Androgen deprivation therapy exacerbates Alzheimer's-associated cognitive decline via increased brain immune cell infiltration.

Androgen deprivation therapy (ADT) for prostate cancer is associated with an increased risk of dementia, including Alzheimer's disease (AD). The mechanistic connection between ADT and AD-related cognitive impairment in patients with prostate cancer remains elusive. We established a clinically relevant prostate cancer-bearing AD mouse model to explore this. Both tumor-bearing and ADT induce complex changes in immune and inflammatory responses in peripheral blood and in the brain. ADT disrupts the integrity of the blood-brain barrier (BBB) and promotes immune cell infiltration into the brain, enhancing neuroinflammation and gliosis without affecting the amyloid plaque load. Moreover, treatment with natalizumab, an FDA-approved drug targeting peripheral immune cell infiltration, reduces neuroinflammation and improves cognitive function in this model. Our study uncovers an inflammatory mechanism, extending beyond amyloid pathology, that underlies ADT-exacerbated cognitive deficits, and suggests natalizumab as a potentially effective treatment in alleviating the detrimental effects of ADT on cognition.

Dual-Energy-Barrier Stable Superhydrophobic Structures for Long Icing Delay.

Using superhydrophobic surfaces (SHSs) with the water-repellent Cassie-Baxter (CB) state is widely acknowledged as an effective approach for anti-icing performances. Nonetheless, the CB state is susceptible to diverse physical phenomena (e.g., vapor condensation, gas contraction, etc.) at low temperatures, resulting in the transition to the sticky Wenzel state and the loss of anti-icing capabilities. SHSs with various micronanostructures have been empirically examined for enhancing the CB stability; however, the energy barrier transits from the metastable CB state to the stable Wenzel state and thus the CB stability enhancement is currently not enough to guarantee a well and appliable anti-icing performance at low temperatures. Here, we proposed a dual-energy-barrier design strategy on superhydrophobic micronanostructures. Rather than the typical single energy barrier of the conventional CB-to-Wenzel transition, we introduced two CB states (i.e., CB I and CB II), where the state transition needed to go through CB I and CB II then to Wenzel state, thus significantly improving the entire CB stability. We applied ultrafast laser to fabricate this dual-energy-barrier micronanostructures, established a theoretical framework, and performed a series of experiments. The anti-icing performances were exhibited with long delay icing times (over 27,000 s) and low ice-adhesion strengths (0.9 kPa). The kinetic mechanism underpinning the enhanced CB anti-icing stability was elucidated and attributed to the preferential liquid pinning in the shallow closed structures, enabling the higher CB-Wenzel transition energy barrier to sustain the CB state. Comprehensive durability tests further corroborated the potentials of the designed dual-energy-barrier structures for anti-icing applications.

Comparison of the dural puncture epidural and the standard epidural techniques in patients having labor analgesia maintained using programmed epidural boluses: a prospective double-blinded randomized clinical trial.

BACKGROUND: The dural puncture epidural technique has been shown in some studies to improve the onset and quality of the initiation of labor analgesia compared with the standard epidural technique. However, few studies have investigated whether this technique confers advantages during the maintenance of analgesia. This randomized double-blinded controlled study compared dural puncture epidural analgesia with standard epidural analgesia when analgesia was maintained using programmed intermittent epidural boluses. METHODS: 400 parturients requesting epidural labor analgesia were randomized to have analgesia initiated with a test dose of 3 mL lidocaine 1.5% with epinephrine 15 µg, followed by 12 mL ropivacaine 0.15% mixed with sufentanil 0.5 µg/mL using the dural puncture epidural or the standard epidural technique. After confirming satisfactory analgesia, analgesia was maintained with ropivacaine 0.1% and sufentanil 0.5 µg/mL via programmed intermittent epidural boluses (fixed volume 8 mL, intervals 40 min). We compared local anesthetic consumption, pain scores, obstetric and neonatal outcomes and patient satisfaction. RESULTS: A total of 339 patients completed the study and had data analyzed. There were no differences between the dural puncture epidural and standard epidural groups in ropivacaine consumption (mean difference -0.724 mg, 95% CI of difference -1.450 to 0.001 mg, p=0.051), pain scores, time to first programmed intermittent epidural bolus, the number of programmed intermittent epidural boluses, the number of manual epidural boluses, obstetric outcome or neonatal outcome. Patient satisfaction scores were statistically higher in the dural puncture epidural group but the absolute difference in scores was small. CONCLUSION: Our findings suggest that when labor analgesia is maintained using the programmed intermittent epidural bolus method, there is no significant advantage to initiating analgesia using the dural puncture epidural compared with the standard epidural technique. TRIAL REGISTRATION NUMBER: ChiCTR2200062349.

