Bump-and-Hole Engineering Identifies Specific Substrates of Glycosyltransferases in Living Cells.

Studying posttranslational modifications classically relies on experimental strategies that oversimplify the complex biosynthetic machineries of living cells. Protein glycosylation contributes to essential biological processes, but correlating glycan structure, underlying protein, and disease-relevant biosynthetic regulation is currently elusive. Here, we engineer living cells to tag glycans with editable chemical functionalities while providing information on biosynthesis, physiological context, and glycan fine structure. We introduce a non-natural substrate biosynthetic pathway and use engineered glycosyltransferases to incorporate chemically tagged sugars into the cell surface glycome of the living cell. We apply the strategy to a particularly redundant yet disease-relevant human glycosyltransferase family, the polypeptide N-acetylgalactosaminyl transferases. This approach bestows a gain-of-chemical-functionality modification on cells, where the products of individual glycosyltransferases can be selectively characterized or manipulated to understand glycan contribution to major physiological processes.

Design principles of heterointerfacial redox chemistry for highly reversible lithium metal anode.

High electrochemical reversibility is required for the application of high-energy-density lithium (Li) metal batteries; however, inactive Li formation and SEI (solid electrolyte interface)-instability-induced electrolyte consumption cause low Coulombic efficiency (CE). The prior interfacial chemical designs in terms of alloying kinetics have been used to enhance the CE of Li metal anode; however, the role of its redox chemistry at heterointerfaces remains a mystery. Herein, the relationship between heterointerfacial redox chemistry and electrochemical transformation reversibility is investigated. It is demonstrated that the lower redox potential at heterointerface contributes to higher CE, and this enhancement in CE is primarily due to the regulation of redox chemistry to Li deposition behavior rather than the formation of SEI films. Low oxidation potential facilitates the formation of the surface with the highly electrochemical binding feature after Li stripping, and low reduction potential can maintain binding ability well during subsequent Li plating, both of which homogenize Li deposition and thus optimize CE. In particular, Mg hetero-metal with ultra-low redox potential enables Li metal anode with significantly improved CE (99.6%) and stable cycle life for 700 cycles at 3.0 mA cm-2. This work provides insight into the heterointerfacial design principle of next-generation negative electrodes for highly reversible metal batteries.

Human microbiota from drug-naive patients with obsessive-compulsive disorder drives behavioral symptoms and neuroinflammation via succinic acid in mice.

Emerging evidence suggests that the gut microbiota is closely related to psychiatric disorders. However, little is known about the role of the gut microbiota in the development of obsessive-compulsive disorder (OCD). Here, to investigate the contribution of gut microbiota to the pathogenesis of OCD, we transplanted fecal microbiota from first-episode, drug-naive OCD patients or demographically matched healthy individuals into antibiotic-treated specific pathogen-free (SPF) mice and showed that colonization with OCD microbiota is sufficient to induce core behavioral deficits, including abnormal anxiety-like and compulsive-like behaviors. The fecal microbiota was analyzed using 16 S rRNA full-length sequencing, and the results demonstrated a clear separation of the fecal microbiota of mice colonized with OCD and control microbiota. Notably, microbiota from OCD-colonized mice resulted in injured neuronal morphology and function in the mPFC, with inflammation in the mPFC and colon. Unbiased metabolomic analyses of the serum and mPFC region revealed the accumulation of succinic acid (SA) in OCD-colonized mice. SA impeded neuronal activity and induced an inflammatory response in both the colon and mPFC, impacting intestinal permeability and brain function, which act as vital signal mediators in gut microbiota-brain-immune crosstalk. Manipulations of dimethyl malonate (DM) have been reported to exert neuroprotective effects by suppressing the oxidation of accumulated succinic acid, attenuating the downstream inflammatory response and neuronal damage, and can help to partly improve abnormal behavior and reduce neuroinflammation and intestinal inflammation in OCD-colonized mice. We propose that the gut microbiota likely regulates brain function and behaviors in mice via succinic acid signaling, which contributes to the pathophysiology of OCD through gut-brain crosstalk and may provide new insights into the treatment of this disorder.

iASPP suppresses Gp78-mediated TMCO1 degradation to maintain Ca2+ homeostasis and control tumor growth and drug resistance.

