Tailored UPRE2 variants for dynamic gene regulation in yeast.

Genetic elements are foundational in synthetic biology serving as vital building blocks. They enable programming host cells for efficient production of valuable chemicals and recombinant proteins. The unfolded protein response (UPR) is a stress pathway in which the transcription factor Hac1 interacts with the upstream unfolded protein response element (UPRE) of the promoter to restore endoplasmic reticulum (ER) homeostasis. Here, we created a UPRE2 mutant (UPRE2m) library. Several rounds of screening identified many elements with enhanced responsiveness and a wider dynamic range. The most active element m84 displayed a response activity 3.72 times higher than the native UPRE2. These potent elements are versatile and compatible with various promoters. Overexpression of HAC1 enhanced stress signal transduction, expanding the signal output range of UPRE2m. Through molecular modeling and site-directed mutagenesis, we pinpointed the DNA-binding residue Lys60 in Hac1(Hac1-K60). We also confirmed that UPRE2m exhibited a higher binding affinity to Hac1. This shed light on the mechanism underlying the Hac1-UPRE2m interaction. Importantly, applying UPRE2m for target gene regulation effectively increased both recombinant protein production and natural product synthesis. These genetic elements provide valuable tools for dynamically regulating gene expression in yeast cell factories.

Prohibitin 1 regulates mtDNA release and downstream inflammatory responses.

Exposure of mitochondrial DNA (mtDNA) to the cytosol activates innate immune responses. But the mechanisms by which mtDNA crosses the inner mitochondrial membrane are unknown. Here, we found that the inner mitochondrial membrane protein prohibitin 1 (PHB1) plays a critical role in mtDNA release by regulating permeability across the mitochondrial inner membrane. Loss of PHB1 results in alterations in mitochondrial integrity and function. PHB1-deficient macrophages, serum from myeloid-specific PHB1 KO (Phb1MyeKO) mice, and peripheral blood mononuclear cells from neonatal sepsis patients show increased interleukin-1ß (IL-1ß) levels. PHB1 KO mice are also intolerant of lipopolysaccharide shock. Phb1-depleted macrophages show increased cytoplasmic release of mtDNA and inflammatory responses. This process is suppressed by cyclosporine A and VBIT-4, which inhibit the mitochondrial permeability transition pore (mPTP) and VDAC oligomerization. Inflammatory stresses downregulate PHB1 expression levels in macrophages. Under normal physiological conditions, the inner mitochondrial membrane proteins, AFG3L2 and SPG7, are tethered to PHB1 to inhibit mPTP opening. Downregulation of PHB1 results in enhanced interaction between AFG3L2 and SPG7, mPTP opening, mtDNA release, and downstream inflammatory responses.

Comprehensive exploration of multi-modal and multi-branch imaging markers for autism diagnosis and interpretation: insights from an advanced deep learning model.

Autism spectrum disorder is a complex neurodevelopmental condition with diverse genetic and brain involvement. Despite magnetic resonance imaging advances, autism spectrum disorder diagnosis and understanding its neurogenetic factors remain challenging. We propose a dual-branch graph neural network that effectively extracts and fuses features from bimodalities, achieving 73.9% diagnostic accuracy. To explain the mechanism distinguishing autism spectrum disorder from healthy controls, we establish a perturbation model for brain imaging markers and perform a neuro-transcriptomic joint analysis using partial least squares regression and enrichment to identify potential genetic biomarkers. The perturbation model identifies brain imaging markers related to structural magnetic resonance imaging in the frontal, temporal, parietal, and occipital lobes, while functional magnetic resonance imaging markers primarily reside in the frontal, temporal, occipital lobes, and cerebellum. The neuro-transcriptomic joint analysis highlights genes associated with biological processes, such as "presynapse," "behavior," and "modulation of chemical synaptic transmission" in autism spectrum disorder's brain development. Different magnetic resonance imaging modalities offer complementary information for autism spectrum disorder diagnosis. Our dual-branch graph neural network achieves high accuracy and identifies abnormal brain regions and the neuro-transcriptomic analysis uncovers important genetic biomarkers. Overall, our study presents an effective approach for assisting in autism spectrum disorder diagnosis and identifying genetic biomarkers, showing potential for enhancing the diagnosis and treatment of this condition.

