and diminish disease severity in several pathophysiologic conditions. In particular, recent groundbreaking studies have shown that lymphangiogenesis, which describes the formation of new lymphatic vessels from the existing lymphatic vasculature, can be beneficial for the alleviation and resolution of metabolic and cardiovascular diseases. Therefore, promoting lymphangiogenesis represents a promising therapeutic approach. This brief review summarizes the most recent findings related to the modulation of lymphatic function to treat metabolic and cardiovascular diseases such as obesity, myocardial infarction, atherosclerosis, and hypertension. We also discuss experimental and therapeutic approaches to enforce lymphatic growth and remodeling as well as efforts to define the molecular and cellular mechanisms underlying these processes.

Effect of the pipeline embolization device placement on branching vessels in anterior circulation: a systematic review and meta-analysis.

BACKGROUND AND PURPOSE: Pipeline embolization device (PED) is widely used in intracranial aneurysms, and the scope of applications for the PED, which is frequently used to treat cerebral aneurysms, is also growing. It has some effect on branching vessels as a result of its inherent properties. The effects of PED on the complications rate and branching vessels blockage have not yet been thoroughly investigated. OBJECTIVE: We conducted a systematic review searching reports from multiple databases on PED use for intracranial aneurysms, and analyzed the influence of PED on the occlusion rate of different branching vessels, and the influence of the amount of PED on the occlusion rate of branching vessels by meta-analysis. METHODS: We searched the literature using PUBMED, Web of Science, and OVID databases until August 2023. Inclusion criteria were that the study used only PED, included at least 10 patients, and recorded branching vessels occlusion rates, mortality, and neurological complications. RESULTS: Nine studies were analyzed consisting of 706 patients with 986 side branches. The results of the meta-analysis showed that application of more than one PED did not significantly elevate the rate of branching vessels occlusion compared to application of one PED (OR = 0.70; 95% CI: 0.34 to 1.43; P = 0.33). In the comparison of branching vessels occlusion rates in the anterior circulation, the anterior cerebral artery (ACA) had a significantly higher occlusion rate compared to the ophthalmic artery (OphA) (OR = 6.54; 95% CI: 3.05 to 14.01; P < 0.01), ACA also had a higher occlusion rate compared to the anterior choroidal artery (AchA) (OR = 15.44; 95% CI: 4.11 to 57.94 P < 0.01), ACA versus posterior communicating artery (PcomA) occlusion rate difference was not statistically significant (OR = 2.58; 95% CI: 0.63 to 12.82; P = 0.17), OphA versus AchA occlusion rate difference was not statistically significant (OR = 2.56; 95% CI: 0.89 to 7.38; P = 0.08), and the occlusion rate was significantly higher for PcomA compared to AchA (OR = 7.22; 95% CI: 2.49 to 20.95; P < 0.01) and lower for OphA compared to PcomA (OR = 0.33; 95% CI: 0.19 to 0.55; P < 0.01). CONCLUSION: The meta-analysis shows that use of multiple PEDs did not significantly increase the occlusion rate of branching vessels, and the larger the diameter of branching vessels covered by PED, the higher the occlusion rate of branching vessels. However, the incidence of complications is low after branching vessels occlusion in anterior circulation, which is related to the collateral circulation compensation of the branching vessels.

Transcriptome Analysis of Tomato Leaves Reveals Candidate Genes Responsive to Tomato Brown Rugose Fruit Virus Infection.

