Phosphorylation as an Effective Tool to Improve Stability and Reduce Toxicity of Antimicrobial Peptides.

Developing a straightforward and effective strategy to modify antimicrobial peptides (AMPs) is crucial in overcoming the challenges posed by their instability and toxicity. Phosphorylation can reduce toxicity and improve the stability of AMPs. Based on these, we designed a series of peptides and their corresponding phosphorylated forms. The results showed that all phosphorylated peptides displayed reduced toxicity and enhanced stability compared to their unphosphorylated counterparts. Among them, W3BipY8-P stood out as the most promising peptide, exhibiting similar antibacterial activity as its unphosphorylated analog W3BipY8 but with significantly reduced hemolytic activity (19-fold decrease), cytotoxicity (3.3-fold decrease), and an extended serum half-life 6.3 times longer than W3BipY8. W3BipY8-P exerted bactericidal effects by disrupting bacterial membranes. Notably, W3BipY8-P significantly prolonged the survival of bacteria-infected animals while its LD50 was 4.2 times higher than that of W3BipY8. These findings highlight phosphorylation as an effective strategy for improving the antimicrobial properties of AMPs.

The roles of G protein-coupled receptor kinase 2 in renal diseases.

G protein-coupled receptor (GPCR) kinase 2 (GRK2) is an integrative node in many signalling network cascades. An emerging study indicates that GRK2 can interact with GPCRs and non-GPCR substrates in both kinase-dependent and -independent modes. Alterations in the functional levels of GRK2 have been found in a variety of renal diseases, such as hypertension-related kidney injury, sepsis-associated acute kidney injury (S-AKI), cardiorenal syndrome (CRS), acute kidney injury (AKI), age-related kidney injury or hyperglycemia-related kidney injury. Abnormal GRK2 expression contribute to the development of renal diseases, making them promising molecular targets for treating renal diseases. Blocking the prostaglandin E2 (PGE2)-EP1-Gaq-Ca2+ signal pathway in glomerular mesangial cells (GMCs) by internalizing prostaglandin E2 receptor 1 (EP1) with GRK2 may be a potential treatment for diabetic nephropathy (DN). In addition, GRK2 inhibition may have therapeutic effects in a variety of renal diseases, such as SLE-related kidney injury, DN, age-related kidney injury, hypertension-related kidney injury, and CRS. However, there is still a long way to go for the large-scale application of GRK2 inhibition in the field of renal diseases. In this review, we discuss recent updates in understanding the role of GRK2 in kidney dysfunction. Furthermore, we explore the potential of GRK2 as a possible therapeutic target for renal pathologies. We believe it will shed light on the future development of small-molecule inhibitors of GRK, as well as the clinical applications in renal diseases.

Towards novel small-molecule inhibitors blocking PD-1/PD-L1 pathway: From explainable machine learning models to molecular dynamics simulation.

Molecular design of small-molecule inhibitors targeting programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) pathway has been recognized as an active research area by the clinical success of cancer immunotherapy. In recent years, using machine learning (ML) methods to accelerate drug design have been confirmed. However, the black box character of ML methods makes model interpretation and ligands optimization obscured. Herein, five explainable ML models were constructed by integrating five ML models with the SHAP method, where these ML models were pretrained with >4000 molecules and their R2 ranged from 0.835 to 0.86 on test set. Subsequently, the explainable ML models were employed to identify the relationship between fragments and bio-activity of a small molecule inhibitor BMS-1166, leading to the modification of BMS-1166 into 60 novel compounds. After consensus docking and ADMET test, 3 small molecules (C27, C52 and C54) with better docking scores and lower toxicity than BMS-1166 were screened out further. Finally, the improved binding affinity of C27, C52 to the PD-L1 dimer was validated by the MD simulation. Overall, this work proposed an efficient protocol on the basis of explainable ML models for designing small-molecule inhibitors targeting PD-1/PD-L1 pathway in a rational way.

Interaction between intestinal mycobiota and microbiota shapes lung inflammation.