Enhanced group-level dorsolateral prefrontal cortex subregion parcellation through functional connectivity-based distance-constrained spectral clustering with application to autism spectrum disorder.

The dorsolateral prefrontal cortex (DLPFC) assumes a central role in cognitive and behavioral control, emerging as a crucial target region for interventions in autism spectrum disorder neuroregulation. Consequently, we endeavor to unravel the functional subregions within the DLPFC to shed light on the intricate functions of the brain. We introduce a distance-constrained spectral clustering (SC-DW) methodology that leverages functional connection to identify distinctive functional subregions within the DLPFC. Furthermore, we verify the relationship between the functional characteristics of these subregions and their clinical implications. Our methodology begins with principal component analysis to extract the salient features. Subsequently, we construct an adjacency matrix, which is constrained by the spatial properties of the brain, by linearly combining the distance matrix and a similarity matrix. The quality of spectral clustering is further optimized through multiple cluster evaluation coefficient. The results from SC-DW revealed four uniform and contiguous subregions within the bilateral DLPFC. Notably, we observe a substantial positive correlation between the functional characteristics of the third and fourth subregions in the left DLPFC with clinical manifestations. These findings underscore the unique insights offered by our proposed methodology in the realms of brain subregion delineation and therapeutic targeting.

Small nucleolar RNA Snora73 promotes psoriasis progression by sponging miR-3074-5p and regulating PBX1 expression.

Chronic psoriasis is a kind of immune-mediated skin illness and the underlying molecular mechanisms of pathogenesis remain incompletely understood. Here, we used small RNA microarray assays to scan the differential expressed RNAs in psoriasis patient samples. The downstream miRNAs and its targets were predicted using bioinformatics analysis from online bases and confirmed using fluorescence in situ hybridization and dual­luciferase report gene assay. Cell ability of proliferation and migration were detected using CCK-8 and transwell assays. The results showed that a new snoRNA Snora73 was upregulated in psoriasis patient samples. Overexpression of Snora73 significantly increased psoriasis cells viability and migration, while knockdown of Snora73 got the opposite results. Mechanistically, our results showed that Snora73 acted as a sponge for miR-3074-5p and PBX1 is a direct target of miR-3074-5p in psoriasis cells. Furthermore, miR-3074-5p suppressed psoriasis cell proliferation and migration, while PBX1 promoted cell proliferation and migration in psoriasis. Collectively, these findings reveal a crucial role of Snora73 in progression of psoriasis through miR-3074-5p/PBX1 signaling pathway and suggest a potential therapeutic strategy.

Overexpressing S100A9 ameliorates NK cell dysfunction in estrogen receptor-positive breast cancer.

BACKGROUND: Estrogen receptor (ER) positive human epidermal growth factor receptor 2 (HER2) negative breast cancer (ER+/HER2-BC) and triple-negative breast cancer (TNBC) are two distinct breast cancer molecular subtypes, especially in tumor immune microenvironment (TIME). The TIME of TNBC is considered to be more inflammatory than that of ER+/HER2-BC. Natural killer (NK) cells are innate lymphocytes that play an important role of tumor eradication in TME. However, studies focusing on the different cell states of NK cells in breast cancer subtypes are still inadequate. METHODS: In this study, single-cell mRNA sequencing (scRNA-seq) and bulk mRNA sequencing data from ER+/HER2-BC and TNBC were analyzed. Key regulator of NK cell suppression in ER+/HER2-BC, S100A9, was quantified by qPCR and ELISA in MCF-7, T47D, MDA-MB-468 and MDA-MB-231 cell lines. The prognosis predictability of S100A9 and NK activation markers was evaluated by Kaplan-Meier analyses using TCGA-BRAC data. The phenotype changes of NK cells in ER+/HER2-BC after overexpressing S100A9 in cancer cells were evaluated by the production levels of IFN-gamma, perforin and granzyme B and cytotoxicity assay. RESULTS: By analyzing scRNA-seq data, we found that multiple genes involved in cellular stress response were upregulated in ER+/HER2-BC compared with TNBC. Moreover, TLR regulation pathway was significantly enriched using differentially expressed genes (DEGs) from comparing the transcriptome data of ER+/HER2-BC and TNBC cancer cells, and NK cell infiltration high/low groups. Among the DEGs, S100A9 was identified as a key regulator. Patients with higher expression levels of S100A9 and NK cell activation markers had better overall survival. Furthermore, we proved that overexpression of S100A9 in ER+/HER2-cells could improve cocultured NK cell function. CONCLUSION: In conclusion, the study we presented demonstrated that NK cells in ER+/HER2-BC were hypofunctional, and S100A9 was an important regulator of NK cell function in ER+BC. Our work contributes to elucidate the regulatory networks between cancer cells and NK cells and may provide theoretical basis for novel drug development.

