DBT affects sleep in both circadian and non-circadian neurons.

Sleep is a very important behavior observed in almost all animals. Importantly, sleep is subject to both circadian and homeostatic regulation. The circadian rhythm determines the daily alternation of the sleep-wake cycle, while homeostasis mediates the rise and dissipation of sleep pressure during the wake and sleep period. As an important kinase, dbt plays a central role in both circadian rhythms and development. We investigated the sleep patterns of several ethyl methanesulfonate-induced dbt mutants and discuss the possible reasons why different sleep phenotypes were shown in these mutants. In order to reduce DBT in all neurons in which it is expressed, CRISPR-Cas9 was used to produce flies that expressed GAL4 in frame with the dbt gene at its endogenous locus, and knock-down of DBT with this construct produced elevated sleep during the day and reduced sleep at night. Loss of sleep at night is mediated by dbt loss during the sleep/wake cycle in the adult, while the increased sleep during the day is produced by reductions in dbt during development and not by reductions in the adult. Additionally, using targeted RNA interference, we uncovered the contribution of dbt on sleep in different subsets of neurons in which dbt is normally expressed. Reduction of dbt in circadian neurons produced less sleep at night, while lower expression of dbt in noncircadian neurons produced increased sleep during the day. Importantly, independently of the types of neurons where dbt affects sleep, we demonstrate that the PER protein is involved in DBT mediated sleep regulation.

UGT1A1 genotype-guided irinotecan dosing during neoadjuvant chemoradiotherapy for locally advanced rectal cancer: A prospective analysis of SN-38 concentration.

Irinotecan plays a crucial role in the neoadjuvant chemoradiotherapy (nCRT) of rectal cancer, but its optimal dosing is still unclear. In this study, we included 101 eligible patients with the UGT1A1*28 genotype of UGT1A1*1*1 (74.3%) and UGT1A1*1*28 (25.7%) and UGT1A1*6 genotypes of GG (63.4%), GA (32.7%), and AA (3.9%). All patients received preoperative radiotherapy (50 Gy/25 fractions) with concurrent irinotecan (UGT1A1*1*1: 80 mg/m2 ; UGT1A1*1*28: 65 mg/m2 ) and capecitabine (CapIri). SN-38 concentrations were measured at 1.5, 24, and 49 h post-administration. Patients were divided into four groups (Q1-Q4) based on the SN-38 concentration. The complete-response (CR) rate was the primary endpoint. The analysis demonstrated that the 49 h SN-38 concentration was relatively optimal for predicting efficacy and toxicity. The Q4 group had a significantly higher CR rate than the Q1 group (p = .019), but also higher rates of adverse events (p = .009). We screened the recommended 49 h SN-38, with a 0.5-1.0 ng/mL concentration range. We also validated the correlation between UGT1A1*6 polymorphism and SN-38 concentration, along with the clinical efficacy of irinotecan. In conclusion, our study identified the relatively optimal timepoint and concentration range for monitoring SN38 concentrations and revealed the clinical significance of UGT1A1*6 and UGT1A1*28 polymorphisms in guiding irinotecan administration, offering meaningful insights for personalised irinotecan dosing.

Quantification of MicroRNA in a Single Living Cell via Ionic Current Rectification-Based Nanopore for Triple Negative Breast Cancer Diagnosis.

Accurate analysis of microRNAs (miRNAs) at the single-cell level is extremely important for deeply understanding their multiple and intricate biological functions. Despite some advancements in analyzing single-cell miRNAs, challenges such as intracellular interferences and insufficient detection limits still remain. In this work, an ultrasensitive nanopore sensor for quantitative single-cell miRNA-155 detection is constructed based on ionic current rectification (ICR) coupled with enzyme-free catalytic hairpin assembly (CHA). Benefiting from the enzyme-free CHA amplification strategy, the detection limit of the nanopore sensor for miRNA-155 reaches 10 fM and the nanopore sensor is more adaptable to complex intracellular environments. With the nanopore sensor, the concentration of miRNA-155 in living single cells is quantified to realize the early diagnosis of triple-negative breast cancer (TNBC). Furthermore, the nanopore sensor can be applied in screening anticancer drugs by tracking the expression level of miRNA-155. This work provides an adaptive and universal method for quantitatively analyzing intracellular miRNAs, which will greatly improve our understanding of cell heterogeneity and provide a more reliable scientific basis for exploring major diseases at the single-cell level.

