Streptococcus pneumoniae endopeptidase O induces trained immunity against numerous pathogen infections, a key role for G-CSF.

Antibiotic resistance and the surge of infectious diseases during the pandemic present significant threats to human health. Trained immunity emerges as a promising and innovative approach to address these infections. Synthetic or natural fungal, parasitic and viral components have been reported to induce trained immunity. However, it is not clear whether bacterial virulence proteins can induce protective trained immunity. Our research demonstrates Streptococcus pneumoniae virulence protein PepO, is a highly potent trained immunity inducer for combating broad-spectrum infection. Our findings showcase that rPepO training confers robust protection to mice against various pathogenic infections by enhancing macrophage functionality. rPepO effectively re-programs macrophages, re-configures their epigenetic modifications and bolsters their immunological responses, which is independent of T or B lymphocytes. In vivo and in vitro experiments confirm that trained macrophage-secreted complement C3 activates peritoneal B lymphocyte and enhances its bactericidal capacity. In addition, we provide the first evidence that granulocyte colony-stimulating factor (G-CSF) derived from trained macrophages plays a pivotal role in shaping central-trained immunity. In summation, our research demonstrates the capability of rPepO to induce both peripheral and central trained immunity in mice, underscoring its potential application in broad-spectrum anti-infection therapy. Our research provides a new molecule and some new target options for infectious disease prevention.

Recessively Inherited Deficiency of Secreted WFDC2 (HE4) Causes Nasal Polyposis and Bronchiectasis.

RATIONALE: Bronchiectasis is a pathological dilatation of the bronchi in the respiratory airways associated with environmental or genetic causes (e.g., cystic fibrosis, primary ciliary dyskinesia and primary immunodeficiency disorders), but most cases remain idiopathic. OBJECTIVES: To identify novel genetic defects in unsolved cases of bronchiectasis presenting with severe rhinosinusitis, nasal polyposis, and pulmonary Pseudomonas aeruginosa infection. METHODS: DNA was analyzed by next-generation or targeted Sanger sequencing. RNA was analyzed by quantitative PCR and single-cell RNA sequencing. Patient-derived, cells, cell cultures and secretions (mucus, saliva, seminal fluid) were analyzed by Western blotting and immunofluorescence microscopy, and mucociliary activity was measured. Blood serum was analyzed by electrochemiluminescence immunoassay. Protein structure and proteomic analyses were used to assess the impact of a disease-causing founder variant. MEASUREMENTS AND MAIN RESULTS: We identified bi-allelic pathogenic variants in WFDC2 in 11 individuals from 10 unrelated families originating from the United States, Europe, Asia, and Africa. Expression of WFDC2 was detected predominantly in secretory cells of control airway epithelium and also in submucosal glands. We demonstrate that WFDC2 is below the limit of detection in blood serum and hardly detectable in samples of saliva, seminal fluid, and airway surface liquid from WFDC2-deficient individuals. Computer simulations and deglycosylation assays indicate that the disease-causing founder variant p.Cys49Arg structurally hampers glycosylation and thus secretion of mature WFDC2. CONCLUSIONS: WFDC2 dysfunction defines a novel molecular etiology of bronchiectasis characterized by the deficiency of a secreted component of the airways. A commercially available blood test combined with genetic testing allows its diagnosis. This article is open access and distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).

Rare earth elements applied to phytoremediation: Enhanced endocytosis promotes remediation of antimony contamination with different valence levels in Solanum nigrum L.

Antimony (Sb) pollution poses a noteworthy risk to human health and ecosystem sustainability, therefore effective, eco-friendly, and widely accepted restoration methods are urgently needed. This study introduces a new approach of using La(III) foliar application on Solanum nigrum L. (S. nigrum), a cadmium hyperaccumulator, to improve its photosynthetic and root systems under Sb stress, resulting in a higher biomass. Notably, La(III) also enhances endocytosis in root cells, facilitating efficient and non-selective remediation of both Sb(III) and Sb(V) forms. The absorption of Sb by root cell endocytosis was observed visually with a confocal laser scanning microscope. The subcellular distribution of Sb in the cell wall of S. nigrum is reduced. And the antioxidant enzyme activity system is improved, resulting in an enhanced Sb tolerance in S. nigrum. Based on the existing bibliometric analysis, this paper identified optimal conditions for S. nigrum to achieve maximum translocation and bioconcentration factor values for Sb. The foliar application of La(III) on plants treated with Sb(III), Sb(V), and a combination of both resulted in translocation factor values of 0.89, 1.2, 1.13 and bioconcentration factor values of 11.3, 12.81, 14.54, respectively. Our work suggests that La(III)-enhanced endocytosis of S. nigrum root cells is a promising remediation strategy for Sb-contaminated environments.