Error compensation for near optical coaxial phase measuring deflectometry with refraction error model.

Phase measuring deflectometry (PMD) is a key measurement technology for specular surfaces form measurement. Compared with conventional PMD techniques, the near optical coaxial PMD (NCPMD) can achieve compact configuration, light weight and reducing measurement error caused by shadows of the surface structures through utilizing a plate beamsplitter. However, the introduction of the plate beamsplitter will affect the measurement accuracy of the NCPMD system. The refraction of the plate beamsplitter needs to be considered. In this work, a virtual system of NCPMD was established, and an error model of the NCPMD system by considering the refraction influence of the plate beamsplitter was presented to analyze the shape reconstruction error caused by the plate beamsplitter. Moreover, the calibration method of the beamsplitter and the ray tracing algorithm to achieve error compensation of the beamsplitter were proposed. The proposed error compensation method can effectively improve the measurement accuracy of NCPMD system which has been confirmed by surface measurement experiments.

Downregulation of PTPRT elevates the expression of survivin and promotes the proliferation, migration, and invasion of lung adenocarcinoma.

BACKGROUND: Receptor-type tyrosine-protein phosphatase T (PTPRT) is a transmembrane protein that is involved in cell adhesion. We previously found that PTPRT was downregulated in multiple cancer types and the mutation of PTPRT was associated with cancer early metastasis. However, the impacts of PTPRT downregulation on tumour proliferation, invasion, and clinical interventions such as immune checkpoint inhibitor (ICI) therapies remained largely unknown. METHODS: Gene expression data of non-small cell lung cancer (NSCLC) samples from The Cancer Genome Atlas database were downloaded and used to detect the differential expressed genes between PTPRT-high and PTPRT-low subgroups. Knockdown and overexpress of PTPRT in lung cancer cell lines were performed to explore the function of PTPRT in vitro. Western blot and qRT-PCR were used to evaluate the expression of cell cycle-related genes. CCK-8 assays, wound-healing migration assay, transwell assay, and colony formation assay were performed to determine the functional impacts of PTPRT on cell proliferation, migration, and invasion. KM-plotter was used to explore the significance of selected genes on patient prognosis. RESULTS: PTPRT was found to be downregulated in tumours and lung cancer cell lines compared to normal samples. Cell cycle-related genes (BIRC5, OIP5, and CDCA3, etc.) were specifically upregulated in PTPRT-low lung adenocarcinoma (LUAD). Modulation of PTPRT expression in LUAD cell lines affected the expression of BIRC5 (survivin) significantly, as well as the proliferation, migration, and invasion of tumour cells. In addition, low PTPRT expression level was correlated with worse prognosis of lung cancer and several other cancer types. Furthermore, PTPRT downregulation was associated with elevated tumour mutation burden and tumour neoantigen burden in lung cancer, indicating the potential influence on tumour immunogenicity. CONCLUSION: Our findings uncovered the essential roles of PTPRT in the regulation of proliferation, migration, and invasion of LUAD, and highlighted the clinical significance of PTPRT downregulation in lung cancer.

TIMP-3 Alleviates White Matter Injury After Subarachnoid Hemorrhage in Mice by Promoting Oligodendrocyte Precursor Cell Maturation.

