NK-cell-elicited gasdermin-D-dependent hepatocyte pyroptosis induces neutrophil extracellular traps that facilitate HBV-related acute-on-chronic liver failure.

BACKGROUND AND AIMS: HBV infection is a major etiology of acute-on-chronic liver failure (ACLF). At present, the pattern and regulation of hepatocyte death during HBV-ACLF progression are still undefined. Evaluating the mode of cell death and its inducers will provide new insights for developing therapeutic strategies targeting cell death. In this study, we aimed to elucidate whether and how immune landscapes trigger hepatocyte death and lead to the progression of HBV-related ACLF. APPROACH AND RESULTS: We identified that pyroptosis represented the main cell death pattern in the liver of patients with HBV-related ACLF. Deficiency of MHC-I in HBV-reactivated hepatocytes activated cytotoxic NK cells, which in turn operated in a perforin/granzyme-dependent manner to trigger GSDMD/caspase-8-dependent pyroptosis of hepatocytes. Neutrophils selectively accumulated in the pyroptotic liver, and HMGB1 derived from the pyroptotic liver constituted an important factor triggering the generation of pathogenic extracellular traps in neutrophils (NETs). Clinically, elevated plasma levels of myeloperoxidase-DNA complexes were a promising prognostic biomarker for HBV-related ACLF. More importantly, targeting GSDMD pyroptosis-HMGB1 release in the liver abrogates NETs that intercept the development of HBV-related ACLF. CONCLUSIONS: Studying the mechanisms that selectively modulate GSDMD-dependent pyroptosis, as well as its immune landscapes, will provide a novel strategy for restoring the liver function of patients with HBV-related ACLF.

Genomes of autotetraploid wild and cultivated Ziziphus mauritiana reveal polyploid evolution and crop domestication.

Indian jujube (Ziziphus mauritiana) holds a prominent position in the global fruit and pharmaceutical markets. Here, we report the assemblies of haplotype-resolved, telomere-to-telomere genomes of autotetraploid wild and cultivated Indian jujube plants using a two-stage assembly strategy. The generation of these genomes permitted in-depth investigations into the divergence and evolutionary history of this important fruit crop. Using a graph-based pan-genome constructed from eight monoploid genomes, we identified structural variation (SV)-FST hotspots and SV hotspots. Gap-free genomes provide a means to obtain a global view of centromere structures. We identified presence-absence variation-related genes in four monoploid genomes (cI, cIII, wI, and wIII) and resequencing populations. We also present the population structure and domestication trajectory of the Indian jujube based on the resequencing of 73 wild and cultivated accessions. Metabolomic and transcriptomic analyses of mature fruits of wild and cultivated accessions unveiled the genetic basis underlying loss of fruit astringency during domestication of Indian jujube. This study reveals mechanisms underlying the divergence, evolution, and domestication of the autotetraploid Indian jujube and provides rich and reliable genetic resources for future research.

The interaction effect between BMI, diabetes and age at diabetes onset on the risk of thyroid cancer: A population-based cohort study in Shanghai, China.

AIM: To determine the association of the presence of diabetes and, among persons with diabetes, the age at type 2 diabetes mellitus (T2DM) onset, BMI and the interactive effect with the subsequent thyroid cancer risk. MATERIALS AND METHODS: We conducted a population register-based longitudinal cohort study in Shanghai, including 428 568 persons with new-onset T2DM matched with the general population. The risk of thyroid cancer among subgroups was calculated based on standardized incidence ratio (SIR), hazard ratio (HR) and Cox proportional hazards models. RESULTS: In total, 1142 thyroid cancer cases were identified during 8 years of follow-up, with an incidence rate of 59.01/100 000 person-years and a higher risk (SIR = 1.21) compared with the general population. The earlier age at T2DM onset and higher BMI were associated with an increasing risk of thyroid cancer independently (onset age <50, SIR: 1.46; BMI ≥30.0 kg/m2, SIR: 1.93), with the highest risk in patients with both BMI ≥30.0 kg/m2 and onset age <50 years (SIR = 3.91, HR = 3.04). Among patients with T2DM onset age <60 years, SIR increased with higher BMI, while there were no trends when onset age ≥60 years. Among patients with BMI ≥25.0 kg/m2, SIR increased with an earlier onset age, whereas no trends were shown in the BMI <24.9 kg/m2 groups. Obese (BMI ≥30.0 kg/m2) patients had a significantly higher HR of thyroid cancer only when T2DM onset age <60 years. CONCLUSIONS: Both earlier age of T2DM onset (<50 years) and higher BMI (≥30 kg/m2) contributed to the higher risk of thyroid cancer. Patients with young-onset T2DM and obesity are considered more vulnerable to thyroid cancer development.

