Health-related quality of life measurements in children and adolescents with refractive errors: A scoping review.

Background: Refractive errors, particularly myopia, are the leading visual disorders worldwide, significantly affecting the quality of life (QOL) even after correction. This scoping review focuses on health-related quality of life (HRQOL) measurements for children and adolescents with refractive errors. Main text: We explored generic and disease-specific HRQOL tools, examining their content, psychometric properties, and the impact of various interventions on QOL. Two English databases-PubMed, Embase, and one Chinese database, CNKI, were searched for relevant studies published from January 2001 to October 2023. Inclusion criteria encompassed studies using standardized instruments to assess the QOL of children aged 0-18 with refractive errors. The review compares prevalent HRQOL measurements, analyzes children's refractive error assessments, and discusses intervention effects on patient QOL. Conclusions: The study underlines the necessity of developing disease-specific QOL instruments for very young children and serves as a practical guide for researchers in this field. The findings advocate for a targeted approach in HRQOL assessment among the pediatric population, identifying critical gaps in current methodologies.

Numerical Simulation of Reversed Austenite Evolution during Intercritical Tempering of Low-Carbon Martensitic Stainless Steel.

Since the formation of reversed austenite during critical tempering treatment is an important factor affecting the mechanical properties of 13Cr4Ni martensitic stainless steel, a detailed study of the content and morphology of reversed austenite in heat treatment is needed. In this study, the variation curves of a reversed austenite volume fraction with holding time at different tempering temperatures were measured by in situ X-ray diffraction (XRD), and the reversed austenite and carbides of each process were evaluated by transmission electron microscopy (TEM). The austenite content shows a parabolic change with the increase in the tempering temperature; the maximum can reach a peak of about 6.8% at 610 °C, and drops to 0% at 660 °C. It also shows a parabolic change with the extension of the holding time, reaching a maximum of about 9.2% at 5 h of holding time, and a decreasing trend at 10 h of holding time, about 6.8%. The results show that the precipitation of carbides in the microstructure causes elemental segregation at grain boundaries and inside, which is one of the main factors affecting the thermal stability of reversed austenite formation. The kinetic process of reversed austenite during the tempering process was simulated using the JMAK model and the KM model, which can describe the trend of reversed austenite content during the tempering process. Combining the two models, a mathematical model for the room-temperature reversed austenite content under different processes was obtained, and this can predict the room-temperature austenite content.

Tear cytokine levels are reduced in patients treated with intravitreal injections.

PURPOSE: To investigate cytokine levels in the tear fluid of patients receiving serial intravitreal injections (IVI) with anti-vascular endothelial growth factor (anti-VEGF) for neovascular age-related macular degeneration (nAMD). METHODS: Concentrations of six cytokines (IFN-γ, IL-1ß, IL-6, IL-8, TNF and VEGF) in tears of patients receiving anti-VEGF in one eye were assayed using multiplex cytometric bead array. The fellow untreated eye served as control. Tear sampling was performed on a single occasion at a minimum of four weeks after IVI. Patients underwent a pre-IVI antisepsis protocol with povidone-iodine. RESULTS: Tear fluid from thirty patients with a mean age of 78.8 years (range 58-90) was assayed. Subjects received a median of 43.5 (range 22-106) IVI in one eye. The median level of IFN-γ was 0.33 (interquartile range (IQR) 0.22-0.52) pg/mg of total protein in injected eyes versus 0.41 (IQR 0.21-1.05) pg/mg in fellow eyes (p = 0.017). For TNF, a median level of 0.12 (IQR 0.08-0.18) pg/mg of total protein was found in injected eyes versus 0.14 (IQR 0.07-0.33) pg/mg of total protein in fellow eyes (p = 0.019). There were no differences between injected and fellow eyes regarding the levels of IL-1ß, IL-6, IL-8 and VEGF. CONCLUSION: Tear fluid in eyes receiving serial IVI with anti-VEGF and preoperative povidone-iodine antisepsis constitutes lower levels of the pro-inflammatory cytokines IFN-γ and TNF compared to fellow eyes. This provides biochemical support of previous findings of reduced signs of inflammation and healthier tear film parameters in patients treated with serial IVI.

