Tumor-repopulating cells evade ferroptosis via PCK2-dependent phospholipid remodeling.

Whether stem-cell-like cancer cells avert ferroptosis to mediate therapy resistance remains unclear. In this study, using a soft fibrin gel culture system, we found that tumor-repopulating cells (TRCs) with stem-cell-like cancer cell characteristics resist chemotherapy and radiotherapy by decreasing ferroptosis sensitivity. Mechanistically, through quantitative mass spectrometry and lipidomic analysis, we determined that mitochondria metabolic kinase PCK2 phosphorylates and activates ACSL4 to drive ferroptosis-associated phospholipid remodeling. TRCs downregulate the PCK2 expression to confer themselves on a structural ferroptosis-resistant state. Notably, in addition to confirming the role of PCK2-pACSL4(T679) in multiple preclinical models, we discovered that higher PCK2 and pACSL4(T679) levels are correlated with better response to chemotherapy and radiotherapy as well as lower distant metastasis in nasopharyngeal carcinoma cohorts.

Phenotypic and transcriptome profiling of spikes reveals the regulation of light regimens on spike growth and fertile floret number in wheat.

The spike growth phase is critical for the establishment of fertile floret (grain) numbers in wheat (Triticum aestivum L.). Then, how to shorten the spike growth phase and increase grain number synergistically? Here, we showed high-resolution analyses of floret primordia (FP) number, morphology and spike transcriptomes during the spike growth phase under three light regimens. The development of all FP in a spike could be divided into four distinct stages: differentiation (Stage I), differentiation and morphology development concurrently (Stage II), morphology development (Stage III), and polarization (Stage IV). Compared to the short photoperiod, the long photoperiod shortened spike growth and stimulated early flowering by shortening Stage III; however, this reduced assimilate accumulation, resulting in fertile floret loss. Interestingly, long photoperiod supplemented with red light shortened the time required to complete Stages I-II, then raised assimilates supply in the spike and promoted anther development before polarization initiation, thereby increasing fertile FP number during Stage III, and finally maintained fertile FP development during Stage IV until they became fertile florets via a predicted dynamic gene network. Our findings proposed a light regimen, critical stages and candidate regulators that achieved a shorter spike growth phase and a higher fertile floret number in wheat.

Low sucrose availability reduces basal spikelet fertility by inducing abscisic acid and jasmonic acid synthesis in wheat.

Within a spike of wheat, the central spikelets usually generate three to four fertile florets, while the basal spikelets generate zero to one fertile floret. The physiological and transcriptional mechanism behind the difference in fertility between the basal and central spikelets is unclear. This study reports a high temporal resolution investigation of transcriptomes, number and morphology of floret primordia, and physiological traits. The W6.5-W7.5 stage was regarded as the boundary to distinguish between fertile and abortive floret primordia; those floret primordia reaching the W6.5-W7.5 stage during the differentiation phase (3-9 d after terminal spikelet stage) usually developed into fertile florets in the next dimorphism phase (12-27 d after terminal spikelet stage), whereas the others aborted. The central spikelets had a greater number of fertile florets than the basal spikelets, which was associated with more floret primordia reaching the W6.5-W7.5 stage. Physiological and transcriptional results demonstrated that the central spikelets had a higher sucrose content and lower abscisic acid (ABA) and jasmonic acid (JA) accumulation than the basal spikelets due to down-regulation of genes involved in ABA and JA synthesis. Collectively, we propose a model in which ABA and JA accumulation is induced under limiting sucrose availability (basal spikelet) through the up-regulation of genes involved in ABA and JA synthesis; this leads to floret primordia in the basal spikelets failing to reach their fertile potential (W6.5-W7.5 stage) during the differentiation phase and then aborting. This fertility repression model may also regulate spikelet fertility in other cereal crops and potentially provides genetic resources to improve spikelet fertility.

Renewable Electroconductive Hydrogels for Accelerated Diabetic Wound Healing and Motion Monitoring.