Native mass spectrometry analysis of conjugated HSA and BSA complexes with various flavonoids.

Mass spectrometry was used to study the binding interaction between serum albumin proteins (BSA and HSA) and flavone dyes, which is known to induce large fluorescence signals for protein detection. By electrospray ionization mass spectrometry (ESI-MS), multiple charged species/states could be produced in ammonium acetate buffer, while preserving the native structures of the proteins. Subsequent introduction of a flavone dye into the buffered solution resulted in an immediate interaction, forming the respective protein-dye conjugates associated by non-covalent interactions. Formation of protein-dye conjugates induced a notable response in the ESI-MS spectra, including changes in both the charge states and molecular mass of the protein species. The resulting data pointed out that the protein-flavone dye maintained a 1 : 1 ratio in the conjugate, although multiple binding sites for drug molecules are present in albumin proteins.

A novel colorectal cancer screening framework with feature interpretability to identify high-risk populations for colonoscopy.

BACKGROUND AND AIM: Risk assessment is of paramount importance for the detection and treatment of colorectal cancer. We developed and validated a feature interpretability screening framework to identify high-risk populations and recommend colonoscopy for them. METHODS: We utilized a training cohort consisting of 1 252 605 participants who underwent colonoscopies in Shanghai from 2013 to 2015 to develop the screening framework. We incorporated Shapley additive explanation values into feature selection to provide interpretability for the framework. Two sampling methods were separately employed to mitigate potential model bias caused by class imbalance. Furthermore, we employed various machine learning algorithms to construct risk assessment models and compared their performance. We tested the screening models on an external validation cohort of 359 462 samples and conducted comprehensive evaluation and statistical analysis of the validation results. RESULTS: The external validation results demonstrated that the models in the proposed framework achieved sensitivity over 0.734, specificity over 0.790, and area under the receiver operating characteristic curve ranging from 0.808 to 0.859. In the predictions of the best-performing model, the prevalence rates of colorectal cancer were 0.059% and 1.056% in the low- and high-risk groups, respectively. If colonoscopies were performed only on the high-risk group predicted by the model, only 14.36% of total colonoscopies would be needed to detect 74.86% of colorectal cancer cases. CONCLUSIONS: We developed and validated a novel framework to identify populations at high risk for colorectal cancer. Those classified as high risk should undergo colonoscopy for further diagnosis.

Efficacy, immunogenicity and safety of respiratory syncytial virus prefusion F vaccine: systematic review and meta-analysis.

OBJECTIVE: A notable research gap exists in the systematic review and meta-analysis concerning the efficacy, immunogenicity, and safety of the respiratory syncytial virus (RSV) prefusion F vaccine. METHODS: We conducted a comprehensive search across PubMed, Embase, the Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov to retrieve articles related to the efficacy, immunogenicity, and safety of RSV prefusion F vaccines, published through September 8, 2023. We adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. RESULTS: A total of 22 randomized controlled trials involving 78,990 participants were included in this systematic review and meta-analysis. The RSV prefusion F vaccine exhibited a vaccine effectiveness of 68% (95% CI: 59-75%) against RSV-associated acute respiratory illness, 70% (95% CI: 60-77%) against medically attended RSV-associated lower respiratory tract illness, and 87% (95% CI: 71-94%) against medically attended severe RSV-associated lower respiratory tract illness. Common reported local adverse reactions following RSV prefusion F vaccination include pain, redness, and swelling at the injection site, and systemic reactions such as fatigue, headache, myalgia, arthralgia, nausea, and chills. CONCLUSIONS: Our meta-analysis suggests that vaccines using the RSV prefusion F protein as antigen exhibit appears broadly acceptable efficacy, immunogenicity, and safety in the population. In particular, it provides high protective efficiency against severe RSV-associated lower respiratory tract disease.