Advances of Photothermal Agents with Fluorescence Imaging/Enhancement Ability in the Field of Photothermal Therapy and Diagnosis.

Photothermal therapy (PTT) is an effective cancer treatment method. Due to its easy focusing and tunability of the irradiation light, direct and accurate local treatment can be performed in a noninvasive manner by PTT. This treatment strategy requires the use of photothermal agents to convert light energy into heat energy, thereby achieving local heating and triggering biochemical processes to kill tumor cells. As a key factor in PTT, the photothermal conversion ability of photothermal agents directly determines the efficacy of PTT. In addition, photothermal agents generally have photothermal imaging (PTI) and photoacoustic imaging (PAI) functions, which can not only guide the optimization of irradiation conditions but also achieve the integration of disease diagnosis. If the photothermal agents have function of fluorescence imaging (FLI) or fluorescence enhancement, they can not only further improve the accuracy in disease diagnosis but also accurately determine the tumor location through multimodal imaging for corresponding treatment. In this paper, we summarize recent advances in photothermal agents with FLI or fluorescence enhancement functions for PTT and tumor diagnosis. According to the different recognition sites, the application of specific targeting photothermal agents is introduced. Finally, limitations and challenges of photothermal agents with fluorescence imaging/enhancement in the field of PTT and tumor diagnosis are prospected.

Self-Delivery Nanoplatform Based on Amphiphilic Apoptosis Peptide for Precise Mitochondria-Targeting Photothermal Therapy.

Mitochondria-targeting photothermal therapy could significantly enhance the tumor cell killing effect. However, since therapeutic reagents need to overcome a series of physiological obstacles to arrive at mitochondria accurately, precise mitochondria-targeting photothermal therapy still faces great challenges. In this study, we developed a self-delivery nanoplatform that specifically targeted the mitochondria of tumor cells for precise photothermal therapy. Photothermal agent IR780 was encapsulated by amphiphilic apoptotic peptide KLA with mitochondria-targeting ability to form nanomicelle KI by self-assembly through hydrophilic and hydrophobic interactions. Subsequently, negatively charged tumor-targeting polymer HA was coated on the surface of KI through electrostatic interactions, to obtain tumor mitochondria-targeting self-delivery nanoplatform HKI. Through CD44 receptor-mediated recognition, HKI was internalizated by tumor cells and then disassembled in an acidic environment with hyaluronidase in endosomes, resulting in the release of apoptotic peptide KLA and photothermal agent IR780 with mitochondria anchoring capacity, which achieved precise mitochondria guidance and destruction. This tumor mitochondria-targeting self-delivery nanoplatform was able to effectively deliver photothermal agents and apoptotic peptides to tumor cell mitochondria, resulting in precise destruction to mitochondria and enhancing tumor cell inhibition at the subcellular organelle level.

Study of the antivirus function mediated by STING in Micropterus salmoides.

Stimulator of interferon genes (STING) has been demonstrated as a critical mediator in the innate immune response to cytosolic DNA and RNA derived from different pathogens. While the role of Micropterus salmoides STING (MsSTING) in largemouth bass virus is still unknown. In this study, RT-qPCR assay and Western-blot assay showed that the expression levels of MsSTING and its downstream genes were up-regulated after LMBV infection. Pull down experiment proved that a small peptide called Fusion peptide (FP) that previously reported to target to marine and human STING as a selective inhibitor also interacted with MsSTING in vitro. Comparing with the RNA-seq of Largemouth bass infected with LMBV singly, 326 genes were significantly up-regulated and 379 genes were significantly down-regulated in the FP plus LMBV group in which Largemouth bass was treatment with FP before LMBV-challenged. KEGG analysis indicated that the differentially expressed genes (DEGs) were mainly related to signaling transduction, infectious disease viral, immune system and endocrine system. Besides, the survival rate of LMBV-infected largemouth bass was highly decreased following FP treatment. Taken together, our study showed that MsSTING played an important role in immune response against LMBV infection.