Tomato brown rugose fruit virus (ToBRFV) is a newly-emerging tobamovirus which was first reported on tomatoes in Israel and Jordan, and which has now spread rapidly in Asia, Europe, North America, and Africa. ToBRFV can overcome the resistance to other tobamoviruses conferred by tomato Tm-1, Tm-2, and Tm-22 genes, and it has seriously affected global crop production. The rapid and comprehensive transcription reprogramming of host plant cells is the key to resisting virus attack, but there have been no studies of the transcriptome changes induced by ToBRFV in tomatoes. Here, we made a comparative transcriptome analysis between tomato leaves infected with ToBRFV for 21 days and those mock-inoculated as controls. A total of 522 differentially expressed genes were identified after ToBRFV infection, of which 270 were up-regulated and 252 were down-regulated. Functional analysis showed that DEGs were involved in biological processes such as response to wounding, response to stress, protein folding, and defense response. Ten DEGs were selected and verified by qRT-PCR, confirming the reliability of the high-throughput sequencing data. These results provide candidate genes or signal pathways for the response of tomato leaves to ToBRFV infection.

Physicochemical properties of esterified/crosslinked quinoa starches and their influence on bread quality.

BACKGROUND: Starch is the main component of quinoa seeds. However, quinoa starch has poor solubility in cold water and poor mechanical resistance and is easily aged, which limit its application. Therefore, modification of its structure to improve its functional properties is necessary. RESULTS: This research used acetic anhydride and sodium trimetaphosphate to modify the structure of starch molecules and investigated their influence on bread quality. The results showed that both esterification and crosslinking prevented the aggregation behavior of starch molecules. Moreover, they both decreased the gelatinization enthalpy change and relative crystallinity of the starch. Compared with native starch, modification significantly decreased the gelatinization temperature from 57.01 to 52.01 °C and the esterified starch exhibited the lowest enthalpy change with a 44.2% decrease. Modified starch increased the specific volume and decreased the hardness and chewiness of bread. Modification did not influence the moisture content in bread but impacted the water retention capacity, depending on the degree of modification. Low and medium degrees of modification improved the water retention capacity during storage. By contrast, a high degree of modification (10 g kg-1 crosslinking agent) decreased the water retention capacity. The dually modified quinoa starch (esterified and crosslinked) showed no influence on the textural properties of bread. CONCLUSION: This study demonstrated that both esterification and crosslinking significantly improved the functional properties of quinoa starch. Crosslinked or esterified quinoa starches have the potential to improve the textural properties of bakery products. © 2024 Society of Chemical Industry.

Postinfantile Giant Cell Hepatitis in Native and Allograft Livers: A Multi-Institutional Clinicopathologic Study of 70 Cases.

Postinfantile giant cell hepatitis (PIGCH) is a rare hepatitis pattern in adults with variable etiologies and clinical outcomes. We conducted a multi-institutional retrospective study to define the clinicopathologic characteristics of patients with PIGCH. A total of 70 PIGCH cases were identified and reviewed for pathological features, including fibrosis, cholestasis, inflammation, steatosis, necrosis, and apoptosis, as well as the distribution of giant cells and the maximum number of giant cells per high-power field. Demographic and clinical data, including age, sex, laboratory results, etiologies, and follow-up results, were recorded. Among the 70 cases, 40% (28/70) were associated with autoimmune liver diseases, followed by 9 (13%) with unknown etiology, 8 (11%) with viral infection, 5 (7%) with medications, 5 with combined etiologies, and 4 (6%) with malignancies (mostly chronic lymphocytic leukemia). Notably, another 16% were de novo PIGCH in liver allografts, most of which occurred after a rejection event. During follow-up, 26 (37%) patients died of the disease and 44 (63%) were alive. Deceased patients were characterized by older age (mean age, 54.9 vs 45.5 years; P = .02), higher alkaline phosphatase level (mean value, 253.3U/L vs 166.3 U/L; P = .03), higher fibrosis stage (stage 3-4 vs stage 0-2, 57.7% vs 29.6%; P = .03), being more likely to have de novo PIGCH after transplantation (23.1% vs 11.4%; P = .04), and being less likely to have primary autoimmune liver disease etiology (26.9% vs 47.7%; P = .04). These results indicate that PIGCH is a rare pattern of liver injury associated with different etiologies and variable clinical outcomes. Autoimmune liver disease with PIGCH is associated with better survival, whereas de novo PIGCH in allografts is associated with poorer survival. Older age, higher alkaline phosphatase level, and advanced fibrosis are adverse prognostic factors.

