Altered gait patterns during arch important development period in children with persistent obesity: An experimental longitudinal study.

BACKGROUND: Obesity can cause structural changes and functional adjustments in growing children's feet. However, there is a lack of continuous observation of changes in feet in children with persistent obesity during important developmental periods. This makes it challenging to provide precise preventive measures. OBJECTIVE: This study aimed to investigate the effects of persistent obesity on gait patterns in children at an important stage in the formation of a robust foot arch. METHODS: The Footscan® plantar pressure system was used for 3 checks over two years. A total of 372 children aged 7-8 years participated in the study, and gait data from 33 children who maintained normal weight and 26 children with persistent obesity were finally selected. Repeated measures ANOVA or Friedman's test were used for longitudinal comparisons. Independent-Sample t-tests or the Mann-Whitney-Wilcoxon tests were used for cross-sectional comparisons. RESULTS: During the important period of development, children with persistent obesity did not exhibit a significant decrease in the arch index and had significantly higher values than the normal group in the third check. The persistently obese children showed increased load accumulation in the lateral rearfoot, first metatarsophalangeal joints, and the great toe regions. Children with persistent obesity had significantly greater medial-lateral displacements in the initial contact phase and forefoot contact phase than normal children in the first check. These differences diminished between the second and third checks. SIGNIFICANCE: Persistent obesity during an important period of foot development leads to slow or abnormal development of arch structure and affects foot loading patterns with heel inverted and forefoot everted. Additionally, the development of gait stability is not limited by persistent obesity.

Synthetic lethal combination of CHK1 and WEE1 inhibition for treatment of castration-resistant prostate cancer.

WEE1 and CHEK1 (CHK1) kinases are critical regulators of the G2/M cell cycle checkpoint and DNA damage response pathways. The WEE1 inhibitor AZD1775 and the CHK1 inhibitor SRA737 are in clinical trials for various cancers, but have not been thoroughly examined in prostate cancer, particularly castration-resistant (CRPC) and neuroendocrine prostate cancers (NEPC). Our data demonstrated elevated WEE1 and CHK1 expressions in CRPC and NEPC cell lines and patient samples. AZD1775 resulted in rapid and potent cell killing with comparable IC50s across different prostate cancer cell lines, while SRA737 displayed time-dependent progressive cell killing with 10- to 20-fold differences in IC50s. Notably, their combination synergistically reduced the viability of all CRPC cell lines and tumor spheroids in a concentration- and time-dependent manner. Importantly, in a transgenic mouse model of NEPC, both agents alone or in combination suppressed tumor growth, improved overall survival, and reduced the incidence of distant metastases, with SRA737 exhibiting remarkable single agent anticancer activity. Mechanistically, SRA737 synergized with AZD1775 by blocking AZD1775-induced feedback activation of CHK1 in prostate cancer cells, resulting in increased mitotic entry and accumulation of DNA damage. In summary, this preclinical study shows that CHK1 inhibitor SRA737 alone and its combination with AZD1775 offer potential effective treatments for CRPC and NEPC.

A multicellular brain spheroid model for studying the mechanisms and bioeffects of ultrasound-enhanced drug penetration beyond the blood‒brain barrier.

The blood‒brain barrier (BBB) acts as a hindrance to drug therapy reaching the brain. With an increasing incidence of neurovascular diseases and brain cancer metastases, there is a need for an ideal in vitro model to develop novel methodologies for enhancing drug delivery to the brain. Here, we established a multicellular human brain spheroid model that mimics the BBB both architecturally and functionally. Within the spheroids, endothelial cells and pericytes localized to the periphery, while neurons, astrocytes, and microglia were distributed throughout. Ultrasound-targeted microbubble cavitation (UTMC) is a novel noninvasive technology for enhancing endothelial drug permeability. We utilized our three-dimensional (3D) model to study the feasibility and mechanisms regulating UTMC-induced hyperpermeability. UTMC caused a significant increase in the penetration of 10 kDa Texas red dextran (TRD) into the spheroids, 100 µm beyond the BBB, without compromising cell viability. This hyperpermeability was dependent on UTMC-induced calcium (Ca2+) influx and endothelial nitric oxide synthase (eNOS) activation. Our 3D brain spheroid model, with its intact and functional BBB, offers a valuable platform for studying the bioeffects of UTMC, including effects occurring spatially distant from the endothelial barrier.

