Risk prediction models for intensive care unit-acquired weakness in critically ill patients: A systematic review.

BACKGROUND: Intensive care unit (ICU)-acquired weakness (ICU-AW) is a critical complication that significantly worsens patient prognosis. It is widely thought that risk prediction models can be harnessed to guide preventive interventions. While the number of ICU-AW risk prediction models is increasing, the quality and applicability of these models in clinical practice remain unclear. OBJECTIVE: The objective of this study was to systematically review published studies on risk prediction models for ICU-AW. METHODS: We searched electronic databases (PubMed, Web of Science, The Cochrane Library, Embase, Cumulative Index to Nursing and Allied Health Literature (CINAHL), China National Knowledge Infrastructure (CNKI), China Science and Technology Periodical Database (VIP), and Wanfang Database) from inception to October 2023 for studies on ICU-AW risk prediction models. Two independent researchers screened the literature, extracted data, and assessed the risk of bias and applicability of the included studies. RESULTS: A total of 2709 articles were identified. After screening, 25 articles were selected, encompassing 25 risk prediction models. The area under the curve for these models ranged from 0.681 to 0.926. Evaluation of bias risk indicated that all included models exhibited a high risk of bias, with three models demonstrating poor applicability. The top five predictors among these models were mechanical ventilation duration, age, Acute Physiology and Chronic Health Evaluation II score, blood lactate levels, and the length of ICU stay. The combined area under the curve of the ten validation models was 0.83 (95% confidence interval: 0.77-0.88), indicating a strong discriminative ability. CONCLUSIONS: Overall, ICU-AW risk prediction models demonstrate promising discriminative ability. However, further optimisation is needed to address limitations, including data source heterogeneity, potential biases in study design, and the need for robust statistical validation. Future efforts should prioritise external validation of existing models or the development of high-quality predictive models with superior performance. REGISTRATION: The protocol for this study is registered with the International Prospective Register of Systematic Reviews (registration number: CRD42023453187).

Predictors of post-healing recurrence in patients with diabetic foot ulcers: A systematic review and meta-analysis.

BACKGROUND: Diabetic foot ulcer is one of the most prevalent, serious, and costly consequences of diabetes, often associated with peripheral neuropathy and peripheral arterial disease. These ulcers contribute to high disability and mortality rates in patients and pose a major challenge to clinical management. OBJECTIVE: To systematically review the risk prediction models for post-healing recurrence in diabetic foot ulcer (DFU) patients, so as to provide a reference for clinical staff to choose appropriate prediction models. METHODS: The authors searched five databases (Cochrane Library, PubMed, Web of Science, EMBASE, and Chinese Biomedical Database) from their inception to September 23, 2023, for relevant literature. After data extraction, the quality of the literature was evaluated using the Predictive Model Research Bias Risk and Suitability Assessment tool (PROBAST). Meta-analysis was performed using STATA 17.0 software. RESULTS: A total of 9 studies involving 5956 patients were included. The recurrence rate after DFU healing ranged from 6.2 % to 41.4 %. Nine studies established 15 risk prediction models, and the area under the curve (AUC) ranged from 0.660 to 0.940, of which 12 models had an AUC≥0.7, indicating good prediction performance. The combined AUC value of the 9 validation models was 0.83 (95 % confidence interval: 0.79-0.88). Hosmer-Lemeshow test was performed for 10 models, external validation for 5 models, and internal validation for 6 models. Meta-analysis showed that 14 predictors, such as age and living alone, could predict post-healing recurrence in DFU patients (p < 0.05). CONCLUSION: To enhance the quality of these risk prediction models, there is potential for future improvements in terms of follow-up duration, model calibration, and validation processes.

MSI-DTI: predicting drug-target interaction based on multi-source information and multi-head self-attention.

