Electrophysiological techniques in marine microalgae study: A new perspective for harmful algal bloom (HAB) research.

Electrophysiological techniques, by measuring bioelectrical signals and ion channel activities in tissues and cells, are now widely utilized to study ion channel-related physiological functions and their underlying mechanisms. Electrophysiological techniques have been extensively employed in the investigation of animals, plants, and microorganisms; however, their application in marine algae lags behind that in other organisms. In this paper, we present an overview of current electrophysiological techniques applicable to algae while reviewing the historical usage of such techniques in this field. Furthermore, we explore the potential specific applications of electrophysiological technology in harmful algal bloom (HAB) research. The application prospects in the studies of stress tolerance, competitive advantage, nutrient absorption, toxin synthesis and secretion by HAB microalgae are discussed and anticipated herein with the aim of providing novel perspectives on HAB investigations.

Characteristics of Serum Lipid Metabolism among Women Complicated with Hypertensive Disorders in Pregnancy: A Retrospective Cohort Study in Mainland China.

Background: Altered maternal serum lipid metabolism is associated with hypertensive disorders in pregnancy (HDP). However, its range in pregnancy and characteristic among different subgroups of HDPs are unclear. Methods: Pregnant women with HDP who underwent antenatal care and delivered in Obstetrics and Gynecology Hospital of Fudan University during January 2018 to August 2022 were enrolled. The levels of total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDLC), low-density lipoprotein cholesterol (LDLC), apolipoprotein (Apo)-A, B, and E, free fatty acids (FFA), and small and dense low-density lipoprotein cholesterol (sdLDL) were measured during 4-16 weeks and 28-42 weeks of pregnancy. Results: A total of 2648 pregnant women were diagnosed with HDP, 1,880 of whom were enrolled for final analysis, including 983 (52.3%) preeclampsia (PE), 676 (36.0%) gestational hypertension (GH), and 221 (11.7%) chronic hypertension (CH). For all HDPs, serum TC, TG, LDLC, HDLC, Apo-A, Apo-B, Apo-E, and sdLDL increased significantly during pregnancy, while FFA decreased significantly. Notably, the levels of TC, LDLC, Apo-B, and sdLDL in PE group were equal to or lower than those in CH group at 4-16 weeks of pregnancy, but increased greatly during pregnancy (P < 0.05). Conclusions: Maternal serum lipid levels changed through pregnancy among women with HDPs. Women complicated with PE seem to have undergone a more significant serum lipid change compared to those with GH or CH.

Integrated bioinformatics and machine-learning screening for immune-related genes in diagnosing non-alcoholic fatty liver disease with ischemic stroke and RRS1 pan-cancer analysis.

Background: The occurrence of ischemic stroke (IS) is associated with nonalcoholic fatty liver disease (NAFLD). The cancer burden of NAFLD complicated by IS also warrants attention. This study aimed to identify candidate immune biomarkers linked to NAFLD and IS and analyze their association with cancer. Methods: Two of each of the NAFLD and IS datasets were downloaded, differentially expressed genes (DEGs) were identified, and module genes were screened via weighted gene coexpression network analysis (WGCNA). Subsequently, utilizing machine learning (least absolute shrinkage and selection operator regression, random forest and support vector machine-recursive feature elimination) and immune cell infiltration analysis, immune-related candidate biomarkers for NAFLD with IS were determined. Simultaneously, a nomogram was established, the diagnostic efficacy was assessed, and the role of candidate biomarkers in cancer was ascertained through pan-cancer analyses. Results: In this study, 117 and 98 DEGs were identified from the combined NAFLD and IS datasets, respectively, and 279 genes were obtained from the most significant modules of NAFLD. NAFLD module genes and IS DEGs were intersected to obtain nine genes, which were enriched in the inflammatory response and immune regulation. After overlapping the results of the three machine learning algorithms, six candidate genes were obtained, based on which a nomogram was constructed. The calibration curve demonstrated good accuracy, and the candidate genes had high diagnostic values. The genes were found to be related to the immune dysregulation of stroke, and RRS1 was strongly associated with the prognosis, immune cell infiltration, microsatellite instability (MSI), and tumor mutation burden (TMB). Conclusion: Six common candidate immune-related genes (PTGS2, FCGR1A, MMP9, VNN3, S100A12, and RRS1) of NAFLD and IS were identified, and a nomogram for diagnosing NAFLD with IS was established. RRS1 may serve as a candidate gene for predicting the prognosis of patients with cancer who have NAFLD complicated by IS, which could aid in their diagnosis and treatment.