Ca2+ release from the endoplasmic reticulum (ER) is an essential event in the modulation of Ca2+ homeostasis, which is coordinated by multiple biological processes, ranging from cell proliferation to apoptosis. Deregulated Ca2+ homeostasis is linked with various cancer hallmarks; thus, uncovering the mechanisms underlying Ca2+ homeostasis dynamics may lead to new anticancer treatment strategies. Here, we demonstrate that a reported Ca2+-channel protein TMCO1 (transmembrane and coiled-coil domains 1) is overexpressed in colon cancer tissues at protein levels but not at messenger RNA levels in colon cancer. Further study revealed that TMCO1 is a substrate of ER-associated degradation E3 ligase Gp78. Intriguingly, Gp78-mediated TMCO1 degradation at K186 is under the control of the iASPP (inhibitor of apoptosis-stimulating protein of p53) oncogene. Mechanistically, iASPP robustly reduces ER Ca2+ stores, mainly by competitively binding with Gp78 and interfering with Gp78-mediated TMCO1 degradation. A positive correlation between iASPP and TMCO1 proteins is further validated in human colon tissues. Inhibition of iASPP-TMCO1 axis promotes cytosolic Ca2+ overload-induced apoptotic cell death, reducing tumor growth both in vitro and in vivo. Thus, iASPP-TMCO1 represents a promising anticancer treatment target by modulating Ca2+ homeostasis.

Identification of pyruvic and maleic acid as potential markers for disease activity and prognosis in chronic urticaria.

BACKGROUND: Population-based studies have highlighted the link between chronic urticaria (CU) and metabolic syndrome, and metabolic alterations have been revealed in CU. However, to our knowledge, a comprehensive metabolomics study on a large cohort of patients with CU has not been reported. OBJECTIVE: We sought to explore the underlying metabolic subtypes and novel metabolite biomarkers for CU diagnosis and therapy. METHODS: Plasma samples from 80 patients with CU and 82 healthy controls were collected for metabolomics quantification and bioinformatics analysis. Another independent cohort consisting of 144 patients with CU was studied to validate the findings. Bone marrow-derived mast cells and mice with IgE-induced passive cutaneous anaphylaxis were used for in vitro and in vivo experiments, respectively. RESULTS: We observed clear metabolome differences between CU patients and healthy controls. Meanwhile, differential metabolites N6-acetyl-l-lysine, l-aspartate, maleic acid, and pyruvic acid were used to construct random forest classifiers and achieved area under receiver operating characteristic curve values greater than 0.85, suggesting their potential as diagnostic biomarkers of CU. More importantly, by exploring the underlying metabolic subtypes of CU, we found that the low abundance of pyruvic acid and maleic acid was significantly related to the activity of CU, poor efficacy of second-generation H1 antihistamines, and short relapse-free time. The results were validated in the independent cohort. Moreover, supplementation with pyruvate or maleate could significantly attenuate IgE-mediated mast cell activation in vitro and in vivo. CONCLUSIONS: Plasma pyruvic acid and maleic acid may be effective biomarkers for predicting disease activity, therapeutic efficacy, and prognosis for patients with CU.

CCL4 contributes to aging related angiogenic insufficiency through activating oxidative stress and endothelial inflammation.

Aging is a natural process associated with chronic inflammation in the development of vascular dysfunction. We hypothesized that chemokine C-C motif ligands 4 (CCL4) might play a vital role in aging-related vascular dysfunction. Circulating CCL4 was up-regulated in elderly subjects and in aged animals. CCL4 inhibition reduced generation of reactive oxygen species (ROS), attenuated inflammation, and restored cell functions in endothelial progenitor cells from elderly subjects and in aged human aortic endothelial cells. CCL4 promoted cell aging, with impaired cell functioning, by activating ROS production and inflammation. CCL4 knockout mice and therapeutic administration of anti-CCL4 neutralizing antibodies exhibited vascular and dermal anti-aging effects, with improved wound healing, via the down-regulation of inflammatory proteins and the activation of angiogenic proteins. Altogether, our findings suggested that CCL4 may contribute to aging-related vascular dysfunction via activating oxidative stress and endothelial inflammation. CCL4 may be a potential therapeutic target for vascular protections during aging.