Boosting Ammonium Oxidation in Wastewater by the BiOCl-Functionalized Anode.

Mixed metal oxide (MMO) anodes are commonly used for electrochlorination of ammonium (NH4+) in wastewater treatment, but they suffer from low efficiency due to inadequate chlorine generation at low Cl- concentrations and sluggish reaction kinetics between free chlorine and NH4+ under acidic pH conditions. To address this challenge, we develop a straightforward wet chemistry approach to synthesize BiOCl-functionalized MMO electrodes using the MMO as an efficient Ohmic contact for electron transfer. Our study demonstrates that the BiOCl@MMO anode outperforms the pristine MMO anode, exhibiting higher free chlorine generation (24.6-60.0 mg Cl2 L-1), increased Faradaic efficiency (75.5 vs 31.0%), and improved rate constant of NH4+ oxidation (2.41 vs 0.76 mg L-1 min-1) at 50 mM Cl- concentration. Characterization techniques including electron paramagnetic resonance and in situ transient absorption spectra confirm the production of chlorine radicals (Cl• and Cl2•-) by the BiOCl/MMO anode. Laser flash photolysis reveals significantly higher apparent second-order rate constants ((4.3-4.9) × 106 M-1 s-1 at pH 2.0-4.0) for the reaction between NH4+ and Cl•, compared to the undetectable reaction between NH4+ and Cl2•-, as well as the slower reaction between NH4+ and free chlorine (102 M-1 s-1 at pH < 4.0) within the same pH range, emphasizing the significance of Cl• in enhancing NH4+ oxidation. Mechanistic studies provide compelling evidence of the capacity of BiOCl for Cl- adsorption, facilitating chlorine evolution and Cl• generation. Importantly, the BiOCl@MMO anode exhibits excellent long-term stability and high catalytic activity for NH4+-N removal in a real landfill leachate. These findings offer valuable insights into the rational design of electrodes to improve electrocatalytic NH4+ abatement, which holds great promise for wastewater treatment applications.

Synthetic lethal combination of CHK1 and WEE1 inhibition for treatment of castration-resistant prostate cancer.

WEE1 and CHEK1 (CHK1) kinases are critical regulators of the G2/M cell cycle checkpoint and DNA damage response pathways. The WEE1 inhibitor AZD1775 and the CHK1 inhibitor SRA737 are in clinical trials for various cancers, but have not been examined in prostate cancer, particularly castration-resistant (CRPC) and neuroendocrine prostate cancers (NEPC). Our data demonstrated elevated WEE1 and CHK1 expressions in CRPC/NEPC cell lines and patient samples. AZD1775 resulted in rapid and potent cell killing with comparable IC50s across different prostate cancer cell lines, while SRA737 displayed time-dependent progressive cell killing with 10- to 20-fold differences in IC50s. Notably, their combination synergistically reduced the viability of all CRPC cell lines and tumor spheroids in a concentration- and time-dependent manner. Importantly, in a transgenic mouse model of NEPC, both agents alone or in combination suppressed tumor growth, improved overall survival, and reduced the incidence of distant metastases, with SRA737 exhibiting remarkable single agent anticancer activity. Mechanistically, SRA737 synergized with AZD1775 by blocking AZD1775-induced feedback activation of CHK1 in prostate cancer cells, resulting in increased mitotic entry and accumulation of DNA damage. In summary, this preclinical study shows that CHK1 inhibitor SRA737 alone and its combination with AZD1775 offer potential effective treatments for CRPC and NEPC.

Neuronal dysfunction in individuals at early stage of schizophrenia, A resting-state fMRI study.