Identifying drug-target interactions (DTIs) holds significant importance in drug discovery and development, playing a crucial role in various areas such as virtual screening, drug repurposing and identification of potential drug side effects. However, existing methods commonly exploit only a single type of feature from drugs and targets, suffering from miscellaneous challenges such as high sparsity and cold-start problems. We propose a novel framework called MSI-DTI (Multi-Source Information-based Drug-Target Interaction Prediction) to enhance prediction performance, which obtains feature representations from different views by integrating biometric features and knowledge graph representations from multi-source information. Our approach involves constructing a Drug-Target Knowledge Graph (DTKG), obtaining multiple feature representations from diverse information sources for SMILES sequences and amino acid sequences, incorporating network features from DTKG and performing an effective multi-source information fusion. Subsequently, we employ a multi-head self-attention mechanism coupled with residual connections to capture higher-order interaction information between sparse features while preserving lower-order information. Experimental results on DTKG and two benchmark datasets demonstrate that our MSI-DTI outperforms several state-of-the-art DTIs prediction methods, yielding more accurate and robust predictions. The source codes and datasets are publicly accessible at https://github.com/KEAML-JLU/MSI-DTI.

PATrans: Pixel-Adaptive Transformer for edge segmentation of cervical nuclei on small-scale datasets.

Transformer has shown excellent performance in various visual tasks, making its application in medicine an inevitable trend. Nevertheless, simply using transformer for small-scale cervical nuclei datasets will result in disastrous performance. Scarce nuclei pixels are not enough to compensate for the lack of CNNs-inherent intrinsic inductive biases, making transformer difficult to model local visual structures and deal with scale variations. Thus, we propose a Pixel Adaptive Transformer(PATrans) to improve the segmentation performance of nuclei edges on small datasets through adaptive pixel tuning. Specifically, to mitigate information loss resulting from mapping different patches into similar latent representations, Consecutive Pixel Patch (CPP) embeds rich multi-scale context into isolated image patches. In this way, it can provide intrinsic scale invariance for 1D input sequences to maintain semantic consistency, allowing the PATrans to establish long-range dependencies quickly. Futhermore, due to the existing handcrafted-attention is agnostic to the widely varying pixel distributions, the Pixel Adaptive Transformer Block (PATB) effectively models the relationships between different pixels across the entire feature map in a data-dependent manner, guided by the important regions. By collaboratively learning local features and global dependencies, PATrans can adaptively reduce the interference of irrelevant pixels. Extensive experiments demonstrate the superiority of our model on three datasets(Ours, ISBI, Herlev).

The prevalence of diabetes distress in Chinese patients with type 2 diabetes: A systematic review and meta-analysis.

OBJECTIVE: To systematically evaluate the prevalence of Diabetes Distress (DD) in type 2 diabetes mellitus (T2DM) patients in China. METHODS: The PubMed, PsycInfo, Web of Science, The Cochrane Library, EMBASE, China Knowledge Resource in Integrated Database (CNKI), WanFang Database, Weipu Database (VIP), and Chinese Biomedical Database (CBM) electronic databases were searched from inception to August 2022, for cross-sectional studies, that reported prevalence of DD. RESULTS: This study included 55 articles involving 13,160 patients with T2DM. The pooled prevalence of DD was 53.2%. The results of the subgroup analysis showed that among the five regions in China, the highest prevalence of DD was observed in Central China (66%), while the lowest prevalence was recorded in North China (23%). The highest prevalence of DD was 82% in unmarried people. while the lowest prevalence of DD among outpatients was as low as 42%. The results of meta-regression showed that there was no correlation between the prevalence of DD and the year of publication, the average age of the patients, or the duration of the disease. CONCLUSION: More than half of T2DM patients in China may suffer from DD, which is not conducive to the self-management of diabetes patients. The burden on the healthcare system and the burden of disease on individual patients may increase as a result. Medical staff should pay attention to the monitoring and management of the mental health status of patients with T2DM.

Fear of disease progression among breast cancer patients in China: a meta-analysis of studies using the fear of progression questionnaire short form.

Background: Fear of disease progression (FoP) is among the most prevalent and major psychological burdens breast cancer patients encounter. Excessive FoP may result in serious adverse effects for patients. FoP in breast cancer patients has gained attention recently; however, its prevalence in China is unknown. Objectives: This meta-analysis and systematic review aimed to assess the overall FoP among Chinese breast cancer patients to make recommendations for treatment and care. Methods: Systematic search databases included PubMed, EMbase, The Cohrane Library, Web of Science, CINAHL, PsycINFO and 4 Chinese databases (Wan Fang Data, CBM, VIP and CNKI). The retrieval time ranged from the database's establishment to March 20, 2023. After two researchers independently evaluated the literature, retrieved information, and assessed the risk of bias for the included literature, Stata 15.1 software was used to conduct a meta-analysis. Results: A total of 37 moderate or high-quality studies involving 9,689 breast cancer patients were included. Meta-analysis showed that the pooled mean score of FoP for Chinese breast cancer patients was 33.84 [95% CI (31.91, 35.77)], prediction interval (21.57 ~ 46.11). The subgroup study found that FoP levels varied among breast cancer patients of different regions, ages, educational levels, marital statuses, residences, illness stages, and disease statuses. Conclusion: Breast cancer patients have higher FoP scores. Healthcare workers should be concerned. We expect that more relevant research will be undertaken and more effective interventions will be developed. Patients can manage their illness and improve their quality of life by reducing their fears. Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier: PROSPERO CRD42023408914.