Optimization of Briquette Fuels by Co-Torrefaction of Residual Biomass and Plastic Waste Using Response Surface Methodology.

Combining biomass, a clean and renewable energy source, with waste plastic, which serves as a good auxiliary fuel, can produce high-quality clean fuel. The performance of biomass-derived fuel can be improved by torrefaction. This study optimized the co-torrefaction of fungus bran and polypropylene (PP) waste plastic to obtain clean solid biofuel with high calorific value and low ash content (AC) using response surface methodology. Two sets of mixed biochars were investigated using a multiobjective optimization method: mass yield-higher heating value-ash content (MY-HHV-AC) and energy yield-ash content (EY-AC). PP increased the heat value, decreased AC, and acted as a binder. The optimal operating conditions regarding reaction temperature, reaction time, and PP blending ratio were 230.68 °C, 30 min, and 20%, respectively, for the MY-HHV-AC set and 220 °C, 30 min, 20%, respectively, for the EY-AC set. The MY-HHV-AC set had properties close to those of peat and lignite. Furthermore, compared with that of the pure biochar, the AC of the two sets decreased by 15.71% and 14.88%, respectively, indicating that the prepared mixed biochars served as ideal biofuels. Finally, a circular economy framework for biobriquette fuel was proposed and prospects for preparing pellets provided.

gem-Bromonitroalkane Involved Radical 1,2-Aryl Migration of α,α-Diaryl Allyl Alcohol TMS Ether via Visible-Light Photoredox Catalysis.

A mild and efficient coupling method concerning the reactions of gem-bromonitroalkanes with α,α-diaryl allyl alcohol trimethylsilyl ethers was reported. A cascade consisting of visible-light-induced generation of an α-nitroalkyl radical and a subsequent neophyl-type rearrangement was key to realize the coupling reactions. Structurally diverse α-aryl-γ-nitro ketones, especially those bearing a nitrocyclobutyl structure, were prepared in moderate to high yields, which could be converted into spirocyclic nitrones and imines.

Allosteric potentiation of GABAA receptor single-channel conductance by netrin-1 during neuronal-excitation-induced inhibitory synaptic homeostasis.

As the principal receptor that mediates both synaptic and tonic inhibition of neurons in the brain, the A-type gamma-aminobutyric acid receptor (GABAAR) is functionally important for maintaining the balance between neuronal excitation and inhibition. Here, we report the identification of netrin-1 as an endogenous allosteric modulator of GABAARs. Following increased neuronal excitability, netrin-1 is secreted and binds to the extracellular domains of GABAAR subunits, thereby inducing homeostatic upscaling of GABAAR-mediated synaptic efficacy and currents. Surprisingly, this homeostatic plasticity is primarily mediated by increasing GABAAR single-channel conductance. Our study reveals an important role of netrin-1 as an endogenous GABAAR allosteric modulator in maintaining neuronal excitation-inhibition balance, a fundamental process for brain function and dysfunction.

Glutamate and GABAA receptor crosstalk mediates homeostatic regulation of neuronal excitation in the mammalian brain.