Subarachnoid hemorrhage (SAH) is associated with high mortality and disability rates, and secondary white matter injury is an important cause of poor prognosis. However, whether brain capillary pericytes can directly affect the differentiation and maturation of oligodendrocyte precursor cells (OPCs) and subsequently affect white matter injury repair has still been revealed. This study was designed to investigate the effect of tissue inhibitor of metalloproteinase-3 (TIMP-3) for OPC differentiation and maturation. PDGFRßret/ret and wild-type C57B6J male mice were used to construct a mouse model of SAH via endovascular perforation in this study. Mice were also treated with vehicle, TIMP-3 RNAi or TIMP-3 RNAi + TIMP-3 after SAH. The effect of TIMP-3 on the differentiation and maturation of OPCs was determined using behavioral score, ELISA, transmission electron microscopy, immunofluorescence staining and cell culture. We found that TIMP-3 was secreted mainly by pericytes and that SAH and TIMP-3 RNAi caused a significant decrease in the TIMP-3 content, reaching a nadir at 24 h, followed by gradual recovery. In vitro, the myelin basic protein content of oligodendrocytes after oxyhemoglobin treatment was increased by TIMP-3 overexpression. The data indicates TIMP-3 could promote the differentiation and maturation of OPCs and subsequently improve neurological outcomes after SAH. Therefore, TIMP-3 could be beneficial for repair after white matter injury and could be a potential therapeutic target in SAH.

Contamination bias in the estimation of child maltreatment causal effects on adolescent internalizing and externalizing behavior problems.

BACKGROUND: When unaddressed, contamination in child maltreatment research, in which some proportion of children recruited for a nonmaltreated comparison group are exposed to maltreatment, downwardly biases the significance and magnitude of effect size estimates. This study extends previous contamination research by investigating how a dual-measurement strategy of detecting and controlling contamination impacts causal effect size estimates of child behavior problems. METHODS: This study included 634 children from the LONGSCAN study with 63 cases of confirmed child maltreatment after age 8 and 571 cases without confirmed child maltreatment. Confirmed child maltreatment and internalizing and externalizing behaviors were recorded every 2 years between ages 4 and 16. Contamination in the nonmaltreated comparison group was identified and controlled by either a prospective self-report assessment at ages 12, 14, and 16 or by a one-time retrospective self-report assessment at age 18. Synthetic control methods were used to establish causal effects and quantify the impact of contamination when it was not controlled, when it was controlled for by prospective self-reports, and when it was controlled for by retrospective self-reports. RESULTS: Rates of contamination ranged from 62% to 67%. Without controlling for contamination, causal effect size estimates for internalizing behaviors were not statistically significant. Causal effects only became statistically significant after controlling contamination identified from either prospective or retrospective reports and effect sizes increased by between 17% and 54%. Controlling contamination had a smaller impact on effect size increases for externalizing behaviors but did produce a statistically significant overall effect, relative to the model ignoring contamination, when prospective methods were used. CONCLUSIONS: The presence of contamination in a nonmaltreated comparison group can underestimate the magnitude and statistical significance of causal effect size estimates, especially when investigating internalizing behavior problems. Addressing contamination can facilitate the replication of results across studies.

Discovery and Bioinspired Synthesis of Salpratone A.

Salpratone A (1), a novel abietane diterpenoid containing a unique cis-fused A/B ring, was isolated from Salvia prattii. Bioactivity studies showed that 1 has potent activity in inhibiting platelet aggregation induced by multiple agonists as well as antithrombotic efficacy in the FeCl3-induced rat in vivo thrombosis model. Furthermore, a bioinspired synthesis of 1 from the abundant natural product ferruginol was achieved in 6 steps with a 22% overall yield. The key steps include a stereoselective allyl oxidation and a subsequent regioselective Meinwald rearrangement.

MiR-214_L-1R+4 regulate gossypol-induced immune response through MyD88-dependent signaling pathway in Cyprinus carpio.

MicroRNAs (miRNAs) have been demonstrated to act as crucial modulators with considerable impacts on the immune system. Cottonseed meal is often used as a protein source in aqua feed, cottonseed meal contains gossypol, which is harmful to animals. However, there is a lack of research on the role of miRNAs in fish exposed to gossypol stress. To determine the regulatory effects of miRNAs on gossypol toxicity, Cyprinus carpio were given to oral administration of 20 mg/kg gossypol for 7 days, and the gossypol concentration in the tissues was tested. Then, we detected spleen index, histology, immune enzyme activities of fish induced by gossypol. The results of miRNA sequencing revealed 8 differentially expressed miRNAs in gossypol group, and miR-214_L-1R+4 was found involved in immune response induced by gossypol. The potential targets of miR-214_L-1R+4 were predicted, and found a putative miR-214_L-1R+4 binding site in the 3'UTR of MyD88a. Furthermore, dual-luciferase reporter assays displayed miR-214_L-1R+4 decreased MyD88a expression through binding to the 3'UTR of MyD88a. Moreover, miR-214_L-1R+4 antagomir were intraperitoneally administered to C. carpio, down-regulated miR-214_L-1R+4 could increase MyD88a expression, as well as inflammatory cytokines and anti-inflammatory cytokines expression. These findings revealed that miR-214_L-1R+4 via the MyD88-dependent signaling pathway modulate the immune response to gossypol in C. carpio spleen.