Body mass index, diet, and outdoor activity linked with meibomian gland abnormalities in children.

SIGNIFICANCE: Dry eye disease is frequently underdiagnosed in pediatric patients. Meibomian gland morphology abnormalities (atrophy and tortuosity) may be associated with dry eye. This study examined risk factors for gland morphology abnormalities in children. PURPOSE: This study aimed to characterize meibomian gland morphological abnormalities (atrophy and tortuosity) and identify risk factors for the same in children. METHODS: A total of 160 children, primarily African American and Hispanic, aged 5 to <18 years underwent a comprehensive eye exam including slit-lamp examination to evaluate the meibomian glands, conjunctival papillae, and tear film. Infrared photography was performed including assessment of noninvasive tear film breakup time and tear meniscus height. Meibomian gland atrophy and tortuosity were assessed. A modified Ocular Surface Disease Index survey was administered along with surveys on screen time, diet, and outdoor activity. Linear multiple regression was performed to determine risk factors for meibomian gland abnormalities. RESULTS: The average age of participants (76 male, 84 female) was 10.9 ± 3.0 years. Severe meibomian gland atrophy (score ≥2) was found in 31.0% of participants in at least one eyelid. Severe meibomian gland tortuosity (score ≥2) was found in 84.0% of participants in at least one eyelid. The median symptom score was 9.8 (range, 0 to 71), with 16.9, 8.8, and 12.5% of the children having mild, moderate, and severe dry eye symptoms, respectively. Elevated body mass index (p<0.001), reduced outdoor activity (p=0.02), and unhealthy diet (p=0.01) were found to be risk factors for meibomian gland abnormalities. Screen time, symptom score, age, gender, and race/ethnicity were not associated with gland abnormalities (all p values >0.05). CONCLUSIONS: This study determined that meibomian gland morphological abnormalities were commonly found in children aged 5 to <18 years. Risk factors for these abnormalities include elevated body mass index, an unhealthy diet, and reduced outdoor activity.

Longitudinal refractive errors over 36 months in Hispanic and Black children.

SIGNIFICANCE: This study brings awareness of racial/ethnic difference of refractive error characteristics in clinics. PURPOSE: This study aimed to assess longitudinal change in refractive errors over a 36-month period in Hispanic and Black children. METHODS: Children (2.4 to 15 years old) were studied. Cycloplegic refraction was measured annually. Spherical equivalent was calculated. Astigmatism was evaluated by magnitude of cylinder and power vector (J 0 and J 45 ). Absolute value of interocular spherical equivalent difference was used to calculate anisometropia. Mixed-linear model was used to analyze longitudinal annual change in spherical equivalent, cylinder, J 0 , and J 45 over 36 months. RESULTS: A total of 485 participants (310 Black, 175 Hispanic) met the criteria. At the baseline examination, prevalence of myopia, emmetropia, and hyperopia was 39% (n = 187), 31% (n = 150), and 30% (n = 148), respectively. Spherical equivalent of Black children was not significantly different from that in Hispanic children (0.10 ± 2.92 vs. -0.37 ± 2.05 D, p=0.06); however, the Hispanic children had a significantly higher cylinder compared with Black children (Hispanic: 1.46 ± 1.57 D vs. Black: 0.92 ± 1.07 D; p<0.001). Both J 0 (p<0.001) and J 45 (p=0.01) were significantly different between two groups; the Hispanic children had more with-the-rule astigmatism and oblique astigmatism than the Black children. Prevalence of anisometropia (≥1 D) was higher in Black children (14%) compared with Hispanic children (5%, p=0.006). Over 36 months, spherical equivalent significantly decreased an average of 0.69 D (0.23 D/y, p<0.001) for both groups; neither astigmatism nor anisometropia changed significantly (p>0.05). CONCLUSIONS: Astigmatism in the Hispanic children was significantly higher than in Black children. However, the Black children had a higher prevalence and degree of anisometropia than the Hispanic children.