Maintaining a proper balance between the glutamate receptor-mediated neuronal excitation and the A type of GABA receptor (GABAAR) mediated inhibition is essential for brain functioning; and its imbalance contributes to the pathogenesis of many brain disorders including neurodegenerative diseases and mental illnesses. Here we identify a novel glutamate-GABAAR interaction mediated by a direct glutamate binding of the GABAAR. In HEK293 cells overexpressing recombinant GABAARs, glutamate and its analog ligands, while producing no current on their own, potentiate GABA-evoked currents. This potentiation is mediated by a direct binding at a novel glutamate binding pocket located at the α+/ß- subunit interface of the GABAAR. Moreover, the potentiation does not require the presence of a γ subunit, and in fact, the presence of γ subunit significantly reduces the potency of the glutamate potentiation. In addition, the glutamate-mediated allosteric potentiation occurs on native GABAARs in rat neurons maintained in culture, as evidenced by the potentiation of GABAAR-mediated inhibitory postsynaptic currents and tonic currents. Most importantly, we found that genetic impairment of this glutamate potentiation in knock-in mice resulted in phenotypes of increased neuronal excitability, including decreased thresholds to noxious stimuli and increased seizure susceptibility. These results demonstrate a novel cross-talk between excitatory transmitter glutamate and inhibitory GABAAR. Such a rapid and short feedback loop between the two principal excitatory and inhibitory neurotransmission systems may play a critical homeostatic role in fine-tuning the excitation-inhibition balance (E/I balance), thereby maintaining neuronal excitability in the mammalian brain under both physiological and pathological conditions.

Establishment and preliminary study of electrophysiological techniques in a typical red tide species.

Electrophysiology studies the electrical properties of cells and tissues including bioelectrical signals and membrane ion channel activities. As an important means to reveal ion channel related physiological functions and the underlying mechanisms, electrophysiological techniques have been widely used in studies of animals, higher plants and algae that are closely related to higher plants. However, few electrophysiological studies have been carried out in red tide organisms, especially in dinoflagellates, which is mainly due to the complex surface structure of dinoflagellate amphiesma. In this study, the surface amphiesma of Alexandrium pacificum, a typical red tide species, was removed by centrifugation, low-temperature treatment and enzymatic treatment. In all three treatments, low-temperature treatment with 4 °C for 2 h had high ecdysis rate and high fixation rate, and the treated cells were easy to puncture, so low-temperature treatment was used as a preprocessing treatment for subsequent current recording. Acquired protoplasts of A. pacificum were identified by calcofluor fluorescence and immobilized by poly-lysine. A modified "puncture" single-electrode voltage-clamp recording was first applied to dinoflagellates, and voltage-gated currents, which had the characteristics of outward K+ current and inward Cl- current, were recorded and confirmed by ion replacement, indicating the voltage-gated currents were mixed. This method can be used as a technical basis for the electrophysiological study of dinoflagellates and provides a new perspective for the study of stress tolerance, red tide succession, and the regulation of physiological function of dinoflagellates.

Risk and predictive factors for severe dengue infection: A systematic review and meta-analysis.

BACKGROUND: Dengue is a major public health issue worldwide and severe dengue (SD) is life threatening. It is critical to triage patients with dengue infection in the early stage. However, there is limited knowledge on early indicators of SD. The objective of this study is to identify risk factors for the prognosis of SD and try to find out some potential predictive factors for SD from dengue fever (DF) in the early of infection. METHODS: The PubMed, Cochrane Library and Web of Science databases were searched for relevant studies from June 1999 to December 2020. The pooled odds ratio (OR) or standardized mean difference (SMD) with 95% confidence intervals (CI) of identified factors was calculated using a fixed or random effect model in the meta-analysis. Tests for heterogeneity, publication bias, subgroup analyses, meta-regression, and a sensitivity analysis were further performed. FINDINGS: A total of 6,848 candidate articles were retrieved, 87 studies with 35,184 DF and 8,173 SD cases met the eligibility criteria. A total of 64 factors were identified, including population and virus characteristics, clinical symptoms and signs, laboratory biomarkers, cytokines, and chemokines; of these factors, 34 were found to be significantly different between DF and SD, while the other 30 factors were not significantly different between the two groups after pooling the data from the relevant studies. Additionally, 9 factors were positive associated with SD within 7 days after illness when the timing subgroup analysis were performed. CONCLUSIONS: Practical factors and biomarkers for the identification of SD were established, which will be helpful for a prompt diagnosis and early effective treatment for those at greatest risk. These outcomes also enhance our knowledge of the clinical manifestations and pathogenesis of SD.