Diabetic foot ulcers (DFUs), a prevalent complication of diabetes mellitus, may result in an amputation. Natural and renewable hydrogels are desirable materials for DFU dressings due to their outstanding biosafety and degradability. However, most hydrogels are usually only used for wound repair and cannot be employed to monitor motion because of their inherent poor mechanical properties and electrical conductivity. Given that proper wound stretching is beneficial for wound healing, the development of natural hydrogel patches integrated with wound repair properties and motion monitoring was expected to achieve efficient and accurate wound healing. Here, we designed a dual-network (chitosan and sodium alginate) hydrogel embedded with lignin-Ag and quercetin-melanin nanoparticles to achieve efficient wound healing and motion monitoring. The double network formed by the covalent bond and electrostatic interaction confers the hydrogel with superior mechanical properties. Instead of the usual chemical reagents, genipin extracted from Gardenia was used as a cross-linking agent for the hydrogel and consequently improved its biosafety. Furthermore, the incorporation of lignin-Ag nanoparticles greatly enhanced the mechanical strength, antibacterial efficacy, and conductivity of the hydrogel. The electrical conductivity of hydrogels gives them the capability of motion monitoring. The motion sensing mechanism is that stretching of the hydrogel induced by motion changes the conductivity of the hydrogel, thus converting the motion into an electrical signal. Meanwhile, quercetin-melanin nanoparticles confer exceptional adhesion, antioxidant, and anti-inflammatory properties to the hydrogels. The system ultimately achieved excellent wound repair and motion monitoring performance and was expected to be used for stretch-assisted safe and accurate wound repair in the future.

Interaction of Asn297-Linked Glycan Ligands with the Fc Fragment of the Immunoglobulin Class G1: A Molecular Dynamics Simulation Study.

The allosteric modulation of the homodimeric H10-03-6 protein to glycan ligands L1 and L2, and the STAB19 protein to glycan ligands L3 and L4, respectively, has been studied by molecular dynamics simulations and free energy calculations. The results revealed that the STAB19 protein has a significantly higher affinity for L3 (-11.38 ± 2.32 kcal/mol) than that for L4 (-5.51 ± 1.92 kcal/mol). However, the combination of the H10-03-6 protein with glycan L2 (1.23 ± 6.19 kcal/mol) is energetically unfavorable compared with that of L1 (-13.96 ± 0.35 kcal/mol). Further, the binding of glycan ligands L3 and L4 to STAB19 would result in the significant closure of the two CH2 domains of the STAB19 conformation with the decrease of the centroid distances between the two CH2 domains compared with the H10-03-6/L1/L2 complex. The CH2 domain closure of STAB19 relates directly to the formation of new hydrogen bonds and hydrophobic interactions between the residues Ser239, Val240, Asp265, Glu293, Asn297, Thr299, Ser337, Asp376, Thr393, Pro395, and Pro396 in STAB19 and glycan ligands L3 and L4, which suggests that these key residues would contribute to the specific regulation of STAB19 to L3 and L4. In addition, the distance analysis revealed that the EF loop in the H10-03-6/L1/L2 model presents a high flexibility and partial disorder compared with the stabilized STAB19/L3/L4 complex. These results will be helpful in understanding the specific regulation through the asymmetric structural characteristics in the CH2 and CH3 domains of the H10-03-6 and STAB19 proteins.

Mitochondrial KATP channel-mediated autophagy contributes to angiotensin II-induced vascular dysfunction in mice.

BACKGROUND AND AIM: The present study aimed to investigate whether the mitochondrial KATP channel contributes to angiotensin II (Ang II)-induced vascular dysfunction, the development of hypertension, and atherosclerosis. METHODS AND RESULTS: ApoE (-/-) mice fed a high-fat diet were chronically infused with Ang II for eight weeks and concomitantly treated with losartan (ARB), apocynin, or 5-hydroxy decanoate (5-HD), or 3-methyladenine (3-MA). Systolic blood pressure was measured, and pathological changes of aortic or liver tissue were observed. Nitric oxide (NO), superoxide dismutase 2 (SOD2) levels and vasorelaxation rate were measured, and protein and mRNA expressions were examined by western blot and RT-PCR. Ang II-induced development of hypertension was suppressed not only by ARB, and apocynin but also by 5-HD or 3-MA. Ang II infusion decreased aortic NO production and relaxation, as well as SOD2 activity in liver, which were improved by all treatments. In addition, Ang II-induced activation of autophagy was suppressed by 5-HD in aortic tissue, furthermore, Ang II increases the atherosclerotic index in plasma and exacerbates the development of atherosclerosis by increases of fat deposition in the aorta and liver. Lipid metabolism-related mRNA expressions (LXR-α, LDLR, SRBI, Acca, and FASN) were changed by Ang II. Similarly, not only ARB, and apocynin, but also 5-HD and 3-MA suppressed Ang II-induced these changes. CONCLUSIONS: Our present findings evidence that mitochondrial KATP channel-mediated autophagy contributes to Ang II-induced vascular dysfunction, development of hypertension, and atherosclerosis.