Gut microbiota is an intricate microbial community containing bacteria, fungi, viruses, archaea, and protozoa, and each of them contributes to diverse aspects of host health. Nevertheless, the influence of interaction among gut microbiota on host health remains uncovered. Here, we showed that the interaction between intestinal fungi and bacteria shaped lung inflammation during infection. Specifically, antifungal drug-induced dysbiosis of gut mycobiota enhanced lung inflammation during infection. Dysbiosis of gut mycobiota led to gut Escherichia coli (E. coli) overgrowth and translocation to the lung during infection, which induced lung accumulation of the CD45+F4/80+Ly6G-Ly6C-CD11b+CD11c+ macrophages. Clearance of macrophages or deletion of TLR4 (Toll-like receptor 4, recognition of LPS) rather than Dectin-1 (recognition of beta-1,3/1,6 glucans on fungi) blocked the antifungal drug-induced aggravation of lung inflammation during infection. These findings suggest that the interaction between intestinal mycobiota and commensal bacteria affects host health through the gut-lung axis, offering a potential therapeutic target for ameliorating lung inflammation during infection.

Investigation of in vitro susceptibility and resistance mechanisms to amikacin among diverse carbapenemase-producing Enterobacteriaceae.

OBJECTIVE: This study aims to assess the in vitro drug susceptibility of various Carbapenemase-Producing Enterobacteriaceae (CPE) genotypes and elucidate the underlying mechanisms of amikacin resistance. METHODS: A total of 72 unique CPE strains were collected from the Second Hospital of Jiaxing between 2019 and 2022, including 51 strains of Klebsiella pneumoniae, 11 strains of Escherichia coli, 6 strains of Enterobacter cloacae, 2 strains of Klebsiella aerogenes, 1 strain of Citrobacter freundii, and 1strain of Citrobacter werkmanii. Among these strains, 24 carried blaKPC gene, 20 carried blaNDM gene, 23 carried blaOXA-48-like gene, and 5 carried both blaKPC and blaNDM. We measured the in vitro activity of amikacin and other common antibiotics. Strains carrying blaOXA-48-like gene were selected for whole genome sequencing (WGS) via next-generation sequencing to identify genes related to antimicrobial resistance (AMR) and virulence factor (VF). RESULTS: Out of the 72 CPE strains tested, 41.7% exhibited resistance to amikacin. The drug resistance rates for K. pneumoniae, E. coli, and Enterobacter spp. were 51.0%, 27.3%, and 10.0%, respectively. The majority of the CPE strains (> 90%) displayed resistance to cephalosporins and carbapenems, while most of them were sensitive to polymyxin B and tigecycline (97.2% and 94.4%). The amikacin resistance rate was 100% for strains carrying blaOXA-48, 20.8% for those with blaKPC, 5.0% for those with blaNDM, and 20.0% for those with both blaKPC and blaNDM. These differences were statistically significant (P < 0.05). Through sequencing, we detected aminoglycoside resistance genes rmtF and aac(6')-Ib, VF genes iucABCD and rmpA2 in OXA-48-producing multidrug resistance and highly virulent strains. These genes were located on a IncFIB- and IncHI1B-type plasmid, respectively. Both plasmids were highly homologous to the plasmid from OXA-232 strains in Zhejiang province and Shanghai province. Integration of these resistance genes into the IncFIB plasmid, facilitated by the IS6 and/or Tn3 transposons, resulted in OXA232-producing K. pneumoniae with amikacin resistance. CONCLUSION: This study identified significant amikacin resistance in CPE strains, particularly in those carrying the blaOXA-48 gene. Resistance genes rmtF and aac(6')-Ib were identified on plasmids. These results highlight the need for careful monitoring of amikacin resistance.

Draft genome sequence of Pseudomonas sp. ZS001 isolated from peanut plantation soil.

Pseudomonas sp. ZS001 is a bacterium potentially degrading soluble starch isolated from peanut plantation soil sprayed with starch-based material in Dasi Town, Tianjin. Reporting the genome sequence of strain ZS001 can help us understand the genome composition, potential functional characteristics, and application value of Pseudomonas members at the genetic level.

Prognostic significance of ER-to-PR difference in ER+/HER2- early breast cancer.