Light-Induced, Structural Matrix Guided Stepwise Spin-State Switching in 3d-5d Molecular Assembly.

A new iron(II) molecular complex {[W(CN)8][Fe(bik*)3]2}BF4·7H2O·1.5CH3OH (1.7H2O·1.5CH3OH) was synthesized using a versatile octacyanotungstate(V) building block and N-donor bidentate ligand (bik* = bis(1-ethyl-1H-imidazol-2-yl)ketone) and detailed characterizations were carried out. The crystal structure of 1.7H2O·1.5CH3OH is composed of an ionic salt from one anionic [W(CN)8]3- unit, two isolated cationic [Fe(bik*)3]2+ units, and one BF4- counteranion in the asymmetric unit. Magnetic studies of 1.7H2O·1.5CH3OH display interesting two-step reversible thermo-induced spin-state switching and the partially desolvated form 1.7H2O shows a photomagnetic effect at low temperatures. Additionally, the physical properties of 1.7H2O·1.5CH3OH were compared with the monomeric unit of {[Fe(bik*)3]2}·4ReO4·H2O (2.H2O) and detailed photophysical investigations were also performed to study the effect of a structural matrix {[W(CN)8]3- and ReO4- unit} on the spin-state switching properties of the [Fe(bik*)3]2+ unit in both systems (1.7H2O·1.5CH3OH and 2.H2O).

Classification of major depressive disorder using an attention-guided unified deep convolutional neural network and individual structural covariance network.

Major depressive disorder (MDD) is the second leading cause of disability worldwide. Currently, the structural magnetic resonance imaging-based MDD diagnosis models mainly utilize local grayscale information or morphological characteristics in a single site with small samples. Emerging evidence has demonstrated that different brain structures in different circuits have distinct developmental timing, but mature coordinately within the same functional circuit. Thus, establishing an attention-guided unified classification framework with deep learning and individual structural covariance networks in a large multisite dataset could facilitate developing an accurate diagnosis strategy. Our results showed that attention-guided classification could improve the classification accuracy from primary 75.1% to ultimate 76.54%. Furthermore, the discriminative features of regional covariance connectivities and local structural characteristics were found to be mainly located in prefrontal cortex, insula, superior temporal cortex, and cingulate cortex, which have been widely reported to be closely associated with depression. Our study demonstrated that our attention-guided unified deep learning framework may be an effective tool for MDD diagnosis. The identified covariance connectivities and structural features may serve as biomarkers for MDD.

The regulatory relationship between transcription factor STAT3 and noncoding RNA.

Signal transducer and activator of transcription 3 (STAT3), as a key node in numerous carcinogenic signaling pathways, is activated in various tumor tissues and plays important roles in tumor formation, metastasis, and drug resistance. STAT3 is considered a potential subtarget for tumor therapy. Noncoding RNA (ncRNA) is a special type of RNA transcript. Transforming from "junk" transcripts into key molecules involved in cell apoptosis, growth, and functional regulation, ncRNA has been proven to be closely related to various epithelial-mesenchymal transition and drug resistance processes in tumor cells over the past few decades. Research on the relationship between transcription factor STAT3 and ncRNAs has attracted increased attention. To date, existing reviews have mainly focused on the regulation by ncRNAs on the transcription factor STAT3; there has been no review of the regulation by STAT3 on ncRNAs. However, understanding the regulation of ncRNAs by STAT3 and its mechanism is important to comprehensively understand the mutual regulatory relationship between STAT3 and ncRNAs. Therefore, in this review, we summarize the regulation by transcription factor STAT3 on long noncoding RNA, microRNA, and circular RNA and its possible mechanisms. In addition, we provide an update on research progress on the regulation of STAT3 by ncRNAs. This will provide a new perspective to comprehensively understand the regulatory relationship between transcription factor STAT3 and ncRNAs, as well as targeting STAT3 or ncRNAs to treat diseases such as tumors.