Baseline factors associated with myopia progression and axial elongation over 30 months in children 5 to 12 years of age.

PURPOSE: This study aimed to identify baseline factors associated with greater myopia progression and axial elongation in children with myopia. METHODS: This study performed a post hoc analysis of data from a 30-month randomized trial of atropine 0.01% versus placebo in children 5 to <13 years old with baseline spherical equivalent refractive error (SER) of -1.00 to -6.00 D, astigmatism of ≤1.50 D, and anisometropia of <1.00 D SER. Data from atropine 0.01% and placebo groups were pooled given outcomes were similar. Baseline factors of age, SER, axial length, race, sex, parental myopia, and iris color were evaluated for association with changes in SER and with changes in axial length at 30 months (24 months on treatment and then 6 months off) using backward model selection. RESULTS: Among 187 randomized participants, 175 (94%) completed 30 months of follow-up. The mean change in SER was greater among younger children (-0.19 D per 1 year younger; 95% confidence interval [CI], -0.25 to -0.14 D; p<0.001) and children with higher myopia (-0.14 D per 1 D more myopia at baseline; 95% CI, -0.23 to -0.05 D; p=0.002). The mean change in axial length was also greater among younger children (0.13 mm per 1 year younger; 95% CI, 0.10 to 0.15 mm; p<0.001) and children with higher baseline myopia (0.04 mm per 1 D more myopia; 95% CI, 0.002 to 0.08; p=0.04). CONCLUSIONS: Younger children with higher myopia had greater myopic progression and axial elongation over 30 months than older children with lower myopia. Developing effective treatments to slow the faster myopic progression in younger children should be a target of further research.

DeepIDP-2L: protein intrinsically disordered region prediction by combining convolutional attention network and hierarchical attention network.

MOTIVATION: Intrinsically disordered regions (IDRs) are widely distributed in proteins. Accurate prediction of IDRs is critical for the protein structure and function analysis. The IDRs are divided into long disordered regions (LDRs) and short disordered regions (SDRs) according to their lengths. Previous studies have shown that LDRs and SDRs have different proprieties. However, the existing computational methods fail to extract different features for LDRs and SDRs separately. As a result, they achieve unstable performance on datasets with different ratios of LDRs and SDRs. RESULTS: In this study, a two-layer predictor was proposed called DeepIDP-2L. In the first layer, two kinds of attention-based models are used to extract different features for LDRs and SDRs, respectively. The hierarchical attention network is used to capture the distribution pattern features of LDRs, and convolutional attention network is used to capture the local correlation features of SDRs. The second layer of DeepIDP-2L maps the feature extracted in the first layer into a new feature space. Convolutional network and bidirectional long short term memory are used to capture the local and long-range information for predicting both SDRs and LDRs. Experimental results show that DeepIDP-2L can achieve more stable performance than other exiting predictors on independent test sets with different ratios of SDRs and LDRs. AVAILABILITY AND IMPLEMENTATION: For the convenience of most experimental scientists, a user-friendly and publicly accessible web-server for the new predictor has been established at http://bliulab.net/DeepIDP-2L/. It is anticipated that DeepIDP-2L will become a very useful tool for identification of intrinsically disordered regions. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

All Gauged Curvature-Squared Supergravities in Five Dimensions.