Commonly used antiemetics for prophylaxis of postoperative nausea and vomiting after Caesarean delivery with neuraxial morphine: a network meta-analysis.

BACKGROUND: Dopamine antagonists, 5-HT3 antagonists, and dexamethasone are frequently used in obstetrics to prevent postoperative nausea and vomiting (PONV). However, the superiority of any drug class is yet to be established. This network meta-analysis aimed to compare the efficacy of these antiemetics for PONV prophylaxis in women receiving neuraxial morphine for Caesarean delivery. METHODS: We searched PubMed, Embase, CENTRAL, Web of Science, and Wanfang Data for eligible randomised controlled trials. Primary outcomes were the incidences of postoperative nausea (PON) and postoperative vomiting (POV) within 24 h after surgery. We used a Bayesian random-effects model and calculated odds ratios with 95% credible intervals for dichotomous data. We performed sensitivity and subgroup analyses for primary outcomes. RESULTS: A total of 33 studies with 4238 women were included. In the primary analyses of all women, 5-HT3 antagonists, dopamine antagonists, dexamethasone, and 5-HT3 antagonists plus dexamethasone significantly reduced PON and POV compared with placebo, and 5-HT3 antagonists plus dexamethasone were more effective than monotherapy. In the subgroup analyses, similar results were seen in women receiving epidural morphine or intrathecal morphine alone but not in women receiving intrathecal morphine with fentanyl or sufentanil. However, most included studies had some concerns or a high risk of bias, and the overall certainty of the evidence was low or very low. CONCLUSIONS: Combined 5-HT3 antagonists plus dexamethasone are more effective than monotherapy in preventing PONV associated with neuraxial morphine after Caesarean delivery. Future studies are needed to determine the role of prophylactic antiemetics in women receiving intrathecal morphine and lipophilic opioids. SYSTEMATIC REVIEW PROTOCOL: PROSPERO CRD42023454602.

Tetrabromobisphenol-A/S and their derivatives in surface particulates from workshop floors of three representative e-waste recycling sites in China.

Surface particulates collected from the workshop floors of three major e-waste recycling sites (Taizhou, Qingyuan, and Guiyu) in China were analyzed for tetrabromobisphenol A/S (TBBPA/S) and their derivatives to investigate the environmental pollution caused by e-waste recycling activities. Mean concentrations of total TBBPA/S analogs in surface particulates were 31,471-116,059 ng/g dry weight (dw). TBBPA, TBBPA-BGE, and TBBPA-BDBPE were the most frequently detected in particulates with average concentration ranges of 17,929-78,406, 5601-15,842, and 5929-21,383 ng/g dw, respectively. Meanwhile, TBBPA, TBBPA-BGE, and TBBPA-BDBPE were the most abundant TBBPA/S analogs, accounting for around 96% of the total. The composition profiles of TBBPA/S analogs differed significantly among three e-waste sites. Similarly, principal component analysis uncovered different pollution patterns among different sites. The discrepancy in the profiles of TBBPA/S analogs largely relied on the e-waste types recycled in different areas. E-waste recycling led to the release of TBBPA/S analogs, and TBBPA/S analogs produced differentiation during migration from source (surface particulates) to nearby soil. More researches are necessary to find a definite relationship between pollution status and e-waste types and study differentiation behavior of TBBPA/S analogs in migration and diffusion from source to environmental medium.

Transformer fault diagnosis method based on SMOTE and NGO-GBDT.

In order to improve the accuracy of transformer fault diagnosis and improve the influence of unbalanced samples on the low accuracy of model identification caused by insufficient model training, this paper proposes a transformer fault diagnosis method based on SMOTE and NGO-GBDT. Firstly, the Synthetic Minority Over-sampling Technique (SMOTE) was used to expand the minority samples. Secondly, the non-coding ratio method was used to construct multi-dimensional feature parameters, and the Light Gradient Boosting Machine (LightGBM) feature optimization strategy was introduced to screen the optimal feature subset. Finally, Northern Goshawk Optimization (NGO) algorithm was used to optimize the parameters of Gradient Boosting Decision Tree (GBDT), and then the transformer fault diagnosis was realized. The results show that the proposed method can reduce the misjudgment of minority samples. Compared with other integrated models, the proposed method has high fault identification accuracy, low misjudgment rate and stable performance.