Consent and Educational Sensitive Exams on Anesthetized Patients: Experiences of Medical Students Across Canada.

OBJECTIVES: This study investigates experiences of medical students across Canada related to consent for educational sensitive (i.e., pelvic, rectal) exams under anesthesia (EUAs). METHODS: A bilingual online questionnaire was developed and distributed to medical students across Canada. RESULTS: Of 134 respondents, 63% had performed a pelvic EUA, 35% a rectal EUA, and 11% another sensitive EUA during their training. For those who had performed pelvic EUA, 28% were unsure if consent had taken place, 26% reported no specific consent, 20% reported specific consent, and 25% had mixed experiences of consent. For rectal EUAs, 48% reported no specific consent, 37% were unsure if consent had taken place, 13% reported that there had been specific consent, and 2% reported mixed experiences. Most respondents were uncomfortable (36%) or not sure if they were comfortable (32%) with how the consent process was handled for student pelvic EUAs; 31% were comfortable. In open-ended responses, respondents described experiences related to variability, discomfort, and authority. CONCLUSIONS: Non-consensual educational sensitive EUAs continue to take place in medical training across Canada, although practices of consent are highly variable. The majority of respondents reported being uncomfortable or unsure if they were comfortable with how consent for educational sensitive EUAs was practised during their training, and some respondents struggled to express their discomfort given the power dynamics at play.

The Challenges in Using eHealth Decision Resources for Surrogate Decision-Making in the Intensive Care Unit.

The mortality rate in intensive care units (ICUs) is notably high, with patients often relying on surrogates for critical medical decisions due to their compromised state. This paper provides a comprehensive overview of eHealth. The challenges of applying eHealth tools, including economic disparities and information inaccuracies are addressed. This study then introduces eHealth literacy and the assessment tools to evaluate users' capability and literacy levels in using eHealth resources. A clinical scenario involving surrogate decision-making is presented. This simulated case involves a patient with a hemorrhagic stroke who has lost consciousness and requires medical procedures such as tracheostomy. However, due to the medical surrogate's lack of familiarity with eHealth devices and limited literacy in using eHealth resources, difficulties arise in assisting the patient in making medical decisions. This scenario highlights challenges related to eHealth literacy and solution strategies are proposed. In conclusion, effective ICU decision-making with eHealth tools requires a careful balance between efficiency with inclusivity. Tailoring communication strategies and providing diverse materials are essential for effective eHealth decision resources in the ICU setting. Health professionals should adopt a patient-centered approach to enhance the decision-making experience, particularly for individuals with limited eHealth literacy.

Short-term associations between ambient PM1, PM2.5, and PM10 and hospital admissions, length of hospital stays, and hospital expenses for patients with cardiovascular diseases in rural areas of Fuyang, East China.

Evidence on the impacts of PM1, PM2.5, and PM10 on the hospital admissions, length of hospital stays (LOS), and hospital expenses among patients with cardiovascular disease (CVD) is still limited in China, especially in rural areas. This study was performed in eight counties of Fuyang from 1 January 2015 to 30 June 2017. We use a three-stage time-series analysis to explore the effects of short-term exposure to PM1, PM2.5, and PM10 on hospital admissions, LOS, and hospital expenses for CVDs. An increment of 10 ug/m3 in PM1, PM2.5, and PM10 corresponded to an increment of 1.82% (95% CI: 1.34, 2.30), 0.96% (95% CI: 0.44, 1.48), and 0.79% (95% CI: 0.63%, 0.95%) in CVD hospital admissions, respectively. We observed that daily concentrations of PMs were associated with an increase in hospital admissions, LOS, and expenses for CVDs. Sustained endeavors are required to reduce air pollution so as to attenuate disease burdens from CVDs.