RNA helicase DHX15 exemplifies a unique dependency in acute leukemia.

RNA-binding proteins (RBP) have emerged as essential regulators that control gene expression and modulate multiple cancer traits. T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignancy derived from transformation of T-cell progenitors that normally undergo discrete steps of differentiation in the thymus. The implications of essential RBP during T-cell neoplastic transformation remain largely unclear. Systematic evaluation of RBP identifies RNA helicase DHX15, which facilitates the disassembly of the spliceosome and release of lariat introns, as a T-ALL dependency factor. Functional analysis using multiple murine T-ALL models demonstrates the essential importance of DHX15 in tumor cell survival and leukemogenesis. Moreover, single-cell transcriptomics reveals that DHX15 depletion in T-cell progenitors hinders burst proliferation during the transition from doublenegative to double-positive cells (CD4-CD8- to CD4+CD8+). Mechanistically, abrogation of DHX15 perturbs RNA splicing and leads to diminished levels of SLC7A6 and SLC38A5 transcripts due to intron retention, thereby suppressing glutamine import and mTORC1 activity. We further propose a DHX15 signature modulator drug ciclopirox and demonstrate that it has prominent anti-T-ALL efficacy. Collectively, our data highlight the functional contribution of DHX15 to leukemogenesis through regulation of established oncogenic pathways. These findings also suggest a promising therapeutic approach, i.e., splicing perturbation by targeting spliceosome disassembly, may achieve considerable anti-tumor efficacy.

Focal Nodular Hyperplasia in the Pediatric Population: A Multicenter Experience.

BACKGROUND: Focal nodular hyperplasia (FNH) is a benign liver lesion classically presenting in young females. In children, FNH is rare and its detailed clinicopathologic characteristics remain largely unknown. Furthermore, there are no studies comparing pediatric FNH features to those presenting in adults. METHODS: In this study, we analyzed a total of 47 FNH cases in pediatric patients (age range: 23 days to 18 years) from 3 centers and compared them to a cohort of 31 FNH cases in adult patients (age range: 20-64 years). RESULTS: Of the pediatric cases, 13 cases (28%) had a history of a prior malignancy of which 4 were treated with chemoradiation and stem cell transplantation (SCT), 5 with chemoradiation alone and 3 with chemotherapy and SCT. In the pediatric cases 41 (87%) had a central scar and 46 (98%) had fibrous septa. Both pediatric and adult FNH were more common in female patients. Cases in pediatric patients were also significantly associated with larger size (P = .047), absence of dystrophic vessels (P = .001), absence of sinusoidal dilatation (P = .029), pseudoacini formation (P = .013), and steatosis (P = .029). CONCLUSION: In our experience although most cases of pediatric FNH show the classic histologic features seen in adults, some significant differences exist, and awareness of these findings could aid in the evaluation of these rare cases.

Stable metal anodes enabled by a labile organic molecule bonded to a reduced graphene oxide aerogel.

Metallic anodes (lithium, sodium, and zinc) are attractive for rechargeable battery technologies but are plagued by an unfavorable metal-electrolyte interface that leads to nonuniform metal deposition and an unstable solid-electrolyte interphase (SEI). Here we report the use of electrochemically labile molecules to regulate the electrochemical interface and guide even lithium deposition and a stable SEI. The molecule, benzenesulfonyl fluoride, was bonded to the surface of a reduced graphene oxide aerogel. During metal deposition, this labile molecule not only generates a metal-coordinating benzenesulfonate anion that guides homogeneous metal deposition but also contributes lithium fluoride to the SEI to improve Li surface passivation. Consequently, high-efficiency lithium deposition with a low nucleation overpotential was achieved at a high current density of 6.0 mA cm-2 A Li|LiCoO2 cell had a capacity retention of 85.3% after 400 cycles, and the cell also tolerated low-temperature (-10 °C) operation without additional capacity fading. This strategy was applied to sodium and zinc anodes as well.

