PbrbZIP15 promotes sugar accumulation in pear via activating the transcription of the glucose isomerase gene PbrXylA1.

The composition and abundance of soluble sugars in mature pear (Pyrus) fruit are important for its acceptance by consumers. However, our understanding of the genes responsible for soluble sugar accumulation remains limited. In this study, a S1-group member of bZIP gene family, PbrbZIP15, was characterized from pear genome through the combined analyses of metabolite and transcriptome data followed by experimental validation. PbrbZIP15, located in nucleus, was found to function in fructose, sucrose, and total soluble sugar accumulation in pear fruit and calli. After analyzing the expression profiles of sugar-metabolism-related genes and the distribution of cis-acting elements in their promoters, the glucose isomerase 1 gene (PbrXylA1), whose corresponding protein catalyzed the isomerization of glucose and fructose in vitro, was identified as a downstream target gene of PbrbZIP15. PbrbZIP15 could directly bind to the G-box element in PbrXylA1 promoter and activate its transcription, as evidenced by chromatin immunoprecipitation-quantitative PCR, yeast one-hybrid, electrophoretic mobility shift assay, and dual-luciferase assay. PbrXylA1, featuring a leucine-rich signal peptide in its N-terminal, was localized to the endoplasmic reticulum. It was validated to play a significant role in fructose, sucrose, and total soluble sugar accumulation in pear fruit and calli, which was associated with the upregulated fructose/glucose ratio. Further studies revealed a positive correlation between the sucrose content and the expression levels of several sucrose-biosynthesis-related genes (PbrFRK3/8, PbrSPS1/3/4/8, and PbrSPP1) in PbrbZIP15-/PbrXylA1-transgenic fruit/calli. In conclusion, our results suggest that PbrbZIP15-induced soluble sugar accumulation during pear development is at least partly attributed to the activation of PbrXylA1 transcription.

E3 ligases MAC3A and MAC3B ubiquitinate UBIQUITIN-SPECIFIC PROTEASE14 to regulate organ size in Arabidopsis.

The molecular mechanisms controlling organ size during plant development ultimately influence crop yield. However, a deep understanding of these mechanisms is still lacking. UBIQUITIN-SPECIFIC PROTEASE14 (UBP14), encoded by DA3, is an essential factor determining organ size in Arabidopsis (Arabidopsis thaliana). Here, we identified two suppressors of the da3-1 mutant phenotype, namely SUPPRESSOR OF da3-1 1 and 2 (SUD1 and SUD2), which encode the E3 ligases MOS4-ASSOCIATED COMPLEX 3A (MAC3A) and MAC3B, respectively. The mac3a-1 and mac3b-1 mutations partially suppressed the high ploidy level and organ size phenotypes observed in the da3-1 mutant. Biochemical analysis showed that MAC3A and MAC3B physically interacted with and ubiquitinated UBP14/DA3 to modulate its stability. We previously reported that UBP14/DA3 acts upstream of the B-type cyclin-dependent kinase CDKB1;1 and maintains its stability to inhibit endoreduplication and cell growth. In this work, MAC3A and MAC3B were found to promote the degradation of CDKB1;1 by ubiquitinating UBP14/DA3. Genetic analysis suggests that MAC3A and MAC3B act in a common pathway with UBP14/DA3 to control endoreduplication and organ size. Thus, our findings define a regulatory module, MAC3A/MAC3B-UBP14-CDKB1;1, that plays a critical role in determining organ size and endoreduplication in Arabidopsis.

Evolutionary origin and gradual accumulation with plant evolution of the LACS family.