LincRNA ZNF529-AS1 inhibits hepatocellular carcinoma via FBXO31 and predicts the prognosis of hepatocellular carcinoma patients.

BACKGROUND: Invasion and metastasis of hepatocellular carcinoma (HCC) is still an important reason for poor prognosis. LincRNA ZNF529-AS1 is a recently identified tumour-associated molecule that is differentially expressed in a variety of tumours, but its role in HCC is still unclear. This study investigated the expression and function of ZNF529-AS1 in HCC and explored the prognostic significance of ZNF529-AS1 in HCC. METHODS: Based on HCC information in TCGA and other databases, the relationship between the expression of ZNF529-AS1 and clinicopathological characteristics of HCC was analysed by the Wilcoxon signed-rank test and logistic regression. The relationship between ZNF529-AS1 and HCC prognosis was evaluated by Kaplan‒Meier and Cox regression analyses. The cellular function and signalling pathways involved in ZNF529-AS1 were analysed by GO and KEGG enrichment analysis. The relationship between ZNF529-AS1 and immunological signatures in the HCC tumour microenvironment was analysed by the ssGSEA algorithm and CIBERSORT algorithm. HCC cell invasion and migration were investigated by the Transwell assay. Gene and protein expression were detected by PCR and western blot analysis, respectively. RESULTS: ZNF529-AS1 was differentially expressed in various types of tumours and was highly expressed in HCC. The expression of ZNF529-AS1 was closely correlated with the age, sex, T stage, M stage and pathological grade of HCC patients. Univariate and multivariate analyses showed that ZNF529-AS1 was significantly associated with poor prognosis of HCC patients and could be an independent prognostic indicator of HCC. Immunological analysis showed that the expression of ZNF529-AS1 was correlated with the abundance and immune function of various immune cells. Knockdown of ZNF529-AS1 in HCC cells inhibited cell invasion and migration and inhibited the expression of FBXO31. CONCLUSION: ZNF529-AS1 could be a new prognostic marker for HCC. FBXO31 may be the downstream target of ZNF529-AS1 in HCC.

Short-term and long-term effect of nutrition intervention in the Linxian Dysplasia Nutrition Intervention Trial and the reason for disappearance of the intervention effect: A cohort study.

BACKGROUND: The objective of this study was to determine the short-term and long-term effects of a nutrition intervention in using 37 years of follow-up data. METHODS: The Linxian Dysplasia Population Nutrition Intervention Trial was a randomized, double-blind, placebo-controlled trial with 7 years of intervention and 30 years of follow-up. The Cox proportional hazard model was used for analyses. Subgroup analyses were conducted in age and sex subgroups, and the 30 years of follow-up were divided into two 15-year early and late periods. RESULTS: The results at 37 years did not indicate any effects on mortality from cancers or other diseases. In the first 15 years, the intervention decreased the overall risk of gastric cancer deaths in all participants (hazard ratio [HR], 0.76; 95% confidence interval [CI], 0.58-1.00) and in the subgroup participants younger than 55 years (HR, 0.64; 95% CI, 0.43-0.96). In addition, in the group younger than 55 years (HR, 0.58; 95% CI, 0.35-0.96), the intervention decreased the risk of death from other diseases; and, in the group aged 55 years and older (HR, 0.75; 95% CI, 0.58-0.98), the intervention reduced the risk of death from heart disease. There were no significant results in the later 15 years, which indicated the disappearance of the intervention effect. Comparing demographic characteristics between those who died during the two periods, the participants who died later included more women, had a higher education level, had a lower smoking rate, were younger, and also more had a mild degree of esophageal dysplasia, representing a better lifestyle and health condition. CONCLUSIONS: Long-term follow-up indicated no effect of nutrition on deaths in a population with esophageal squamous dysplasia, further supporting the significance of continuous nutritional intervention for cancer protection. The pattern of protective effect of a nutrition intervention on gastric cancer in patients with esophageal squamous dysplasia was similar to that in the general population. Participants who died in the later period had more protective factors than those who died in the earlier period, contributing to the obvious effect of the intervention in early stage disease.

Global analysis of seed transcriptomes reveals a novel PLATZ regulator for seed size and weight control in soybean.