Effects of different neuraxial analgesia modalities on the need for physician interventions in labour: A network meta-analysis.

BACKGROUND: Neuraxial labour analgesia can be initiated with epidural (EPL), combined spinal epidural (CSE) or dural puncture epidural (DPE) and maintained with continuous epidural infusion (CEI), patient-controlled epidural analgesia (PCEA) or programmed intermittent epidural bolus (PIEB), but the optimal analgesia modality is still controversial. OBJECTIVE: To compare the effects of commonly used neuraxial analgesia modalities on the proportion of women needing physician interventions, as defined by the need for physician-administered epidural top-ups for inadequate analgesia in labour. DESIGN: Bayesian network meta-analysis. DATA SOURCES: PubMed, Embase, CENTRAL, Web of Science and Wanfang Data were searched from January 1988 to August 2023 without language restriction. ELIGIBILITY CRITERIA: Randomised controlled trials comparing two or more modalities of the following six neuraxial analgesia modalities in healthy labouring women: EPL+CEI+PCEA, EPL+PIEB+PCEA, CSE+CEI+PCEA, CSE+PIEB+PCEA, DPE+CEI+PCEA and DPE+PIEB+PCEA. RESULTS: Thirty studies with 8188 women were included. Compared with EPL+CEI+PCEA, EPL+PIEB+PCEA [odds ratio (OR) = 0.44; 95% credible interval (CrI), 0.22 to 0.86], CSE+PIEB+PCEA (OR = 0.29; 95% CrI, 0.12 to 0.71) and DPE+PIEB+PCEA (OR = 0.19; 95% CrI, 0.08 to 0.42) significantly reduced the proportion of women needing physician interventions. DPE+PIEB+PCEA had fewer women needing physician interventions than all other modalities, except for CSE+PIEB+PCEA (OR = 0.63; 95% CrI, 0.25 to 1.62). There were no significant differences in local anaesthetic consumption, maximum pain score, and the incidence of instrumental delivery between the different neuraxial modalities. CONCLUSIONS: PIEB+PCEA is associated with a lower risk of physician interventions in labour than CEI+PCEA. DPE or CSE and PIEB+PCEA may be associated with a lower likelihood of physician interventions than other neuraxial modalities. Otherwise, the new neuraxial analgesia techniques do not appear to offer significant advantages over traditional techniques. However, these results should be interpreted with caution due to limited data and methodological limitations. TRIAL REGISTRATION: PROSPERO (CRD42023402540).

New Iridoids and Acyclic Monoterpenoids from the Roots and Rhizomes of Valeriana officinalis var. latifolia.

Five new iridoids, valeralides A-E (1-5), two new acyclic monoterpenoids, valeralides F (6) and G (7), together with two known iridoids (8 and 9), were isolated from the roots and rhizomes of Valeriana officinalis var. latifolia. Their structures were elucidated based on 1D and 2D NMR, as well as HR-ESI-MS spectroscopic data. The absolute configuration of compounds 1-4 were elucidated based on electronic circular dichroism (ECD) calculation. In addition, all the isolates were evaluated for their inhibition on nitric oxide production, cytotoxicity and anti-influenza A virus activity.

Analysis on determinants of carbon emissions from plaza ground paving during the construction stage based on life cycle assessment.

The carbon emissions of paving projects are the focus of urban managers and researchers. By introducing the life cycle assessment (LCA) method and drawing up the study time and boundary, this study analyzed the carbon emissions activities of the plaza ground paving project and established a computational model of the cast-in-place architectural concrete (CAC) and natural stone pavement's life cycle during the construction stage by comprehensively utilizing the carbon emission coefficient method and the direct source consumption statistics method of the production line. Based on the model, this study employed the ground paving of a top-notch Theme Park Plaza in Beijing as a sample to calculate the carbon emissions of two different types of building materials at various phases of their life cycle and made a comparative evaluation. It is concluded that the carbon emissions (expressed in CO2) produced by the CAC ground in the sample area is 75.46 kg CO2/m2, while that of the natural stone pavement is 110.81 kg CO2/m2. Our results demonstrate significantly linear relationship between the overall emissions of carbon and the material carbon factor. This study adds to the body of knowledge by calculating the carbon emissions and determining the trend of carbon footprint for ground paving. Furthermore, the study's findings can be used to enhance construction management options and choose green materials. The findings can also be used to provide supporting theories for the development of regulations and carbon reduction policies based on constructing energy conservation and greenhouse gas reduction.