Characteristics of cerebrospinal fluid oligoclonal band in anti-myelin oligodendrocyte glycoprotein (MOG) antibody associated disease.

Objective: To analyze the immune parameters of cerebrospinal fluid (CSF) and oligoclonal band (OCB) type in patients with anti-myelin oligodendrocyte glycoprotein (MOG) antibody-associated diseases (MOGAD). Methods: Patients who were seropositive for MOG-IgG and diagnosed with MOGAD according to the diagnosis criteria in the Department of Neurology, Huashan Hospital, Fudan University from December 2020 to June 2022 were retrospectively included in this study. Complete clinical data, blood and cerebrospinal fluid samples were collected from all the participants. Paired serum and CSF MOG-IgG and autoimmune encephalitis antibody were assayed by Cell Based Assay (CBA) based on transfected target antigens. Paired serum and CSF albumin and IgG were detected by turbidimetric scattering method, and OCB was detected by standard operation procedure as described. Results: A total of 86 patients (44 males and 42 females) with MOGAD were included in this study, with a median age of 30 years (range: 5-82 years). Among all the patients, 73 patients showed OCB type I, 12 patients showed OCB type II, and one patient showed OCB type III. The overall positive rate of CSF-OCB in MOGAD patients was 15.1 %. The 24-h intrathecal synthesis rate of CSF in the OCB-positive group (n = 13) was higher than that in the OCB-negative group [n = 73, 0.62 (0.26) vs 5.11 (13.67), P = 0.003]. Subgroup analysis revealed that the positive rates of CSF-OCB in the single MOG group (n = 61) and the group combined with other antibodies (n = 25) were 14.8 % and 16.0 %, respectively. The incidence of meningoencephalitis (13/61 vs 13/25, P = 0.011) was significantly different between the two groups. The proportion of patients with high (≥1:32) or low (≤1:10) CSF MOG-IgG also showed significant difference in the group combined with other antibodies (P = 0.032). Optic neuritis was more common in the relapse course group (n = 49) than the monophasic course group (n = 37, P < 0.001) No significant diferences of CSF immune parameters were found in the MOG-IgGserum+/CSF- group and the MOG-IgGserum+/CSF + group, and the titer of MOG-IgG in the serum or CSF did not influence CSF immune parameters in different subgroups. Conclusion: The overall positive rate of CSF-OCB in MOGAD patients was 15.1 %. The 24-h intrathecal synthesis rate of cerebrospinal fluid in the OCB-positive group was higher than that in the OCB-negative group. This study illustrated OCB characterization in MOGAD patients, and will shed light on the standardization of OCB test in the study of immune diseases.

A Preservative-Free Approach - Effects on Dry Eye Signs and Symptoms After Cataract Surgery.

Purpose: To compare the effect of treatment with preservative-free dexamethasone, NSAIDs and trehalose/hyaluronic acid eye drops with the preservative benzalkonium chloride containing dexamethasone and NSAIDs after cataract surgery in dry versus non-dry eyes. Patients and Methods: In this prospective randomized intervention study, dry eye tests were performed before and 6 weeks after cataract surgery. Patients were considered as having dry eye, SDE (sign of dry eye), if at least one of the following dry eye tests were abnormal; corneal fluorescein staining (CFS), non-invasive keratograph breakup time (NIKBUT) or tear osmolarity. Patients with SDE were randomly assigned to one of two groups. Group 1 patients were treated with dexamethasone and bromfenac eye drops with the preservative benzalkonium chloride (BAC). Group 2 patients were treated with preservative-free dexamethasone and preservative-free diclofenac, as well as a preservative-free lubricant with trehalose and hyaluronic acid both before and after surgery. Patients with normal tear film status acted as the control group (group 3) and received same treatment as group 1. Results: A total of 215 patients were enrolled six weeks after surgery, the number of patients with SDE decreased significantly in groups 1 and 2 (p <0.001). Subjective symptoms and objective measures including osmolarity, NIKBUT, CFS, and tear film thickness (TFT) improved after surgery, tear production remained unchanged, while corneal sensitivity and meibomian gland dysfunction (MGD) parameters worsened. In the control group with normal tear-film status, SDE increased significantly after the surgery (p <0.001). There were no statistically significant differences in tear film parameters between the three groups after surgery. Conclusion: After cataract surgery, patients with mild to moderate dry eyes may experience improved tear film status and reduced symptoms. However, we found no additional beneficial effect on dry eye parameters with treatment with preservative-free dexamethasone, NSAIDs, and lubricants compared to preservative-containing eye drops.