Short-term postoperative changes in the choroidal vascularity index in patients with a unilateral epiretinal membrane.

BACKGROUND: To investigate short-term choroidal structural and vascular changes after epiretinal membrane (ERM) surgery. METHODS: In this retrospective study, 65 patients with unilateral ERM underwent pars plana vitrectomy combined with cataract surgery and were examined one day before surgery and one week, one month, and three months after surgery. Choroidal thickness (CT) and choroidal vascular index (CVI) were evaluated using horizontal enhanced depth imaging optical coherence tomography (EDI-OCT) scans and were further calculated using semi-automatic algorithms using MATLAB R2017a. RESULTS: Preoperatively, CVI was higher in eyes with ERM (61.70 ± 5.17%) than in fellow eyes (59.99 ± 5.26%). CVI increased significantly at one week after surgery (62.14 ± 5.02%) and decreased at 1 and 3 months after surgery (60.76 ± 4.97% and 60.4 ± 4.83%, respectively). The change was pronounced in the nasal region (p < 0.001) and central region (p < 0.05). CT in the temporal macula increased at 1 week (239.65 ± 72.98 µm) after surgery and decreased at 1 and 3 months after surgery (222.15 ± 71.91 µm and 222.33 ± 65.72 µm, respectively; p < 0.01). CONCLUSIONS: Short-term postoperative variations in the choroid have been demonstrated in eyes with ERM. This may be related to the release of macular traction. CVI assessment using EDI-OCT may be a useful tool for investigating choroidal structural changes accompanying ERM and postoperative period.

A peptide derived from the N-terminal of NS2A for the preparation of ZIKV NS2A recognition polyclonal antibody.

Zika virus non-structural protein NS2A participates in viral replication, organization, and budding, as well as escaping host immunity. NS2A also involved in the induction of microcephaly by ZIKV. However, the above studies were mainly performed through NS2A with a tag due to the lack of available antibodies against NS2A. ZIKV NS2A is a multiplex transmembrane protein, which leads to difficulties in the preparation of its recognition antibodies, thus seriously affecting the study of ZIKV NS2A. In this study, we found that a peptide (GSTDHMDHFSLGVLC) derived from the N-terminal of ZIKV NS2A coupled to KLH induced antibodies recognizing ZIKV NS2A in rabbits. The purified polyclonal antibody recognized ZIKV NS2A in ZIKV-infected cells with high efficiency and specificity, as detected by western blot and immunofluorescence assay. Our study has important implications for the preparation of ZIKV NS2A antibodies and the in-depth study of ZIKV NS2A.

The prevalence of alexithymia in psoriasis: A systematic review and meta-analysis.

OBJECTIVES: Alexithymia is characterized by an inability to identify and describe feelings, which may increase the psychological burden of patients with psoriasis. The prevalence of alexithymia in psoriasis has been investigated with variable results. This study aimed to estimate the overall alexithymia prevalence in psoriasis. METHODS: The PubMed, PsycInfo, Web of Science, The Cochrane Library, EMBASE, China Knowledge Resource in Integrated Database (CNKI), WanFang Database, Weipu Database (VIP), and Chinese Biomedical Database (CBM) electronic databases were searched from inception to March 28, 2022, for cross-sectional studies, that reported prevalence of alexithymia. The included studies were evaluated for quality, data synthesis, subgroup analysis, sensitivity analysis, and publication bias. RESULTS: This systematic review and meta-analysis included 16 articles involving 3752 patients with psoriasis from eight countries. The pooled prevalence of alexithymia was 28% (95% CI: 25-32%), with heterogeneity between studies (I2 = 80.03%, p < .001). There was a higher prevalence of alexithymia in women with psoriasis, patients with a Psoriasis Area Severity Index (PASI) score >10, patients with psoriatic arthritis, and patients with psoriasis with visible skin lesions had a higher prevalence of alexithymia. CONCLUSION: More than a quarter of people with psoriasis have alexithymia., But due to the small sample size of the included studies, the results of the subgroup analysis should be interpreted with caution. More research is needed to elucidate the mechanism of alexithymia development in psoriasis. These findings may provide a theoretical basis for the screening and intervention of alexithymia in patients with psoriasis.