Seed size and weight are important factors that influence soybean yield. Combining the weighted gene co-expression network analysis (WGCNA) of 45 soybean accessions and gene dynamic changes in seeds at seven developmental stages, we identified candidate genes that may control the seed size/weight. Among these, a PLATZ-type regulator overlapping with 10 seed weight QTLs was further investigated. This zinc-finger transcriptional regulator, named as GmPLATZ, is required for the promotion of seed size and weight in soybean. The GmPLATZ may exert its functions through direct binding to the promoters and activation of the expression of cyclin genes and GmGA20OX for cell proliferation. Overexpression of the GmGA20OX enhanced seed size/weight in soybean. We further found that the GmPLATZ binds to a 32-bp sequence containing a core palindromic element AATGCGCATT. Spacing of the flanking sequences beyond the core element facilitated GmPLATZ binding. An elite haplotype Hap3 was also identified to have higher promoter activity and correlated with higher gene expression and higher seed weight. Orthologues of the GmPLATZ from rice and Arabidopsis play similar roles in seeds. Our study reveals a novel module of GmPLATZ-GmGA20OX/cyclins in regulating seed size and weight and provides valuable targets for breeding of crops with desirable agronomic traits.

Dynamic gene regulatory networks improving spike fertility through regulation of floret primordia fate in wheat.

The developmental process of spike is critical for spike fertility through affecting floret primordia fate in wheat; however, the genetic regulation of this dynamic and complex developmental process remains unclear. Here, we conducted a high temporal-resolution analysis of spike transcriptomes and monitored the number and morphology of floret primordia within spike. The development of all floret primordia in a spike was clearly separated into three distinct phases: differentiation, pre-dimorphism and dimorphism. Notably, we identified that floret primordia with meiosis ability at the pre-dimorphism phase usually develop into fertile floret primordia in the next dimorphism phase. Compared to control, increasing plant space treatment achieved the maximum increasement range (i.e., 50%) in number of fertile florets by accelerating spike development. The process of spike fertility improvement was directed by a continuous and dynamic regulatory network involved in transcription factor and genes interaction. This was based on the coordination of genes related to heat shock protein and jasmonic acid biosynthesis during differentiation phase, and genes related to lignin, anthocyanin and chlorophyll biosynthesis during dimorphism phase. The multi-dimensional association with high temporal-resolution approach reported here allows rapid identification of genetic resource for future breeding studies to realise the maximum spike fertility potential in more cereal crops.

Sugars and sucrose transporters in pollinia of Phalaenopsis aphrodite (Orchidaceae).

The pollen grains of Phalaenopsis orchids are clumped tightly together, packed in pollen dispersal units called pollinia. In this study, the morphology, cytology, biochemistry, and sucrose transporters in pollinia of Phalaenopsis orchids were investigated. Histochemical detection was used to characterize the distribution of sugars and callose at the different development stages of pollinia. Ultra-performance liquid chromatography-high resolution-tandem mass spectrometry data indicated that P. aphrodite accumulated abundant saccharides such as sucrose, galactinol, myo-inositol, and glucose, and trace amounts of raffinose and trehalose in mature pollinia. We found that galactinol synthase (PAXXG304680) and trehalose-6-phosphate phosphatase (PAXXG016120) genes were preferentially expressed in mature pollinia. The P. aphrodite genome was identified as having 11 sucrose transporters (SUTs). Our qRT-PCR confirmed that two SUTs (PAXXG030250 and PAXXG195390) were preferentially expressed in the pollinia. Pollinia germinated in pollen germination media (PGM) supplemented with 10% sucrose showed increased callose production and enhanced pollinia germination, but there was no callose or germination in PGM without sucrose. We show that P. aphrodite accumulates high levels of sugars in mature pollinia, providing nutrients and enhanced SUT gene expression for pollinia germination and tube growth.

Phospholipase iPLA2ß averts ferroptosis by eliminating a redox lipid death signal.