Healthcare utilisation in people with long COVID: an OpenSAFELY cohort study.

BACKGROUND: Long COVID potentially increases healthcare utilisation and costs. However, its impact on the NHS remains to be determined. METHODS: This study aims to assess the healthcare utilisation of individuals with long COVID. With the approval of NHS England, we conducted a matched cohort study using primary and secondary care data via OpenSAFELY, a platform for analysing anonymous electronic health records. The long COVID exposure group, defined by diagnostic codes, was matched with five comparators without long COVID between Nov 2020 and Jan 2023. We compared their total healthcare utilisation from GP consultations, prescriptions, hospital admissions, A&E visits, and outpatient appointments. Healthcare utilisation and costs were evaluated using a two-part model adjusting for covariates. Using a difference-in-difference model, we also compared healthcare utilisation after long COVID with pre-pandemic records. RESULTS: We identified 52,988 individuals with a long COVID diagnosis, matched to 264,867 comparators without a diagnosis. In the 12 months post-diagnosis, there was strong evidence that those with long COVID were more likely to use healthcare resources (OR: 8.29, 95% CI: 7.74-8.87), and have 49% more healthcare utilisation (RR: 1.49, 95% CI: 1.48-1.51). Our model estimated that the long COVID group had 30 healthcare visits per year (predicted mean: 29.23, 95% CI: 28.58-29.92), compared to 16 in the comparator group (predicted mean visits: 16.04, 95% CI: 15.73-16.36). Individuals with long COVID were more likely to have non-zero healthcare expenditures (OR = 7.66, 95% CI = 7.20-8.15), with costs being 44% higher than the comparator group (cost ratio = 1.44, 95% CI: 1.39-1.50). The long COVID group costs approximately £2500 per person per year (predicted mean cost: £2562.50, 95% CI: £2335.60-£2819.22), and the comparator group costs £1500 (predicted mean cost: £1527.43, 95% CI: £1404.33-1664.45). Historically, individuals with long COVID utilised healthcare resources more frequently, but their average healthcare utilisation increased more after being diagnosed with long COVID, compared to the comparator group. CONCLUSIONS: Long COVID increases healthcare utilisation and costs. Public health policies should allocate more resources towards preventing, treating, and supporting individuals with long COVID.

Lipidomic studies revealing serological markers associated with the occurrence of retinopathy in type 2 diabetes.

PURPOSE: The duration of type 2 diabetes mellitus (T2DM) and blood glucose levels have a significant impact on the development of T2DM complications. However, currently known risk factors are not good predictors of the onset or progression of diabetic retinopathy (DR). Therefore, we aimed to investigate the differences in the serum lipid composition in patients with T2DM, without and with DR, and search for potential serological indicators associated with the development of DR. METHODS: A total of 622 patients with T2DM hospitalized in the Department of Endocrinology of the First Affiliated Hospital of Xi'an JiaoTong University were selected as the discovery set. One-to-one case-control matching was performed according to the traditional risk factors for DR (i.e., age, duration of diabetes, HbA1c level, and hypertension). All cases with comorbid chronic kidney disease were excluded to eliminate confounding factors. A total of 42 pairs were successfully matched. T2DM patients with DR (DR group) were the case group, and T2DM patients without DR (NDR group) served as control subjects. Ultra-performance liquid chromatography-mass spectrometry (LC-MS/MS) was used for untargeted lipidomics analysis on serum, and a partial least squares discriminant analysis (PLS-DA) model was established to screen differential lipid molecules based on variable importance in the projection (VIP) > 1. An additional 531 T2DM patients were selected as the validation set. Next, 1:1 propensity score matching (PSM) was performed for the traditional risk factors for DR, and a combined 95 pairings in the NDR and DR groups were successfully matched. The screened differential lipid molecules were validated by multiple reaction monitoring (MRM) quantification based on mass spectrometry. RESULTS: The discovery set showed no differences in traditional risk factors associated with the development of DR (i.e., age, disease duration, HbA1c, blood pressure, and glomerular filtration rate). In the DR group compared with the NDR group, the levels of three ceramides (Cer) and seven sphingomyelins (SM) were significantly lower, and one phosphatidylcholine (PC), two lysophosphatidylcholines (LPC), and two SMs were significantly higher. Furthermore, evaluation of these 15 differential lipid molecules in the validation sample set showed that three Cer and SM(d18:1/24:1) molecules were substantially lower in the DR group. After excluding other confounding factors (e.g., sex, BMI, lipid-lowering drug therapy, and lipid levels), multifactorial logistic regression analysis revealed that a lower abundance of two ceramides, i.e., Cer(d18:0/22:0) and Cer(d18:0/24:0), was an independent risk factor for the occurrence of DR in T2DM patients. CONCLUSION: Disturbances in lipid metabolism are closely associated with the occurrence of DR in patients with T2DM, especially in ceramides. Our study revealed for the first time that Cer(d18:0/22:0) and Cer(d18:0/24:0) might be potential serological markers for the diagnosis of DR occurrence in T2DM patients, providing new ideas for the early diagnosis of DR.