Mechanical force determines chimeric antigen receptor microclustering and signaling.

Chimeric antigen receptor (CAR) T cells are activated to trigger the lytic machinery after antigen engagement, and this has been successfully applied clinically as therapy. The mechanism by which antigen binding leads to the initiation of CAR signaling remains poorly understood. Here, we used a set of short double-stranded DNA (dsDNA) tethers with mechanical forces ranging from ∼12 to ∼51 pN to manipulate the mechanical force of antigen tether and decouple the microclustering and signaling events. Our results revealed that antigen-binding-induced CAR microclustering and signaling are mechanical force dependent. Additionally, the mechanical force delivered to the antigen tether by the CAR for microclustering is generated by autonomous cell contractility. Mechanistically, the mechanical-force-induced strong adhesion and CAR diffusion confinement led to CAR microclustering. Moreover, cytotoxicity may have a lower mechanical force threshold than cytokine generation. Collectively, these results support a model of mechanical-force-induced CAR microclustering for signaling.

Cataract-related variant R114C increases ßA3-crystallin susceptibility to environmental stresses by disrupting the protein senior structure.

Congenital cataract is a major cause of childhood blindness worldwide, with crystallin mutations accounting for over 40 % of gene-mutation-related cases. Our research focused on a novel R114C mutation in a Chinese family, resulting in bilateral coronary cataract with blue punctate opacity. Spectroscopic experiments revealed that ßA3-R114C significantly altered the senior structure, exhibiting aggregation, and reduced solubility at physiological temperature. The mutant also displayed decreased resistance and stability under environmental stresses such as UV irradiation, oxidative stress, and heat. Further, cellular models confirmed its heightened sensitivity to environmental stresses. These data suggest that the R114C mutation impairs the hydrogen bond network and structural stability of ßA3-crystallin, particularly at the boundary of the second Greek-key motif. This study revealed the pathological mechanism of ßA3-R114C and may help in the development of potential treatment strategies for related cataracts.

Mesoporous carbon nanoparticles embedded with iron in hydrogen-photothermal synergistic therapy.

We developed a new method to synthesize polyethylene glycol modified ultra small iron embedded in mesoporous carbon nanoparticle (C/Fe-PEG NP) for hydrogen (H2) assisted photothermal synergistic therapy. Herein, we use a simple in-situ reduction method to obtain the C/Fe NP in one-step carbonizing process, which is further modified by the biocompatible polyethylene glycol (PEG) on the surface of C/Fe NP to acquire high stability in physiological solutions. Utilizing the excellent photothermal property from the mesoporous carbon and the controllable H2 release property in the weakly acidic tumor microenvironment by the ultra-small Fe, the obtained C/Fe-PEG NPs can effective kill the cancer cells, meanwhile, protect normal cells without drugs. This selective anti-cancer mechanism of C/Fe-PEG NPs may because the produced H2 selective change the mitochondrial energy metabolism. In vivo results prove that the C/Fe-PEG NPs achieve excellent tumor ablation therapeutic effect and normal tissue protecting ability benefit from the H2-assisted photothermal therapy, promising the use of novel nanomaterials with more safety method for future cancer therapy.

Heritability of tear fluid cytokines in healthy twins.