Nonstructural Protein NSs Activates Inflammasome and Pyroptosis through Interaction with NLRP3 in Human Microglial Cells Infected with Severe Fever with Thrombocytopenia Syndrome Bandavirus.

Severe fever with thrombocytopenia syndrome (SFTS) is a tick-borne febrile disease caused by SFTS virus (SFTSV), or Dabie bandavirus, in the Phenuiviridae family. Clinically neurological disorders in SFTS have been commonly reported, but their neuropathogenesis has rarely been studied. Microglia are a type of neuroglia accounting for 10 to 12% of all cells in the brain. As resident immune cells, microglial cells are the first line of immune defense present in the central nervous system (CNS). Here, we report that SFTSV was able to infect microglial cells and stimulate interleukin 1ß (IL-1ß) secretion in the brains of infected neonatal BALB/c mice. We characterized the cell death induced in infected human microglial HMC3 cells, also susceptible to SFTSV, and found that the NOD-like receptor protein 3 (NLRP3) inflammasome was activated, leading to secretion of IL-1ß and pyroptosis. Knockdown of NLRP3 or inhibition of the NLRP3 inflammasome activation suppressed the viral replication, suggesting that the activation of the NLRP3 inflammasome may support SFTSV replication in microglial cells. Viral nonstructural protein NSs, a known modulator of immune responses, interacted and colocalized with NLRP3 for the inflammasome activation. It appeared that the N-terminal fragment, amino acids 1 to 66, of NSs was critical to promote the assembly of the inflammasome complex by interacting with NLRP3 for its activation in microglial cells. Our findings provide evidence that SFTSV may cause neurological disorders through infecting microglia and activating the inflammasome through its nonstructural protein NSs for neural cell death and inflammation. This study may have revealed a novel mechanism of SFTSV NSs in dysregulating host response. IMPORTANCE Encephalitis or encephalopathy during severe fever with thrombocytopenia syndrome (SFTS) is considered a critical risk factor leading to high mortality, but there have been no studies to date on the pathogenesis of encephalitis or encephalopathy caused by SFTS virus. Here, we report that SFTSV infection can active the NLRP3 inflammasome and induce IL-1ß secretion in the brains of infected newborn mice. In infected human HMC3 microglia, SFTSV activated the NLRP3 inflammasome via the viral nonstructural protein NSs through interaction with its N-terminal fragment. Notably, our findings suggest that the activation of the NLRP3 inflammasome may promote SFTSV replication in infected microglial cells. This study may reveal a novel mechanism by SFTSV to dysregulate host responses through its nonstructural protein, which could help us understand viral neuropathogenesis in SFTS patients.

Intrinsic features of Zika Virus non-structural proteins NS2A and NS4A in the regulation of viral replication.

Zika virus (ZIKV) is a mosquito-borne flavivirus and can cause neurodevelopmental disorders in fetus. As a neurotropic virus, ZIKV persistently infects neural tissues during pregnancy but the viral pathogenesis remains largely unknown. ZIKV has a positive-sense and single-stranded RNA genome, which encodes 7 non-structural (NS) proteins, participating in viral replication and dysregulation of host immunity. Like those in many other viruses, NS proteins are considered to be products evolutionarily beneficiary to viruses and some are virulence factors. However, we found that some NS proteins encoded by ZIKV genome appeared to function against the viral replication. In this report we showed that exogenously expressed ZIKV NS2A and NS4A inhibited ZIKV infection by inhibiting viral RNA replication in microglial cells and astrocytes. To understand how viral NS proteins suppressed viral replication, we analyzed the transcriptome of the microglial cells and astrocytes and found that expression of NS4A induced the upregulation of ISGs, including MX1/2, OAS1/2/3, IFITM1, IFIT1, IFI6, IFI27, ISG15 or BST2 through activating the ISGF3 signaling pathway. Upregulation of these ISGs seemed to be related to the inhibition of ZIKV replication, since the anti-ZIKV function of NS4A was partially attenuated when the cells were treated with Abrocitinib, an inhibitor of the ISGF3 signaling pathway, or were knocked down with STAT2. Aborting the protein expression of NS4A, but not its nucleic acid, eliminated the antiviral activity of NS4A effectively. Dynamic expression of viral NS proteins was examined in ZIKV-infected microglial cells and astrocytes, which showed comparatively NS4A occurred later than other NS proteins during the infection. We hypothesize that NS4A may possess intrinsic features to serve as a unique type of pathogen associated molecular pattern (PAMP), detectable by the cells to induce an innate immune response, or function with other mechanisms, to restrict the viral replication to a certain level as a negative feedback, which may help ZIKV maintain its persistent infection in fetal neural tissues.