Schizophrenia has been associated with abnormal intrinsic brain activity, involving various cognitive impairments. Qualitatively similar abnormalities are seen in individuals at ultra-high risk (UHR) for psychosis. In this study, resting-state fMRI (rs-fMRI) data were collected from 44 drug-naïve first-episode schizophrenia (Dn-FES) patients, 48 UHR individuals, and 40 healthy controls (HCs). The fractional amplitude of low-frequency fluctuations (fALFF), regional homogeneity (ReHo), and functional connectivity (FC), were performed to evaluate resting brain function. A support vector machine (SVM) was applied for classification analysis. Compared to HCs, both clinical groups showed increased fALFF in the central executive network (CEN), decreased ReHo in the ventral visual pathway (VVP) and decreased FC in temporal-sensorimotor regions. Excellent performance was achieved by using fALFF value in distinguishing both FES (sensitivity=83.21%, specificity=80.58%, accuracy=81.37%, p=0.009) and UHR (sensitivity=75.88%, specificity=85.72%, accuracy=80.72%, p<0.001) from HC group. Moreover, the study highlighted the importance of frontal and temporal alteration in the pathogenesis of schizophrenia. However, no fMRI features were observed that could well distinguish Dn-FES from UHR group. To conclude, fALFF in the CEN may provide potential power for identifying individuals at the early stage of schizophrenia and the alteration in the frontal and temporal lobe may be important to these individuals.

Truncated ring-A amaryllidaceae alkaloid modulates the host cell integrated stress response, exhibiting antiviral activity to HSV-1 and SARSCoV-2.

The total synthesis of four novel mono-methoxy and hydroxyl substituted ring-A dihydronarciclasine derivatives enabled identification of the 7-hydroxyl derivative as a potent and selective antiviral agent targeting SARSCoV-2 and HSV-1. The concentration of this small molecule that inhibited HSV-1 infection by 50% (IC50), determined by using induced pluripotent stem cells (iPCS)-derived brain organ organoids generated from two iPCS lines, was estimated to be 0.504 µM and 0.209 µM. No significant reduction in organoid viability was observed at concentrations up to 50 mM. Genomic expression analyses revealed a significant effect on host-cell innate immunity, revealing activation of the integrated stress response via PERK kinase upregulation, phosphorylation of eukaryotic initiation factor 2α (eIF2α) and type I IFN, as factors potentiating multiple host-defense mechanisms against viral infection. Following infection of mouse eyes with HSV-1, treatment with the compound dramatically reduced HSV-1 shedding in vivo.

A Bipolar Membrane-Integrated Electrochlorination Process for Highly Efficient Ammonium Removal in Mature Landfill Leachate: The Importance of ClO• Generation.

Electrochemical oxidation has been demonstrated to be a useful method for removing biorefractory organic pollutants in mature landfill leachate but suffers from low efficiency in eliminating ammonium because of its resistance to being oxidized by HO• or free chlorine (FC) at decreased pH. Here, we propose a new bipolar membrane-electrochlorination (BPM-EC) process to address this issue. We found that the BPM-EC system was significantly superior to both the undivided and divided reactors with monopolar membranes in terms of elevated rate of ammonium removal, attenuated generation of byproducts (e.g., nitrate and chloramines), increased Faradaic efficiency, and decreased energy consumption. Mechanistic studies revealed that the integration of BPM was helpful in creating alkaline environments in the vicinity of the anode, which facilitated production of surface-bound HO• and FC and eventually promoted in situ generation of ClO•, a crucial reactive species mainly responsible for accelerating ammonium oxidation and selective transformation to nitrogen. The efficacy of BPM-EC in treating landfill leachates with different ammonium concentrations was verified under batch and continuous-flow conditions. A kinetic model that incorporates the key parameters was developed, which can successfully predict the optimal number of BPM-EC reactors (e.g., 2 and 5 for leachates containing 589.4 ± 5.5 and 1258.1 ± 9.6 mg L-1 NH4+-N, respectively) necessary for complete removal of ammonium. These findings reveal that the BPM-EC process shows promise in treating ammonium-containing wastewater, with advantages that include effectiveness, adaptability, and flexibility.

Herpesvirus Infections in the Human Brain: A Neural Cell Model of the Complement System Derived from Induced Pluripotent Stem Cells.