PURPOSE: Ocular surface disease is common and it is associated with elevated concentration levels of cytokines in tear fluid. Studies of the normal variation in tear fluid inflammatory markers are lacking. New knowledge may help guide research into ocular surface disease biomarkers and therapeutics. METHODS: In this prospective twin cohort study, healthy individuals were recruited from a population-based registry. Tear fluid was collected with the Schirmer test strips was submerged in phosphate buffered saline and stored at -80° before undergoing 27-cytokine multiplex immunoassay analysis. Broad-sense heritability (h2) of cytokine concentrations was analyzed. RESULTS: 90 participants (23 monozygotic and 22 dizygotic twin pairs) were included. Data availability allowed for heritability analysis of 15 cytokines, and a h2 >50% was seen for 10 cytokines. A statistical power of >80% was achieved for heritability analyses of the cytokines interferon gamma induced protein 10 (h2 = 94.8%), eotaxin (89.8%), interleukin 7 (86.6%), interleukin 1ß (82.2%) and monocyte chemoattractant protein 1 (68.2%). CONCLUSIONS: The tear fluid concentration of several analyzed cytokines was found to be highly heritable. A considerable amount of the inter-individual variation observed for the concentration of certain tear fluid cytokines can be linked to hereditary factors that cannot easily be modified by changing factors in the environment of patients. This suggests that a higher success in ocular surface disease drug discovery may be anticipated for drugs that have targets in specific populations, and points to the importance of emphasizing known preventive measures of ocular surface disease and examinations of close relatives of patients with ocular surface disease, such as dry eye disease.

Cholesterol metabolism: physiological regulation and diseases.

Cholesterol homeostasis is crucial for cellular and systemic function. The disorder of cholesterol metabolism not only accelerates the onset of cardiovascular disease (CVD) but is also the fundamental cause of other ailments. The regulation of cholesterol metabolism in the human is an extremely complex process. Due to the dynamic balance between cholesterol synthesis, intake, efflux and storage, cholesterol metabolism generally remains secure. Disruption of any of these links is likely to have adverse effects on the body. At present, increasing evidence suggests that abnormal cholesterol metabolism is closely related to various systemic diseases. However, the exact mechanism by which cholesterol metabolism contributes to disease pathogenesis remains unclear, and there are still unknown factors. In this review, we outline the metabolic process of cholesterol in the human body, especially reverse cholesterol transport (RCT). Then, we discuss separately the impact of abnormal cholesterol metabolism on common diseases and potential therapeutic targets for each disease, including CVD, tumors, neurological diseases, and immune system diseases. At the end of this review, we focus on the effect of cholesterol metabolism on eye diseases. In short, we hope to provide more new ideas for the pathogenesis and treatment of diseases from the perspective of cholesterol.

Amphiphilic Janus nanoparticles for nitric oxide synergistic photodynamic eradication of MRSA biofilms.

Biofilms pose significant threats to public health by causing persistent clinical infections. The development of innovative antibacterial approaches for eliminating biofilms is an urgent necessity. In this study, we developed amphiphilic Janus nanoparticles (JNPs), loaded with hydrophobic chlorin e6 (Ce6) and hydrophilic S-nitrosoglutathione (GSNO), denoted as Ce6-PDA/CaP-GSNO, with the aim to effectively eradicate biofilms and combat methicillin-resistant Staphylococcus aureus (MRSA) infections through nitric oxide (NO) synergistic photodynamic therapy (PDT). Ce6-PDA/CaP-GSNO demonstrated remarkable biofilm penetration ability, efficiently reaching the acidic inner layers, which triggered the rapid release of GSNO, resulting in the generation of an abundant supply of NO. NO not only exhibited potent bactericidal activity but also effectively lowered the GSH level of the biofilm, leading to enhanced efficacy of Ce6. Additionally, the interaction between NO and reactive oxygen species (ROS) resulted in the generation of reactive nitrogen species (RNS), further enhancing PDT efficacy both in vitro and in vivo. In summary, Ce6-PDA/CaP-GSNO demonstrated remarkable biofilm penetration capacity and effective reduction of the GSH level in the biofilms, leading to enhanced PDT efficacy at low photosensitizer doses and laser intensities, thereby minimizing adverse effects on normal tissues. These findings highlight the promising potential of our approach for combating biofilm-related infections.

Sex Differences in the Prevalence of Meibomian Gland Dysfunction: A Mini Review.