First report of Fusarium commune Causing Bulb Rot on Lily (Lilium brownii var. Viridulum Baker) in Hunan Province of China.

Lily (Lilium brownii var. Viridulum Baker) is a well-known edible plant with large, white and sweet bulb scales that has important medicinal value (Zhou et al. 2021) and is grown mainly in the Hebei, Shanxi and Henan provinces of China. In May 2021, a case of bulb rot was discovered in a 3.33 hm2 plantation in Huaihua, Hunan Province, affecting 20% of the area (27°59'30″N, 110°32'20″E). The disease is most severe during the rainy season in May and June. In the early stage, irregular brown spots appeared on the lily scales, the necrosis was depressed and gradually enlarges, and in the later stage, the scales were scattered from the base of the disc and slough off. Ten samples were taken randomly from different plants in the plantation area to isolate the pathogens. After washing with sterile water, they were cut into small pieces and sterilised with 3% hydrogen peroxide for 30 s, 75% ethanol for 90 s, rinsed three times with sterile water and dried on sterile filter paper, then placed on a water agar plate and incubated in the dark in a constant temperature incubator at 28℃ for 3 to 5 days. After 2 days, the mycelium at the edge of the colony was transferred to a PDA plate and incubated for 3-5 days at 28°C in the dark to obtain pure fungal isolates. Eighteen purified fungal isolates were obtained, of which sixteen looked like Fusarium (88.9% isolation rate) and three representative isolates (BHBR2, BHBR3 and BHBR5) were selected for further study. The surface of this fungus was white with dense aerial mycelium. Some had an orange centre in the medium. Microconidia were oval in shape and appeared either straight or slightly curved. These microconidia were colourless, had 0-1 septa and measured 3.334 to 14.724 × 2.216 to 5.385 µm (n=100). Macroconidia were predominantly three-septate, crescent-shaped structures that were thin-walled and slightly curved. Cells at the apex and base were similarly curved. Macroconidia measured 17.956 to 32.150 × 2.788 to 4.492 µm (n=100). The mitochondrial small subunit (mtSSU) and translation elongation factor 1-α (TEF1) genes were amplified and sequenced using the NMS1/NMS2 and TEF-R/TEF-F primers to verify the identity of the pathogens (Stewart et al. 2006). The sequences were submitted to GenBank (BHBR2: mtSSU, PP273435; TEF, OR900976; BHBR3: mtSSU, PP277729; TEF, OR900977; BHBR5: mtSSU, PP277728; TEF, OR900978). A concatenated phylogenetic tree of the two genes was constructed and analysis showed that BHBR2, BHBR3 and BHBR5 were significantly clustered with Fusarium commune. Based on the results of morphological identification and phylogenetic tree analysis, the three isolates were identified as Fusarium commune. We carried out pathogenicity tests using two methods, one in which 6 × 6 mm fungal blocks were inoculated on lily (L. brownie var. viridulum Baker) scales and controls inoculated with sterile blocks, and the other in which strain BHBR2 was selected to carry out pathogenicity tests on bulbs of live plants soaked with 50 ml of a 1 × 106 conidial suspension and bulbs of control plants soaked with sterile water, all in three replicates. They were placed in a growth chamber at 28°C and 80% relative humidity, and the scales were moistened with moistened sterile filter paper. After 3 days of rearing treated scales, lesions appeared on lily scales inoculated with mycelial blocks and expanded with time, whereas no lesions appeared on lily scales inoculated with sterile blocks. One month later, whole plants soaked in the spore suspension wilted, while the control plants grew well. The pathogens re-isolated from the diseased tissues had the same morphological characteristics as representative isolates. This confirms Koch's hypothesis. Fusarium commune has been shown to be the most important pathogenic fungus causing root rot in Alfalfa (Medicago sativa) (Yang et al. 2022) and blueberry (Vaccinium uliginosum L.) (Li et al. 2023) in China. To our knowledge, this is the first report of Fusarium commune causing lily bulb rot in the world, which will lay the foundation for future control of lily bulb rot.