A spontaneous hyperglycaemic cynomolgus monkey presents cognitive deficits, neurological dysfunction and cataract.

Chronic hyperglycaemia is a chief feature of diabetes mellitus and complicates with many systematic anomalies. Non-human primates (NHPs) are excellent for studying hyperglycaemia or diabetes and associated comorbidities, but lack behavioural observation. In the study, behavioural, brain imaging and histological analysis were performed in a case of spontaneously hyperglycaemic (HGM) Macaca fascicularis. The results were shown that the HGM monkey had persistent body weight loss, long-term hyperglycaemia, insulin resistance, dyslipidemia, but normal concentrations of insulin, C-peptide, insulin autoantibody, islet cell antibody and glutamic acid decarboxylase antibody. Importantly, an impaired working memory in a delayed response task and neurological dysfunctions were found in the HGM monkey. The tendency for atrophy in hippocampus was observed by magnetic resonance imaging. Lenticular opacification, lens fibres disruptions and vacuole formation also occurred to the HGM monkey. The data suggested that the spontaneous HGM monkey might present diabetes-like characteristics and associated neurobehavioral anomalies in this case. This study first reported cognitive deficits in a spontaneous hyperglycaemia NHPs, which might provide evidence to use macaque as a promising model for translational research in diabetes and neurological complications.

Nail psoriasis in China: A prospective multicentre study.

BACKGROUND: Data on nail psoriasis (PsO) in China are scarce. OBJECTIVES: To provide nail PsO-related data regarding epidemiologic characteristics, manifestations, fungal infections, arthritic complaints and treatments that may facilitate improved patient management globally. METHODS: From August 2021 to August 2022, patients with nail PsO were enrolled in a prospective multicentre observational study at 25 hospitals in China. We collected and analysed data concerning nail PsO demography, clinical signs, fungal detection, arthritic symptoms and treatment. RESULTS: A total of 817 patients with nail PsO were involved, with a mean body mass index of 24.13 ± 2.93. In addition, 71.41% of the patients were male. The Nail PsO Severity Index score was weakly positively correlated with body surface area. The percentage of nail involvement was 95.29% for fingernails and 57.18% for toenails, with pitting (67.11%) and subungual hyperkeratosis (60.40%) being the most prevalent manifestations, respectively. Toenails showed a significantly higher frequency of nailfold scales, subungual hyperkeratosis and nail plate crumbling and a lower frequency of splinter haemorrhages, pitting and erythema of the lunula. A total of 13.26% of the PsO patients had onychomycosis, and 77.08% were observed in the toenails. Articular symptoms were reported by 12.17% of the patients, with the peripheral type being predominant. Significant associations between articular symptoms and nailfold swelling, subungual hyperkeratosis, nailfold scales, onycholysis and longitudinal ridges were found. Only 2.30% (20 out of 871) of patients with nail PsO received treatment. The most frequently employed therapy for cutaneous PsO with nail involvement was biologic therapy (n = 366). CONCLUSIONS: PsO showed distinct manifestations in the toenails and fingernails. Additionally, toenail PsO combined with onychomycosis requires special attention. Articular symptoms in psoriatic patients are associated with specific nail changes. It is important to research and advocate for more potent treatments for nail PsO.

Efficacy and safety of topical minocycline foam (FMX101 4%) in treatment of Chinese subjects with moderate-to-severe facial acne vulgaris: A phase 3, multi-centre, randomized, double-blind, vehicle-controlled study.