Concomitant pyroptotic and apoptotic cell death triggered in macrophages infected by Zika virus.

Zika virus (ZIKV) is a positive-sense RNA flavivirus and can cause serious neurological disorders including microcephaly in infected fetuses. As a mosquito-borne arbovirus, it enters the bloodstream and replicates in various organs. During pregnancy, it can be transmitted from the blood of the viremic mother to the fetus by crossing the placental barrier. Monocytes and macrophages are considered the earliest blood cell types to be infected by ZIKV. As a first line defense, these cells are crucial components in innate immunity and host responses and may impact viral pathogenesis in humans. Previous studies have shown that ZIKV infection can activate inflammasomes and induce proinflammatory cytokines in monocytes. In this report, we showed that ZIKV could infect and induce cell death in human and murine macrophages. In addition to the presence of cleaved caspase-3, indicating that apoptosis was involved, we identified the cleaved caspase-1 and gasdermin D (GSDMD) as well as increased secretion of IL-1ß and IL-18. This suggests that the inflammasome was activated and that may lead to pyroptosis in infected macrophages. The pyroptosis was NLRP3-dependent and could be suppressed in the macrophages treated with shRNA to target and knockdown caspase-1. It was also be inhibited by an inhibitor for caspase-1, indicating that the pyroptosis was triggered via a canonical approach. Our findings in this study demonstrate a concomitant occurrence of apoptosis and pyroptosis in ZIKV-infected macrophages, with two mechanisms involved in the cell death, which may have potentially significant impacts on viral pathogenesis in humans.

Exogenous Melatonin Activates Antioxidant Systems to Increase the Ability of Rice Seeds to Germinate under High Temperature Conditions.

High temperatures are a major concern that limit rice germination and plant growth. Although previous studies found that melatonin can promote seed germination, the physiological regulation mechanism by which exogenous melatonin mediates high temperature tolerance during rice seed germination is still largely unknown. In order to overcome these challenges, the present study investigates the effects of melatonin on the characteristics of rice seed germination as well as on antioxidant properties, under different high temperature conditions. The results show that 100 µM melatonin seed-soaking treatment under high temperature conditions effectively improves the germination potential, the germination index, and the vigor index of rice seeds; increases the length of the shoot and the root; improves the activity of the antioxidant enzymes; and significantly reduces the malondialdehyde content. The gray relational grade of the shoot peroxidase activity and the melatonin soaking treatment was the highest, which was used to evaluate the effect of melatonin on the heat tolerance of rice. The subordinate function method was used to comprehensively evaluate the tolerance, and the results show that the critical concentration of melatonin is 100 µM, and the critical interactive treatment is the germination at 38 °C and followed by the recovery at 26 °C for 1 day + 100 µM. In conclusion, 100 µM of melatonin concentration improved the heat resistance of rice seeds by enhancing the activity of the antioxidant enzymes.

Flavivirus Entry Inhibitors.