BACKGROUND: LACS (long-chain acyl-CoA synthetase) genes are widespread in organisms and have multiple functions in plants, especially in lipid metabolism. However, the origin and evolutionary dynamics of the LACS gene family remain largely unknown. RESULTS: Here, we identified 1785 LACS genes in the genomes of 166 diverse plant species and identified the clades (I, II, III, IV, V, VI) of six clades for the LACS gene family of green plants through phylogenetic analysis. Based on the evolutionary history of plant lineages, we found differences in the origins of different clades, with Clade IV originating from chlorophytes and representing the origin of LACS genes in green plants. The structural characteristics of different clades indicate that clade IV is relatively independent, while the relationships between clades (I, II, III) and clades (V, VI) are closer. Dispersed duplication (DSD) and transposed duplication (TRD) are the main forces driving the evolution of plant LACS genes. Network clustering analysis further grouped all LACS genes into six main clusters, with genes within each cluster showing significant co-linearity. Ka/Ks results suggest that LACS family genes underwent purifying selection during evolution. We analyzed the phylogenetic relationships and characteristics of six clades of the LACS gene family to explain the origin, evolutionary history, and phylogenetic relationships of different clades and proposed a hypothetical evolutionary model for the LACS family of genes in plants. CONCLUSIONS: Our research provides genome-wide insights into the evolutionary history of the LACS gene family in green plants. These insights lay an important foundation for comprehensive functional characterization in future research.

Rational Design of Nitride Phosphor-In-Glass with Robust Stability and Photoluminescence Performance.

Phosphor-in-glass represents a promising avenue for merging the luminous efficiency of high-quality phosphor and the thermal stability of a glass matrix. Undoubtedly, the glass matrix system and its preparation are pivotal factors in achieving high stability and preserving the original performance of embedded phosphor particles. In contrast to the well-established commercial Y3Al5O12:Ce3+ oxide phosphor, red nitride phosphor, which plays a critical role in high-quality lighting, exhibits greater structural instability during the high-temperature synthesis of inorganic glasses. A telluride glass with a refractive index (RI = 2.15@615 nm) akin to that of nitride phosphor (∼2.19) has been devised, demonstrating high efficiency in photon utilization. The lower glass-transition temperature plays a crucial role in safeguarding phosphor particles against erosion resulting from exposure to high-temperature melts. Phosphor-in-glass retains 93% of the quantum efficiency observed for pure phosphor. The assembled white light-emitting diodes module has precise color tuning capabilities, achieving an optimal color rendering index of 93.7, a luminous efficacy of 80.4 lm/W, and a correlated color temperature of 5850 K. These outcomes hold potential for advancing the realm of inorganic package and high-quality white light illumination.

High performance plasma amyloid-ß biomarkers for Alzheimer's disease.

To facilitate clinical trials of disease-modifying therapies for Alzheimer's disease, which are expected to be most efficacious at the earliest and mildest stages of the disease, supportive biomarker information is necessary. The only validated methods for identifying amyloid-ß deposition in the brain-the earliest pathological signature of Alzheimer's disease-are amyloid-ß positron-emission tomography (PET) imaging or measurement of amyloid-ß in cerebrospinal fluid. Therefore, a minimally invasive, cost-effective blood-based biomarker is desirable. Despite much effort, to our knowledge, no study has validated the clinical utility of blood-based amyloid-ß markers. Here we demonstrate the measurement of high-performance plasma amyloid-ß biomarkers by immunoprecipitation coupled with mass spectrometry. The ability of amyloid-ß precursor protein (APP)669-711/amyloid-ß (Aß)1-42 and Aß1-40/Aß1-42 ratios, and their composites, to predict individual brain amyloid-ß-positive or -negative status was determined by amyloid-ß-PET imaging and tested using two independent data sets: a discovery data set (Japan, n = 121) and a validation data set (Australia, n = 252 including 111 individuals diagnosed using 11C-labelled Pittsburgh compound-B (PIB)-PET and 141 using other ligands). Both data sets included cognitively normal individuals, individuals with mild cognitive impairment and individuals with Alzheimer's disease. All test biomarkers showed high performance when predicting brain amyloid-ß burden. In particular, the composite biomarker showed very high areas under the receiver operating characteristic curves (AUCs) in both data sets (discovery, 96.7%, n = 121 and validation, 94.1%, n = 111) with an accuracy approximately equal to 90% when using PIB-PET as a standard of truth. Furthermore, test biomarkers were correlated with amyloid-ß-PET burden and levels of Aß1-42 in cerebrospinal fluid. These results demonstrate the potential clinical utility of plasma biomarkers in predicting brain amyloid-ß burden at an individual level. These plasma biomarkers also have cost-benefit and scalability advantages over current techniques, potentially enabling broader clinical access and efficient population screening.