Cetuximab Combined With Sonodynamic Therapy Achieves Dual-Modal Image Monitoring for the Treatment of EGFR-Sensitive Non-Small-Cell Lung Cancer.

BACKGROUND: Blocking signaling by epidermal growth factor receptor (EGFR), can effectively inhibit the proliferation and differentiation of non-small-cell lung cancer (NSCLC). Additionally, an increasing number of NSCLC patients have treatment limitations caused by EGFR overexpression or mutations. Therefore, we constructed a nanotherapy platform consisting of cetuximab (CTX) to target EGFR-sensitive NSCLC with an iron tetroxide core loading the sound-sensitive agent IR780 for dual-mode imaging diagnosis by combining targeting and sonodynamic therapy (SDT) to reshape the tumor microenvironment (TME), enhance the SDT antitumor effects and improve the therapeutic effects of EGFR sensitivity. METHODS: IR780@INPs were prepared by reverse rotary evaporation, CTX was adsorbed/coupled to obtain IR780@INPs-CTX, and the morphology and structure were characterized. Intracellular ROS levels and cell apoptosis first verified its killing effects against tumor cells. Then, a nude mouse lung cancer subcutaneous xenograft model was established with HCC827 cells. A real-time fluorescence IVIS imaging system determined the targeting and live distribution of IR780@INPs-CTX in the transplanted tumors and the imaging effects of the T2 sequence of the INPs by magnetic resonance imaging (MRI) 0 h, 2 h, 4 h and 6 h after administration to confirm drug efficacy. RESULTS: In vitro, US+IR780@INPs-CTX produced a large amount of ROS after SDT to induce cell apoptosis, and significant cell death after live/dead staining was observed. In vivo fluorescence imaging showed the IR780@INPs-CTX was mainly concentrated in the tumor with a small amount in the liver. MRI displayed rapid enrichment of the IR780@INPs into tumor tissue 0h after injection and the T2 signal intensity gradually decreases with time without obvious drug enrichment in the surrounding tissues. In vivo, at the end of treatment, the US+IR780@INPs-CTX group showed disappearance or a continued decrease in tumor volume, indicating strong SDT killing effects. CONCLUSION: The combination of CTX and SDT is expected to become a novel treatment for EGFR-sensitive NSCLC.

Distinct Functional Alterations and Therapeutic Options of Two Pathological De Novo Variants of the T292 Residue of GABRA1 Identified in Children with Epileptic Encephalopathy and Neurodevelopmental Disorders.

Mutations of GABAAR have reportedly led to epileptic encephalopathy and neurodevelopmental disorders. We have identified a novel de novo T292S missense variant of GABRA1 from a pediatric patient with grievous global developmental delay but without obvious epileptic activity. This mutation coincidentally occurs at the same residue as that of a previously reported GABRA1 variant T292I identified from a pediatric patient with severe epilepsy. The distinct phenotypes of these two patients prompted us to compare the impacts of the two mutants on the receptor function and to search for suitable therapeutics. In this study, we used biochemical techniques and patch-clamp recordings in HEK293 cells overexpressing either wild-type or mutated rat recombinant GABAARs. We found that the α1T292S variant significantly increased GABA-evoked whole-cell currents, shifting the dose-response curve to the left without altering the maximal response. In contrast, the α1T292I variant significantly reduced GABA-evoked currents, shifting the dose-response curve to the right with a severely diminished maximum response. Single-channel recordings further revealed that the α1T292S variant increased, while the α1T292I variant decreased the GABAAR single-channel open time and open probability. Importantly, we found that the T292S mutation-induced increase in GABAAR function could be fully normalized by the negative GABAAR modulator thiocolchicoside, whereas the T292I mutation-induced impairment of GABAAR function was largely rescued with a combination of the GABAAR positive modulators diazepam and verapamil. Our study demonstrated that α1T292 is a critical residue for controlling GABAAR channel gating, and mutations at this residue may produce opposite impacts on the function of the receptors. Thus, the present work highlights the importance of functionally characterizing each individual GABAAR mutation for ensuring precision medicine.