Extracranial-Intracranial Bypass and Risk of Stroke and Death in Patients With Symptomatic Artery Occlusion: The CMOSS Randomized Clinical Trial.

Importance: Prior trials of extracranial-intracranial (EC-IC) bypass surgery showed no benefit for stroke prevention in patients with atherosclerotic occlusion of the internal carotid artery (ICA) or middle cerebral artery (MCA), but there have been subsequent improvements in surgical techniques and patient selection. Objective: To evaluate EC-IC bypass surgery in symptomatic patients with atherosclerotic occlusion of the ICA or MCA, using refined patient and operator selection. Design, Setting, and Participants: This was a randomized, open-label, outcome assessor-blinded trial conducted at 13 centers in China. A total of 324 patients with ICA or MCA occlusion with transient ischemic attack or nondisabling ischemic stroke attributed to hemodynamic insufficiency based on computed tomography perfusion imaging were recruited between June 2013 and March 2018 (final follow-up: March 18, 2020). Interventions: EC-IC bypass surgery plus medical therapy (surgical group; n = 161) or medical therapy alone (medical group; n = 163). Medical therapy included antiplatelet therapy and stroke risk factor control. Main Outcomes and Measures: The primary outcome was a composite of stroke or death within 30 days or ipsilateral ischemic stroke beyond 30 days through 2 years after randomization. There were 9 secondary outcomes, including any stroke or death within 2 years and fatal stroke within 2 years. Results: Among 330 patients who were enrolled, 324 patients were confirmed eligible (median age, 52.7 years; 257 men [79.3%]) and 309 (95.4%) completed the trial. For the surgical group vs medical group, no significant difference was found for the composite primary outcome (8.6% [13/151] vs 12.3% [19/155]; incidence difference, -3.6% [95% CI, -10.1% to 2.9%]; hazard ratio [HR], 0.71 [95% CI, 0.33-1.54]; P = .39). The 30-day risk of stroke or death was 6.2% (10/161) in the surgical group and 1.8% (3/163) in the medical group, and the risk of ipsilateral ischemic stroke beyond 30 days through 2 years was 2.0% (3/151) and 10.3% (16/155), respectively. Of the 9 prespecified secondary end points, none showed a significant difference including any stroke or death within 2 years (9.9% [15/152] vs 15.3% [24/157]; incidence difference, -5.4% [95% CI, -12.5% to 1.7%]; HR, 0.69 [95% CI, 0.34-1.39]; P = .30) and fatal stroke within 2 years (2.0% [3/150] vs 0% [0/153]; incidence difference, 1.9% [95% CI, -0.2% to 4.0%]; P = .08). Conclusions and Relevance: Among patients with symptomatic ICA or MCA occlusion and hemodynamic insufficiency, the addition of bypass surgery to medical therapy did not significantly change the risk of the composite outcome of stroke or death within 30 days or ipsilateral ischemic stroke beyond 30 days through 2 years. Trial Registration: ClinicalTrials.gov Identifier: NCT01758614.

Transient post-operative overexpression of CXCR2 on monocytes of traumatic brain injury patients drives monocyte chemotaxis toward cerebrospinal fluid and enhances monocyte-mediated immunogenic cell death of neurons in vitro.