Sigma-1 receptor activation mediates the sustained antidepressant effect of ketamine in mice via increasing BDNF levels.

Sigma-1 receptor (S1R) is a unique multi-tasking chaperone protein in the endoplasmic reticulum. Since S1R agonists exhibit potent antidepressant-like activity, S1R has become a novel target for antidepression therapy. With a rapid and sustained antidepressant effect, ketamine may also interact with S1R. In this study, we investigated whether the antidepressant action of ketamine was related to S1R activation. Depression state was evaluated in the tail suspension test (TST) and a chronic corticosterone (CORT) procedure was used to induce despair-like behavior in mice. The neuronal activities and structural changes of pyramidal neurons in medial prefrontal cortex (mPFC) were assessed using fiber-optic recording and immunofluorescence staining, respectively. We showed that pharmacological manipulation of S1R modulated ketamine-induced behavioral effect. Furthermore, pretreatment with an S1R antagonist BD1047 (3 mg·kg-1·d-1, i.p., for 3 consecutive days) significantly weakened the structural and functional restoration of pyramidal neuron in mPFC caused by ketamine (10 mg·kg-1, i.p., once). Ketamine indirectly triggered the activation of S1R and subsequently increased the level of BDNF. Pretreatment with an S1R agonist SA4503 (1 mg·kg-1·d-1, i.p., for 3 consecutive days) enhanced the sustained antidepressant effect of ketamine, which was eliminated by knockdown of BDNF in mPFC. These results reveal a critical role of S1R in the sustained antidepressant effect of ketamine, and suggest that a combination of ketamine and S1R agonists may be more beneficial for depression patients.

Association of antenatal corticosteroids with mortality and morbidities in very preterm infants born to women with hypertensive disorders of pregnancy: a multicenter prospective cohort study.

BACKGROUND: Hypertensive disorders of pregnancy (HDP) is the most common cause of indicated preterm delivery, but the impact of prenatal steroid exposure on the outcomes of preterm infants born to HDP mothers, who may be at risk for intrauterine hypoxia-ischemia, remains uncertain. The study objective is to evaluate the mortality and morbidities in HDP for very preterm infants (VPIs) exposed to different course of ANS. METHODS: This is a prospective cohort study comprising infants with < 32 weeks gestation born to women with HDP only from 1 Jan. 2019 to 31 Dec. 2021 within 40 participating neonatal intensive care units (NICUs) in Sino-northern network. ANS courses included completed, partial, repeated, and no ANS. Univariate and multivariable analyses were performed on administration of ANS and short-term outcomes before discharge. RESULTS: Among 1917 VPIs born to women with HDP only, 987(51.4%) received a complete course of ANS within 48 h to 7 days before birth, 560(29.2%) received partial ANS within 24 h before delivery, 100(5.2%) received repeat ANS and 270 (14.1%) did not receive any ANS. Compared to infants who received complete ANS, infants unexposed to ANS was associated with higher odds of death (AOR 1.85; 95%CI 1.10, 3.14), Severe Neurological Injury (SNI) or death (AOR 1.68; 95%CI 1.29,3.80) and NEC or death (AOR 1.78; 95%CI 1.55, 2.89), the repeated ANS group exhibits a significant negative correlation with the duration of oxygen therapy days (correlation coefficient - 18.3; 95%CI-39.2, -2.1). However, there were no significant differences observed between the full course and partial course groups in terms of outcomes. We can draw similar conclusions in the non-SGA group, while the differences are not significant in the SGA group. From KM curve, it showed that the repeated group had the highest survival rate, but the statistical analysis did not indicate a significant difference. CONCLUSIONS: Even partial courses of ANS administered within 24 h before delivery proved to be protective against death and other morbidities. The differences mentioned above are more pronounced in the non-SGA group. Repeat courses demonstrate a trend toward protection, but this still needs to be confirmed by larger samples.

Cradling disparities: A descriptive qualitative study of maternal experiences of mothers from low-socioeconomic status in the first month postpartum.