We present a complete basis to study gauged curvature-squared supergravity in five dimensions. We replace the conventional ungauged Riemann-squared action with a new log invariant, offering a comprehensive framework for all gauged curvature-squared supergravities. Our findings address long-standing challenges and have implications for precision tests in the AdS/CFT correspondence.

Maternal immune activation alters fetal and neonatal microglia phenotype and disrupts neurogenesis in mice.

BACKGROUND: Activation of microglia, increase in cortical neuron density, and reduction in GABAergic interneurons are some of the key findings in postmortem autism spectrum disorders (ASD) subjects. The aim of this study was to investigate how maternal immune activation (MIA) programs microglial phenotypes and abnormal neurogenesis in offspring mice. METHODS: MIA was induced by injection of lipopolysaccharide (LPS, i.p.) to pregnant mice at embryonic (E) day 12.5. Microglial phenotypes and neurogenesis were investigated between E15.5 to postnatal (P) day 21 by immunohistochemistry, flow cytometry, and cytokine array. RESULTS: MIA led to a robust increase in fetal and neonatal microglia in neurogenic regions. Homeostatic E15.5 and P4 microglia are heterogeneous, consisting of M1 (CD86+/CD206-) and mixed M1/M2 (CD86+/CD206+)-like subpopulations. MIA significantly reduced M1 but increased mixed M1/M2 microglia, which was associated with upregulation of numerous cytokines with pleotropic property. MIA resulted in a robust increase in Ki67+/Nestin+ and Tbr2+ neural progenitor cells in the subventricular zone (SVZ) of newborn mice. At juvenile stage, a male-specific reduction of Parvalbumin+ but increase in Reelin+ interneurons in the medial prefrontal cortex was found in MIA offspring mice. CONCLUSIONS: MIA programs microglia towards a pleotropic phenotype that may drive excessive neurogenesis in ASD patients. IMPACT: Maternal immune activation (MIA) alters microglial phenotypes in the brain of fetal and neonatal mouse offspring. MIA leads to excessive proliferation and overproduction of neural progenitors in the subventricular zone (SVZ). MIA reduces parvalbumin+ while increases Reelin+ interneurons in the prefrontal cortex. Our study sheds light on neurobiological mechanisms of abnormal neurogenesis in certain neurodevelopmental disorders, such as autism spectrum disorder (ASD).

BioSeq-BLM: a platform for analyzing DNA, RNA and protein sequences based on biological language models.

In order to uncover the meanings of 'book of life', 155 different biological language models (BLMs) for DNA, RNA and protein sequence analysis are discussed in this study, which are able to extract the linguistic properties of 'book of life'. We also extend the BLMs into a system called BioSeq-BLM for automatically representing and analyzing the sequence data. Experimental results show that the predictors generated by BioSeq-BLM achieve comparable or even obviously better performance than the exiting state-of-the-art predictors published in literatures, indicating that BioSeq-BLM will provide new approaches for biological sequence analysis based on natural language processing technologies, and contribute to the development of this very important field. In order to help the readers to use BioSeq-BLM for their own experiments, the corresponding web server and stand-alone package are established and released, which can be freely accessed at http://bliulab.net/BioSeq-BLM/.

Effect of Low-dose Atropine on Binocular Vision and Accommodation in Children Aged 6 to 17 Years.