ER+/HER2- breast cancer is a common subtype of breast cancer. This study aimed to evaluate the prognostic value of ER-to-PR difference (EPD) in ER+/HER2- early breast cancer (EBC). A retrospective cohort study was conducted, including 3,340 ER+/HER2- EBC patients, divided into a training cohort of 2,873 patients and a validation cohort of 467 patients. The optimal EPD cutoff value for stratifying patients was determined using X-tile. Additionally, the prognostic value of EPD, when combined with other clinicopathological factors, was assessed using the Cox proportional hazards model and five traditional machine learning methods. The optimal cutoff value for EPD was determined as 10%, categorizing patients into EPD-low (ER-PR ≤ 10%) and EPD-high (ER-PR > 10%) expression groups. Patients with EPD-high tumors exhibited a poorer prognosis compared to those with EPD-low tumors. In the multivariate Cox model, EPD was identified as an independent prognostic factor for disease-free survival (DFS) (HR: 1.496, P = 0.004). Integrating EPD with clinicopathological parameters into a predictive model effectively predicts DFS in ER+/HER2- EBC patients. In the most effective CoxPH model, the area under the curve (AUC) values for predicting 3-year, 5-year, and 7-year DFS were 0.718, 0.702, and 0.701, respectively, in the WCH cohort, and 0.770, 0.739, and 0.743, respectively, in the FUSCC cohort. EPD may serve as a novel prognostic marker, allowing for the identification of a population with a poor prognosis in ER+/HER2- EBC, thereby aiding clinical decision-making.

Clinical significance and different strategies for re-elevation of plasma EBV-DNA during treatment in pediatric EBV-associated hemophagocytic lymphohistiocytosis

Abstract Objective Monitoring the disease status of Epstein-Barr virus (EBV)-related hemophagocytic lymphohistiocytosis (HLH) patients is crucial. This study aimed to investigate the different strategies and outcomes of patients with EBV-HLH and re-elevated EBV-DNA. Method A retrospective analysis was conducted on 20 patients diagnosed with EBV-HLH. Clinical features, laboratory tests, treatments, plasma EBV-DNA levels, and outcomes were assessed. Three cases were highlighted for detailed analysis. Results Nine of the 20 patients had a re-elevation of EBV-DNA during treatment, and 55.5 % (5/9) experienced relapses. Patients with persistently positive plasma EBV-DNA (n = 4) and those with re-elevated EBV-DNA after conversion (n = 9) showed a significantly higher relapse rate compared to those with persistently negative EBV-HLH (n = 7) (p < 0.05). Among the highlighted cases, Case 1 exhibited plasma EBV-DNA re-elevation after four weeks of treatment without relapse, maintaining stability with the original treatment regimen, and eventually, his plasma EBV-DNA turned negative. In Case 2, plasma EBV-DNA was elevated again with a recurrence of HLH after L-DEP. Consequently, she underwent allogeneic hematopoietic stem cell transplantation and eventually achieved complete remission (CR) with negative plasma EBV-DNA. Case 3 experienced plasma EBV-DNA re-elevation after L-DEP but remained in CR, discontinuing chemotherapy without relapse. Conclusion The re-elevation of plasma EBV-DNA during EBV-HLH treatment poses challenges in determining disease status and treatment strategies. Optimal management decisions require a combination of the level of elevated EBV-DNA, the intensity of hyperinflammation, and the patient's immune function.

First report of ISKpn26 element mediating mgrB gene disruption in the ST1 colistin- and carbapenem-resistant Klebsiella pneumoniae cluster isolated from a patient with chest infection.