BACKGROUND: Herpesviruses alter cognitive functions in humans following acute infections; progressive cognitive decline and dementia have also been suggested. It is important to understand the pathogenic mechanisms of such infections. The complement system - comprising functionally related proteins integral for systemic innate and adaptive immunity - is an important component of host responses. The complement system has specialized functions in the brain. Still, the dynamics of the brain complement system are still poorly understood. Many complement proteins have limited access to the brain from plasma, necessitating synthesis and specific regulation of expression in the brain; thus, complement protein synthesis, activation, regulation, and signaling should be investigated in human brain-relevant cellular models. Cells derived from human-induced pluripotent stem cells (hiPSCs) could enable tractable models. METHODS: Human-induced pluripotent stem cells were differentiated into neuronal (hi-N) and microglial (hi-M) cells that were cultured with primary culture human astrocyte-like cells (ha-D). Gene expression analyses and complement protein levels were analyzed in mono- and co-cultures. RESULTS: Transcript levels of complement proteins differ by cell type and co-culture conditions, with evidence for cellular crosstalk in co-cultures. Hi-N and hi-M cells have distinct patterns of expression of complement receptors, soluble factors, and regulatory proteins. hi-N cells produce complement factor 4 (C4) and factor B (FB), whereas hi-M cells produce complement factor 2 (C2) and complement factor 3 (C3). Thus, neither hi-N nor hi-M cells can form either of the C3-convertases - C4bC2a and C3bBb. However, when hi-N and hi-M cells are combined in co-cultures, both types of functional C3 convertase are produced, indicated by elevated levels of the cleaved C3 protein, C3a. CONCLUSIONS: hiPSC-derived co-culture models can be used to study viral infection in the brain, particularly complement receptor and function in relation to cellular "crosstalk." The models could be refined to further investigate pathogenic mechanisms.

Reactive species conversion into 1O2 promotes substantial inhibition of chlorinated byproduct formation during electrooxidation of phenols in Cl--laden wastewater.

The generation of chlorinated byproducts during the electrochemical oxidation (EO) of Cl--laden wastewater is a significant concern. We aim to propose a concept of converting reactive species (e.g., reactive chlorines and HO• resulting from electrolysis) into 1O2 via the addition of H2O2, which substantially alleviates chlorinated organic formation. When phenol was used as a model organic compound, the results showed that the H2O2-involving EO system outperformed the H2O2-absent system in terms of higher rate constants (5.95 × 10-2 min-1vs. 2.97 × 10-2 min-1) and a much lower accumulation of total organic chlorinated products (1.42 mg L-1vs. 8.18 mg L-1) during a 60 min operation. The rate constants of disappearance of a variety of phenolic compounds were positively correlated with the Hammett constants (σ), suggesting that the reactive species preferred oxidizing phenols with electron-rich groups. After the identification of 1O2 that was abundant in the bulk solution with the use of electron paramagnetic resonance and computational kinetic simulation, the routes of 1O2 generation were revealed. Despite the consensus as to the contribution of reaction between H2O2 and ClO- to 1O2 formation, we conclude that the predominant pathway is through H2O2 reaction with electrogenerated HO• or chlorine radicals (Cl• and Cl2•-) to produce O2•-, followed by self-combination. Density functional theory calculations theoretically showed the difficulty in forming chlorinated byproducts for the 1O2-initiated phenol oxidation in the presence of Cl-, which, by contrast, easily occurred for the Cl•-or HO•-initiated phenol reaction. The experiments run with real coking wastewater containing high-concentration phenols further demonstrated the superiority of the H2O2-involving EO system. The findings imply that this unique method for treating Cl--laden organic wastewater is expected to be widely adopted for generalizing EO technology for environmental applications.

Archaea: An under-estimated kingdom in livestock animals.

Archaea are considered an essential group of gut microorganisms in both humans and animals. However, they have been neglected in previous studies, especially those involving non-ruminants. In this study, we re-analyzed published metagenomic and metatranscriptomic data sequenced from matched samples to explore the composition and the expression activity of gut archaea in ruminants (cattle and sheep) and monogastric animals (pig and chicken). Our results showed that the alpha and beta diversity of each host species, especially cattle and chickens, calculated from metagenomic and metatranscriptomic data were significantly different, suggesting that metatranscriptomic data better represent the functional status of archaea. We detected that the relative abundance of 17 (cattle), 7 (sheep), 20 (pig), and 2 (chicken) archaeal species were identified in the top 100 archaeal taxa when analyzing the metagenomic datasets, and these species were classified as the "active archaeal species" for each host species by comparison with corresponding metatranscriptomic data. For example, The expressive abundance in metatranscriptomic dataset of Methanosphaera cuniculi and Methanosphaera stadtmanae were 30- and 27-fold higher than that in metagenomic abundance, indicating their potentially important function in the pig gut. Here we aim to show the potential importance of archaea in the livestock digestive tract and encourage future research in this area, especially on the gut archaea of monogastric animals.