Flaviviruses, including Dengue virus, Zika virus, Yellow fever virus, Japanese encephalitis virus, West Nile virus, cause thousands of deaths and millions of illnesses each year. The large outbreak of ZIKV in 2016 reminds us that flaviviruses can pose a serious threat to human safety and public health as emerging and re-emerging viruses. However, there are no specific drugs approved for the treatment of flavivirus infections. Due to no need to enter the cells, viral entry inhibitors have the unique advantage in suppressing viral infections. Flaviviruses bind to receptors and attach to the cell surface, then enter the endosome in a clathrin-dependent manner and finalizes the viral entry process after fusion with the cell membrane in a low pH environment. Small molecules, antibodies or peptides can inhibit flavivirus entry by targeting the above processes. Here, we focus on flavivirus entry inhibitors with well-defined target and antiviral activity. We hope that our review will provide a theoretical basis for flavivirus treatment and drug research and help to accelerate the clinical application of flavivirus entry inhibitors.

Hyperspectral Image Classification via Discriminant Gabor Ensemble Filter.

For a broad range of applications, hyperspectral image (HSI) classification is a hot topic in remote sensing, and convolutional neural network (CNN)-based methods are drawing increasing attention. However, to train millions of parameters in CNN requires a large number of labeled training samples, which are difficult to collect. A conventional Gabor filter can effectively extract spatial information with different scales and orientations without training, but it may be missing some important discriminative information. In this article, we propose the Gabor ensemble filter (GEF), a new convolutional filter to extract deep features for HSI with fewer trainable parameters. GEF filters each input channel by some fixed Gabor filters and learnable filters simultaneously, then reduces the dimensions by some learnable 1×1 filters to generate the output channels. The fixed Gabor filters can extract common features with different scales and orientations, while the learnable filters can learn some complementary features that Gabor filters cannot extract. Based on GEF, we design a network architecture for HSI classification, which extracts deep features and can learn from limited training samples. In order to simultaneously learn more discriminative features and an end-to-end system, we propose to introduce the local discriminant structure for cross-entropy loss by combining the triplet hard loss. Results of experiments on three HSI datasets show that the proposed method has significantly higher classification accuracy than other state-of-the-art methods. Moreover, the proposed method is speedy for both training and testing.

Peptides derived from viral glycoprotein Gc Inhibit infection of severe fever with thrombocytopenia syndrome virus.

Severe fever with thrombocytopenia syndrome (SFTS) is an acute infectious disease caused by a novel phlebovirus (SFTSV), characterized by fever, thrombocytopenia and leukocytopenia which lead to multiple organ failure with high mortality in severe cases. The SFTSV has spread rapidly in recent years and posed a serious threat to public health in endemic areas. However, specific antiviral therapeutics for SFTSV infection are rare. In this study, we demonstrated that two peptides, SGc1 and SGc8, derived from a hydrophobic region of the SFTSV glycoprotein Gc, could potently inhibit SFTSV replication in a dose-dependent manner without apparent cytotoxicity in various cell lines and with low immunogenicity and good stability. The IC50 (50% inhibition concentration) values for both peptides to inhibit 2 MOI of SFTSV infection were below 10 µM in L02, Vero and BHK21 cells. Mechanistically, SGc1 and SGc8 mainly inhibited viral entry at the early stage of the viral infection. Inhibition of SFTSV replication was specific by both peptides because no inhibitory effect was shown against other viruses including Zika virus and Enterovirus A71. Taken together, our results suggested that viral glycoprotein-derived SGc1 and SGc8 peptides have antiviral potential and warrant further assessment as an SFTSV-specific therapeutic.

RIPK3-Dependent Necroptosis Is Induced and Restricts Viral Replication in Human Astrocytes Infected With Zika Virus.