PURPOSE: In this review, we aimed to investigate the literature on sex-specific prevalence of meibomian gland dysfunction (MGD) and to determine whether women or men are more at risk for MGD. METHODS: A search was conducted on PubMed using the terms: (Sex OR Gender OR prevalence) AND (Meibomian gland). RESULTS: Twenty-four relevant studies on MGD prevalence were identified, including 10 population-based and 14 hospital-based studies. Among the population-based studies, five studies reported higher rates among men, three studies found no differences, and one study observed higher rates among women. In the hospital-based studies, 10 studies reported no difference, two found higher rates among men, and one found higher among women. In the reviewed literature, there was a considerable variation between studies in terms of quality, sample size, age ranges, diagnostic criteria. CONCLUSIONS: While most of the population-based studies suggest a higher prevalence among men, the majority of clinic-based studies show no significant difference. Further research with larger samples and standardized criteria is needed to determine whether men are indeed more susceptible to MGD.

Colocalization of Increased Midbrain Signals in Neuroinflammation and Tau PET Imaging Suggests the Diagnosis of Progressive Supranuclear Palsy.

ABSTRACT: Clinical overlap with multiple other neurological diseases makes the diagnosis of autoimmune encephalitis challenging; consequently, a broad range of neurological diseases are misdiagnosed as autoimmune encephalitis. A 58-year-old man presented with abnormal behavior, irritability for 3 years, oculomotor disturbance, unsteady walking, and dysphagia and was suspected as having anti-dipeptidyl-peptidase-like protein 6 (DPPX) encephalitis as the anti-DPPX antibody was positive in the serum. However, the therapeutic effect of immunotherapy was unsatisfactory. Subsequently, colocalization of increased midbrain signals was observed in neuroinflammation PET using [ 18 F]DPA-714 and in tau PET using [ 18 F]florzolotau, suggesting the diagnosis of progressive supranuclear palsy.

Optimizing the aldosterone-to-renin ratio cut-off for screening primary aldosteronism based on cardiovascular risk: a collaborative study.

OBJECTIVES: Aldosterone-to-renin ratio (ARR) based screening is the first step in the diagnosis of primary aldosteronism (PA). However, the guideline-recommended ARR cutoff covers a wide range, from the equivalent of 1.3 to 4.9 ng·dl-1/mIU∙l-1. We aimed to optimize the ARR cutoff for PA screening based on the risk of cardiovascular diseases (CVD). METHODS: Longitudinally, we included hypertensive participants from the Framingham Offspring Study (FOS) who attended the sixth examination cycle and followed up until 2014. At baseline (1995-1998), we used circulating concentrations of aldosterone and renin to calculate ARR (unit: ng·dl-1/mIU∙l-1) among 1,433 subjects who were free of CVD. We used spline regression to calculate the ARR threshold based on the incident CVD. We used cross-sectional data from the Chongqing Primary Aldosteronism Study (CONPASS) to explore whether the ARR cutoff selected from FOS is applicable to PA screening. RESULTS: In FOS, CVD risk increased with an increasing ARR until a peak of ARR 1.0, followed by a plateau in CVD risk (hazard ratio 1.49, 95%CI 1.19-1.86). In CONPASS, when compared to essential hypertension with ARR < 1.0, PA with ARR ≥ 1.0 carried a higher CVD risk (odds ratio 2.24, 95%CI 1.41-3.55), while essential hypertension with ARR ≥ 1.0 had an unchanged CVD risk (1.02, 0.62-1.68). Setting ARR cutoff at 2.4 ~ 4.9, 10% ~30% of PA subjects would be unrecognized although they carried a 2.45 ~ 2.58-fold higher CVD risk than essential hypertension. CONCLUSIONS: The CVD risk-based optimal ARR cutoff is 1.0 ng·dl-1/mIU∙l-1 for PA screening. The current guideline-recommended ARR cutoff may miss patients with PA and high CVD risk. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov (NCT03224312).