BACKGROUND: FMX101 4%, as a topical foam formulation of minocycline, has been approved by US Food and Drug Administration for the treatment of moderate-to-severe acne vulgaris (AV). OBJECTIVE: To evaluate the efficacy and safety of FMX101 4% in treating Chinese subjects with moderate-to-severe facial AV. METHODS: This was a multi-centre, randomized, double-blind, vehicle-controlled phase 3 study in Chinese subjects with moderate-to-severe AV. Eligible subjects were randomized 2:1 to receive either FMX101 4% or vehicle foam treatment for 12 weeks. The primary efficacy endpoint was the change in inflammation lesion count (ILC) from baseline at week 12. The key secondary endpoint was the treatment success rate according to Investigator's Global Assessment (IGA) at week 12. RESULTS: In total, 372 subjects were randomized into two groups (FMX101 4% group, n = 248; vehicle group, n = 124). After 12 weeks treatment, the reduction in ILC from baseline was statistically significant in favour of FMX101 4%, compared with vehicle foam (-21.0 [0.08] vs. -12.3 [1.14]; LSM [SE] difference, -8.7 [1.34]; 95% CI [-11.3, -6.0]; p < 0.001). FMX101 4% treatment yielded significantly higher IGA treatment success rate at week 12 as compared to the control treatment (8.06% vs. 0%). Applying FMX101 4% also resulted in significant reduction in noninflammatory lesion count (nILC) versus vehicle foam at week 12 (-19.4 [1.03] vs. -14.9 [1.47]; LSM [SE] difference, -4.5 [1.74]; 95% CI [-8.0, -1.1]; p = 0.009). Most treatment-emergent adverse events (TEAEs) were mild-to-moderate in severity, and no treatment-related treatment-emergent serious adverse event (TESAE) occurred. Thus, FMX101 4% was considered to be a safe and well-tolerated product during the 12-week treatment period. CONCLUSION: FMX101 4% treatment for 12 weeks could lead to significantly reduced ILC and nILC, and improved IGA treatment success rate in Chinese subjects with moderate-to-severe facial AV. It also showed a well acceptable safe and tolerability profile.

Effects of castration and eucalyptus oil supplementation on growth performance, nutrient digestibility, and blood-immunity indicators of male Holstein calves.

The purpose of this study was to investigate the effects of early castration and eucalyptus oil (EUC) supplementation on dry matter intake (DMI), growth performance, and immune response of Holstein calves. Fifty-six male Holstein calves 52 d old and with an initial body weight (BW) of 63.5 ± 5.27 kg were used. The animals were blocked by BW and randomly assigned into 1 of the 4 treatment groups in a randomized complete block design with a 2 (no castration vs. castration) × 2 (without vs. with EUC) factorial arrangement of treatments. The treatments were (1) uncastrated calves fed without EUC, (2) uncastrated calves fed 0.5 g/d EUC (EUC group), (3) castrated calves (steers) fed without EUC (castrated group), and (4) steers fed with 0.5 g/d EUC (castrated + EUC). The experiment was 8 wk long, including pre- and postweaning (weaned at 72 d). The EUC × castrated interactions were not significant for DMI, growth performance, nutrient digestibility, and immune response. Castration did not affect the DMI, final BW, average daily gain (ADG), or feed efficiency, except that the ADG was greater for bull calves than for steers at postweaning. Supplementation with EUC increased DMI pre- and postweaning and increased the ADG of weaned calves. Digestibility in the total digestive tract was not affected by castration (except for organic matter digestibility), whereas adding EUC improved the digestibility of dry matter, acid detergent fiber, and crude protein. Blood concentration of IL-6 at d 94 was decreased by feeding EUC. These results indicate that the EUC could be fed to either intact or castrated dairy calves to promote growth and health postweaning; castration before weaning may reduce ADG and cause inflammatory stress without affecting feed intake or feed efficiency.

Multiple Imputation with Factor Scores: A Practical Approach for Handling Simultaneous Missingness Across Items in Longitudinal Designs.

Missingness in intensive longitudinal data triggered by latent factors constitute one type of nonignorable missingness that can generate simultaneous missingness across multiple items on each measurement occasion. To address this issue, we propose a multiple imputation (MI) strategy called MI-FS, which incorporates factor scores, lag/lead variables, and missing data indicators into the imputation model. In the context of process factor analysis (PFA), we conducted a Monte Carlo simulation study to compare the performance of MI-FS to listwise deletion (LD), MI with manifest variables (MI-MV, which implements MI on both dependent variables and covariates), and partial MI with MVs (PMI-MV, which implements MI on covariates and handles missing dependent variables via full-information maximum likelihood) under different conditions. Across conditions, we found MI-based methods overall outperformed the LD; the MI-FS approach yielded lower root mean square errors (RMSEs) and higher coverage rates for auto-regression (AR) parameters compared to MI-MV; and the PMI-MV and MI-MV approaches yielded higher coverage rates for most parameters except AR parameters compared to MI-FS. These approaches were also compared using an empirical example investigating the relationships between negative affect and perceived stress over time. Recommendations on when and how to incorporate factor scores into MI processes were discussed.