Ferroptosis, triggered by discoordination of iron, thiols and lipids, leads to the accumulation of 15-hydroperoxy (Hp)-arachidonoyl-phosphatidylethanolamine (15-HpETE-PE), generated by complexes of 15-lipoxygenase (15-LOX) and a scaffold protein, phosphatidylethanolamine (PE)-binding protein (PEBP)1. As the Ca2+-independent phospholipase A2ß (iPLA2ß, PLA2G6 or PNPLA9 gene) can preferentially hydrolyze peroxidized phospholipids, it may eliminate the ferroptotic 15-HpETE-PE death signal. Here, we demonstrate that by hydrolyzing 15-HpETE-PE, iPLA2ß averts ferroptosis, whereas its genetic or pharmacological inactivation sensitizes cells to ferroptosis. Given that PLA2G6 mutations relate to neurodegeneration, we examined fibroblasts from a patient with a Parkinson's disease (PD)-associated mutation (fPDR747W) and found selectively decreased 15-HpETE-PE-hydrolyzing activity, 15-HpETE-PE accumulation and elevated sensitivity to ferroptosis. CRISPR-Cas9-engineered Pnpla9R748W/R748W mice exhibited progressive parkinsonian motor deficits and 15-HpETE-PE accumulation. Elevated 15-HpETE-PE levels were also detected in midbrains of rotenone-infused parkinsonian rats and α-synuclein-mutant SncaA53T mice, with decreased iPLA2ß expression and a PD-relevant phenotype. Thus, iPLA2ß is a new ferroptosis regulator, and its mutations may be implicated in PD pathogenesis.

A retrospective assessment of real-world experience with venetoclax and azacitidine therapy in elderly acute myeloid leukemia.

This study aimed to examine the effect of venetoclax coupled with azacytidine in treating older adults with relapsed and refractory (R/R) acute myeloid leukemia (AML). The clinical data of 10 senior patients with AML over 65 years old who were treated with venetoclax and azacytidine, including six patients with R/R AML, were retrospectively evaluated. This study comprised seven males and three females with a median age of 71 years. Five patients had at least one relapse, and one patient did not achieve remission after four cycles of azacytidine monotherapy, considering it resistant. AML with myelodysplasia-related changes was found in four cases. One of the 10 patients died early after 1-13 cycles of venetoclax plus azacytidine treatment due to a protracted period of neutropenia and severe lung infection induced by medications. Six of the remaining nine patients, including six R/R patients, achieved a complete remission (CR) or a CR with incomplete hematologic recovery (CRi). After two cycles of therapy, one patient did not react. Neutropenia lasted an average of 10.5 (6-15) days in all patients, with the most severe cases occurring in the second and third weeks of therapy. Three patients who tested positive for the TP53 gene mutation had the following outcomes: One relapsed patient has been in progression-free remission (PFS) for the past 24 months, whereas another has been in full remission but relapsed 2 months later. Another patient experienced complete remission in myelology for 4 months, but the variable allele fraction (VAF) value steadily rose, suggesting that the illness was on the verge of progressing. IDH2 gene alterations were found in three of four patients who obtained maintained CR for more than 18 months following recurrence. Venetoclax in combination with azacytidine is a successful and well-tolerated therapy for R/R AML in the elderly. Venetoclax and azacytidine may help patients with TP53 mutations and reduce VAF. The IDH2 mutation might be a good predictor of veneclax sensitivity. A notable adverse response in the treatment phase of the regimen is severe infection induced by neutropenia.

ALOX5 inhibition protects against dopaminergic neurons undergoing ferroptosis.

Oxidative disruption of dopaminergic neurons is regarded as a crucial pathogenesis in Parkinson's disease (PD), eventually causing neurodegenerative progression. (-)-Clausenamide (Clau) is an alkaloid isolated from plant Clausena lansium (Lour.), which is well-known as a scavenger of lipid peroxide products and exhibiting neuroprotective activities both in vivo and in vitro, yet with the in-depth molecular mechanism unrevealed. In this study, we evaluated the protective effects and mechanisms of Clau on dopaminergic neuron. Our results showed that Clau directly interacted with the Ser663 of ALOX5, the PKCα-phosphorylation site, and thus prevented the nuclear translocation of ALOX5, which was essential for catalyzing the production of toxic lipids 5-HETE. LC-MS/MS-based phospholipidomics analysis demonstrated that the oxidized membrane lipids were involved in triggering ferroptotic death in dopaminergic neurons. Furthermore, the inhibition of ALOX5 was found to significantly improving behavioral defects in PD mouse model, which was confirmed associated with the effects of attenuating the accumulation of lipid peroxides and neuronal damages. Collectively, our findings provide an attractive strategy for PD therapy by targeting ALOX5 and preventing ferroptosis in dopaminergic neurons.