A biomarker panel of secondary hypertension is simultaneously quantified by coupling of magnetic solid-phase extraction and liquid chromatography-tandem mass spectrometry.

RATIONALE: Secondary hypertension is often caused by activation of complex multi-organ endocrine systems, while renin activity indicated by angiotensins (Angs), aldosterone (ALD) and cortisol (COR) in such systems are generally accepted as its diagnostic markers. As antibody-based methods cannot offer comparable quantification for these biomarkers, a liquid chromatography (LC)-tandem mass spectrometry (MS/MS)-based approach was developed to quantify them simultaneously and accurately. METHODS: Five different beads for magnetic solid-phase extraction (MSPE) were evaluated towards their enrichment efficiency for these biomarkers. An LC system with optimized elution gradient and a triple-quadrupole MS with tuned parameters were coupled to quantitatively monitor the extracted analytes. The method performance was further examined such as linearity, precision, stability, recovery rate and matrix effect. Based on the developed method, the abundance of Ang II, ALD and COR in plasma was measured and the quantification was compared with that derived from commercial ELISA kits. RESULTS: As compared with other MSPEs, Angs, ALD and COR were highly enriched by the HLB magnetic beads with satisfactory recoveries. These analytes were simultaneously quantified by LC/MS/MS and all the method parameters for quantification were well matched with the requirements of clinical testing. Comparison of the quantitative results derived from ELISA and LC/MS/MS exhibited that the two methods offered basically comparable values with Pearson r values at 0.896, 0.895 and 0.835, respectively. The stability test for plasma Angs at room temperature indicated that the abundance of Ang II was relatively stable within 3 h, whereas that of Ang I and Ang 1-7 was time-dependently changed. CONCLUSIONS: Coupling of HLB beads and LC/MS/MS thus enables simultaneous quantification of a set of biomarkers related to secondary hypertension.

Prostaglandin E2-Induced AKT Activation Regulates the Life Span of Short-Lived Plasma Cells by Attenuating IRE1α Hyperactivation.

The mechanism regulating the life span of short-lived plasma cells (SLPCs) remains poorly understood. Here we demonstrated that the EP4-mediated activation of AKT by PGE2 was required for the proper control of inositol-requiring transmembrane kinase endoribonuclease-1α (IRE1α) hyperactivation and hence the endoplasmic reticulum (ER) homeostasis in IgM-producing SLPCs. Disruption of the PGE2-EP4-AKT signaling pathway resulted in IRE1α-induced activation of JNK, leading to accelerated death of SLPCs. Consequently, Ptger4-deficient mice (C57BL/6) exhibited a markedly impaired IgM response to T-independent Ags and increased susceptibility to Streptococcus pneumoniae infection. This study reveals a highly selective impact of the PGE2-EP4 signal on the humoral immunity and provides a link between ER stress response and the life span of SLPCs.

Revealing the Singlet Fission Mechanism for a Silane-Bridged Thienotetracene Dimer.