BACKGROUND: After traumatic brain injury (TBI), peripheral monocytes infiltrate into the central nervous system due to disruption of the blood-brain barrier, and play an important role in neuroinflammation. However, the mechanisms regulating the movement and function of peripheral monocytes after TBI have not been fully investigated. METHODS: TBI patients who underwent surgery at our hospital were recruited. CXCR2 expression in CD14+ monocytes from peripheral blood and cerebrospinal fluid (CSF) of TBI patients around surgery was analyzed by flow cytometry and compared with that of patients who suffered TBI 2-24 months prior and underwent cranioplasty. In vitro, serum or CSF from TBI/non-TBI patients were used to treat peripheral monocytes isolated from healthy volunteers to evaluate their effect on CXCR2 expression. Transwell experiments were performed to analyze the role of CXCR2 in monocyte chemotaxis toward the CSF. The role of CXCR2 in monocyte-mediated immunogenic cell death (ICD) of nerve cells was explored in an indirect co-culture system. RESULTS: Transient CXCR2 upregulation in monocytes from the peripheral blood and CSF of TBI patients was detected soon after surgery and was associated with unfavorable outcomes. TBI serum and CSF promoted CXCR2 expression in monocytes, and dexamethasone reversed this effect. Peripheral monocytes from TBI patients showed enhanced chemotaxis toward the CSF and increased inflammatory cytokine secretion. The CXCR2 antagonist SB225002 decreased monocyte chemotaxis toward TBI CSF, and lowered pro-inflammatory cytokine secretion in monocytes treated with TBI serum. SB225002 also relieved ICD in nerve cells co-cultured with TBI serum-treated monocytes. CONCLUSIONS: CXCR2 is transiently overexpressed in the peripheral monocytes of TBI patients post-surgery, and drives peripheral monocyte chemotaxis toward CSF and monocyte-mediated ICD of nerve cells. Therefore, CXCR2 may be a target for monocyte-based therapies for TBI.

Association between Helicobacter pylori and risk of childhood asthma: a meta-analysis of 18 observational studies.

Objective: The association between Helicobacter pylori (H. pylori) and childhood asthma is unclear. Thus, the aim of this study was to explore the association between H. pylori and childhood asthma.Methods: A literature search, study selection, and data extraction were performed independently and in duplicate. Data were analyzed using STATA software.Results: Eighteen studies enrolling 17,196 children were analyzed. All studies were of moderate-to-high quality. Four studies subcategorized H. pylori infection according to CagA status. Overall, there was a significant negative association between H. pylori and risk for childhood asthma (OR = 0.68; 95% CI, 0.54-0.87; P = 0.002), with no/marginal publication bias identified by the Egger's test and the Begg's test (P = 0.162 and P = 0.198, respectively). The observed inverse association persisted for CagA(+) strains of H. pylori (OR = 0.58; 95% CI, 0.35-0.96; P = 0.034) but not for CagA(-) strains (OR = 0.52; 95% CI, 0.12-2.28; P = 0.387). There was no significant difference between studies with respect to study design, participant age, geographical region, and method of measuring H. pylori.Conclusion: The evidence suggests that H. pylori infection, particularly CagA(+) H. pylori infection, is inversely associated with the risk of childhood asthma. Supplemental data for this article can be accessed at publisher's website.

Inverse association between Helicobacter pylori infection and childhood asthma in a physical examination population: a cross-sectional study in Chongqing, China.

BACKGROUND: Childhood asthma has substantial effects on children's health. It is important to identify factors in early life that influence childhood asthma. Accumulating evidence indicates that Helicobacter pylori may protect against allergic diseases. This study aimed to evaluate the relationship between H. pylori infection and pediatric asthma in Chongqing, China. MATERIALS AND METHODS: This cross-sectional study included healthy children aged 4-18 years who underwent a 13C urea breath test during medical checkups in 2021. All medical information was extracted from electronic medical records and a big data system. Logistic regression was used to evaluate the association between H. pylori infection and pediatric asthma, and multivariate regression models were adjusted for covariates. RESULTS: In our study, 2241 participants, including 1240 boys (55.33%) and 1001 girls (44.67%), underwent urea breath testing (average age: 8.67 ± 2.70 years). Among them, 292 (13.03%) were positive for H. pylori and 152 (6.78%) had asthma. The rates of asthma diagnosis in H. pylori-negative and -positive children were 7.23% and 3.77%, respectively (odds ratio = 1.995; 95% confidence interval: 1.003-3.968; P < .05). Furthermore, family history of asthma and the percentage of eosinophils in routine blood examination were associated with childhood asthma; however, the body mass index, platelet count, and serum vitamin D level were not. CONCLUSIONS: We demonstrated a significant inverse association between H. pylori infection and pediatric asthma in Chongqing, China. Further studies are required to determine the causal association and underlying mechanisms to prevent and control childhood asthma.