AIM: To explore the experiences, expectations and needs of mothers from low-socioeconomic status at 1 month postpartum. DESIGN: Descriptive qualitative. METHODS: Mothers from low-socioeconomic status and irrespective of their parity were invited to participate in one-to-one interviews at 1 month postpartum. Semi-structured interviews were conducted until data saturation. Interviews were audio recorded, transcribed verbatim and analysed thematically. Written informed consent was obtained. RESULTS: Twenty mothers participated and six themes were identified: (1) No choice but to find meaning; (2) Father as a major pillar of support; (3) 'Kampung' Spirit; (4) Trials and Tribulations of Transition to Motherhood; (5) Shame, guilt and internalized stigma and (6) Reclaiming the power. CONCLUSION: This study reflected the unique struggles of mothers from low-socioeconomic status with pregnancy, childbirth and early postpartum and the wider health inequities within Singapore's maternal health system. To provide much-needed support and improved care, the stakeholders within government, healthcare providers and social organizations should consider the niche needs of this community. IMPLICATIONS FOR PATIENT CARE: Nurses need to reflect on their own biases and ensure consistent care delivery regardless of socioeconomic status. When delivering patient education, patient-centred and sincere advice rooted in personal experience can help to establish rapport. IMPACT: This study is the first to explore the experiences of mothers from low-socioeconomic status in the Singapore context. Low-socioeconomic status mothers experienced less autonomy over their health, the care they received and their childcare options. As mothers adjusted to their new roles, they struggled to cope. However, as they were wary of the stigma surrounding poverty and their guilt of not being a 'good mother', they preferred to seek informal support from their family, friends and self-help through learning from social media, as compared to formal, external help. REPORTING METHOD: COREQ checklist. PATIENT OR PUBLIC CONTRIBUTION: No patient or public contribution.

Nurturing networks: A prospective longitudinal study of factors influencing help-seeking behaviours among mothers from low socioeconomic status.

AIM: To explore the factors influencing help-seeking behaviours amongst mothers with low socioeconomic status at pregnancy, 1 month postpartum and 3 months postpartum. METHODS: A prospective cohort study was conducted from September 2022 to August 2023. A total of 209 mothers aged 21 years and above, with low socioeconomic status and irrespective of parity, were recruited from a local hospital using convenience sampling. Self-administered questionnaires were used to collect data at (1) third trimester of pregnancy, (2) 1 month postpartum and (3) 3 months postpartum. Multiple regression analysis was used to identify significant factors influencing help-seeking behaviour at 3 months postpartum. Sub-analyses were conducted between primiparous mothers and multiparous mothers. General linear model repeated measures were used to identify longitudinal trends in outcomes of help-seeking behaviour. RESULTS: Help-seeking behaviour at pregnancy and 1 month postpartum, sources of social support at 3 months postpartum, birth order of the child, attendance of antenatal classes, paternal involvement in feeding and changing diapers and mode of delivery significantly predicted mothers' help-seeking behaviour at 3 months postpartum. Amongst primiparous mothers, help-seeking behaviour at pregnancy at 1 month, social support at 3 months postpartum, employment in part-time jobs and exclusively breastfeeding their infant were significant factors in influencing their help-seeking behaviours at 3 months postpartum. For multiparous mothers, help-seeking behaviour at pregnancy and 1 month postpartum, number of hours of antenatal class attended, Malay ethnicity, educational background, parental satisfaction at 3 months postpartum and infant bonding at both time points were significant factors influencing their help-seeking behaviours at 3 months postpartum. CONCLUSION: Primiparous mothers with low socioeconomic status who underwent caesarean section exhibited less help-seeking behaviours. Attendance of antenatal classes and greater paternal involvement in infant care encouraged mothers with low socioeconomic status to help-seeking behaviours. A tailored approach is needed to support mothers with low socioeconomic status by providing additional support in improving the accessibility of antenatal classes and involving fathers in infant care. IMPACT: What Problem Did the Study Address? Mothers with low socioeconomic status tend to exhibit lower help-seeking behaviours due to limited support and access to care services. What Were the Main Findings? First-time mothers who underwent caesarean section, did not attend antenatal classes, and had husbands uninvolved in feeding and diaper changing were significantly less likely to seek help in the third month postpartum. One and 3 months postpartum are crucial time points when mothers with low socioeconomic status could benefit from additional support. Hospitals should explore online informational resources, forums, teleconsultations and virtual antenatal classes as possible alternative options to improve accessibility for mothers with low socioeconomic status. Where and on Whom Will the Research Have an Impact? Mothers with low socioeconomic status and healthcare providers of mothers with low socioeconomic status will benefit from the findings of this research. This study was conducted within the Singapore context. Findings could be generalizable to other cultural contexts with similar multi-ethnic populations. REPORTING METHOD: STROBE checklist. PATIENT OR PUBLIC CONTRIBUTION: No patient or public contribution.