Apoptosis, pyroptosis and necroptosis are regulated processes of cell death which can be crucial for viral disease outcomes in hosts because of their effects on viral pathogenicity and host resistance. Zika virus (ZIKV) is a mosquito-borne flavivirus, which infects humans and can cause neurological disorders. Neural developmental disorders and microcephaly could occur in infected fetuses. Several types of nervous cells have been reported to be susceptible to ZIKV infection. Human astrocytes play important roles in the nutritional support and defense of neurons. In this study, we show that human astrocytes are susceptible to ZIKV infection and undergo progressive cell death after infection. In infected astrocytes we detected no cleavage or activation of pro-caspase-3 and pro-caspase-1. Apoptotic substrates and increased secretion of interleukin (IL)-1ß or IL-18 were not detected, either. These ruled out the occurrence of apoptosis or pyroptosis in ZIKV-infected astrocytes. We detected, however, an increase of phosphorylated receptor-interacting serine/threonine-protein kinase (RIPK)1, RIPK3, and mixed lineage kinase domain-like (MLKL) protein, indicating that programmed necrosis, or necroptosis, was induced in infected astrocytes. The phosphorylation and cell death were inhibited in cells pre-treated with GSK'872, an inhibitor of RIPK3, while inhibition of RIPK1 with an inhibitor, Necrostatin-1, had no effect, suggesting that ZIKV-induced necroptosis was RIPK1-independent in astrocytes. Consistent with this finding, the inhibition of RIPK1 had no effect on the phosphorylation of MLKL. We showed evidence that MLKL phosphorylation was RIPK3-dependent and ZBP-1, which could stimulate RIPK3, was upregulated in ZIKV-infected astrocytes. Finally, we demonstrated that in GSK'872-pre-treated astrocytes, viral replication increased significantly, which indicates that necroptosis may be protective against viral replication in astrocytes. Our finding that astrocytes uniquely underwent necroptosis in response to ZIKV infection provides insight and helps us better understand the viral pathogenesis in the ZIKV-infected central nervous system.

Fludarabine Inhibits Infection of Zika Virus, SFTS Phlebovirus, and Enterovirus A71.

Viral infections are one of the leading causes in human mortality and disease. Broad-spectrum antiviral drugs are a powerful weapon against new and re-emerging viruses. However, viral resistance to existing broad-spectrum antivirals remains a challenge, which demands development of new broad-spectrum therapeutics. In this report, we showed that fludarabine, a fluorinated purine analogue, effectively inhibited infection of RNA viruses, including Zika virus, Severe fever with thrombocytopenia syndrome virus, and Enterovirus A71, with all IC50 values below 1 µM in Vero, BHK21, U251 MG, and HMC3 cells. We observed that fludarabine has shown cytotoxicity to these cells only at high doses indicating it could be safe for future clinical use if approved. In conclusion, this study suggests that fludarabine could be developed as a potential broad-spectrum anti-RNA virus therapeutic agent.

Comparison of tooth movement and biological response resulting from different force magnitudes combined with osteoperforation in rabbits.

OBJECTIVE: To compare tooth movement rate and histological responses with three different force magnitude designs under osteoperforation in rabbit models. METHODOLOGY: 48 rabbits were divided into three groups: Group A, Group B, and Group C, with traction force of 50 g, 100 g, 150 g, respectively. Osteoperforation was performed at the mesial of the right mandibular first premolar, the left side was not affected. One mini-screw was inserted into bones between two central incisors. Coil springs were fixed to the first premolars and the mini-screw. Tooth movement distance was calculated, and immunohistochemical staining of PCNA, OCN, VEGF, and TGF-ß1 was analyzed. RESULTS: The tooth movement distance on the surgical side was larger than the control side in all groups (P<0.01). No significant intergroup difference was observed for the surgical side in tooth movement distance among the three groups (P>0.05). For the control side, tooth movement distance in Group A was significantly smaller than Groups B and C (P<0.001); no significant difference in tooth movement distance between Group B and Group C was observed (P>0.05). On the tension area of the moving premolar, labeling of PCNA, OCN, VEGF and TGF-ß1 were confirmed in alveolar bone and periodontal ligament in all groups. PCNA, OCN, VEGF and TGF-ß1 on the surgical side was larger than the control side in all groups (P<0.001). CONCLUSION: Osteoperforation could accelerate orthodontic tooth movement rate in rabbits. Fast osteoperforation-assisted tooth movement in rabbits was achieve with light 50 g traction.

Joint Transformation Learning via the L2,1-Norm Metric for Robust Graph Matching.

Establishing correspondence between two given geometrical graph structures is an important problem in computer vision and pattern recognition. In this paper, we propose a robust graph matching (RGM) model to improve the effectiveness and robustness on the matching graphs with deformations, rotations, outliers, and noise. First, we embed the joint geometric transformation into the graph matching model, which performs unary matching over graph nodes and local structure matching over graph edges simultaneously. Then, the L2,1 -norm is used as the similarity metric in the presented RGM to enhance the robustness. Finally, we derive an objective function which can be solved by an effective optimization algorithm, and theoretically prove the convergence of the proposed algorithm. Extensive experiments on various graph matching tasks, such as outliers, rotations, and deformations show that the proposed RGM model achieves competitive performance compared to the existing methods.