Antioxidant Properties of Hemp Proteins: From Functional Food to Phytotherapy and Beyond.

As one of the oldest plants cultivated by humans, hemp used to be banned in the United States but returned as a legal crop in 2018. Since then, the United States has become the leading hemp producer in the world. Currently, hemp attracts increasing attention from consumers and scientists as hemp products provide a wide spectrum of potential functions. Particularly, bioactive peptides derived from hemp proteins have been proven to be strong antioxidants, which is an extremely hot research topic in recent years. However, some controversial disputes and unknown issues are still underway to be explored and verified in the aspects of technique, methodology, characteristic, mechanism, application, caution, etc. Therefore, this review focusing on the antioxidant properties of hemp proteins is necessary to discuss the multiple critical issues, including in vitro structure-modifying techniques and antioxidant assays, structure-activity relationships of antioxidant peptides, pre-clinical studies on hemp proteins and pathogenesis-related molecular mechanisms, usage and potential hazard, and novel advanced techniques involving bioinformatics methodology (QSAR, PPI, GO, KEGG), proteomic analysis, and genomics analysis, etc. Taken together, the antioxidant potential of hemp proteins may provide both functional food benefits and phytotherapy efficacy to human health.

Quantitative assessment of wheat quality using near-infrared spectroscopy: A comprehensive review.

Wheat is one of the most widely cultivated crops throughout the world. A great need exists for wheat quality assessment for breeding, processing, and products production purposes. Near-infrared spectroscopy (NIRS) is a rapid, low-cost, simple, and nondestructive assessment method. Many advanced studies associated with NIRS for wheat quality assessment have been published recently, either introducing new chemometrics or attempting new assessment parameters to improve model robustness and accuracy. This review provides a comprehensive overview of NIRS methodology including its principle, spectra pretreatments, spectral wavelength selection, outlier disposal, dataset division, regression methods, and model evaluation. More importantly, the applications of NIRS in the determination of analytical parameters, rheological parameters, and end product quality of wheat are summarized. Although NIRS showed great potential in the quantitative determination of analytical parameters, there are still challenges in model robustness and accuracy in determining rheological parameters and end product quality for wheat products. Future model development needs to incorporate larger databases, integrate different spectroscopic techniques, and introduce cutting-edge chemometrics methods. In addition, calibration based on external factors should be considered to improve the predicted results of the model. The NIRS application in micronutrients needs to be extended. Last, the idea of combining standard product sensory attributes and spectra for model development deserves further study.

A comprehensive review of wheat phytochemicals: From farm to fork and beyond.

The health benefits of whole wheat consumption can be partially attributed to wheat's phytochemicals, including phenolic acids, flavonoids, alkylresorcinols, carotenoids, phytosterols, tocopherols, and tocotrienols. It is of increasing interest to produce whole wheat products that are rich in bioactive phytochemicals. This review provides the fundamentals of the chemistry, extraction, and occurrence of wheat phytochemicals and includes critical discussion of several long-lasting issues: (1) the commonly used nomenclature on distribution of wheat phenolic acids, namely, soluble-free, soluble-conjugated, and insoluble-bound phenolic acids; (2) different extraction protocols for wheat phytochemicals; and (3) the chemistry and application of in vitro antioxidant assays. This review further discusses recent advances on the effects of genotypes, environments, field management, and processing techniques including ultrafine grinding, germination, fermentation, enzymatic treatments, thermal treatments, and food processing. These results need to be interpreted with care due to varied sample preparation protocols and limitations of in vitro assays. The bioaccessibility, bioavailability, metabolism, and potential health benefits of wheat phytochemicals are also reviewed. This comprehensive and critical review will benefit scientific researchers in the field of bioactive compounds of cereal grains and also those in the cereal food industry to produce high-quality functional foods.