Localized in-situ deposition: a new dimension to control in fabricating surface micro/nano structures via ultrafast laser ablation.

Controllable fabrication of surface micro/nano structures is the key to realizing surface functionalization for various applications. As a versatile approach, ultrafast laser ablation has been widely studied for surface micro/nano structuring. Increasing research efforts in this field have been devoted to gaining more control over the fabrication processes to meet the increasing need for creation of complex structures. In this paper, we focus on the in-situ deposition process following the plasma formation under ultrafast laser ablation. From an overview perspective, we firstly summarize the different roles that plasma plumes, from pulsed laser ablation of solids, play in different laser processing approaches. Then, the distinctive in-situ deposition process within surface micro/nano structuring is highlighted. Our experimental work demonstrated that the in-situ deposition during ultrafast laser surface structuring can be controlled as a localized micro-additive process to pile up secondary ordered structures, through which a unique kind of hierarchical structure with fort-like bodies sitting on top of micro cone arrays were fabricated as a showcase. The revealed laser-matter interaction mechanism can be inspiring for the development of new ultrafast laser fabrication approaches, adding a new dimension and more flexibility in controlling the fabrication of functional surface micro/nano structures.

1000 °C High-Temperature Wetting Behaviors of Molten Metals on Laser-Microstructured Metal Surfaces.

The melting of metals at high temperatures is common and important in many fields, e.g., metallurgy, refining, casting, welding, brazing, even newly developed batteries, and nuclear fusion, which is thus of great value in modern industrialization. However, the knowledge of the wetting behaviors of molten metals on various substrate surfaces remains insufficient, especially when the temperature is over 1000 °C and with microstructured metal substrate surfaces. Herein, we selected molten cerium (Ce) on a tantalum (Ta) substrate as an example and investigated in detail its wetting at temperatures up to 1000 °C by modulating the microstructures of the substrate surfaces via laser processing. We discovered that the wetting states of molten Ce on Ta surfaces at temperatures over 900 °C could be completely altered by modifying the laser-induced surface microstructures and the surface compositions. The molten Ce turned superlyophilic with its contact angle (CA) below 10° on the only laser-microstructured surfaces, while it exhibited lyophobicity with a CA of about 135° on the laser-microstructured plus oxidized ones, which demonstrated remarkably enhanced resistance against the melt with only tiny adhesion in this circumstance. In contrast, the CA of molten Ce on Ta substrate surfaces only changed from ∼25 to ∼95° after oxidization without laser microstructuring. We proved that modulating the substrate surface microstructures via laser together with oxidization was capable of efficiently controlling various molten metals' wetting behaviors even at very high temperatures. These findings not only enrich the understanding of molten metal high-temperature wettability but also enable a novel practical approach to control the wetting states for relevant applications.

Machine learning in predicting T-score in the Oxford classification system of IgA nephropathy.

Background: Immunoglobulin A nephropathy (IgAN) is one of the leading causes of end-stage kidney disease (ESKD). Many studies have shown the significance of pathological manifestations in predicting the outcome of patients with IgAN, especially T-score of Oxford classification. Evaluating prognosis may be hampered in patients without renal biopsy. Methods: A baseline dataset of 690 patients with IgAN and an independent follow-up dataset of 1,168 patients were used as training and testing sets to develop the pathology T-score prediction (T pre) model based on the stacking algorithm, respectively. The 5-year ESKD prediction models using clinical variables (base model), clinical variables and real pathological T-score (base model plus T bio), and clinical variables and T pre (base model plus T pre) were developed separately in 1,168 patients with regular follow-up to evaluate whether T pre could assist in predicting ESKD. In addition, an external validation set consisting of 355 patients was used to evaluate the performance of the 5-year ESKD prediction model using T pre. Results: The features selected by AUCRF for the T pre model included age, systolic arterial pressure, diastolic arterial pressure, proteinuria, eGFR, serum IgA, and uric acid. The AUC of the T pre was 0.82 (95% CI: 0.80-0.85) in an independent testing set. For the 5-year ESKD prediction model, the AUC of the base model was 0.86 (95% CI: 0.75-0.97). When the T bio was added to the base model, there was an increase in AUC [from 0.86 (95% CI: 0.75-0.97) to 0.92 (95% CI: 0.85-0.98); P = 0.03]. There was no difference in AUC between the base model plus T pre and the base model plus T bio [0.90 (95% CI: 0.82-0.99) vs. 0.92 (95% CI: 0.85-0.98), P = 0.52]. The AUC of the 5-year ESKD prediction model using T pre was 0.93 (95% CI: 0.87-0.99) in the external validation set. Conclusion: A pathology T-score prediction (T pre) model using routine clinical characteristics was constructed, which could predict the pathological severity and assist clinicians to predict the prognosis of IgAN patients lacking kidney pathology scores.