Tetraceno[2,3-b]thiophene is regarded as a strong candidate for singlet fission-based solar cell applications due to its mixed characteristics of tetracene and pentacene that balance exothermicity and triplet energy. An electronically weakly coupled tetraceno[2,3-b]thiophene dimer (Et2Si(TIPSTT)2) with a single silicon atom bridge has been synthesized, providing a new platform to investigate the singlet fission mechanism involving the two acene chromophores. We study the excited state dynamics of Et2Si(TIPSTT)2 by monitoring the evolution of multiexciton coupled triplet states, 1TT to 5TT to 3TT to T1 + S0, upon photoexcitation with transient absorption, temperature-dependent transient absorption, and transient/pulsed electron paramagnetic resonance spectroscopies. We find that the photoexcited singlet lifetime is 107 ps, with 90% evolving to form the TT state, and the complicated evolution between the multiexciton states is unraveled, which can be an important reference for future efforts toward tetraceno[2,3-b]thiophene-based singlet fission solar cells.

Cryopreservation-enhanced differentiation capacity of embryogenic cultures of Castanea mollissima.

A cryopreservation protocol has been developed for embryogenic cultures (ECs) of Castanea mollissima, an important economic species of the Castanea genus in China. We achieved 100 % regrowth when ECs were treated with Plant Vitrification Solution 2 (PVS2) for 30, 60 and 90 min on ice. Optimal PVS2 treatment for cryopreservation was determined to be 30 min on ice based on the highest biomass regrowth after thawing. Fluorescein diacetate (FDA) staining could rapidly and reliably determine post-thaw cell viability and its use facilitated the optimization of the cryopreservation protocols. Although the proliferation rate of the re-established ECs remained largely unchanged compared to non-cryopreserved ECs, the capacity of the re-established ECs to differentiate (on two media) into somatic embryos nearly doubled to approximately 2200-2300 globular somatic embryos per 1 g of re-established ECs. Based on cell cluster size analysis, this enhanced growth is primarily attributed to the presence of significantly greater cell clusters with a diameter of 100-200 µm, which have the highest level of differentiation ability. In order to understand the increased embryogenic potential following cryopreservation, we analyzed the expression of key genes related to somatic embryogenesis. Genes CmWUS and CmABP1 were downregulated while CmLEC1, CmAGL15, CmGRF2, and CmFUS3 were upregulated in re-established ECs when compared to non-cryopreserved ECs.

Follow-up care and assessment of comorbidities and complications in patients with primary aldosteronism: The clinical practice guideline of the Taiwan Society of aldosteronism.

Primary aldosteronism (PA) is the most common form of endocrine hypertension, characterized by excess aldosterone production that leads to an increased risk of cardiovascular events and target organ damage. Both adrenalectomy and medical treatment have shown efficacy in improving clinical outcomes and comorbidities associated with PA, including a specific subtype of PA with autonomous cortisol secretion (ACS). Understanding the comorbidities of PA and establishing appropriate follow-up protocols after treatment are crucial for physicians to enhance morbidity and mortality outcomes in patients with PA. Additionally, the screening for hypercortisolism prior to surgery is essential, as the prognosis of patients with coexisting PA and ACS differs from those with PA alone. In this review, we comprehensively summarize the comorbidities of PA, encompassing cardiovascular, renal, and metabolic complications. We also discuss various post-treatment outcomes and provide insights into the strategy for glucocorticoid replacement in patients with overt or subclinical hypercortisolism. This clinical practice guideline aims to equip medical professionals with up-to-date information on managing concurrent hypercortisolism, assessing treatment outcomes, and addressing comorbidities in patients with PA, thereby improving follow-up care.

The predictors of long-term outcomes after targeted therapy for primary Aldosteronism.

Unilateral primary aldosteronism is thought to be a surgically curable disease, and unilateral adrenalectomy is the mainstay treatment. The Primary Aldosteronism Surgical Outcome (PASO) consensus was developed to assess clinical and biochemical outcomes to standardize the classification of surgical outcomes. However, fewer than half of patients are cured of hypertension after adrenalectomy; therefore, preoperative patient counseling and evaluation might be necessary. Moreover, current studies show that genetic mutations and histopathology classification are associated with the treatment outcome. The Task Force of Taiwan PA recommends using a specific scoring system, including the PASO score and nomogram-based preoperative score, to predict the clinical outcome before adrenalectomy. Herein, we discuss the associations of current histopathological classification and specific somatic gene mutations with clinical outcomes after surgery.

Tailoring Li Deposition by Regulating Structural Connectivity of Electrochemical Li Reservoir in Li-metal Batteries.