Colistin is used as a last-line therapy against carbapenem-resistant Klebsiella pneumoniae (CRKP). However, colistin resistance in Klebsiella pneumoniae is increasingly reported worldwide. This study aims to investigate the instrumental role of insertion sequence (IS) elements in colistin resistance through mgrB disruption in K. pneumoniae during treatment. Five clinical isolates of CRKP, designated KPN1~KPN5 were collected from the lower respiratory tract of a patient with chest infection before and after treatment with colistin. Antimicrobial susceptibility testing was performed using the broth microdilution method. Whole genome sequencing and bioinformatics were used to analyze the sequence types (STs), resistance genes, and genetic characteristics of the five isolates of K. pneumoniae. Antimicrobial susceptibility testing indicated that all five K. pneumoniae isolates were resistant to cephalosporins (ceftriaxone, ceftazidime, and cefepime), several carbapenems (imipenem, meropenem), cefoperazone-sulbactam, piperacillin-tazobactam, ciprofloxacin, and fosfomycin, whereas they were sensitive to amikacin and tigecycline. In addition, three of these isolates were resistant to colistin, with minimum inhibitory concentration values of >8 mg/L. Whole genome sequencing revealed that all five K. pneumoniae isolates belonged to sequence type 1 (ST1), which shared an identical blaKPC-2. Notably, disruption of mgrB by the ISKpn26 insertion sequence was shown to be the primary colistin resistance mechanism during the treatment. To our knowledge, this is the first report of ISKpn26 element mediating mgrB disruption in the ST1 colistin and CRKP obtained from a patient with chest infection in mainland China. This study provides new research ideas to explore the clinical drug resistance mechanism of CRKP and the critical need to monitor and understand resistance mechanisms to preserve the efficacy of last-line antibiotics such as colistin. IMPORTANCE: Of note, this chapter gives an update on colistin resistance in sequence type 1 Klebsiella pneumoniae, by focusing on the mgrB disrupted by ISKpn26 element.

Initiation of Insulin Degludec in Chinese Hospitalized Patients with Type 2 Diabetes - A Single Center's Experience.

Introduction: The long-acting insulin analogue insulin degludec (IDeg) is increasingly recommended for type two diabetes (T2DM), yet clinical experience in China remains limited. This retrospective study aimed to delineate the initiation strategy for IDeg in Chinese hospitalized patients with T2DM. Methods: We retrospectively analyzed 217 Chinese hospitalized patients with T2DM who initiated IDeg from December 2018 to June 2020, calculating the initial dose and examining correlations between clinical characteristics and glucose profiles. Results: The initial IDeg doses ranged from 0.15 to 0.18 IU/kg·d, showing no association with clinical characteristics. During titration, mean blood glucose levels (MEAN) correlated positively with diabetes duration, age, and Glycosylated Hemoglobin (HbA1c), and negatively with body mass index (BMI), triglycerides (TG), and low-density lipoprotein (LDL). The coefficient of variation (CV) in glucose levels correlated positively with HbA1c and negatively with BMI and TG. The mean amplitude of glycemic excursions (MAGE) mirrored these trends, with additional negative correlations to estimated glomerular filtration rate (eGFR) and serum albumin (ALB). Notably, glycemic variability parameters did not correlate with the presence of diabetic ketoacidosis (DKA) at admission. Hypoglycemia was observed in 21 patients, with differences in MEAN and CV during titration being the only significant findings. Conclusion: The initial IDeg dosing was inadequate and not tailored to clinical features, and there were weak correlations between diabetes duration, age, BMI, eGFR, LDL, and ALB levels and glucose profile post-initiation.

Very severe aplastic anemia in a child with pulmonary mucormycosis: a case report.

Aplastic anemia (AA), is a rare but potentially life-threatening disease characterized by pancytopenia and a hypocellular bone marrow. Pulmonary mucormycosis (PM) is a rare but life-threatening fungal infection observed in immunocompromised patients, particularly those with neutropenia and those using corticosteroids, with a high mortality rate from 40 to 80%. However, PM diagnosis and treatment remain challenging. This study reports a case of very severe aplastic anemia (VSAA) in a male child with PM. The innovation of this article lies in the following aspects: the patient exhibited typical clinical manifestations, the reverse halo sign (RHS) on chest computed tomography (CT), and a positive metagenomic next-generation sequencing (mNGS) analysis; despite aggressive anti-infective treatment and left lower lobectomy, he experienced a poor clinical outcome. Reflecting on cases with poor prognosis can indeed offer valuable insights and opportunities for learning. This study underlines the diagnostic challenges in mucormycosis, which should be considered in persistent fever that is unresponsive to standard antibiotic and antifungal therapies, and conduct a comprehensive examination to achieve early detection, diagnosis and treatment. It was concluded that, in addition to antifungal treatment, early surgery is essential for treating mucormycosis.