Enhancing extracellular monascus pigment production in submerged fermentation with engineered microbial consortia.

In this study, we investigated the impact of microbial interactions on Monascus pigment (MP) production. We established diverse microbial consortia involving Monascus purpureus and Lactobacillus fermentum. The addition of Lactobacillus fermentum (4% at 48 h) to the submerged fermentation of M. purpureus resulted in a significantly higher MP production compared to that achieved using the single-fermentation system. Co-cultivation with immobilized L. fermentum led to a remarkable increase of 59.18% in extracellular MP production, while mixed fermentation with free L. fermentum caused a significant decrease of 66.93% in intracellular MPs, contrasting with a marginal increase of 4.52% observed during co-cultivation with immobilized L. fermentum and the control group respectively. The findings indicate an evident enhancement in cell membrane permeability of M. purpureus when co-cultivated with immobilized L. fementum. Moreover, integrated transcriptomic and metabolomic analyses were conducted to elucidate the regulatory mechanisms underlying MP biosynthesis and secretion following inoculation with immobilized L. fementum, with specific emphasis on glycolysis, steroid biosynthesis, fatty acid biosynthesis, and energy metabolism.

Current trends and possibilities of typical microbial protein production approaches: a review.

Global population growth and demographic restructuring are driving the food and agriculture sectors to provide greater quantities and varieties of food, of which protein resources are particularly important. Traditional animal-source proteins are becoming increasingly difficult to meet the demand of the current consumer market, and the search for alternative protein sources is urgent. Microbial proteins are biomass obtained from nonpathogenic single-celled organisms, such as bacteria, fungi, and microalgae. They contain large amounts of proteins and essential amino acids as well as a variety of other nutritive substances, which are considered to be promising sustainable alternatives to traditional proteins. In this review, typical approaches to microbial protein synthesis processes were highlighted and the characteristics and applications of different types of microbial proteins were described. Bacteria, fungi, and microalgae can be individually or co-cultured to obtain protein-rich biomass using starch-based raw materials, organic wastes, and one-carbon compounds as fermentation substrates. Microbial proteins have been gradually used in practical applications as foods, nutritional supplements, flavor modifiers, and animal feeds. However, further development and application of microbial proteins require more advanced biotechnological support, screening of good strains, and safety considerations. This review contributes to accelerating the practical application of microbial proteins as a promising alternative protein resource and provides a sustainable solution to the food crisis facing the world.

Research advancements in the maintenance mechanism of Sporidiobolus pararoseus enhancing the quality of soy sauce during fermentation.

Soy sauce is a traditional condiment that undergoes microbial fermentation of various ingredients to achieve its desired color, scent, and flavor. Sporidiobolus pararoseus, which is a type of Rhodocerevisiae, shows promising potential as a source of lipids, carotenoids, and enzymes that can enrich the taste and color of soy sauce. However, there is currently a lack of systematic and comprehensive studies on the functions and mechanisms of action of S. pararoseus during soy sauce fermentation. In this review, it is well established that S. pararoseus produces lipids that are abundant in unsaturated fatty acids, particularly oleic acid, as well as various carotenoids, such as ß-carotene, torulene, and torularhodin. These pigments are synthesized through the mevalonic acid pathway and possess remarkable antioxidant properties, acting as natural colorants. The synthesis of carotenoids is stimulated by high salt concentrations, which induces oxidative stress caused by NaCl. This stress further activates crucial enzymes involved in carotenoid production, ultimately leading to pigment formation. Moreover, S. pararoseus can produce high-quality enzymes that aid in the efficient utilization of soy sauce substrates during fermentation. Furthermore, this review focused on the impact of S. pararoseus on the color and quality of soy sauce and comprehensively analyzed its characteristics and ingredients. Thus, this review serves as a basis for screening high-quality oleaginous red yeast strains and improving the quality of industrial soy sauce production through the wide application of S. pararoseus.

Exploration of the impact of dysbiosis in the gut microbiota on microbial composition in children's neurodevelopment.