Design, Synthesis, and Bioactivity of Aldisine Derivatives Containing Oxime and Hydrazine Moieties Based on Hydrogen Bonds.

Marine natural products have attracted more and more attention in drug research and development due to their unique structure, diverse biological activities, and novel mode of action. Using antiviral alkaloid aldisine as the lead compound and drawing on the hydrogen bond effect widely used in drug design, derivatives containing oxime and hydrazone moieties were designed and synthesized by introducing functional groups with hydrogen-bond receptors or donors into molecules. The configuration of derivatives was systematically studied through nuclear Overhauser effect (NOE) spectroscopy and single crystal analysis. The antiviral activity test result showed that most derivatives had antiviral activity against tobacco mosaic virus (TMV), and some compounds had better activity than the commercial antiviral drug ribavirin, especially compounds 2 and 24, which had comparable activity to the most effective commercial antiviral drug ningnanmycin. Preliminary mode of action studies showed that compound 2 could affect the assembly of rod-shaped TMVs by promoting the aggregation and fragmentation of TMV coat proteins. Molecular docking experiments demonstrated that the introduction of oxime and hydrazone moieties could indeed increase the hydrogen bond between molecules and target proteins. In addition, we conducted fungicidal and larvicidal activities study of these derivatives. Most of these derivatives had good larvicidal activities against Mythimna separata and Plutella xylostella and showed broad-spectrum fungicidal activities.

Eating healthy under work stress: A gene stress interaction model.

OBJECTIVE: Some employees tend to eat less healthy food when under work stress, while others tend to maintain a healthy diet. The factors underlying these different dietary choices are not yet clear. Individual differences in people's reactions to environmental stress may help explain this phenomenon. This study proposed a Gene × Stress interaction model of dietary choice, suggesting that different dietary choices under stress may be related to DRD2 genes, which moderate the reward circuitry and have been associated with habitual use of alcohol, obesity, and eating behaviors. METHOD: 12,269 employees completed genotyping of their saliva samples and questionnaires on work stress, healthy dietary intentions, and healthy dietary behaviors. Nonlinear multiple regressions were used to test the hypothesized interaction of DRD2 genes and work stress on healthy dietary intentions and healthy dietary behaviors. RESULTS: Individuals with higher work stress reported lower healthy dietary intentions, whereas healthy dietary behaviors exhibited an inverted U shape. DRD2 genes significantly moderated this relationship, and the above relationship was only detected among C allele carriers, whereas for the AA genotype, work stress was not associated with healthy dietary intentions or behaviors. CONCLUSIONS: Healthy dietary intentions and healthy dietary behaviors showed different patterns of association with work stress. The DRD2 genes helped explain the individual differences in dietary choice under work stress. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Self-Driven Droplet Motions Below their Icing Points.

Liquid fluidity is a most key prerequisite for a broad range of technologies, from energy, fluid machineries, microfluidic devices, water, and oil transportation to bio-deliveries. While from thermodynamics, the liquid fluidity gradually diminishes as temperature decreases until completely solidified below icing points. Here, self-driven droplet motions are discovered and demonstrated occurring in icing environments and accelerating with both moving distances and droplet volumes. The self-driven motions, including self-depinning and continuous wriggling, require no surface pre-preparation or energy input but are triggered by the overpressure spontaneously established during icing and then continuously accelerated by capillary pulling of frosts. Such self-driven motions are generic to a broad class of liquid types, volumes, and numbers on various micro-nanostructured surfaces and can be facilely manipulated by introducing pressure gradients spontaneously or externally. The discovery and control of self-driven motions below icing points can greatly broaden liquid-related applications in icing environments.