Efficacy and safety of recombinant human thrombopoietin for the treatment of chronic primary immune thrombocytopenia in children and adolescents: A multicentre, randomized, double-blind, placebo-controlled phase III trial.

The efficacy and safety of recombinant human thrombopoietin (rhTPO) in children and adolescent patients with chronic primary immune thrombocytopenia (ITP) remains unclear. A multicentre, randomized, double-blind, placebo-controlled phase III trial was performed. Patients aged 6-17 years, diagnosed with ITP and resistant or relapsed to corticosteroid treatment were included. For the trial, part 1 was exploratory and part 2 was the main analysis, with part 1 determining whether part 2 was stratified by age. Patients in part 1 were treated with rhTPO (the 6- to 11-/12- to 17-year-old groups; 1:1). Patients in part 2 were randomized (3:1) to receive either rhTPO treatment or placebo. Patients received rhTPO or placebo at a dose of 300 U/kg once daily for up to 14 days. A total of 68 patients were included [part 1 (12 patients), part 2 (56 patients)]. The total response rate (TRR) in part 1 was 50.0% (95% CI: 21.09%-78.91%). For part 2, the TRR was 58.5% (95% CI: 42.11%-73.68%) and 13.3% (95% CI: 1.66%-40.46%) in the rhTPO and placebo groups (FAS) respectively. The difference in TRR between the rhTPO group and placebo group was 45.2% (95% CI: 22.33%-68.08%) and 44.6% (95% CI: 21.27%-67.85%) on the FAS and per-protocol set (PPS), respectively, which indicates the superiority of rhTPO treatment.

Moderating effects of clock genes DNA methylation on the relationship between physical activity trajectories and depressive symptoms among Chinese college students.

OBJECTIVES: To explore the 2-year physical activity trajectory of Chinese college students and further examine the longitudinal relationship between physical activity trajectory and depressive symptoms. Furthermore, our study aimed to clarify the potential role of clock genes deoxyribonucleic acid (DNA) methylation in the association between physical activity and depressive symptoms. METHOD: From April 2019 to May 2021, College Student Behavior and Health Cohort Study was conducted among 1,179 students from two universities in Anhui and Jiangxi provinces. Latent Class Growth Model was applied to simulate and group physical activity in a total of five surveys. The PROCESS macro for SPSS was used to analyze the moderating effects of clock genes DNA methylation on the association between physical activity and depressive symptoms. RESULTS: Two physical activity trajectories were identified: "continued high level" and "gradual low level." Multinomial logistic regression analysis showed that the "gradual low level" of physical activity trajectory was independently associated with moderate-to-severe depressive symptoms. Furthermore, DNA methylation of the PER2 and CRY1 genes had negatively moderating effects between physical activity and depressive symptoms, and there was sex-specific effect for CRY1 gene. CONCLUSIONS: Our findings suggests that long-term low physical activity was connected to more severe depressive symptoms among college students, and clock genes DNA methylation may play a negative moderating role, attenuating the positive effect of high intensity physical activity levels on depressive symptoms. In this regard, intervention programs regarding depressive symptoms among Chinese college students should consider multiple approaches such as increasing the duration and intensity of physical activity. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Distinct FLT3 Pathways Gene Expression Profiles in Pediatric De Novo Acute Lymphoblastic and Myeloid Leukemia with FLT3 Mutations: Implications for Targeted Therapy.