Cerebrospinal fluid neurofilament light predicts longitudinal diagnostic change in patients with psychiatric and neurodegenerative disorders.

OBJECTIVE: People with neuropsychiatric symptoms often experience delay in accurate diagnosis. Although cerebrospinal fluid neurofilament light (CSF NfL) shows promise in distinguishing neurodegenerative disorders (ND) from psychiatric disorders (PSY), its accuracy in a diagnostically challenging cohort longitudinally is unknown. METHODS: We collected longitudinal diagnostic information (mean = 36 months) from patients assessed at a neuropsychiatry service, categorising diagnoses as ND/mild cognitive impairment/other neurological disorders (ND/MCI/other) and PSY. We pre-specified NfL > 582 pg/mL as indicative of ND/MCI/other. RESULTS: Diagnostic category changed from initial to final diagnosis for 23% (49/212) of patients. NfL predicted the final diagnostic category for 92% (22/24) of these and predicted final diagnostic category overall (ND/MCI/other vs. PSY) in 88% (187/212), compared to 77% (163/212) with clinical assessment alone. CONCLUSIONS: CSF NfL improved diagnostic accuracy, with potential to have led to earlier, accurate diagnosis in a real-world setting using a pre-specified cut-off, adding weight to translation of NfL into clinical practice.

Bifunctional Chiral Electrocatalysts Enable Enantioselective α-Alkylation of Aldehydes.

Herein, we describe an innovative approach to the asymmetric electrochemical α-alkylation of aldehydes facilitated by a newly designed bifunctional chiral electrocatalyst. The highly efficient bifunctional chiral electrocatalyst combines a chiral aminocatalyst with a redox mediator. It plays a dual role as a redox mediator for electrooxidation, while simultaneously providing remarkable asymmetric induction for the stereoselective α-alkylation of aldehydes. Additionally, this novel catalyst exhibits enhanced catalytic activity and excellent stereoselective control comparable to conventional catalytic systems. As a result, this strategy provides a new avenue for versatile asymmetric electrochemistry. The electrooxidation of diverse phenols enables the C-H/C-H oxidative α-alkylation of aldehydes in a highly chemo- and stereoselective fashion. Detailed mechanistic studies by control experiments and cyclic voltammetry analysis demonstrate possible reaction pathways and the origin of enantio-induction.

Let-7a promotes periodontal bone regeneration of bone marrow mesenchymal stem cell aggregates via the Fas/FasL-autophagy pathway.

Periodontal bone regeneration using bone marrow mesenchymal stem cell (BMMSC) transplantation is a promising method; however, the method for osteogenic differentiation of BMMSCs needs to be improved. In this research, we sought to identify the roles of let-7a in the osteogenesis of BMMSCs and to provide a potential method for periodontal bone regeneration. Our previous study revealed that Fas/FasL is a target of let-7a. In this study, we demonstrated that let-7a overexpression significantly enhanced BMMSC-CAs osteogenesis both in vitro and in vivo. Mechanistically, upregulation of Fas/FasL using the rfas/rfaslg plasmid obstructed the osteogenesis of BMMSCs by inhibiting autophagy. Furthermore, we confirmed that overexpression of let-7a activated autophagy and alleviated the inhibited osteogenesis by the autophagy inhibitor 3-MA and the rfas/rfaslg plasmid of BMMSCs. In general, our findings showed that let-7a promoted the osteogenesis of BMMSCs through the Fas/FasL-autophagy pathway, suggesting that the application of let-7a in BMMSC-CAs based periodontal bone regeneration could be a promising strategy.

Quantitative proteomics of tau and Aß in detergent fractions from Alzheimer's disease brains.