SIGNIFICANCE: Low-dose atropine is one of the leading treatments of myopia progression in children. However, the effect of low-dose atropine on binocular vision measurements has not been thoroughly studied. PURPOSE: This study aimed to determine the effect of 0.01, 0.03, and 0.05% atropine on visual acuity, pupil size, binocular vision, and accommodation in children aged 6 to 17 years. METHODS: Forty-six children (28 girls and 18 boys) were randomized into four groups: placebo (n = 10) and 0.01% (n = 13), 0.03% (n = 11), and 0.05% (n = 12) atropine. One drop of atropine or placebo was administered into each eye once. The following measurements were collected before applying the eye drops and 30 minutes, 60 minutes, and 24 hours after application of eye drops: habitual visual acuity at distance and near, pupil size, dissociated phoria at distance and near, negative and positive fusional vergence, near point convergence, near point convergence stamina and fragility, accommodative lag, and amplitude of accommodation. Repeated-measures analysis of variance was used, and P < .05 was considered statistically significant. RESULTS: Differences in pupil diameters under photopic and scotopic conditions were statistically significant when comparing all three atropine groups with placebo over time ( P < .001). Pupil size in both the 0.03 and 0.05% atropine groups was enlarged from baseline at the 30-minute, 60-minute, and 24-hour time points ( P < .05) in both photopic and scotopic conditions. Pupil size in the 0.01% atropine group had minimal change, and only the scotopic 60-minute time point was statistically significant ( P = .02). All three concentrations of atropine eye drops have no significant effect on accommodation, binocular vision measurements, or visual acuity compared with the control group. CONCLUSIONS: Pupil size was significantly enlarged by 0.03 and 0.05% atropine in both photopic and scotopic conditions. Low-dose atropine eye drops have no significant effect on accommodation, binocular vision measurements, or visual acuity compared with control.

Convergence insufficiency symptom survey: A tool to evaluate convergence excess in young adults.

PURPOSE: To determine the effectiveness of the Convergence Insufficiency Symptom Survey (CISS) in evaluating visual symptoms in young adults with convergence excess (CE). METHODS: A cross-sectional study was performed based on a population of optometry students. Comprehensive binocular vision tests including cover test, near point of convergence, fusional vergence and accommodative amplitude, were performed. Participants were categorised into three groups: normal binocular vision (NBV), CE and CE + accommodative insufficiency (AI) (i.e., CE + AI). The CISS was administered to each participant. An analysis of variance with Bonferroni correction was performed to compare clinical measures among the three groups. A receiver-operating characteristic (ROC) curve was constructed to evaluate the ability of CISS to differentiate CE from the NBV population. RESULTS: A total of 181 participants were enrolled, including 96 in the NBV group, 66 in the CE group and 19 in the CE + AI group. A significant difference in CISS score was detected between the three groups (p < 0.001). Post-hoc tests showed significantly higher CISS scores in the CE group (16.7 ± 10.8) and the CE + AI group (19.7 ± 10.9) compared with the NBV group (12.2 ± 7.8) (p = 0.01 and p = 0.005, respectively), with no difference between the CE and the CE + AI groups (p = 0.52). The ROC curve showed the CISS poorly (but significantly) differentiated CE from NBV (area under the curve = 0.62, p = 0.01). The optimal cutoff value for a CISS score to differentiate CE was 16, with sensitivity and specificity of 52% and 72%, respectively. CONCLUSIONS: Young adults with CE had significantly higher CISS scores than those with NBV. Although using the CISS solely for diagnosing CE is not recommended, it can be used to provide a measure of symptoms in individuals identified as having CE based on clinical measurements.

Comparison of Cirrus spectral domain OCT with disc-macula distance to disc diameter ratio in diagnosing congenital optic nerve hypoplasia.