Activating FLT3 mutations plays a crucial role in leukemogenesis, but identifying the optimal candidates for FLT3 inhibitor therapy remains controversial. This study aims to explore the impacts of FLT3 mutations in pediatric acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) and to compare the mutation profiles between the two types to inspire the targeted application of FLT3 inhibitors. We retrospectively analyzed 243 ALL and 62 AML cases, grouping them into FLT3-mutant and wild-type categories, respectively. We then assessed the associations between FLT3 mutations and the clinical manifestations, genetic characteristics, and prognosis in ALL and AML. Additionally, we compared the distinct features of FLT3 mutations between ALL and AML. In ALL patients, those with FLT3 mutations predominantly exhibited hyperdiploidy (48.6% vs. 14.9%, p < 0.001) and higher FLT3 expression (108.02 [85.11, 142.06] FPKM vs. 23.11 [9.16, 59.14] FPKM, p < 0.001), but lower expression of signaling pathway-related genes such as HRAS, PIK3R3, BAD, MAP2K2, MAPK3, and STAT5A compared to FLT3 wild-type patients. There was no significant difference in prognosis between the two groups. In contrast, AML patients with FLT3 mutations were primarily associated with leucocytosis (82.90 [47.05, 189.76] G/L vs. 20.36 [8.90, 55.39] G/L, p = 0.001), NUP98 rearrangements (30% vs. 4.8%, p = 0.018), elevated FLT3 expression (74.77 [54.31, 109.46] FPKM vs. 34.56 [20.98, 48.28] FPKM, p < 0.001), and upregulated signaling pathway genes including PIK3CB, AKT1, MTOR, BRAF, and MAPK1 relative to FLT3 wild-type, correlating with poor prognosis. Notably, internal tandem duplications were the predominant type of FLT3 mutation in AML (66.7%) with higher inserted base counts, whereas they were almost absent in ALL (6.3%, p < 0.001). In summary, our study demonstrated that the forms and impacts of FLT3 mutations in ALL differed significantly from those in AML. The gene expression profiles of FLT3-related pathways may provide a rationale for using FLT3 inhibitors in AML rather than ALL when FLT3 mutations are present.

Unveiling Cu Nanoparticles Formed During Li Deposition in Anode-Free Batteries.

Developing high-energy-density Li metal batteries is essential for sustainable progress, necessitating in-depth studies of complex battery reactions. The presence of metallic Cu impurities detrimentally impacts battery performance, leading to issues such as self-discharging and internal soft short-circuit. Nevertheless, their formation mechanism and structural characteristics have not been revealed clearly. Here the formation of single-crystalline Cu nanoparticles during the Li deposition process in anode-free cells was identified by transmission electron microscopy. Through investigation of the chemical state of Cu before and after Li deposition, the formation of Cu NPs was attributed to the reduction of the oxide layers formed on the surface of Cu current collectors. Additionally, it was observed that Cu nanoparticles can be formed inside of deposited Li metal. This work reveals the formation pathway and microstructural characteristics of Cu nanoparticles appearing during Li deposition, underscoring the importance of nanoscale investigations into the underlying battery reactions.

The motive cocktail in altruistic behaviors.

Prosocial motives such as social equality and efficiency are key to altruistic behaviors. However, predicting the range of altruistic behaviors in varying contexts and individuals proves challenging if we limit ourselves to one or two motives. Here we demonstrate the numerous, interdependent motives in altruistic behaviors and the possibility to disentangle them through behavioral experimental data and computational modeling. In one laboratory experiment (N = 157) and one preregistered online replication (N = 1,258), across 100 different situations, we found that both third-party punishment and third-party helping behaviors (that is, an unaffected individual punishes the transgressor or helps the victim) aligned best with a model of seven socioeconomic motives, referred to as a motive cocktail. For instance, the inequality discounting motives imply that individuals, when confronted with costly interventions, behave as if the inequality between others barely exists. The motive cocktail model also provides a unified explanation for the differences in intervention willingness between second parties (victims) and third parties, and between punishment and helping.

Associating prenatal antibiotics exposure with attention deficit hyperactivity disorder symptoms in preschool children: The role of maternal vitamin D.