The two hallmarks of Alzheimer's disease (AD) are amyloid-ß (Aß) plaques and neurofibrillary tangles marked by phosphorylated tau. Increasing evidence suggests that aggregating Aß drives tau accumulation, a process that involves synaptic degeneration leading to cognitive impairment. Conversely, there is a realization that non-fibrillar (oligomeric) forms of Aß mediate toxicity in AD. Fibrillar (filamentous) aggregates of proteins across the spectrum of the primary and secondary tauopathies were the focus of recent structural studies with a filament structure-based nosologic classification, but less emphasis was given to non-filamentous co-aggregates of insoluble proteins in the fractions derived from post-mortem human brains. Here, we revisited sarkosyl-soluble and -insoluble extracts to characterize tau and Aß species by quantitative targeted mass spectrometric proteomics, biochemical assays, and electron microscopy. AD brain sarkosyl-insoluble pellets were greatly enriched with Aß42 at almost equimolar levels to N-terminal truncated microtubule-binding region (MTBR) isoforms of tau with multiple site-specific post-translational modifications (PTMs). MTBR R3 and R4 tau peptides were most abundant in the sarkosyl-insoluble materials with a 10-fold higher concentration than N-terminal tau peptides. This indicates that the major proportion of the enriched tau was the aggregation-prone N-terminal and proline-rich region (PRR) of truncated mixed 4R and 3R tau with more 4R than 3R isoforms. High concentration and occupancies of site-specific phosphorylation pT181 (~22%) and pT217 (~16%) (key biomarkers of AD) along with other PTMs in the PRR and MTBR indicated a regional susceptibility of PTMs in aggregated tau. Immunogold labelling revealed that tau may exist in globular non-filamentous form (N-terminal intact tau) co-localized with Aß in the sarkosyl-insoluble pellets along with tau filaments (N-truncated MTBR tau). Our results suggest a model that Aß and tau interact forming globular aggregates, from which filamentous tau and Aß emerge. These characterizations contribute towards unravelling the sequence of events which lead to end-stage AD changes.

Solvent Effects on the 1 H-NMR Chemical Shifts of Imidazolium-Based Ionic Liquids.

The 1 H nuclear magnetic resonance (1 H-NMR) spectrum is a useful tool for characterizing the hydrogen bonding (H-bonding) interactions in ionic liquids (ILs). As the main hydrogen bond (H-bond) donor of imidazolium-based ILs, the chemical shift (δH2 ) of the proton in the 2-position of the imidazolium ring (H2) exhibits significant and complex solvents, concentrations and anions dependence. In the present work, based on the dielectric constants (ϵ) and Kamlet-Taft (KT) parameters of solvents, we identified that the δH2 are dominated by the solvents polarity and the competitive H-bonding interactions between cations and anions or solvents. Besides, the solvents effects on δH2 are understood by the structure of ILs in solvents: 1) In diluted solutions of inoizable solvents, ILs exist as free ions and the cations will form H-bond with solvents, resulting in δH2 being independent with anions but positively correlated with ßS . 2) In diluted solutions of non-ionzable solvents, ILs exist as contact ion-pairs (CIPs) and H2 will form H-bond with anions. Since non-ionizable solvents hardly influence the H-bonding interactions between H2 and anions, the δH2 are not related to ßS but positively correlated with ßIL .

Cholesterol-Mediated Anchoring of Phospholipids onto Proteinosomes for Switching Membrane Permeability.

Modulated membrane functionalization is a necessary and overarching step for hollow microcompartments toward their application as nanoreactors or artificial cells. In this study, we show a way to generate phospholipid hybrid proteinosomes that could show superposed virtues of liposomes and proteinosomes. In comparison to pure proteinosomes, both the membrane fluidity and permeability are improved obviously after forming the phospholipid hybrid proteinosomes. Specifically, the integration of phospholipids also endows the hybrid proteinosomes demonstrating a stepwise release of the encapsulants of FITC-dextran (70 and 150 kDa) triggered sequentially by phospholipase and protease, and then a modulated cascaded enzymatic reaction between two different populations of proteinosomes are achieved. Therefore, it is anticipated that such constructed phospholipid hybrid proteinosomes could be employed as an improved microcompartmental model for further advanced artificial cell design toward achieving logic signal communication within the various artificial cellular populations as well as potential applications in the field of microreactors.