OBJECTIVE: To investigate the impact of gut microbiota dysbiosis on neurodevelopment in children. METHODS: This study included 338 children aged 0-3 years admitted to our hospital from January to December 2022, The children were divided into a normal neurodevelopment group (169 cases) and a poor neurodevelopment group (169 cases). Basic personal information and clinical data were collected through a detailed questionnaire, and the microbial composition in fecal samples was analyzed using 16S rRNA gene sequencing. RESULTS: Children in the poor neurodevelopment group showed a significant decrease in gut microbiota diversity compared to those in the normal neurodevelopment group (Shannon index, p < 0.05). The abundance of Bifidobacterium and Veillonella genera significantly decreased (p < 0.05), while the abundance of Streptococcus genus increased significantly (p < 0.05). CONCLUSION: There is an association between gut microbiota dysbiosis and poor neurodevelopment in children. The increased abundance of Streptococcus genus and decreased abundance of Bifidobacterium and Veillonella genera in the gut microbiota may be potential risk factors for poor neurodevelopment in preterm infants. Future research should further explore the potential beneficial effects of gut microbiota modulation on neurodevelopment in children.

FAK-LINC01089 negative regulatory loop controls chemoresistance and progression of small cell lung cancer.

The focal adhesion kinase (FAK) tyrosine kinase is activated and upregulated in multiple cancer types including small cell lung cancer (SCLC). However, FAK inhibitors have shown limited efficacy in clinical trials for cancer treatment. With the aim of identifying potential therapeutic strategies to inhibit FAK for cancer treatment, we investigated long non-coding RNAs (lncRNAs) that potentially regulate FAK in SCLC. In this study, we identified a long non-coding RNA LINC01089 that binds and inhibits FAK phosphorylation (activation). Expression analysis revealed that LINC01089 was downregulated in SCLC tissues and negatively correlated with chemoresistance and survival in SCLC patients. Functionally, LINC01089 inhibited chemoresistance and progression of SCLC in vitro and in vivo. Mechanistically, LINC01089 inhibits FAK activation by blocking binding with Src and talin kinases, while FAK negatively regulates LINC01089 transcription by activating the ERK signaling pathway to recruit the REST transcription factor. Furthermore, LINC01089-FAK axis mediates the expression of drug resist-related genes by modulating YBX1 phosphorylation, leading to drug resistance in SCLC. Intriguingly, the FAK-LINC01089 interaction depends on the co-occurrence of the novel FAK variant and the non-conserved region of LINC01089 in primates. In Conclusion, our results indicated that LINC01089 may serve as a novel high-efficiency FAK inhibitor and the FAK-LINC01089 axis represents a valuable prognostic biomarker and potential therapeutic target in SCLC.

Identifying suicide attempter in major depressive disorder through machine learning: the importance of pain avoidance, event-related potential features of affective processing.

How to achieve a high-precision suicide attempt classifier based on the three-dimensional psychological pain model is a valuable issue in suicide research. The aim of the present study is to explore the importance of pain avoidance and its related neural features in suicide attempt classification models among patients with major depressive disorder. By recursive feature elimination with cross-validation and support-vector-machine algorithms, scores from the measurements and the task-based EEG signals were chosen to achieve a suicide attempt classification model. In the multimodal suicide attempt classifier with an accuracy of 83.91% and an area under the curve of 0.90, pain avoidance ranked as the top one in the optimal feature set. Theta (reward positive feedback minus neutral positive feedback) was the shared neural representation ranking as the top one of event-related potential features in pain avoidance and suicide attempt classifiers. In conclusion, the suicide attempt classifier based on pain avoidance and its related affective processing neural features has excellent accuracy among patients with major depressive disorder. Pain avoidance is a stable and strong indicator for identifying suicide risks in both traditional analyses and machine-learning approaches. A novel methodology is needed to clarify the relationship between cognitive and affective processing evoked by punishment stimuli and pain avoidance.

CD19/CD20 dual-targeted chimeric antigen receptor-engineered natural killer cells exhibit improved cytotoxicity against acute lymphoblastic leukemia.