Irregular Li deposition is the major reason for poor reversibility and cycle instability in Li metal batteries, even leading to safety hazards, the causes of which have been extensively explored. The structural disconnection induced by completely dissolving Li in the traditional testing protocol is a key factor accounting for irregular Li growth during the subsequent deposition process. Herein, the critical role played by the structural connectivity of electrochemical Li reservoir in subsequent Li deposition behaviors is elucidated and a morphology-performance correlation is established. The structural connection and resultant well-distributed morphology of the in situ electrochemical Li reservoir ensure efficient electron transfer and Li+ diffusion pathway, finally leading to homogenized Li nucleation and growth. Tailoring the geometry of Li reservoir can improve the coulombic efficiency and cyclability of anode-free Li metal batteries by optimizing Li deposition behavior.

Novel prognostic implications of complement activation in the tumour microenvironment for de novo metastatic BRAF V600E mutant colorectal cancer.

BACKGROUND: Prognosis of metastatic BRAF V600E mutant colorectal cancer (CRC) is poor, and the prognostic implications of immune contextures in the tumour microenvironment (TME) for CRC remain elusive. METHODS: We collected the primary tumour specimens and clinicopathological characteristics of patients with de novo metastatic microsatellite-stable BRAF V600E mutant CRC from two medical centres. Gene expression analysis was performed using the nCounterⓇ PanCancer Immune Profiling Panel. The Cox proportional hazards regression model was used for analysing survival outcomes in association with immune gene expression and immune cells. Our complement score was defined on the basis of the average gene expression in the selected co-expression module. RESULTS: High expression of classical and regulatory complement genes was significantly associated with poor prognosis (N = 54). A high complement score (defined as a score above the median value) indicated significantly shorter survival. The overall survival (OS) impact of the high score remained significant in multivariate analyses. Additionally, our complement score was strongly correlated with C4d expression in immunohistochemical staining and tumour-associated macrophage (TAM) M2 signatures. CONCLUSIONS: Complement activation in the TME was significantly associated with poor OS and was correlated with TAM M2 in patients with de novo metastatic BRAF V600E mutant CRC.

Lipidomic profiling reveals metabolic signatures in psoriatic skin lesions.

Psoriasis is a chronic immune-mediated inflammatory disease. Lipids play an important role in regulating the inflammatory response. However, the alteration of lipids involved in psoriasis particular in skin lesions remain unclear. Here, we performed the lipidomics to investigate lipid profiling in the skin lesions of the imiquimod-induced psoriasis-like dermatitis and psoriasis patients. The findings showed that ceramides phosphate (CerP) and ceramides were enriched in psoriatic lesions compared with controls from both psoriasis patients and psoriasis-like mouse model. Psoriasis patients were classified into two subtypes, the CC1 and CC2, by consensus clustering of these lipid signatures. The CC1 was characterized by the higher levels of CerP, uric acid, and more severe psoriasis, compared with CC2 subtype. Interestingly, ceramide-1-phosphate (C1P), dramatically enriched in CC1 subtype, facilitated imiquimod-induced psoriasis-like inflammatory responses. Mechanistically, C1P induced the expression of inflammatory factors and activated DNA replication and cell cycle signaling pathways in the primary keratinocytes. Inhibiting the production of C1P with ceramide kinase inhibitor effectively alleviated the imiquimod-induced psoriasis-like inflammation. Taken together, we described the landscape of lipids alteration and established lipids classification based on pattern of abundance of lipids in psoriatic skin lesions. Suppression of C1P pathway is a novel potential strategy for psoriasis treatment.

LC-MS/MS-Based Absolute Quantitation of Hemoglobin Subunits from Dried Blood Spots Reveals Novel Biomarkers for α-Thalassemia Silent Carriers.