The prognostic value of systematic genetic screening in amyotrophic lateral sclerosis patients.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with complex genetic architecture. Emerging evidence has indicated comorbidity between ALS and autoimmune conditions, suggesting a potential shared genetic basis. The objective of this study is to assess the prognostic value of systematic screening for rare deleterious mutations in genes associated with ALS and aberrant inflammatory responses. METHODS: A discovery cohort of 494 patients and a validation cohort of 69 patients were analyzed in this study, with population-matched healthy subjects (n = 4961) served as controls. Whole exome sequencing (WES) was performed to identify rare deleterious variants in 50 ALS genes and 1177 genes associated with abnormal inflammatory responses. Genotype-phenotype correlation was assessed, and an integrative prognostic model incorporating genetic and clinical factors was constructed. RESULTS: In the discovery cohort, 8.1% of patients carried confirmed ALS variants, and an additional 15.2% of patients carried novel ALS variants. Gene burden analysis revealed 303 immune-implicated genes with enriched rare variants, and 13.4% of patients harbored rare deleterious variants in these genes. Patients with ALS variants exhibited a more rapid disease progression (HR 2.87 [95% CI 2.03-4.07], p < 0.0001), while no significant effect was observed for immune-implicated variants. The nomogram model incorporating genetic and clinical information demonstrated improved accuracy in predicting disease outcomes (C-index, 0.749). CONCLUSION: Our findings enhance the comprehension of the genetic basis of ALS within the Chinese population. It also appears that rare deleterious mutations occurring in immune-implicated genes exert minimal influence on the clinical trajectories of ALS patients.

Chalazion Treatment: A Concise Review of Clinical Trials.

A chalazion is one of the most common eye conditions presenting as a mass lesion of the eyelids. It is seen in all age groups. Chalazion is a non-inflammatory process and develops due to retained secretion of the meibomian or Zeis glands. Treatment of choice differs among clinicians and may include application of warm compress onto eyelids, lid hygiene, using local antibiotic ointment with or without steroids, injecting steroid solution (triamcinolone acetonide) into the lesion and surgical removal of the lesion by incision and curettage. In addition, there are some other experimented methods such as injection of botulinum toxin A, tarsal trephination, removal of chalazion by application of CO2 laser or cryogenic action. However, there is currently no commonly agreed treatment of choice. In this review, we aimed to summarize findings from clinical trials and hopefully, identify a treatment of choice in chalazion.

Dent disease 1-linked novel CLCN5 mutations result in aberrant location and reduced ion currents.

Dent disease is a rare renal tubular disease with X-linked recessive inheritance characterized by low molecular weight proteinuria (LMWP), hypercalciuria, and nephrocalcinosis. Mutations disrupting the 2Cl-/1H+ exchange activity of chloride voltage-gated channel 5 (CLCN5) have been causally linked to the most common form, Dent disease 1 (DD1), although the pathophysiological mechanisms remain unclear. Here, we conducted the whole exome capture sequencing and bioinformatics analysis within our DD1 cohort to identify two novel causal mutations in CLCN5 (c.749 G > A, p. G250D, c.829 A > C, p. T277P). Molecular dynamics simulations of ClC-5 homology model suggested that these mutations potentially may induce structural changes, destabilizing ClC-5. Overexpression of variants in vitro revealed aberrant subcellular localization in the endoplasmic reticulum (ER), significant accumulation of insoluble aggregates, and disrupted ion transport function in voltage clamp recordings. Moreover, human kidney-2 (HK-2) cells overexpressing either G250D or T277P displayed higher cell-substrate adhesion, migration capability but reduced endocytic function, as well as substantially altered transcriptomic profiles with G250D resulting in stronger deleterious effects. These cumulative findings supported pathogenic role of these ClC-5 mutations in DD1 and suggested a cellular mechanism for disrupted renal function in Dent disease patients, as well as a potential target for diagnostic biomarker or therapeutic strategy development.

Comparative analysis of permeability model construction and risk fields evaluation by roof cutting along the gob in a coal mine.

The productivity of coal mines is seriously threatened by the combined disasters of gas and coal spontaneous combustion, which have become a common disaster mode. It is unclear how the gas and coal spontaneously combusted in the roof cutting along gob working face. The goal of this study is to identify the distinctive features of combined disasters in gob from two different types of roof cutting along working faces. In these two different types of roof cutting along gob working faces, the paper constructs the permeability model of the gob. The findings demonstrate that the data from the field experiment and the simulation results agree, which validates the simulation's reliability. In contrast to single sided roof cutting along gob working faces, double sided roof cutting along gob working faces clearly has a thinner oxidation zone. Moreover, the oxidation zone of the double side roof cutting along gob working faces is closer to the working face, which is located in the shallow area of the gob 50 m behind the working face. The gas explosion area and the coal spontaneous combustion area are divided by the double side roof cutting along gob working face, which reduces the risk of compound disasters. Important theoretical direction for the prevention and control of gob disasters in the roof cutting along gob working face is provided by the simulation results.