Proteomic profiling reveals a distinctive molecular signature for critically ill COVID-19 patients compared with asthma and chronic obstructive pulmonary disease.

OBJECTIVE: The mortality rate for critically ill COVID-19 cases was more than 80%. Nonetheless, research about the effect of common respiratory diseases on critically ill COVID-19 expression and outcomes is scarce. DESIGN: We performed proteomic analyses on airway mucus obtained by bronchoscopy from patients with severe COVID-19, or induced sputum from patients with chronic obstructive pulmonary disease (COPD), asthma, and healthy controls. RESULTS: Of the total identified and quantified proteins, 445 differentially expressed proteins (DEPs) were found in different comparison groups. In comparison with COPD, asthma, and controls, 11 proteins were uniquely present in COVID-19 patients. Apart from DEPs associated with COPD versus controls and asthma versus controls, there was a total of 59 DEPs specific to COVID-19 patients. Finally, the findings revealed that there were 8 overlapping proteins in COVID-19 patients, including C9, FGB, FGG, PRTN3, HBB, HBA1, IGLV3-19, and COTL1. Functional analyses revealed that most of them were associated with complement and coagulation cascades, platelet activation, or iron metabolism, and anemia-related pathways. CONCLUSIONS: This study provides fundamental data for identifying COVID-19-specific proteomic changes in comparison with COPD and asthma, which may suggest molecular targets for specialized therapy.

MRI-Based Back Propagation Neural Network Model as a Powerful Tool for Predicting the Response to Induction Chemotherapy in Locoregionally Advanced Nasopharyngeal Carcinoma.

BACKGROUND: Pretreatment individualized assessment of tumor response to induction chemotherapy (ICT) is a need in locoregionally advanced nasopharyngeal carcinoma (LANPC). Imaging method plays vital role in tumor response assessment. However, powerful imaging method for ICT response prediction in LANPC is insufficient. PURPOSE: To establish a robust model for predicting response to ICT in LANPC by comparing the performance of back propagation neural network (BPNN) model with logistic regression model. STUDY TYPE: Retrospective. POPULATION: A total of 286 LANPC patients were assigned to training (N = 200, 43.8 ± 10.9 years, 152 male) and testing (N = 86, 43.5 ± 11.3 years, 57 male) cohorts. FIELD STRENGTH/SEQUENCE: T2 -weighted imaging, contrast enhanced-T1 -weighted imaging using fast spin echo sequences at 1.5 T scanner. ASSESSMENT: Predictive clinical factors were selected by univariate and multivariate logistic models. Radiomic features were screened by interclass correlation coefficient, single-factor analysis, and the least absolute shrinkage selection operator (LASSO). Four models based on clinical factors (Modelclinic ), radiomics features (Modelradiomics ), and clinical factors + radiomics signatures using logistic (Modelcombined ), and BPNN (ModelBPNN ) methods were established, and model performances were compared. STATISTICAL TESTS: Student's t-test, Mann-Whitney U-test, and Chi-square test or Fisher's exact test were used for comparison analysis. The performance of models was assessed by area under the receiver operating characteristic (ROC) curve (AUC) and Delong test. P < 0.05 was considered statistical significance. RESULTS: Three significant clinical factors: Epstein-Barr virus-DNA (odds ratio [OR] = 1.748; 95% confidence interval [CI], 0.969-3.171), sex (OR = 2.883; 95% CI, 1.364-6.745), and T stage (OR = 1.853; 95% CI, 1.201-3.052) were identified via univariate and multivariate logistic models. Twenty-four radiomics features were associated with treatment response. ModelBPNN demonstrated the highest performance among Modelcombined , Modelradiomics , and Modelclinic (AUC of training cohort: 0.917 vs. 0.808 vs. 0.795 vs. 0.707; testing cohort: 0.897 vs. 0.755 vs. 0.698 vs. 0.695). CONCLUSION: A machine-learning approach using BPNN showed better ability than logistic regression model to predict tumor response to ICT in LANPC. EVIDENCE LEVEL: 3 TECHNICAL EFFICACY: Stage 2.