[Effect of BDNF-AS/miR-145-5p axis on renal tubular epithelial cell injury induced by high glucose].

OBJECTIVE: To investigate the effect and possible mechanism of BDNF-AS on renal tubular epithelial cell injury induced by high glucose. METHODS: Human renal tubular epithelial cells HK-2 were cultured in vitro and transfected with BDNF-AS small interfering RNA or miR-145-5p mimic, or co-transfected with BDNF-AS small interfering RNA and miR-145-5p inhibitor, respectively. The cells were then intervened with 30 mmol/L glucose for 24 hours. The expression of BDNF-AS and miR-145-5p were detected by RT-qPCR. Cell proliferation was detected by CCK-8, and apoptosis was detected by flow cytometry. The expression of Bcl-2 and Bax proteins were detected by Western blotting, and the levels of IL-1ß and IL-6 in cell culture supernatant were detected by enzyme-linked immunosorbent assay. Dual luciferase reporter gene experiment was used to verify the regulatory relationship of BDNF-AS with miR-145-5p. RESULTS: High glucose promoted the expression of BDNF-AS in HK-2 cells (P<0.05), but inhibited that of miR-145-5p (P<0.05). Interfering with BDNF-AS or overexpression of miR-145-5p decreased the inhibition rate, apoptosis rate and expression of Bax protein, IL-1ß and IL-6 of HK-2 cells induced by high glucose (P<0.05), but promoted the expression of Bcl-2 protein (P<0.05). Interfering with miR-145-5p reversed the effect of interfering with BDNF-AS on the proliferation, apoptosis rate and the expression of IL-1ß and IL-6 of HK-2 cells induced by high glucose. BDNF-AS could target and down-regulate miR-145-5p. CONCLUSION: Interfering with BDNF-AS may promote the proliferation of renal tubular epithelial cells induced by high glucose and inhibit cell apoptosis and the expression of inflammatory factor by down-regulating miR-145-5p.

WEE1 inhibition induces glutamine addiction in T-cell acute lymphoblastic leukemia.

T-cell acute lymphoblastic leukemias (T-ALLs) are aggressive and heterogeneous hematologic tumors resulting from the malignant transformation of T-cell progenitors. The major challenges in the treatments of T-ALL are dose-limiting toxicities of chemotherapeutics and drug resistance. Despite important progress in deciphering the genomic landscape of T-ALL, translation of these findings into effective targeted therapies remains largely unsuccessful. New targeted agents with significant antileukemic efficacy and less toxicity are in urgent need. We herein report that the expression of WEE1, a nuclear tyrosine kinase involved in cell cycle G2-M checkpoint signaling, is significantly elevated in T-ALL. Mechanistically, oncogenic MYC directly binds to the WEE1 promoter and activates its transcription. T-ALL cells particularly rely on the elevated WEE1 for cell viability. Pharmacological inhibition of WEE1 elicits global metabolic reprogramming which results in a marked suppression of aerobic glycolysis in T-ALL cells, leading to an increased dependency on glutaminolysis for cell survival. As such, dual targeting of WEE1 and glutaminase (GLS1) induces synergistic lethality in multiple T-ALL cell lines and shows great efficacy in T-ALL patient-derived xenografts. These findings provide mechanistic insights in the regulation of WEE1 kinase in T-ALL and suggest an additional vulnerability during WEE1 inhibitor treatments. In aggregate, we highlight a promising combination strategy of dual inhibition of cell cycle kinase and metabolic enzymes for T-ALL therapeutics.