Boosting the oxidative capacity of the Fe(0)/O2 system via an air-breathing cathode.

The corrosion of Fe(0) in the presence of O2 in nature can lead to the oxidation of organic compounds, but the efficiency is very limited. Herein, attempts were made to establish a galvanic system that separates the anodic Fe(0) oxidation reaction and the cathodic O2 reduction reaction using an air-breathing cathode. Compared with the chemical Fe(0)/O2 system, it exhibited a substantially higher capability of destroying a variety of pollutants, such as organic dyes (12 types), phenol, nitrobenzene, acetaminophen, phenol, and ethylenediaminetetraacetic acid. The degradation rate constant of a model dye (i.e., Rhodamine B) increased from 0.047 min-1 (chemical) to 1.412 min-1 (galvanic) under the passive air-breathing condition. The electric circuit design promoted Fe(0) dissolution to Fe(II) and triggered electron transfer that drives O2 reduction to H2O2, two important species responsible for the generation of HO• at high abundance. In addition, the galvanic Fe(0)/O2 system produces electricity while destroying pollutants. Tests with real Ni plating wastewater further demonstrated the capability of the system to oxidize complexed organics and phosphite. This study provides a new strategy for boosting the oxidative capacity of the Fe(0)/O2 system, which shows promise for acid wastewater treatment.

Minimizing toxic chlorinated byproducts during electrochemical oxidation of Ni-EDTA: Importance of active chlorine-triggered Fe(II) transition to Fe(IV).

The formation of chlorinated byproducts represents a significant threat to the quality of the effluent treated using electrochemical advanced oxidation processes (EAOPs), thus spurring investigation into alleviating their production. This study presents a new strategy to minimize the release of chlorinated intermediates during the electrochemical oxidation of Ni-EDTA by establishing a dual mixed metal oxide (MMO)/Fe anode system. The results indicate that the dual-anode system achieved a substantially higher rate (0.141 min-1) of Ni-EDTA destruction and accordingly allowed a more pronounced removal of aqueous Ni (from 39.85 to 0.63 mg L-1) after alkaline precipitation, compared with its single MMO anode (0.017 min-1 of Ni-EDTA removal, with 14.38 mg L-1 Ni remaining) and single Fe anode (insignificant Ni-EDTA removal, with 38.37 mg L-1 Ni remaining) counterparts. Compared to reactive chlorine species (RCS) produced from the single MMO anode system, Fe(IV) was in situ generated from the dual-anode system and was predominantly responsible for the attenuation of chlorinated byproducts and thus the decrease in the acute toxicity of the treated solution (evaluated using luminescent bacteria). The Fe(IV)-dominated dual-anode system also exhibited superior performance in removing multiple pollutants (including organic ligands, Ni, and phosphite) in the real electroless plating effluent. The findings suggest that the strategy for Fe(II) transition to Fe(IV) by active chlorine paves a new avenue for yielding less chlorinated products with lower toxicity when EAOPs are used to treat chloride-containing organic wastewater.

Variations in Aspects of Neural Precursor Cell Neurogenesis in a Human Model of HSV-1 Infection.

Encephalitis, the most significant of the central nervous system (CNS) diseases caused by Herpes simplex virus 1 (HSV-1), may have long-term sequelae in survivors treated with acyclovir, the cause of which is unclear. HSV-1 exhibits a tropism toward neurogenic niches in CNS enriched with neural precursor cells (NPCs), which play a pivotal role in neurogenesis. NPCs are susceptible to HSV-1. There is a paucity of information regarding the influence of HSV-1 on neurogenesis in humans. We investigated HSV-1 infection of NPCs from two individuals. Our results show (i) HSV-1 impairs, to different extents, the proliferation, self-renewing, and, to an even greater extent, migration of NPCs from these two subjects; (ii) The protective effect of the gold-standard antiherpetic drug acyclovir (ACV) varies with viral dose and is incomplete. It is also subject to differences in terms of efficacy of the NPCs derived from these two individuals. These results suggest that the effects of HSV-1 may have on aspects of NPC neurogenesis may vary among individuals, even in the presence of acyclovir, and this may contribute to the heterogeneity of cognitive sequelae across encephalitis survivors. Further analysis of NPC cell lines from a larger number of individuals is warranted.