PURPOSE: Diagnosis of congenital optic nerve hypoplasia (CONH) can be challenging in children or uncooperative individuals. Misdiagnosis can lead to inappropriate treatment; thus, it is important to identify an objective and reliable measurement. The purpose of this study was to evaluate whether Cirrus spectral domain optical coherence tomography (SD-OCT) is a valid test for diagnosing CONH by comparing it to the disc-macula distance to disc diameter (DM:DD) ratio. METHODS: A total of 93 participants (64 controls and 29 CONH) underwent comprehensive eye examinations, fundus photography and Cirrus SD-OCT. Receiver operating characteristic (ROC) curves for the DM:DD ratio and OCT disc area were constructed for CONH and control eyes. RESULTS: Mean (±SD) OCT disc area was 1.46 (±0.42) mm2 and 1.89 (±0.38) mm2 for CONH and control eyes, respectively (p < 0.0001). The area under the curve for the DM:DD ratio was 0.97 (95% confidence interval: 0.91-0.99) and 0.79 for OCT disc area (95% confidence interval: 0.70-0.86), which were significantly different (p = 0.0005). The optimal cut-off value for OCT disc area was 1.66 mm2 (76% sensitivity, 70% specificity), while the optimal cut-off for DM:DD ratio was 3.10 (85% sensitivity and 95% specificity). The Cirrus SD-OCT showed a tendency to overestimate disc size, especially in cases with no light perception (NLP) or segmental CONH. CONCLUSIONS: Although the DM:DD ratio is superior to OCT in diagnosing CONH with a higher sensitivity and specificity, the ratio is subject to inter-examiner variability and can be challenging to obtain. We found the Cirrus SD-OCT to be a valid objective test for diagnosing CONH. Caution is advised when using SD-OCT in segmental CONH or in an eye with NLP. We suggest 1.66 mm2 as the optimal cut-off value for Cirrus SD-OCT disc area to differentiate a hypoplastic from a normal optic disc.

Azithromycin Protects Oligodendrocyte Progenitor Cells against Lipopolysaccharide-Activated Microglia-Induced Damage.

Oligodendrocyte progenitor cells (OPC) are the primary cellular targets of brain white matter injury (WMI) in very low-birth weight (VLBW) infants. Microglia plays a significant role in inflammation-induced WMI. Our previous study showed that lipopolysaccharide (LPS)-induced OPC damage is mediated by activated microglia in vitro. We hypothesized that azithromycin (AZ) could protect OPCs against LPS-induced cytotoxicity by blocking microglial activation. Highly enriched primary rat microglia and OPCs were treated with LPS. There were 4 groups: control, LPS + Veh, AZ, and LPS + AZ. Microglia conditioned medium (MCM) was used to determine inflammatory cytokines by enzyme-linked immunosorbent assay or subsequent treatment of OPCs. We found that AZ significantly suppressed TNF-α, IL-1ß, and IL-6 in LPS+Veh-treated-microglial MCM and blocked microglial nuclear factor-κB p65 nuclear translocation. AZ prevented LPS-MCM-induced OPC death and improved OPC survival as measured by activated caspase-3 immunostaining and XTT assay, respectively. AZ ameliorated LPS-MCM-induced differentiation arrest and myelin basic protein deficit in oligodendrocytes. Our data suggest that AZ is a potent inhibitor for microglia activation and may hold the therapeutic potential for WMI in VLBW infants.

A NIR Emitting Cyanine with Large Stokes' Shift for Mitochondria and Identification of their Membrane Potential Disruption.

An NIR emitting (λem ≈730 nm) cyanine probe ExCy was synthesized in good yields by extending the π-conjugation length (i. e., with furan moiety) to the donor-accepter system. ExCy exhibited a large Stokes' shift (Δλ≈100 nm) due to strong intramolecular charge transfer (ICT), and high fluorescence quantum yield (Φfl ≈0.47 in DCM). Due to its low fluorescence in an aqueous environment (Φfl ≈0.007 in H2 O), the probe exhibited the potential of achieving a large fluorescence turn-on upon entering a hydrophobic cellular environment. Fluorescence confocal microscopy studies revealed that ExCy was readily excitable with a far-red laser line (i. e., 640 nm) while the corresponding emission was collected in the NIR region. ExCy exhibited excellent selectivity towards live cell mitochondria according to the co-localization studies. The probe also exhibited high photostability, long-term imaging ability and wash-free staining ability, when being applied to live cells. Our studies indicated that the mitochondrial localization of ExCy was dependent on the membrane potential of the mitochondria. ExCy was successfully utilized as a mitochondrial membrane potential dysfunction indicator to visually identify cells with mitochondrial dysfunction via fluorescence confocal microscopy. ExCy was further examined for potential in vivo imaging of zebrafish.