Reducing lipid peroxidation attenuates stress-induced susceptibility to herpes simplex virus type 1.

Psychological stress increases the susceptibility to herpes simplex virus type 1 (HSV-1) infection. There is no effective intervention due to the unknown pathogenesis mechanisms. In this study we explored the molecular mechanisms underlying stress-induced HSV-1 susceptibility and the antiviral effect of a natural compound rosmarinic acid (RA) in vivo and in vitro. Mice were administered RA (11.7, 23.4 mg·kg-1·d-1, i.g.) or acyclovir (ACV, 206 mg·kg-1·d-1, i.g.) for 23 days. The mice were subjected to restraint stress for 7 days followed by intranasal infection with HSV-1 on D7. At the end of RA or ACV treatment, mouse plasma samples and brain tissues were collected for analysis. We showed that both RA and ACV treatment significantly decreased stress-augmented mortality and alleviated eye swelling and neurological symptoms in HSV-1-infected mice. In SH-SY5Y cells and PC12 cells exposed to the stress hormone corticosterone (CORT) plus HSV-1, RA (100 µM) significantly increased the cell viability, and inhibited CORT-induced elevation in the expression of viral proteins and genes. We demonstrated that CORT (50 µM) triggered lipoxygenase 15 (ALOX15)-mediated redox imbalance in the neuronal cells, increasing the level of 4-HNE-conjugated STING, which impaired STING translocation from the endoplasmic reticulum to Golgi; the abnormality of STING-mediated innate immunity led to HSV-1 susceptibility. We revealed that RA was an inhibitor of lipid peroxidation by directly targeting ALOX15, thus RA could rescue stress-weakened neuronal innate immune response, thereby reducing HSV-1 susceptibility in vivo and in vitro. This study illustrates the critical role of lipid peroxidation in stress-induced HSV-1 susceptibility and reveals the potential for developing RA as an effective intervention in anti-HSV-1 therapy.

[Hemoglobin C Variant Affecting Glycated Hemoglobin Test Results: A Rare Case Report].

Hemoglobin (Hb) variants are common factors that affect the results of glycosylated hemoglobin (A1C) tests. Hemoglobin variants react differently to different testing methods. Herein, we presented the first ever report of the effect of hemoglobin C (Hb C) on the test results of A1C in the Chinese population. High performance liquid chromatography (HPLC) and capillary electrophoresis were performed to measure A1C. Hemoglobin electrophoresis was conducted to identify the hemoglobin variants. Hb sequencing was performed to determine the mutation sites on the ß chain. HPLC showed decreased A1C results, which could be corrected by electrophoresis, but the electrophoresis graph still showed abnormal peaks. The hemoglobin electrophoresis results suggested that there were hemoglobin variants, which hemoglobin sequencing results revealed to be Hb C. Uncommon variations in a specific population tend to be overlooked. To avoid clinical decision-making being affected by the results of a single test, we recommend that an explanatory reporting model be routinely adopted for A1C tests so that all reports always contain explanatory notes for the testing methodology and analysis of the graphs.

Cell-membrane-targeted near-infrared fluorescent probe for detecting extracellular ATP.

Extracellular adenosine triphosphate (ATP) as a signal molecule plays a key role in tumor progression and metastasis. Therefore, the development of a fluorescent probe to detect extracellular ATP is crucial for tumor treatment. However, small-molecule fluorescent probes have better advantages than biological probes, such as low price, easy modification, and optical tunability, but still remain highly challenging and rarely explored in extracellular ATP detection. Here, a near-infrared small molecule fluorescent probe (NIR-P) with hydrophobic alkyl chains and hydrophilic macrocyclic polyamines was prepared for the detection of extracellular ATP. The NIR-P exhibited enhanced fluorescence upon binding to ATP by electrostatic interaction and π-π interaction between phosphates and macrocyclic polyamines, adenines and benzene rings with a limit of detection (LOD) of 21 nM. In addition, with similarity and intermiscibility to the cell membrane, the NIR-P can specifically target cell membranes and image extracellular ATP. This work provides a cell-membrane-targeted fluorescent probe used for extracellular ATP detection.