BACKGROUND: The associations between prenatal antibiotics exposure and attention-deficit/hyperactivity disorder (ADHD) in preschoolers, and the role of maternal vitamin D in these associations, remain to be explored. OBJECTIVES: To evaluate the relationships between multiple maternal urinary antibiotics levels and preschoolers' ADHD symptoms, and to identify the potential modifying effects of maternal vitamin D. METHODS: Based on a prospective birth cohort, the present study included 2033 motherchild pairs. Maternal urine and serum samples were collected during all three trimesters to measure the urinary concentrations of 43 antibiotics (including two metabolites) and the serum vitamin D levels. The ADHD symptoms of preschoolers were assessed using the Diagnostic and Statistical Manual-oriented ADHD problems scale in the Achenbach Child Behavior Checklist. Multiple informant models in the form of logistic regression were conducted to investigate the associations between prenatal antibiotics exposure and preschooler ADHD symptoms, and these associations were stratified by child sex and maternal vitamin D status. RESULTS: Compared with the lowest tertile concentrations, maternal exposure to the middle tertile concentrations of doxycycline and human antibiotics/preferred as human antibiotics (HAs/PHAs), and the highest tertile concentrations of doxycycline during the first trimester were associated with an increased risk of ADHD symptoms in children. An increased risk of ADHD symptoms was observed in girls exposed to the highest tertile levels of sulfamethazine during the second trimester. Furthermore, pregnant women with vitamin D deficiency have a greater risk of ADHD symptoms in their offspring after exposure to doxycycline in the first trimester. CONCLUSIONS: Maternal exposure to doxycycline and HAs/PHAs during the first trimester increases the risk of ADHD symptoms in preschoolers. Mid-pregnancy sulfamethazine exposure increases the risk of ADHD symptoms in girls. Maternal vitamin D deficiency during pregnancy may exacerbate the adverse effects of doxycycline exposure on ADHD symptoms.

Engineering high production of fatty alcohols from methanol by constructing coordinated dual biosynthetic pathways.

Microbial cell factories provide an efficient approach for the green manufacturing of chemicals. However, the excessive use of sugars increases the potential risk of food crisis. Methanol, an abundant feedstock, holds promise in facilitating low-carbon production processes. However, the current methanol bioconversion is hindered by limited regulatory strategies and relatively low conversion efficiency. Here, a yeast biocatalyst was extensively engineered for efficient biosynthesis of fatty alcohols through reinforcement of precursor supply and methanol assimilation in Pichia pastoris. Furthermore, the dual cytoplasmic and peroxisomal biosynthetic pathways were constructed by mating and exhibited robust production of 5.6 g/L fatty alcohols by using methanol as the sole carbon source. This study provides a heterozygous diploid P. pastoris strain with dual cytoplasmic and peroxisomal biosynthetic pathways, which achieved the highest fatty alcohol production from one-carbon feedstocks to date.

Association between maternal antibiotic exposure and emotional and behavioural problems in children at four years of age: A biomonitoring-based prospective study.

BACKGROUND: Maternal exposure to multiple antibiotics exposure during pregnancy has attracted extensive attention, but biomonitoring studies linking prenatal antibiotic exposure to emotional and behavioural problems in children are limited. METHODS: A total of 2475 pregnant women from the Ma'anshan Birth Cohort were included, and the Strengths and Difficulties Questionnaire was completed when their children turned four years of age. The levels of 41 maternal urinary antibiotics and two metabolites were measured during the first, second and third trimesters. Generalized estimating equations and binary logistic regression models were applied to analyse the associations between maternal antibiotic exposure and emotional and behavioural problems in children and to determine the sensitive period, respectively. A quantile-based g-computation (QGC) approach was employed to examine the combined effects of multiple antibiotics on emotional and behavioural problems in children. RESULTS: Overall, florfenicol and preferred-as-veterinary antibiotic (PVA) exposure during pregnancy increased the risk of emotional problems in children, and ofloxacin exposure increased the risk of hyperactivity-inattention. Maternal exposure to trimethoprime, ciprofloxacin, florfenicol, other antibiotics and PVA exposure during the first trimester was positively associated with emotional problems in children. Second-trimester trimethoprime concentrations and third-trimester ciprofloxacin concentrations were positively associated with hyperactivity-inattention. Third-trimester veterinary antibiotic (VA) exposure was negatively associated with hyperactivity-inattention, and second-trimester VA and PVA exposure was negatively associated with peer problems. The QGC model revealed that mixed antibiotic exposure in the first trimester exacerbated the risk of childhood emotional problems (the contribution of ciprofloxacin is prominent), and mixed antibiotic exposure in the second trimester increased the risk of hyperactivity-inattention (the contribution of trimethoprime is prominent). CONCLUSION: Maternal mixed antibiotic exposure during the first and second trimesters increases the risk of emotional problems and hyperactivity-inattention in children at four years of age.