IDP-Seq2Seq: identification of intrinsically disordered regions based on sequence to sequence learning.

MOTIVATION: Related to many important biological functions, intrinsically disordered regions (IDRs) are widely distributed in proteins. Accurate prediction of IDRs is critical for the protein structure and function analysis. However, the existing computational methods construct the predictive models solely in the sequence space, failing to convert the sequence space into the 'semantic space' to reflect the structure characteristics of proteins. Furthermore, although the length-dependent predictors showed promising results, new fusion strategies should be explored to improve their predictive performance and the generalization. RESULTS: In this study, we applied the Sequence to Sequence Learning (Seq2Seq) derived from natural language processing (NLP) to map protein sequences to 'semantic space' to reflect the structure patterns with the help of predicted residue-residue contacts (CCMs) and other sequence-based features. Furthermore, the Attention mechanism was used to capture the global associations between all residue pairs in the proteins. Three length-dependent predictors were constructed: IDP-Seq2Seq-L for long disordered region prediction, IDP-Seq2Seq-S for short disordered region prediction and IDP-Seq2Seq-G for both long and short disordered region predictions. Finally, these three predictors were fused into one predictor called IDP-Seq2Seq to improve the discriminative power and generalization. Experimental results on four independent test datasets and the CASP test dataset showed that IDP-Seq2Seq is insensitive with the ratios of long and short disordered regions and outperforms other competing methods. AVAILABILITY AND IMPLEMENTATION: For the convenience of most experimental scientists, a user-friendly and publicly accessible web-server for the powerful new predictor has been established at http://bliulab.net/IDP-Seq2Seq/. It is anticipated that IDP-Seq2Seq will become a very useful tool for identification of IDRs. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Relationships among Clinical Factors and Patient-reported Outcome Measures in Adults with Convergence Insufficiency.

SIGNIFICANCE: When exploring relationships among clinical measures and patient-reported outcome measures in adults with convergence insufficiency, worse symptoms (Convergence Insufficiency Symptom Survey [CISS] score) seemed to be correlated with worse reading function domain score (Adult Strabismus-20 quality-of-life questionnaire). After treatment, improved symptoms were associated with improved reading function quality of life. PURPOSE: This study aimed to explore relationships between clinical measures and patient-reported outcome measures in adults undergoing treatment for symptomatic convergence insufficiency. METHODS: In a prospective multicenter observational study, we evaluated adults with symptomatic convergence insufficiency (i.e., clinical measures of near exodeviation, receded near point of convergence, reduced near positive fusional vergence; CISS score ≥21). Fifty-seven participants treated with vision therapy/exercises (n = 35) or base-in prism (n = 22) were analyzed. Spearman correlation coefficients ( R ) were used to assess associations among the three clinical measures and patient-reported outcome measures (CISS, Diplopia Questionnaire, four Adult Strabismus-20 quality-of-life domains) before treatment (baseline) and after 10 weeks and 1 year. Associations were interpreted to be present when the lower limit of the 95% confidence interval (CI) was moderate to strong ( R ≥ 0.4). RESULTS: Among multiple exploratory analyses, the only moderate to strong baseline correlation was between worse CISS and worse Adult Strabismus-20 reading function scores ( R = 0.62; 95% CI, 0.43 to 0.76). Regarding change in measures with treatment, the only moderate to strong correlations were between improved CISS and improved Adult Strabismus-20 reading function scores for prism at 10 weeks ( R = 0.78; 95% CI, 0.52 to 0.91) and 1 year ( R = 0.85; 95% CI, 0.65 to 0.94) and for vision therapy/exercises at 1 year ( R = 0.78; 95% CI, 0.57 to 0.89). CONCLUSIONS: In exploratory analyses, we found positive correlations between CISS symptom scores and reading function quality-of-life scores. The absence of correlations between symptoms and individual clinical measures is consistent with clinical experience that, in convergence insufficiency, symptoms and clinical findings can be discordant.