Carbon dioxide production index (VCO2i) predicts hyperlactatemia during cardiopulmonary bypass in pediatric carDiac surGery (pGDP- VCO2i): Study protocol for a nested case-control trial.

BACKGROUND: Hyperlactatemia (HL) during cardiopulmonary bypass (CPB) is relatively frequent in infants and associates with increased morbidity and mortality. Studies on adults have shown that carbon dioxide production index (VCO2i) during CPB is linked to the occurrence of HL, with 'critical thresholds' for VCO2i reported to be 60 mL/min/m2. However, considering infants have a higher metabolic rate and lower tolerance to hypoxia, the critical threshold of VCO2i in infants cannot be replied to the existing adults' standards. The objective of this study is to investigate the association of VCO2i during CPB and HL, and explore the critical VCO2i threshold during CPB in infants. METHODS: VCO2i predicts hyperlactatemia during cardiopulmonary bypass in pediatric cardiac surgery (pGDP-VCO2i) is a nested case-control study. A cohort of consecutive pediatric patients of less than 3 years of age, undergoing congenital cardiac surgeries between May 2021 and December 2023 in West China Hospital will be enrolled. The VCO2i levels of each patient will be recorded every 5 min during CPB. The primary outcome is the rate of HL. The infants will be divided into two groups based on the presence or not of HL. Pre- and intraoperative factors will be tested for independent association with HL. Then, we will make an analysis, and the critical value of VCO2i will be obtained. The postoperative outcome of patients with or without HL will be compared. DISCUSSION: This will be the first trial to investigate the association of VCO2i during CPB and HL, and explore the critical VCO2i threshold during CPB in pediatrics. The results of this study are expected to lay a foundation for clinical application of goal-directed perfusion (GDP) management strategy, and optimize the perfusion strategy and improve the prognosis of pediatric patients undergoing cardiac surgery. TRIAL REGISTRATION: Chictr.org.cn, ChiCTR2100044296 on 16 March 2021.

Resource sharing in cognitive control: Behavioral evidence and neural substrates.

Cognitive control is a capacity-limited function responsible for the resolution of conflict among competing cognitive processes. However, whether cognitive control handles multiple concurrent requests through a single bottleneck or a resource sharing mechanism remains elusive. In this functional magnetic resonance imaging study, we examined the effect of dual flanker conflict processing on behavioral performance and on activation in regions of the cognitive control network (CCN). In each trial, participants completed two flanker conflict tasks (T1 and T2) sequentially, with the stimulus onset asynchrony (SOA) varied as short (100 ms) and long (1000 ms). We found a significant conflict effect (indexed by the difference between incongruent and congruent flanker conditions) in reaction time (RT) for both T1 and T2, together with a significant interaction between SOA and T1-conflict on RT for T2 with an additive effect. Importantly, there was a small but significant SOA effect on T1 with a prolonged RT under the short SOA compared to the long SOA. Increased activation in the CCN was associated with conflict processing and the main effect of SOA. The anterior cingulate cortex and anterior insular cortex showed a significant interaction effect between SOA and T1-conflict in activation parallel with the behavioral results. The behavioral and brain activation patterns support a central resource sharing model, in which the core resources for cognitive control are shared when multiple simultaneous conflicting processes are required.

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.

Association between type of drinking water and upper gastrointestinal cancer incidence in the Linxian General Population.