BACKGROUND: Chimeric antigen receptor natural killer (CAR-NK) cells represent a promising advancement in CAR cell therapy, addressing limitations observed in CAR-T cell therapy. However, our prior study revealed challenges in CAR-NK cells targeting CD19 antigens, as they failed to eliminate CD19+ Raji cells in NSG tumor-bearing mice, noting down-regulation or loss of CD19 antigen expression in some Raji cells. In response, this study aims to enhance CD19 CAR-NK cell efficacy and mitigate the risk of tumor recurrence due to target antigen escape by developing CD19 and CD20 (CD19/CD20) dual-targeted CAR-NK cells. METHODS: Initially, mRNA encoding anti-CD19 CARs (FMC63 scFv-CD8α-4-1BB-CD3ζ) and anti-CD20 CARs (LEU16 scFv-CD8α-4-1BB-CD3ζ) was constructed via in vitro transcription. Subsequently, CD19/CD20 dual-targeted CAR-NK cells were generated through simultaneous electrotransfection of CD19/CD20 CAR mRNA into umbilical cord blood-derived NK cells (UCB-NK). RESULTS: Following co-electroporation, the percentage of dual-CAR expression on NK cells was 86.4% ± 1.83%, as determined by flow cytometry. CAR expression was detectable at 8 h post-electric transfer, peaked at 24 h, and remained detectable at 96 h. CD19/CD20 dual-targeted CAR-NK cells exhibited increased specific cytotoxicity against acute lymphoblastic leukemia (ALL) cell lines (BALL-1: CD19+CD20+, REH: CD19+CD20-, Jurkat: CD19-CD20-) compared to UCB-NK, CD19 CAR-NK, and CD20 CAR-NK cells. Moreover, CD19/CD20 dual-targeted CAR-NK cells released elevated levels of perforin, IFN-γ, and IL-15. Multiple activation markers such as CD69 and cytotoxic substances were highly expressed. CONCLUSIONS: The creation of CD19/CD20 dual-targeted CAR-NK cells addressed the risk of tumor escape due to antigen heterogeneity in ALL, offering efficient and safe 'off-the-shelf' cell products. These cells demonstrate efficacy in targeting CD20 and/or CD19 antigens in ALL, laying an experimental foundation for their application in ALL treatment.

Transgenerational toxicity induced by maternal AFB1 exposure in Caenorhabditis elegans associated with underlying epigenetic regulations.

Aflatoxin B1 (AFB1), usually seriously contaminates in grain and oil foods or feed, displayed significant acute and chronic toxic effects in human and animal populations. However, little is known about the transgenerational toxic effects induced by a maternal AFB1 intake at a lower dose on offspring. In our study, only parental wild-type Caenorhabditis elegans was exposed to AFB1 (0-8 µg/ml) and the following three filial generations were grown on AFB1-free NGM. Results showed that the toxic effects of AFB1 on the growth (body length) and reproduction (brood size, generation time and morphology of gonad arm) can be transmitted through generations. Moreover, the levels of MMP and ATP were irreversibly inhibited in the filial generations. By using RNomics and molecular biology techniques, we found that steroid biosynthesis, phagosome, valine/leucine/isoleucine biosynthesis and oxidative phosphorylation (p < 0.05) were the core signaling pathways to exert the transgenerational toxic effects on nematodes. Also, notably increased histone methylation level at H3K36me3 was observed in the first generation. Taken together, our study demonstrated that AFB1 has notable transgenerational toxic effects, which were resulted from the complex regulatory network of various miRNAs, mRNAs and epigenetic modification in C. elegans.

Genomic characterization of peritoneal lavage cytology-positive gastric cancer.

Objective: Positive peritoneal lavege cytology (CY1) gastric cancer is featured by dismal prognosis, with high risks of peritoneal metastasis. However, there is a lack of evidence on pathogenic mechanism and signature of CY1 and there is a continuous debate on CY1 therapy. Therefore, exploring the mechanism of CY1 is crucial for treatment strategies and targets for CY1 gastric cancer. Methods: In order to figure out specific driver genes and marker genes of CY1 gastric cancer, and ultimately offer clues for potential marker and risk assessment of CY1, 17 cytology-positive gastric cancer patients and 31 matched cytology-negative gastric cancer patients were enrolled in this study. The enrollment criteria were based on the results of diagnostic laparoscopy staging and cytology inspection of exfoliated cells. Whole exome sequencing was then performed on tumor samples to evaluate genomic characterization of cytology-positive gastric cancer. Results: Least absolute shrinkage and selection operator (LASSO) algorithm identified 43 cytology-positive marker genes, while MutSigCV identified 42 cytology-positive specific driver genes. CD3G and CDKL2 were both driver and marker genes of CY1. Regarding mutational signatures, driver gene mutation and tumor subclone architecture, no significant differences were observed between CY1 and negative peritoneal lavege cytology (CY0). Conclusions: There might not be distinct differences between CY1 and CY0, and CY1 might represent the progression of CY0 gastric cancer rather than constituting an independent subtype. This genomic analysis will thus provide key molecular insights into CY1, which may have a direct effect on treatment recommendations for CY1 and CY0 patients, and provides opportunities for genome-guided clinical trials and drug development.