Effects of genetic polymorphisms of LINC-PINT gene on liver cancer susceptibility in the Chinese Han population.

Objective: Liver cancer (LC) is the most common cause of cancer mortality. This study aimed to explore the impact of LINC-PINT polymorphisms on LC. Materials & methods: The authors recruited 591 LC patients and 592 healthy controls. The association between LINC-PINT polymorphisms and susceptibility to LC was determined by logistic regression analysis. Results: The authors found that rs157916 and rs16873842 reduced susceptibility to LC. rs157916 decreased LC risk in patients aged <55 years, nondrinkers and those with BMI <24. rs16873842 had a protective role against LC in patients aged ≥55 years, women, nonsmokers and those with BMI ≥24. rs7801029 decreased LC risk in patients with BMI <24. rs28662387 increased LC risk in women. Conclusion: LINC-PINT polymorphisms exert a protective effect against LC.

Cerebrospinal fluid neurofilament light and cerebral atrophy in younger-onset dementia and primary psychiatric disorders.

BACKGROUND AND AIMS: Neurodegeneration underpins the pathological processes of younger-onset dementia (YOD) and has been implicated in primary psychiatric disorders (PSYs). Cerebrospinal fluid (CSF) neurofilament light (NfL) has been used to investigate neurodegeneration severity through correlation with structural brain changes in various conditions, but has seldom been evaluated in YOD and PSYs. METHODS: This retrospective study included patients with YOD or PSYs with magnetic resonance imaging (MRI) of the brain and CSF NfL analysis. Findings from brain MRI were analysed using automated volumetry (volBrain) to measure white matter (WM), grey matter (GM) and whole brain (WB) volumes expressed as percentages of total intracranial volume. Correlations between NfL and brain volume measurements were computed whilst adjusting for age. RESULTS: Seventy patients (47 with YOD and 23 with PSY) were identified. YOD types included Alzheimer disease and behavioural variant frontotemporal dementia. PSY included schizophrenia and major depressive disorder. MRI brain sequences were either fast spoiler gradient-echo (FSPGR) or magnetization-prepared rapid acquisition gradient-echo (MPRAGE). In the total cohort, higher NfL was associated with reduced WB in the FSPGR and MPRAGE sequences (r = -0.402 [95% confidence interval (CI), -0.593 to -0.147], P = 0.008 and r = -0.625 [95% CI, -0.828 to -0.395], P < 0.001, respectively). Higher NfL was related to reduced GM in FSPGR (r = 0.385 [95% CI, -0.649 to -0.014], P = 0.017) and reduced WM in MPRAGE (r = -0.650 [95% CI, -0.777 to -0.307], P < 0.001). Similar relationships were seen in YOD, but not in PSY. CONCLUSION: Higher CSF NfL is related to brain atrophy in YOD, further supporting its use as a nonspecific marker of neurodegeneration severity.

Involvement of CXCL10 in Neuronal Damage under the Condition of Spinal Cord Injury and the Potential Therapeutic Effect of Nrg1.

OBJECTIVE: Few studies have reported the direct effect of C-X-C motif chemokine ligand 10 (CXCL10) and Neuregulin 1 (Nrg1) on neurons after spinal cord injury (SCI). This study reports the role of CXCL10 in the regulation of neuronal damage after SCI and the potential therapeutic effect of Nrg1. METHODS: The expression level of CXCL10 and Nrg1 in SCI mice was analyzed in the Gene Expression Omnibus DataSets, followed by immunohistochemical confirmation using a mouse SCI model. HT22 cells and NSC34 cells were treated with CXCL10 and Nrg1, individually or in combination, and then assayed for cell viability. The percentage of wound closure was determined through the cell scratch injury model using HT22 and NSC34 cells. Potential molecular mechanisms were also tested in response to either the individual administration of CXCL10 and Nrg1 or a mixture of both molecules. RESULTS: CXCL10 expression was significantly increased in both young and old mice subjected to SCI, while Nrg1 expression was significantly decreased. CXCL10 induced a decrease in cell viability, which was partially reversed by Nrg1. CXCL10 failed to inhibit scratch healing in HT22 and NSC34 cells, while Nrg1 promoted scratch healing. At the molecular level, CXCL10-activated cleaved caspase 9 and cleaved caspase 3 were both inhibited by Nrg1 through pERK1/2 signaling in HT22 and NSC34 cells. CONCLUSIONS: CXCL10 is upregulated in SCI. Despite the negative effect on cell viability, CXCL10 failed to inhibit the scratch healing of HT22 and NSC34 cells. Nrg1 may protect neurons by partially antagonizing the effect of CXCL10.