BACKGROUND: This study aimed to explore the association between drinking water source and risk of upper gastrointestinal (UGI) cancer, including esophageal cancer (EC) and gastric cancer (GC), in the Linxian General Population Nutrition Intervention Trial (NIT) cohort. METHODS: In this study, we used data from the Linxian NIT cohort, which included 29,584 healthy adults aged 40 to 69 years. Subjects were enrolled in April 1986 and followed up until March 2016. Tap water drinking status and demographic characteristics were collected at baseline. Subjects who drank tap water were treated as the exposed group. Hazard ratios (HRs) and 95% confidence intervals (95% CIs) were estimated using the Cox proportional hazard model. RESULTS: A total of 5,463 cases of UGI cancer were identified during the 30-year follow-up period. After adjusting for multiple factors, the incidence rate of UGI cancer in participants who drank tap water was significantly lower compared with individuals in the control (HR = 0.91, 95% CI: 0.86-0.97). A similar association was observed between tap water drinking and EC incidence (HR = 0.89, 95% CI: 0.82-0.97). The association between drinking tap water and risk of UGI cancer and EC incidence did not vary across the subgroup by age and gender (All Pinteraction > 0.05). For EC incidence, an interaction effect was observed for riboflavin/niacin supplements and drinking water source (Pinteraction = 0.03). No association was observed between drinking water source and GC incidence. CONCLUSIONS: In this prospective cohort study in Linxian, participants who drank tap water had a lower risk of EC incidence. As a source of drinking water, use of tap water may reduce the risk of EC by avoiding exposure to nitrate/nitrite. Measures should be taken to improve the quality of drinking water in high-incidence areas of EC. TRIAL REGISTRATION: The trial is registered with ClinicalTrials.gov (NCT00342654, 21/06/2006), and the trial name is Nutrition Intervention Trials in Linxian Follow-up Study.

Divergent synthesis of bis(indolyl)methanes via FeIII-catalysed regioselective dehydrogenative coupling reactions: a biomimetic approach to 6,6'-bis-(debromo)-gelliusine F.

The divergent dehydrogenative coupling reactions of tryptamines with the catalysis of nontoxic FeIII salts in the presence of DDQ as the co-oxidant have been developed. Remarkably, the transformations feature a rapid and regioselective assembly of diverse 2,8'- and N1,8'-bis(indolyl) methane derivatives from readily-available starting materials by simply changing the FeIII salt and reaction temperature. Besides, the fast reaction rate, mild reaction conditions, low catalyst cost and easy operations make this methodology quite useful. The synthetic utility was further demonstrated in the biomimetic synthesis of 6,6'-bis-(debromo)-gelliusine F.

Treg cells-derived exosomes promote blood-spinal cord barrier repair and motor function recovery after spinal cord injury by delivering miR-2861.

The blood-spinal cord barrier (BSCB) is a physical barrier between the blood and the spinal cord parenchyma. Current evidence suggests that the disruption of BSCB integrity after spinal cord injury can lead to secondary injuries such as spinal cord edema and excessive inflammatory response. Regulatory T (Treg) cells are effective anti-inflammatory cells that can inhibit neuroinflammation after spinal cord injury, and their infiltration after spinal cord injury exhibits the same temporal and spatial characteristics as the automatic repair of BSCB. However, few studies have assessed the relationship between Treg cells and spinal cord injury, emphasizing BSCB integrity. This study explored whether Treg affects the recovery of BSCB after SCI and the underlying mechanism. We confirmed that spinal cord angiogenesis and Treg cell infiltration occurred simultaneously after SCI. Furthermore, we observed significant effects on BSCB repair and motor function in mice by Treg cell knockout and overexpression. Subsequently, we demonstrated the presence and function of exosomes in vitro. In addition, we found that Treg cell-derived exosomes encapsulated miR-2861, and miR-2861 regulated the expression of vascular tight junction (TJs) proteins. The luciferase reporter assay confirmed the negative regulation of IRAK1 by miR-2861, and a series of rescue experiments validated the biological function of IRAKI in regulating BSCB. In summary, we demonstrated that Treg cell-derived exosomes could package and deliver miR-2861 and regulate the expression of IRAK1 to affect BSCB integrity and motor function after SCI in mice, which provides novel insights for functional repair and limiting inflammation after SCI.