Hemophagocytic lymphohistiocytosis during treatment of intracranial multifocal germinoma: a case report and literature review.

Hemophagocytic lymphohistiocytosis (HLH), also known as hemophagocytic syndrome (HPS), is a benign histiocytosis with hyperreactive proliferation of the mononuclear phagocyte system caused by immune function abnormalities, which often occurs under the background of genetic mutations, inflammation, infection or tumors. Because the research on malignancy-associated HLH (M-HLH) is focused on hematological malignancies, reports on HLH secondary to solid tumors are rare. In this case, we report a 14-year-old girl who developed HLH during treatment for intracranial multifocal germinoma, and the disease was controlled after hormone combined with etoposide(VP-16) and other related treatments. To our knowledge, there have been no documented cases of HLH caused by intracranial multifocal germinoma.

Reaction Thermodynamics of Zerovalent Iron and Hexavalent Chromium at the Solid-Liquid Interface and in Solution.

Zerovalent iron (Fe0) is a promising candidate for remediating hexavalent chromium (Cr(VI)) via adsorption and (or) reduction. Herein, the reaction between Fe0 and Cr(VI) at the solid-liquid interface and in solution under varying pHs was inspected using the methodology of equilibrium thermodynamics. First, species distribution functions of aqueous Cr(VI), Cr(III), Fe(III), and Fe(II) are deduced to illuminate the quantitative distribution of aqueous metal species. Second, the plausible reaction at pH = 0-14 either at the solid-liquid interface or in solution is determined according to the species distribution function. Third, the spontaneity of each reaction is evaluated via a thermodynamic calculation based on the van't Hoff equation. The results present the following. (1) At the solid-liquid interface, the redox reaction 2Cr(VI) + 3Fe0 → 2Cr(III) + 3Fe(II) is spontaneous, inducing complete Cr(VI) → Cr(III) reduction at pH = 0-14. Especially, the high spontaneity of the redox reaction is mainly ascribed to Fe0 oxidation, which serves as a highly spontaneous subreaction. (2) In solution, the redox reaction Cr(VI) + 3Fe(II) → Cr(III) + 3Fe(III) is nonspontaneous at pH = 6 and 7, whereas it is spontaneous at pH = 6-7, 0-5, and 8-14. Accordingly, no Cr(VI) → Cr(III) reduction at pH = 6-7 and complete Cr(VI) → Cr(III) reduction at pH = 0-5 and 8-14 are expected. Particularly, the nonspontaneity of the Cr(VI) reduction at pH = 6-7 is majorly attributed to water ionization, which is involved as a highly nonspontaneous subreaction. On the contrary, the spontaneity of the Cr(VI) reduction at pH = 0-5 and 8-14 is mainly owing to acid-base neutralization, which is involved as a highly spontaneous subreaction. This work may deepen our knowledge about the chemistry involved in hexavalent chromium remediation by the zerovalent iron.

Size and Location of Preterm Brain Injury and Associations With Neurodevelopmental Outcomes.

BACKGROUND AND OBJECTIVES: We examined associations of white matter injury (WMI) and periventricular hemorrhagic infarction (PVHI) volume and location with 18-month neurodevelopment in very preterm infants. METHODS: A total of 254 infants born <32 weeks' gestational age were prospectively recruited across 3 tertiary neonatal intensive care units (NICUs). Infants underwent early-life (median 33.1 weeks) and/or term-equivalent-age (median 41.9 weeks) MRI. WMI and PVHI were manually segmented for quantification in 92 infants. Highest maternal education level was included as a marker of socioeconomic status and was defined as group 1 = primary/secondary school; group 2 = undergraduate degree; and group 3 = postgraduate degree. Eighteen-month neurodevelopmental assessments were completed with Bayley Scales of Infant and Toddler Development, Third Edition. Adverse outcomes were defined as a score of less than 85 points. Multivariable linear regression models were used to examine associations of brain injury (WMI and PVHI) volume with neurodevelopmental outcomes. Voxel-wise lesion symptom maps were developed to assess relationships between brain injury location and neurodevelopmental outcomes. RESULTS: Greater brain injury volume was associated with lower 18-month Motor scores (ß = -5.7, 95% CI -9.2 to -2.2, p = 0.002) while higher maternal education level was significantly associated with higher Cognitive scores (group 3 compared 1: ß = 14.5, 95% CI -2.1 to 26.9, p = 0.03). In voxel-wise lesion symptom maps, brain injury involving the central and parietal white matter was associated with an increased risk of poorer motor outcomes. DISCUSSION: We found that brain injury volume and location were significant predictors of motor, but not cognitive outcomes, suggesting that different pathways may mediate outcomes across domains of neurodevelopment in preterm infants. Specifically, assessing lesion size and location may allow for more accurate identification of infants with brain injury at highest risk of poorer motor outcomes. These data also highlight the importance of socioeconomic status in cognitive outcomes, even in preterm infants with brain injury.