MR/NIRF Dual-Mode Imaging of αvß3 Integrin-Overexpressing Tumors Using a Lipopeptide-Based Contrast Agent.

Early diagnosis and noninvasive detection of hepatocellular carcinoma have profound clinical implications for treatment quality and improved prognosis. To obtain high-resolution macroscopic anatomical information and high-sensitivity microscopic optical signals to detect tumors, it is highly desirable to develop dual-mode magnetic resonance imaging (MRI) and near-infrared fluorescent (NIRF) probes. An MR/NIRF dual-mode targeted contrast agent was created by encapsulating cyclic arginine-glycine-aspartate (cRGD) and Cy5.5 in liposomes and characterized by the particle size distribution, cytotoxicity, targeting, and MRI relaxivity. The MR T2 intensity and fluorescence intensity were evaluated in the tumors, livers, and muscles after the injection of cRGD-Liposome-Cy5.5 and Liposome-Cy5.5 at different time points. The average size of cRGD-Liposome-Cy5.5 was 62.33 ± 4.648 nm. The transverse relaxivity (R2) values had a negative correlation with the concentration of molecular probes. The MR signal intensity was enhanced in tumors after the cRGD-Liposome-Cy5.5 injection and not enhanced in liver parenchyma and muscles at the same time. The fluorescence intensity was enhanced in tumors after cRGD-Liposome-Cy5.5 injection in the targeted group. cRGD -Liposome-Cy5.5 as an entirely organic T2-positive dual-mode MR/NIRF targeted contrast agent is therefore able to detect early-stage hepatocellular carcinoma by targeting integrin αvß3, providing advantages for potential clinical utility and ease of clinical transformation.

Influence of Relative Humidity on Interparticle Capillary Adhesion.

A homemade instrument is designed to directly characterize the adhesion between two rigid polymeric microspheres in the presence of moist air. The tensile load is measured as a function of approach distance at designated relative humidity (RH). The measurement is consistent with our model from the first approximation. The model is further extended to include a rough surface. Capillary adhesion force is shown to be monotonically increasing with RH for smooth surfaces but becomes more pronounced at low RH for rough surfaces. Moisture has a profound influence on interparticle adhesion, which has significant impacts on a wide range of industrial applications.

Switching Reactive Oxygen Species into Reactive Nitrogen Species by Photocleaved O2 -Released Nanoplatforms Favors Hypoxic Tumor Repression.

In various reactive oxygen species (ROS)-based antitumor approaches (e.g., photodynamic therapy), increasing attentions are made to improve ROS level, but the short lifetime that is another decisive hurdle of ROS-based antitumor outcomes is not even explored yet. To address it, a photocleaved O2 -released nanoplatform is constructed to release and switch ROS into reactive nitrogen species (RNS) for repressing hypoxic breast tumor. Systematic explorations validate that the nanoplatforms can attain continuous photocontrolled O2 release, alleviate hypoxia, and elevate ROS level. More significantly, the entrapped PDE5 inhibitor (PDE5-i) in this nanoplatform can be enzymatically decomposed into nitric oxide that further combines with ROS to generate RNS, enabling the persistent antitumor effect since RNS features longer lifetime than ROS. Intriguingly, ROS conversion into RNS can help ROS to evade the hypoxia-induced resistance to ROS-based antitumor. Eventually, RNS production unlocks robust antitumor performances along with ROS elevation and hypoxia mitigation. Moreover, this extraordinary conversion from ROS into RNS also can act as a general method to solve the short lifetime of ROS.