Role of peripheral immune cells in spinal cord injury.

Secondary spinal cord injury is caused by an inflammatory response cascade, and the process is irreversible. The immune system, as a mediator of inflammation, plays an important role in spinal cord injury. The spinal cord retains its immune privilege in a physiological state. Hence, elucidating the mechanisms by which peripheral immune cells are recruited to the lesion site and function after spinal cord injury is meaningful for the exploration of clinical therapeutic targets. In this review, we provide an overview of the multifaceted roles of peripheral immune cells in spinal cord injury.

First report of Fusarium tricinctum Causing Leaf Blight on Amorphophallus konjac in Hunan Province of China.

Konjac (Amorphophallus konjac) is a perennial herbaceous plant of the Araceae family, cultivated mainly in south-western China and used extensively for weight loss (Chua et al. 2010). In June 2022, leaf blight was detected on a 2,00 ha A. konjac plantation in Chenxi County, Huaihua City, Hunan Province. It infected almost 20% of the area under cultivation and tends to occur each year during warm, humid weather from May to July, causing significant economic losses to A. konjac production. There were small brown spots on the leaves which gradually spread to form irregular brown lesions. In severe cases the entire plant turned yellow and died. Nine samples were collected randomly from different plants in three plantation forests to isolate the pathogens. They were washed with sterile water and the lesions were excised. They were subsequently disinfected with 3% hydrogen peroxide for 30 s, 75% ethanol for 90 s and rinsed three times with sterile water. The cut sections were then placed on water agar plates and grown in the dark in a constant temperature incubator at 28℃ for 3-5 days, when mycelia grew they were transferred to potato dextrose agar medium and grown in the dark at 28℃ for 3-5 days. Eleven purified fungal isolates were obtained, ten of which looked like Fusarium (90.9% isolation rate), and three representative isolates (MY5, MY7 and MY9) were chosen for further study. The fungal colonies initially appeared white and gradually turnned dark red. Macroconidia were crescent-shaped, elongated, slightly curved and had 2 to 4 septations, with a predominance of 3 septations. They measured 15.540 to 42.083 × 2.760 to 4.558 µm (n=100). Microconidia were oval or pyriform, with a maximum of one septum and measured 6.135 to 24.990 × 2.158 to 4.412 µm (n=100). Two genetic regions, the translation elongation factor-1 (TEF1-α) and RNA polymerase II largest subunit (RPB1) genes, were amplified and sequenced to verify the identity of the fungus (Qiu et al. 2023). The universal primers TEF1-F/R, G2R/Fa were used for amplification and sequencing, and the sequences were submitted to GenBank (TEF1-α: OR545395, OR545397, OR545399; RPB1: OR545394, OR545396, OR545398). A joint phylogenetic tree of the two genes was constructed and analysis showed that the three isolates were significantly clustered with Fusarium tricinctum. Based on the results of morphological identification and phylogenetic tree analysis, the three isolates were identified as F. tricinctum. Pathogenicity tests were carried out on 12 uniformly growing leaf expansion stages of konjac plants，each inoculated with five young leaves. Mycelial blocks of 6 × 6 mm grown on PDA media for 5 days were placed on the surface of the leaves, while sterile PDA blocks were placed on the control plant. After 10 days of rearing the treated plants in a constant temperature chamber at 28°C and 90% relative humidity, the lesions appeared and the pathogens re-isolated from the diseased tissues had the same morphological characteristics as representative isolates. F. tricinctum has been shown to be the major pathogenic fungus causing leaf blight in wheat (Triticum aestivum L.) (Castañares et al. 2011) and orchardgrass (Dactylis glomerata L.) (Wu et al. 2020). To our knowledge, this is the first time in the world that F. tricinctum has been reported to cause leaf blight in A. konjac. This research could provide a foundation for future control of leaf blight disease.

Representational coding of overt and covert orienting of visuospatial attention in the frontoparietal network.