Coffea arabica Extract Attenuates Atopic Dermatitis-like Skin Lesions by Regulating NLRP3 Inflammasome Expression and Skin Barrier Functions.

Atopic dermatitis (AD) is a common skin disease worldwide. The major causes of AD are skin barrier defects, immune dysfunction, and oxidative stress. In this study, we investigated the anti-oxidation and anti-inflammation effects of Coffea arabica extract (CAE) and its regulation of the skin barrier and immune functions in AD. In vitro experiments revealed that CAE decreased the reactive oxygen species levels and inhibited the translocation of nuclear factor-κB (NF-κB), further reducing the secretion of interleukin (IL)-1ß and IL-6 induced by interferon-γ (IFN-γ)/tumor necrosis factor-α (TNF-α). Moreover, CAE decreased IFN-γ/TNF-α-induced NLR family pyrin domain-containing 3 (NLRP3), caspase-1, high-mobility group box 1 (HMGB1), and receptor for advanced glycation end products (RAGE) expression levels. It also restored the protein levels of skin barrier function-related markers including filaggrin and claudin-1. In vivo experiments revealed that CAE not only reduced the redness of the backs of mice caused by 2,4-dinitrochlorobenzene (DNCB) but also reduced the levels of pro-inflammatory factors in their skin. CAE also reduced transepidermal water loss (TEWL) and immune cell infiltration in DNCB-treated mice. Overall, CAE exerted anti-oxidation and anti-inflammation effects and ameliorated skin barrier dysfunction, suggesting its potential as an active ingredient for AD treatment.

Luteolin alleviated neutrophilic asthma by inhibiting IL-36γ secretion-mediated MAPK pathways.

CONTEXT: Luteolin can affect multiple biological functions, such as anti-inflammatory, antioxidant and immune enhancement processes. Luteolin can inhibit inflammation of T2-high asthma, but its role in neutrophilic asthma has been insufficently studied. OBJECTIVE: This study determines the effect of luteolin on IL-36γ secretion-mediated MAPK pathway signalling in neutrophilic asthma. MATERIALS AND METHODS: The asthma model was established by using ovalbumin/lipopolysaccharide (OVA/LPS). Female 6-8-week-old C57BL/6 mice were divided into control, asthma, luteolin (20 mg/kg) and asthma + luteolin (20 mg/kg) groups. To explore the mechanism of anti-inflammatory effects of luteolin in neutrophilic asthma, Beas-2B cells were treated with luteolin (20 µmol/L), LPS (100 ng/mL), recombinant human IL-36γ protein (rhIL-36γ; 100 ng/mL) or IL-36γ siRNA. RESULTS: IL-36γ secretion and MAPK/IL-1ß signalling were significantly increased in the asthma mouse model compared with the control (p < 0.05). However, the levels of IL-36γ secretion and MAPK/IL-1ß signalling were reduced by luteolin (p < 0.05). In addition, luteolin inhibited IL-36γ and MAPK/IL-1ß levels after LPS (100 ng/mL) stimulation of Beas-2B cells (p < 0.05). We found that in Beas-2B cells, luteolin inhibited activation of the MAPK pathway and IL-1ß secretion following stimulation with rhIL-36γ (100 ng/mL; p < 0.05). Finally, IL-1ß and phosphorylated MAPK levels were found to be lower in the IL-36γ siRNA + LPS (100 ng/mL) group than in the nonspecific control (NC) siRNA + LPS group (p < 0.05). DISCUSSION AND CONCLUSIONS: Luteolin alleviated neutrophilic asthma by inhibiting IL-36γ secretion-mediated MAPK pathways. These findings provided a theoretical basis for the application of luteolin in the treatment of neutrophilic asthma.