Pain Exposure and Brain Connectivity in Preterm Infants.

Importance: Early-life exposure to painful procedures has been associated with altered brain maturation and neurodevelopmental outcomes in preterm infants, although sex-specific differences are largely unknown. Objective: To examine sex-specific associations among early-life pain exposure, alterations in neonatal structural connectivity, and 18-month neurodevelopment in preterm infants. Design, Setting, and Participants: This prospective cohort study recruited 193 very preterm infants from April 1, 2015, to April 1, 2019, across 2 tertiary neonatal intensive care units in Toronto, Canada. Structural connectivity data were available for 150 infants; neurodevelopmental outcomes were available for 123 infants. Data were analyzed from January 1, 2022, to December 31, 2023. Exposure: Pain was quantified in the initial weeks after birth as the total number of invasive procedures. Main Outcome and Measure: Infants underwent early-life and/or term-equivalent-age magnetic resonance imaging with diffusion tensor imaging to quantify structural connectivity using graph theory measures and regional connection strength. Eighteen-month neurodevelopmental outcomes were assessed with the Bayley Scales of Infant and Toddler Development, Third Edition. Stratifying by sex, generalized estimating equations were used to assess whether pain exposure modified the maturation of structural connectivity using an interaction term (early-life pain exposure × postmenstrual age [PMA] at scan). Generalized estimating equations were used to assess associations between structural connectivity and neurodevelopmental outcomes, adjusting for extreme prematurity and maternal education. Results: A total of 150 infants (80 [53%] male; median [IQR] gestational age at birth, 27.1 [25.4-29.0] weeks) with structural connectivity data were analyzed. Sex-specific associations were found between early-life pain and neonatal brain connectivity in female infants only, with greater early-life pain exposure associated with slower maturation in global efficiency (pain × PMA at scan interaction P = .002) and local efficiency (pain × PMA at scan interaction P = .005). In the full cohort, greater pain exposure was associated with lower global efficiency (coefficient, -0.46; 95% CI, -0.78, to -0.15; P = .004) and local efficiency (coefficient, -0.57; 95% CI, -1.04 to -0.10; P = .02) and regional connection strength. Local efficiency (coefficient, 0.003; 95% CI, 0.001-0.004; P = .005) and regional connection strength in the striatum were associated with cognitive outcomes. Conclusions and Relevance: In this cohort study of very preterm infants, greater exposure to early-life pain was associated with altered maturation of neonatal structural connectivity, particularly in female infants. Alterations in structural connectivity were associated with neurodevelopmental outcomes, with potential regional specificities.

Novel compound heterozygous variants in FANCI cause premature ovarian insufficiency.

Premature ovarian insufficiency (POI) is a common reproductive aging disorder due to a dramatic decline of ovarian function before 40 years of age. Accumulating evidence reveals that genetic defects, particularly those related to DNA damage response, are a crucial contributing factor to POI. We have demonstrated that the functional Fanconi anemia (FA) pathway maintains the rapid proliferation of primordial germ cells to establish a sufficient reproductive reserve by counteracting replication stress, but the clinical implications of this function in human ovarian function remain to be established. Here, we screened the FANCI gene, which encodes a key component for FA pathway activation, in our whole-exome sequencing database of 1030 patients with idiopathic POI, and identified two pairs of novel compound heterozygous variants, c.[97C > T];[1865C > T] and c.[158-2A > G];[c.959A > G], in two POI patients, respectively. The missense variants did not alter FANCI protein expression and nuclear localization, apart from the variant c.158-2A > G causing abnormal splicing and leading to a truncated mutant p.(S54Pfs*5). Furthermore, the four variants all diminished FANCD2 ubiquitination levels and increased DNA damage under replication stress, suggesting that the FANCI variants impaired FA pathway activation and replication stress response. This study first links replication stress response defects with the pathogenesis of human POI, providing a new insight into the essential roles of the FA genes in ovarian function.