Orienting of visuospatial attention refers to reallocation of attentional focus from one target or location to another and can occur either with (overt) or without (covert) eye movement. Although it has been demonstrated that both types of orienting commonly involve frontal and parietal brain regions as the frontoparietal network (FPN), the underlying representational coding of these two types of orienting remains unclear. In this functional magnetic resonance imaging study, participants performed a task that elicited overt and covert orienting to endogenously or exogenously cued targets with eye-tracking to monitor eye movement. Although the FPN was commonly activated for both overt and covert orienting, multivariate patterns of the activation of voxels in the FPN accurately predicted whether eye movements were involved or not during orienting. These overt- and covert-preferred voxels were topologically distributed as distinct and interlaced clusters in a millimeter scale. Inclusion of the two types of clusters predicted orienting type more accurately than one type of clusters alone. These findings suggest that overt and covert orienting are represented by interdependent functional clusters of neuronal populations in regions of the FPN, which might reflect a generalizable principle in the nervous system for functional organization of closely associated processes.

Combined risk factors and risk of upper gastrointestinal cancer mortality in the Linxian general population.

We aimed to explore the association of combined risk factors with risk of death from upper gastrointestinal (UGI) cancer, including esophageal squamous cell carcinoma (ESCC), gastric cardia carcinoma (GCC) and gastric noncardia carcinoma (GNCC) in the Linxian Nutrition Intervention Trial (NIT) cohort. The NIT cohort included 29 584 healthy adults. A combined risk score (CRS) was calculated using a point system method based on 10 risk factors collected at baseline, including gender, smoking, alcohol drinking, body mass index, family history of UGI cancer, drinking tap water, tooth loss and consumption of fresh fruit, eggs and meat. Possible score ranged from 0 to 31, and higher score indicated as poorer health status. Subjects were divided into three groups by the CRS (<12 points, 12 to 20 points and >20 points). The group of CRS <12 points was considered as the reference. During the 30-year follow-up, we identified 4553 UGI cancer deaths. Compared to subjects with a CRS <12 points, the adjusted HRs for CRS of 12 to 20 points and >20 points were 1.69 (95% CI: 1.56-1.83) and 3.06 (95% CI: 2.82-3.33) for UGI cancer mortality, respectively (Ptrend < .001). Comparable associations were also observed for ESCC, GCC and GNCC mortality. Results remained similar across different age groups (Pinteraction > .05). All HRs observed in the second half follow-up period were stronger than that observed in the first half follow-up period. Our study indicated that higher CRS was associated with increased risk of UGI cancer mortality. Appropriate measures should be taken to reduce unhealthy lifestyles.

Mortality after multivitamin supplementation: Nearly 35-year follow-up of the randomized Linxian Dysplasia Nutrition Intervention Trial.