HostNet: improved sequence representation in deep neural networks for virus-host prediction.

BACKGROUND: The escalation of viruses over the past decade has highlighted the need to determine their respective hosts, particularly for emerging ones that pose a potential menace to the welfare of both human and animal life. Yet, the traditional means of ascertaining the host range of viruses, which involves field surveillance and laboratory experiments, is a laborious and demanding undertaking. A computational tool with the capability to reliably predict host ranges for novel viruses can provide timely responses in the prevention and control of emerging infectious diseases. The intricate nature of viral-host prediction involves issues such as data imbalance and deficiency. Therefore, developing highly accurate computational tools capable of predicting virus-host associations is a challenging and pressing demand. RESULTS: To overcome the challenges of virus-host prediction, we present HostNet, a deep learning framework that utilizes a Transformer-CNN-BiGRU architecture and two enhanced sequence representation modules. The first module, k-mer to vector, pre-trains a background vector representation of k-mers from a broad range of virus sequences to address the issue of data deficiency. The second module, an adaptive sliding window, truncates virus sequences of various lengths to create a uniform number of informative and distinct samples for each sequence to address the issue of data imbalance. We assess HostNet's performance on a benchmark dataset of "Rabies lyssavirus" and an in-house dataset of "Flavivirus". Our results show that HostNet surpasses the state-of-the-art deep learning-based method in host-prediction accuracies and F1 score. The enhanced sequence representation modules, significantly improve HostNet's training generalization, performance in challenging classes, and stability. CONCLUSION: HostNet is a promising framework for predicting virus hosts from genomic sequences, addressing challenges posed by sparse and varying-length virus sequence data. Our results demonstrate its potential as a valuable tool for virus-host prediction in various biological contexts. Virus-host prediction based on genomic sequences using deep neural networks is a promising approach to identifying their potential hosts accurately and efficiently, with significant impacts on public health, disease prevention, and vaccine development.

MLKL deficiency alleviates neuroinflammation and motor deficits in the α-synuclein transgenic mouse model of Parkinson's disease.

Parkinson's disease (PD), one of the most devastating neurodegenerative brain disorders, is characterized by the progressive loss of dopaminergic neurons in the substantia nigra (SN) and deposits of α-synuclein aggregates. Currently, pharmacological interventions for PD remain inadequate. The cell necroptosis executor protein MLKL (Mixed-lineage kinase domain-like) is involved in various diseases, including inflammatory bowel disease and neurodegenerative diseases; however, its precise role in PD remains unclear. Here, we investigated the neuroprotective role of MLKL inhibition or ablation against primary neuronal cells and human iPSC-derived midbrain organoids induced by toxic α-Synuclein preformed fibrils (PFFs). Using a mouse model (Tg-Mlkl-/-) generated by crossbreeding the SNCA A53T synuclein transgenic mice with MLKL knockout (KO)mice, we assessed the impact of MLKL deficiency on the progression of Parkinsonian traits. Our findings demonstrate that Tg-Mlkl-/- mice exhibited a significant improvement in motor symptoms and reduced phosphorylated α-synuclein expression compared to the classic A53T transgenic mice. Furthermore, MLKL deficiency alleviated tyrosine hydroxylase (TH)-positive neuron loss and attenuated neuroinflammation by inhibiting the activation of microglia and astrocytes. Single-cell RNA-seq (scRNA-seq) analysis of the SN of Tg-Mlkl-/- mice revealed a unique cell type-specific transcriptome profile, including downregulated prostaglandin D synthase (PTGDS) expression, indicating reduced microglial cells and dampened neuron death. Thus, MLKL represents a critical therapeutic target for reducing neuroinflammation and preventing motor deficits in PD.