Abnormal neurobiochemical metabolites in the first- episode schizophrenia and clinical high-risk population. / 首发精神分裂症及临床高危人群脑神经生化代谢物异常.

OBJECTIVES: To explore the metabolite characteristics in medial prefrontal cortex (mPFC) by 1H magnetic resonance spectroscopy (1H-MRS) in the first-episode schizophrenia (FES) and clinical high-risk (CHR) people. METHODS: A total of 46 patients with the first-episode schizophrenia (FES), 49 people with clinical high risk (CHR), 61 people with genetic high risk (GHR), and 58 healthy controls (HC) were enrolled. The levels of N-acetylaspartylglutamate+N-acetylaspartate (tNAA), choline-containing compounds (Cho) and myo-inositol (MI), glutamate+glutamine (Glx) in medial prefrontal cortex were measured by single-voxel 1H-MRS. The clinical symptoms were evaluated in the FES group and the CHR group. Continuous performance test (CPT) were carried out to assess the visual and auditory accuracy and reaction time in the 4 groups. RESULTS: There were significant differences in Glx, tNAA, and MI concentrations among 4 groups (all P<0.05). Compared with the HC group, the FES group showed lower level of MI and Glx. The levels of Glx and tNAA in the CHR group were significantly lower than those in the GHR group (all P<0.05). The visual and auditory accuracies of CPT in the FES group were significantly lower than those in the HC group (P<0.05). In the FES group, Glx was negatively correlated with the reaction time of vision (r=-0.41, P=0.05). CONCLUSIONS: The decreased levels of MI and Glx in the FES patients suggest that there may be glial functional damage and glutamatergic transmitter dysfunction in the early stage of the disease. The compensatory increase of metabolites may be a protective factor for schizophrenia in the genetic individuals.

Facile ammonium oxidation to nitrogen gas in acid wastewater by in situ photogenerated chlorine radicals.

The treatment of low-concentration ammonium (e.g., <50 mg L-1) in highly acidic wastewaters through traditional biological nitrification, physical separation, or chemical stripping remains a huge challenge. Herein, we report that photocatalytic ammonium oxidation using bismuth oxychloride (BiOCl) can successfully occur in Cl--laden solutions within a pH range of 1.0-6.0. All reactions follow pseudo-zero-order kinetics (with rate constants of 0.27-0.32 mg L-1 min-1 at pH 2.0-6.0 and 0.14 mg L-1 min-1 at pH 1.0), indicating the saturation of reactive species by the reactants. The interlayer is self-oxidized by the valence band holes (VB h+), resulting in the formation of Cl• and subsequently HClO, which is excited upon UV irradiation to provoke consecutive photoreactions for chlorine radical generation. Compared to the free chlorine, HO•, Cl•, and Cl2•-, the ClO• produced using the UV/BiOCl system plays a predominant role in oxidizing ammonium under acidic conditions. BiOCl exhibits good stability because of the compensation of Cl- from solution and maintains high activity under different conditions (i.e., different cations and co-existing anions, temperatures, and initial substrate concentrations). The successful removal of ammonium from real wastewater using the UV/BiOCl system suggests that this is a promising method for treating diluted ammonium under highly acidic conditions.

Self-Activated Ni Cathode for Electrocatalytic Nitrate Reduction to Ammonia: From Fundamentals to Scale-Up for Treatment of Industrial Wastewater.

Electrocatalytic reduction has recently received increasing attention as a method of converting waste nitrate into value-added ammonia, but most studies have focused on complex strategies of catalyst preparation and little has been done in the way of large-scale demonstrations. Herein, we report that in situ activation of a pristine Ni electrode, either on a lab scale or a pilot scale, is effective in facilitating nitrate reduction to ammonia, exhibiting extraordinarily high activity, selectivity, and stability. The self-activated Ni cathode has a robust capacity to reduce nitrate over a wide range of concentrations and achieves great conversion yield, NH4+-N selectivity, and Faradaic efficiency, respectively, 95.3, 95.5, and 64.4% at 200 mg L-1 NO3--N and 97.8, 97.1, and 90.4% at 2000 mg L-1 NO3--N, for example. Fundamental research indicates that Ni(OH)2 nanoparticles are formed on the Ni electrode surface upon self-activation, which play crucial roles in governing nitrate reduction reaction (NO3RR) through the atomic H*-mediated pathway and accordingly suppressing hydrogen evolution reaction. More importantly, the self-activated Ni(OH)2@Ni cathode can be easily scaled up to allow large volumes of real industrial wastewater to be processed, successfully transferring nitrate into ammonia with high yields and Faradaic efficiency. This study demonstrates a new, mild, and promising method of cleaning nitrate-laden wastewater that produces ammonia as a valuable byproduct.