Effect of tempo on the age-related changes in temporal expectation driven by rhythms.

Temporal expectation refers to the capacity to allocate resources at a particular point in time, enabling us to enhance our behavior performance. Empirical evidence indicates that, among younger adults, temporal expectation can be driven by rhythm (i.e., regular sequences of stimuli). However, whether there are age-related changes in rhythm-based temporal expectation has not been clearly established. Furthermore, whether tempo can influence the relationship between rhythm-based temporal expectation and aging remains unexplored. To address these questions, both younger and older participants took part in a rhythm-based temporal expectation task, engaging three distinct tempos: 600 ms (fast), 1800 ms (moderate), or 3000 ms (slow). The results demonstrated that temporal expectation effects (i.e., participants exhibited significantly faster responses during the regular trials compared to the irregular trials) were observed in both the younger and older participants under the moderate tempo condition. However, in the fast and slow tempo conditions, the temporal expectation effects were solely observed in the younger participants. These findings revealed that rhythm-based temporal expectations can be preserved during aging but within a specific tempo range. When the tempo falls within the range of either being too fast or too slow, it can manifest age-related declines in temporal expectations driven by rhythms.

Functionalized sampling swabs array-based portable ATP bioluminescence sensor with on-site enrichment and high specificity for live Salmonella detection.

Live food-borne pathogens, featured with rapid proliferative capacity and high pathogenicity, pose an emerging food safety and public health crisis. The high-sensitivity detection of pathogens is particularly imperative yet remains challenging. This work developed a functionalized nylon swab array with enhanced affinity for Salmonella typhimurium (S.T.) for high-specificity ATP bioluminescence-based S.T. detection. In brief, the nylon swabs (NyS) were turned to N-methylation nylon (NyS-OH) by reacting with formaldehyde, and NyS-OH were further converted to NyS-CA by reacting with carboxylic groups of citric acid (CA) and EDC/NHS solution, for altering the NyS surface energy to favor biomodification. The antibody-immobilized nylon swab (MNyS-Ab) was ready for S.T.-specific adsorption. Three prepared MNyS-Ab were installed on a stirrer to form an MNyS-Ab array, allowing for on-site enrichment of S.T. through absorptive extraction. The enriched S.T. was quantified by measuring the bioluminescence of ATP released from cell lysis utilizing a portable ATP bioluminescence sensor. The bioassay demonstrated a detectable range of 102-107 CFU mL-1 with a detection limit (LOD) of 8 CFU/mL within 35 min. The signal of single MNyS-Ab swabs was 500 times stronger than the direct detection of 106 CFU/mL S.T. The MNyS-Ab array exhibited a 100-fold increase in extraction level compared to a single MNyS. This combination of a portable bioluminescent sensor and modified nylon swab array offers a novel strategy for point-of-care testing of live S.T. strains. It holds promise for high-sensitivity measurements of other pathogens and viruses.

pH-induced interaction mechanism of zearalenone with zein: Binding characteristics, conformational structure and intermolecular forces.

Zein-bound zearalenone (ZEN) complexes are naturally existed in maize by their spontaneous interaction, which significantly impacts the risk assessment of ZEN. Additionally, the pH levels in processing could affect the binding or release of zein-bound ZEN. In this study, pH-induced interaction mechanism of ZEN with zein were studied. Results showed that the acid conditions increased the binding constant (Ka) from 3.46 to 10.0 × 104 L/mol, binding energy from -17.38 to -43.49 kJ mol-1. By increasing hydrophobic interaction and hydrogen bond of ZEN with zein, the binding of ZEN with zein was promoted, forming zein-bound ZEN. Whereas, alkaline conditions decreased the Ka to 1.45 × 104 L/mol and binding energy to 148.48 kJ mol-1, weakened ZEN-zein interaction and stretched zein molecules, resulting the release of ZEN from zein. This study could provide important theoretical basis for perfecting risk assessment and controlling zein-bound ZEN during processing.