Boosting water evaporation via continuous formation of a 3D thin film through triple-level super-wicking routes.

Capillary-fed thin-film evaporation via micro/nanoscale structures has attracted increasing attention for its high evaporation flux and pumpless liquid replenishment. However, maximizing thin-film evaporation has been hindered by the intrinsic trade-off between the heat flux and liquid transport. Here, we designed and fabricated nanostructured micro-steam volcanoes on copper surfaces featuring triple-level super-wicking routes to overcome this trade-off and boost water evaporation. The triple-level super-wicking routes enable the continuous formation of a 3D thin film for highly efficient evaporation by continuous self-driven liquid replenishment and extending the thin-film region. The micro-steam volcanoes increased the surface area by 225%, improving the evaporation rate by 141%, with a rapid self-pumping water transport speed up to 80 mm s-1. A remarkable solar-driven water evaporation rate of 3.33 kg m-2 h-1 under one sun vertical incidence was achieved, which is among the highest reported values for metal-based evaporators. When attached to electric-heating plates, the evaporator realized an electrothermal evaporation rate of 12.13 kg m-2 h-1. Moreover, it can also be used for evaporative cooling with enhanced convective heat transfer, reaching a 36.2 °C temperature reduction on a heat source with a heat flux of 6 W cm-2. This study promises a general strategy for designing thin-film evaporators with high efficiencies, low costs, and multi-functional compatibilities.

Design, Synthesis and Various Bioactivity of Acylhydrazone-Containing Matrine Analogues.

Compounds with acylhydrazone fragments contain amide and imine groups that can act as electron donors and acceptors, so they are easier to bind to biological targets and thus generally exhibit significant biological activity. In this work, acylhydrazone fragments were introduced to the C-14 or C-11 position of matrine, a natural alkaloid, aiming to enhance their biological activities. The result of this bioassay showed that many synthesized compounds exhibited excellent anti-virus activity against the tobacco mosaic virus (TMV). Seventeen out of 25 14-acylhydrazone matrine derivatives and 17 out of 20 11-butanehydrazone matrine derivatives had a higher inhibitory activity against TMV than the commercial antiviral agent Ribavirin (the in vitro activity, in vivo inactivation, curative and protection activities at 500 µg/mL were 40.9, 36.5 ± 0.9, 38.0 ± 1.6 and 35.1 ± 2.2%, respectively), and four 11-butanehydrazone matrine derivatives even had similar to or higher activity than the most efficient antiviral agent Ningnanmycin (55.4, 57.8 ± 1.4, 55.3 ± 0.5 and 60.3 ± 1.2% at 500 µg/mL for the above four test modes). Among them, the N-benzyl-11-butanehydrazone of matrine formed with 4-bromoindole-3-carboxaldehyde exhibited the best anti-TMV activity (65.8, 71.8 ± 2.8, 66.8 ± 1.3 and 69.5 ± 3.1% at 500 µg/mL; 29, 33.5 ± 0.7, 24.1 ± 0.2 and 30.3 ± 0.6% at 100 µg/mL for the above four test modes), deserving further investigation as an antiviral agent. Other than these, the two series of acylhydrazone-containing matrine derivatives were evaluated for their insecticidal and fungicidal activities. Several compounds were found to have good insecticidal activities against diamondback moth (Plutella xylostella) and mosquito larvae (Culex pipiens pallens), showing broad biological activities.

Functional mapping of microRNA promoters with dCas9 fused to transcriptional regulators.