A Bioluminescent Biosensor for Quantifying the Interaction of SARS-CoV-2 and Its Receptor ACE2 in Cells and In Vitro.

The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is currently spreading and mutating with increasing speed worldwide. Therefore, there is an urgent need for a simple, sensitive, and high-throughput (HTP) assay to quantify virus-host interactions in order to quickly evaluate the infectious ability of mutant viruses and to develop or validate virus-inhibiting drugs. Here, we developed an ultrasensitive bioluminescent biosensor to evaluate virus-cell interactions by quantifying the interaction between the SARS-CoV-2 receptor binding domain (RBD) and its cellular receptor angiotensin-converting enzyme 2 (ACE2) both in living cells and in vitro. We have successfully used this novel biosensor to analyze SARS-CoV-2 RBD mutants and evaluated candidate small molecules (SMs), antibodies, and peptides that may block RBD:ACE2 interaction. This simple, rapid, and HTP biosensor tool will significantly expedite the detection of viral mutants and the anti-COVID-19 drug discovery process.

Hemophagocytic lymphohistiocytosis during pregnancy: a review of the literature in epidemiology, pathogenesis, diagnosis and treatment.

Hemophagocytic lymphohistiocytosis during pregnancy is rare; it is often misdiagnosed, resulting in a high maternal and foetal mortality rate. Herein, based on limited case reports including antepartum and postpartum cases, we reviewed the current studies of pregnancy-related hemophagocytic lymphohistiocytosis, and compared the epidemiology, aetiology, diagnosis and treatment of pregnancy-related hemophagocytic lymphohistiocytosis with non-pregnancy, enriching the understanding of hemophagocytic lymphohistiocytosis and its treatment in obstetrics.

Development of an α-synuclein knockdown peptide and evaluation of its efficacy in Parkinson's disease models.

Convincing evidence supports the premise that reducing α-synuclein levels may be an effective therapy for Parkinson's disease (PD); however, there has been lack of a clinically applicable α-synuclein reducing therapeutic strategy. This study was undertaken to develop a blood-brain barrier and plasma membrane-permeable α-synuclein knockdown peptide, Tat-ßsyn-degron, that may have therapeutic potential. The peptide effectively reduced the level of α-synuclein via proteasomal degradation both in cell cultures and in animals. Tat-ßsyn-degron decreased α-synuclein aggregates and microglial activation in an α-synuclein pre-formed fibril model of spreading synucleinopathy in transgenic mice overexpressing human A53T α-synuclein. Moreover, Tat-ßsyn-degron reduced α-synuclein levels and significantly decreased the parkinsonian toxin-induced neuronal damage and motor impairment in a mouse toxicity model of PD. These results show the promising efficacy of Tat-ßsyn-degron in two different animal models of PD and suggest its potential use as an effective PD therapeutic that directly targets the disease-causing process.

A broadly protective antibody that targets the flavivirus NS1 protein.

There are no approved flaviviral therapies and the development of vaccines against flaviruses has the potential of being undermined by antibody-dependent enhancement (ADE). The flavivirus nonstructural protein 1 (NS1) is a promising vaccine antigen with low ADE risk but has yet to be explored as a broad-spectrum therapeutic antibody target. Here, we provide the structural basis of NS1 antibody cross-reactivity through cocrystallization of the antibody 1G5.3 with NS1 proteins from dengue and Zika viruses. The 1G5.3 antibody blocks multi-flavivirus NS1-mediated cell permeability in disease-relevant cell lines, and therapeutic application of 1G5.3 reduces viremia and improves survival in dengue, Zika, and West Nile virus murine models. Finally, we demonstrate that 1G5.3 protection is independent of effector function, identifying the 1G5.3 epitope as a key site for broad-spectrum antiviral development.