BACKGROUND: The objective of this study was to update the association between multivitamin supplementation and total or cause-specific mortality in a population with a high prevalence of undernutrition in China. METHODS: The Linxian Dysplasia Nutrition Intervention Trial was a randomized, double-blind, placebo-controlled trial in which 3318 persons aged 40-69 years with esophageal squamous dysplasia were assigned to receive daily multivitamin supplementation or a placebo for 6 years and were followed for 29 years. The primary outcome was esophageal/gastric cardia cancer mortality. The data were analyzed with Cox proportional hazards regression models. Subgroup analyses were performed by common characteristics such as age and gender. RESULTS: The cumulative total mortality was 83.5%. Multivitamin supplementation did not affect total or cause-specific mortality in the participants as a whole (hazard ratio [HR], 0.96; 95% confidence interval [CI], 0.89-1.03). Subgroup analyses showed that no association between multivitamin supplementation and all-cause mortality was observed in men (HR, 0.90; 95% CI, 0.81-1.01), women (HR, 1.01; 95% CI, 0.91-1.12), younger participants (HR, 0.97; 95% CI, 0.87-1.08), or older participants (HR, 0.94; 95% CI, 0.85-1.04). Significant reductions in heart disease mortality (HR, 0.64; 95% CI, 0.47-0.87) and cerebrovascular disease mortality (HR, 0.74; 95% CI, 0.56-1.00) were seen in older men. In a subgroup of younger men and a subgroup of moderate or severe dysplasia, subjects receiving multivitamin supplementation had a lower risk of esophageal/cardia cancer mortality (HR for younger men, 0.76; 95% CI, 0.58-0.99; HR for moderate or severe dysplasia, 0.76; 95% CI, 0.58-1.00). No association between multivitamin supplementation and any cause-specific mortality was observed in a mild dysplasia population. CONCLUSIONS: Multivitamin supplementation in a population with esophageal squamous dysplasia was not associated with the risk of total mortality in the 35-year follow-up of this randomized controlled trial. In light of this and previous trials, multivitamin supplements should be used thoughtfully to improve health status of populations with esophageal squamous dysplasia. LAY SUMMARY: Multivitamin supplementation is common, yet its effect on mortality is unclear. The aim of this study was to update the long-term effects of multivitamin supplementation on total and cause-specific mortality during nearly 35 years of follow-up in the Linxian Dysplasia Nutrition Intervention Trial in China. Multivitamin supplementation in a population with esophageal squamous dysplasia was not associated with the risk of total mortality in the 35-year follow-up of this randomized controlled trial, and this indicates that multivitamin supplements should be used thoughtfully to improve health status.

Compromised long-lived memory CD8+ T cells are associated with reduced IL-7 responsiveness in HIV-infected immunological nonresponders.

Immune deficiency is one of the hallmarks of HIV infection and a major cause of adverse outcomes in people living with HIV (PLWH). Long-lived memory CD8+ T cells (LLMCs) are essential executors of long-term protective immunity; however, the generation and maintenance of LLMCs during chronic HIV infection are not well understood. In the present study, we analyzed circulating LLMCs in healthy controls (HCs) and PLWH with different disease statuses, including treatment naïve patients (TNs), complete responders (CRs), and immunological nonresponders (INRs). We found that both TNs and INRs showed severely compromised LLMCs compared with HCs and CRs, respectively. The decrease of LLMCs in TNs correlated positively with the reduction of their precursors, namely memory precursor effector T cells (MPECs), which might be associated with elevated pro-inflammatory cytokines. Strikingly, INRs showed an accumulation of MPECs, which exhibited diminished responsiveness to interleukin 7 (IL-7), thereby indicating abrogated differentiation into LLMCs. Moreover, in vitro studies showed that treatment with dexamethasone could improve the IL7-phosphorylated (p)-signal transducer and activator of transcription (STAT5) response by upregulating the expression of the interleukin 7 receptor (IL-7Rα) on MPECs in INRs. These findings provide insights that will encourage the development of novel therapeutics to improve immune function in PLWH.

Tumor Antigen Loaded Nanovaccine Induced NIR-Activated Inflammation for Enhanced Antigen Presentation During Immunotherapy of Tumors.

Although anticancer vaccines have achieved certain effects in early clinical practice, T cell immunity as the most common responsive pattern of anticancer vaccines is still limited by unsatisfied tumor recognition and inhibition efficiency. As the critical step of T cell immunity, uptake and presentation of specific antigen by antigen-presenting cells (APC) can be activated by inflammation for enhancing the response of T cells to the antigen source. Here, a hybrid nanovaccine named PTh/MnO2 @M activated with a near-infrared ray (NIR) is prepared by coating an autologous tumor cell membrane on the surface of a polythiophene/MnO2 composite core. The photoelectrical material polythiophene can produce local microinflammation under NIR radiation and activate specific T cell antitumor immunity by promoting APC maturation and autologous tumor antigens presentation. Moreover, the synthesized nanovaccine PTh/MnO2 @M is shown to induce a significant antitumor immune response, effectively inhibit the progression of melanoma in mice, and significantly prolong the survival time of mice in vivo. This strategy aims to enhance T-cell immune responses by promoting antigen presentation, leading to effective and specific cancer therapy.