MicroRNAs are small non-coding RNAs that control gene expression during development, physiology, and disease. Transcription is a key factor in microRNA abundance and tissue-specific expression. Many databases predict the location of microRNA transcription start sites and promoters. However, these candidate regions require functional validation. Here, dCas9 fused to transcriptional activators or repressors - CRISPR activation (CRISPRa) and inhibition (CRISPRi)- were targeted to the candidate promoters of two intronic microRNAs, mmu-miR-335 and hsa-miR-3662, including the promoters of their respective host genes Mest and HBS1L. We report that in mouse embryonic stem cells and brain organoids, miR-335 was downregulated upon CRISPRi of its host gene Mest. Reciprocally, CRISPRa of Mest promoter upregulated miR-335. By contrast, CRISPRa of the predicted miR-335-specific promoter (located in an intron of Mest) did not affect miR-335 levels. Thus, the expression of miR-335 only depends on the promoter activity of its host gene Mest. By contrast, miR-3662 was CRISPR activatable both by the promoter of its host gene HBS1L and an intronic sequence in HEK-293T cells. Thus, CRISPRa and CRISPRi are powerful tools to evaluate the relevance of endogenous regulatory sequences involved in microRNA transcription in defined cell types.

Genome-Wide Association Study in Acute Tubulointerstitial Nephritis.

SIGNIFICANCE STATEMENT: Polymorphisms of HLA genes may confer susceptibility to acute tubulointerstitial nephritis (ATIN), but small sample sizes and candidate gene design have hindered their investigation. The first genome-wide association study of ATIN identified two significant loci, risk haplotype DRB1*14-DQA1*0101-DQB1*0503 (DR14 serotype) and protective haplotype DRB1*1501-DQA1*0102-DQB1*0602 (DR15 serotype), with amino acid position 60 in the peptide-binding groove P10 of HLA-DR ß 1 key. Risk alleles were shared among different causes of ATIN and HLA genotypes associated with kidney injury and immune therapy response. HLA alleles showed the strongest association. The findings suggest that a genetically conferred risk of immune dysregulation is part of the pathogenesis of ATIN. BACKGROUND: Acute tubulointerstitial nephritis (ATIN) is a rare immune-related disease, accounting for approximately 10% of patients with unexplained AKI. Previous elucidation of the relationship between genetic factors that contribute to its pathogenesis was hampered because of small sample sizes and candidate gene design. METHODS: We undertook the first two-stage genome-wide association study and meta-analysis involving 544 kidney biopsy-defined patients with ATIN and 2346 controls of Chinese ancestry. We conducted statistical fine-mapping analysis, provided functional annotations of significant variants, estimated single nucleotide polymorphism (SNP)-based heritability, and checked genotype and subphenotype correlations. RESULTS: Two genome-wide significant loci, rs35087390 of HLA-DQA1 ( P =3.01×10 -39 ) on 6p21.32 and rs2417771 of PLEKHA5 on 12p12.3 ( P =2.14×10 -8 ), emerged from the analysis. HLA imputation using two reference panels suggested that HLA-DRB1*14 mainly drives the HLA risk association . HLA-DRB1 residue 60 belonging to pocket P10 was the key amino acid position. The SNP-based heritability estimates with and without the HLA locus were 20.43% and 10.35%, respectively. Different clinical subphenotypes (drug-related or tubulointerstitial nephritis and uveitis syndrome) seemed to share the same risk alleles. However, the HLA risk genotype was associated with disease severity and response rate to immunosuppressive therapy. CONCLUSIONS: We identified two candidate genome regions associated with susceptibility to ATIN. The findings suggest that a genetically conferred risk of immune dysregulation is involved in the pathogenesis of ATIN.

Targeting intracellular Neu1 for coronavirus infection treatment.

There are currently no effective therapies for COVID-19 or antivirals against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and vaccines appear less effective against new SARS-CoV-2 variants; thus, there is an urgent need to understand better the virulence mechanisms of SARS-CoV-2 and the host response to develop therapeutic agents. Herein, we show that host Neu1 regulates coronavirus replication by controlling sialylation on coronavirus nucleocapsid protein. Coronavirus nucleocapsid proteins in COVID-19 patients and in coronavirus HCoV-OC43-infected cells were heavily sialylated; this sialylation controlled the RNA-binding activity and replication of coronavirus. Neu1 overexpression increased HCoV-OC43 replication, whereas Neu1 knockdown reduced HCoV-OC43 replication. Moreover, a newly developed Neu1 inhibitor, Neu5Ac2en-OAcOMe, selectively targeted intracellular sialidase, which dramatically reduced HCoV-OC43 and SARS-CoV-2 replication in vitro and rescued mice from HCoV-OC43 infection-induced death. Our findings suggest Neu1 inhibitors could be used to limit SARS-CoV-2 replication in patients with COVID-19, making Neu1 a potential therapeutic target for COVID-19 and future coronavirus pandemics.