Insights into bioinformatic approaches for repurposing compounds as anti-viral drugs.

BACKGROUND: Drug repurposing is a cost-effective strategy to identify drugs with novel effects. We searched for drugs exhibiting inhibitory activity to Herpes Simplex virus 1 (HSV-1). Our strategy utilized gene expression data generated from HSV-1-infected cell cultures which was paired with drug effects on gene expression. Gene expression data from HSV-1 infected and uninfected neurons were analyzed using BaseSpace Correlation Engine (Illumina®). Based on the general Signature Reversing Principle (SRP), we hypothesized that the effects of candidate antiviral drugs on gene expression would be diametrically opposite (negatively correlated) to those effects induced by HSV-1 infection. RESULTS: We initially identified compounds capable of inducing changes in gene expression opposite to those which were consequent to HSV-1 infection. The most promising negatively correlated drugs (Valproic acid, Vorinostat) did not significantly inhibit HSV-1 infection further in African green monkey kidney epithelial cells (Vero cells). Next, we tested Sulforaphane and Menadione which showed effects similar to those caused by viral infections (positively correlated). Intriguingly, Sulforaphane caused a modest but significant inhibition of HSV-1 infection in Vero cells (IC50 = 180.4 µM, p = 0.008), but exhibited toxicity when further explored in human neuronal progenitor cells (NPCs) derived from induced pluripotent stem cells. CONCLUSIONS: These results reveal the limits of the commonly used SRP strategy when applied to the identification of novel antiviral drugs and highlight the necessity to refine the SRP strategy to increase its utility.

Modeling Aß42 Accumulation in Response to Herpes Simplex Virus 1 Infection: 2D or 3D?

Alzheimer's disease is a progressive neurodegenerative disease characterized neuropathologically by presence of extracellular amyloid plaques composed of fibrillar amyloid beta (Aß) peptides and intracellular neurofibrillary tangles. Post-mortem and in vivo studies implicate HSV-1 infection in the brain as a precipitating factor in disease/pathology initiation. HSV-1 infection of two-dimensional (2D) neuronal cultures causes intracellular accumulation of Aß42 peptide, but these 2D models do not recapitulate the three-dimensional (3D) architecture of brain tissue.We employed human induced pluripotent stem cells (hiPSCs) to compare patterns of Aß42 accumulation in HSV-1 infected 2D (neuronal monolayers) and 3D neuronal cultures (brain organoids). Akin to prior studies, HSV-1-infected 2D cultures showed Aß42 immunoreactivity in cells expressing the HSV-1 antigen ICP4 (ICP4+). Conversely, accumulation of Aß42 in ICP4+ cells in infected organoids was rarely observed. These results highlight the importance of considering 3D cultures to model host-pathogen interaction.IMPORTANCE The "pathogen" hypothesis of Alzheimer's disease (AD) proposes that brain HSV-1 infection could be an initial source of amyloid beta (Aß) peptide-containing amyloid plaque development. Aß accumulation was reported in HSV-1-infected 2D neuronal cultures and neural stem cell cultures, as well as in HSV-1-infected 3D neuronal culture models.The current study extends these findings by showing different patterns of Aß42 accumulation following HSV-1 infection of 2D compared to 3D neuronal cultures (brain organoids). Specifically, 2D neuronal cultures showed Aß42-immunoreactivity mainly in HSV-1-infected cells and only rarely in uninfected cells or infected cells exposed to antivirals. Conversely, 3D brain organoids showed accumulation of Aß42 mainly in non-infected cells surrounding HSV-1-infected cells. We suggest that because brain organoids better recapitulate architectural features of a developing brain than 2D cultures, they may be a more suitable model to investigate the involvement of HSV-1 in the onset of AD pathology.