Identification of α-thalassemia silent carriers is challenging with conventional phenotype-based screening methods. A liquid chromatography tandem mass spectrometry (LC-MS/MS)-based approach may offer novel biomarkers to address this conundrum. In this study, we collected dried blood spot samples from individuals with three α-thalassemia subtypes for biomarker discovery and validation. We observed differential expression patterns of hemoglobin subunits among various α-thalassemia subtypes and normal controls through proteomic profiling of 51 samples in the discovery phase. Then, we developed and optimized a multiple reaction monitoring (MRM) assay to measure all detectable hemoglobin subunits. The validation phase was conducted in a cohort of 462 samples. Among the measured hemoglobin subunits, subunit µ was significantly upregulated in all the α-thalassemia groups with distinct fold changes. The hemoglobin subunit µ exhibits great potential as a novel biomarker for α-thalassemia, especially for silent α-thalassemia. We constructed predictive models based on the concentrations of hemoglobin subunits and their ratios to classify the various subtypes of α-thalassemia. In the binary classification problems of silent α-thalassemia vs normal, non-deletional α-thalassemia vs normal, and deletional α-thalassemia vs normal, the best performance of the models achieved average ROCAUCs of 0.9505, 0.9430, and 0.9976 in the cross-validation, respectively. In the multiclass model, the best performance achieved an average ROCAUC of 0.9290 in cross-validation. The performance of our MRM assay and models demonstrated that the hemoglobin subunit µ would play a vital role in screening silent α-thalassemia in clinical practice.

Initiation and duration of folic acid supplementation in preventing congenital malformations.

BACKGROUND: Folic acid (FA) supplementation is associated with a lower risk of the neural tube and heart defects and is recommended for women of childbearing age. Although there are detailed recommendations, differences in the initiation time and duration of FA supplementation remain poorly studied. METHODS: A multicentre prospective study of 17,713 women was conducted. The incidence of congenital malformations in women taking a recommended dosage (e.g. 0.4 or 0.8 mg/day) of FA was compared with that in women without supplementation. The predicted probability of malformations by the initiation time and duration of FA use was estimated to determine optimal options. RESULTS: Periconceptional FA supplementation was associated with a lower and insignificant risk of congenital malformations (1.59% vs. 2.37%; odds ratio [OR] 0.69; 95% confidence interval [CI]: 0.44-1.08), heart defects (3.8 vs. 8.0 per 1000 infants; OR, 0.47; 0.21-1.02), and neural tube defects (7.0 vs. 11.5 per 10,000 infants; OR, 0.64; 0.08-5.15). FA use after pregnancy provided greater protection against total malformations. Statistically significant associations were found in women who initiated FA supplementation in the first month of gestation (OR, 0.55; 95% CI: 0.33-0.91) and in those who supplemented for 1 to 2 months (OR, 0.59; 95% CI: 0.36-0.98). Similar results were found for heart defects. The optimal initiation time was 1.5 (optimal range: 1.1 to 1.9) months before pregnancy and a duration of 4.0 (3.7 to 4.4) months was reasonable to achieve the lowest risk of congenital malformations. Heart defect prevention required an earlier initiation (2.2 vs. 1.1 months before pregnancy) and a longer duration (4.7 vs. 3.7 months) than the prevention of other malformations. CONCLUSIONS: The timely initiation of FA supplementation for gestation was associated with a decreased risk of congenital malformations, which was mainly attributed to its protection against heart defects. The initiation of FA supplementation 1.5 months before conception with a duration of 4 months is the preferred option for congenital malformation prevention. TRIAL REGISTRATION: Chictr.org.cn identifier: ChiCTR-SOC-17010976.

Regulation of Interfacial Lattice Oxygen Activity by Full-Surface Modification Engineering towards Long Cycling Stability for Co-Free Li-Rich Mn-Based Cathode.

The construction of a protective layer for stabilizing anion redox reaction is the key to obtaining long cycling stability for Li-rich Mn-based cathode materials. However, the protection of the exposed surface/interface of the primary particles inside the secondary particles is usually ignored and difficult, let alone the investigation of the impact of the surface engineering of the internal primary particles on the cycling stability. In this work, an efficient method to regulate cycling stability is proposed by simply adjusting the distribution state of the boron nickel complexes coating layer. Theoretical calculation and experimental results display that the full-surface boron nickel complexes coating layer can not only passivate the activity of interface oxygen and improve its stability but also play the role of sharing voltage and protective layer to gradually activate the oxygen redox reaction during cycling. As a result, the elaborately designed cobalt-free Li-rich Mn-based cathode displays the highest discharge-specific capacity retentions of 91.1% after 400 cycles at 1 C and 94.3% even after 800 cycles at 5 C. In particular, the regulation strategy has well universality and is suitable for other high-capacity Li-rich cathode materials.