KSR1 Knockout Mouse Model Demonstrates MAPK Pathway's Key Role in Cisplatin- and Noise-induced Hearing Loss.

Hearing loss is a major disability in everyday life and therapeutic interventions to protect hearing would benefit a large portion of the world population. Here we found that mice devoid of the protein kinase suppressor of RAS 1 (KSR1) in their tissues (germline KO mice) exhibit resistance to both cisplatin- and noise-induced permanent hearing loss compared with their wild-type KSR1 littermates. KSR1 is a scaffold protein that brings in proximity the mitogen-activated protein kinase (MAPK) proteins BRAF, MEK1/2 and ERK1/2 and assists in their activation through a phosphorylation cascade induced by both cisplatin and noise insults in the cochlear cells. KSR1, BRAF, MEK1/2, and ERK1/2 are all ubiquitously expressed in the cochlea. Deleting the KSR1 protein tempered down the MAPK phosphorylation cascade in the cochlear cells following both cisplatin and noise insults and conferred hearing protection of up to 30 dB SPL in three tested frequencies in male and female mice. Treatment with dabrafenib, an FDA-approved oral BRAF inhibitor, protected male and female KSR1 wild-type mice from both cisplatin- and noise-induced hearing loss. Dabrafenib treatment did not enhance the protection of KO KSR1 mice, providing evidence dabrafenib works primarily through the MAPK pathway. Thus, either elimination of the KSR1 gene expression or drug inhibition of the MAPK cellular pathway in mice resulted in profound protection from both cisplatin- and noise-induced hearing loss. Inhibition of the MAPK pathway, a cellular pathway that responds to damage in the cochlear cells, can prove a valuable strategy to protect and treat hearing loss.

4D-STEM Mapping of Nanocrystal Reaction Dynamics and Heterogeneity in a Graphene Liquid Cell.

Chemical reaction kinetics at the nanoscale are intertwined with heterogeneity in structure and composition. However, mapping such heterogeneity in a liquid environment is extremely challenging. Here we integrate graphene liquid cell (GLC) transmission electron microscopy and four-dimensional scanning transmission electron microscopy to image the etching dynamics of gold nanorods in the reaction media. Critical to our experiment is the small liquid thickness in a GLC that allows the collection of high-quality electron diffraction patterns at low dose conditions. Machine learning-based data-mining of the diffraction patterns maps the three-dimensional nanocrystal orientation, groups spatial domains of various species in the GLC, and identifies newly generated nanocrystallites during reaction, offering a comprehensive understanding on the reaction mechanism inside a nanoenvironment. This work opens opportunities in probing the interplay of structural properties such as phase and strain with solution-phase reaction dynamics, which is important for applications in catalysis, energy storage, and self-assembly.

Identification of QTNs, QTN-by-environment interactions, and their candidate genes for salt tolerance related traits in soybean.

BACKGROUND: Salt stress significantly reduces soybean yield. To improve salt tolerance in soybean, it is important to mine the genes associated with salt tolerance traits. RESULTS: Salt tolerance traits of 286 soybean accessions were measured four times between 2009 and 2015. The results were associated with 740,754 single nucleotide polymorphisms (SNPs) to identify quantitative trait nucleotides (QTNs) and QTN-by-environment interactions (QEIs) using three-variance-component multi-locus random-SNP-effect mixed linear model (3VmrMLM). As a result, eight salt tolerance genes (GmCHX1, GsPRX9, Gm5PTase8, GmWRKY, GmCHX20a, GmNHX1, GmSK1, and GmLEA2-1) near 179 significant and 79 suggested QTNs and two salt tolerance genes (GmWRKY49 and GmSK1) near 45 significant and 14 suggested QEIs were associated with salt tolerance index traits in previous studies. Six candidate genes and three gene-by-environment interactions (GEIs) were predicted to be associated with these index traits. Analysis of four salt tolerance related traits under control and salt treatments revealed six genes associated with salt tolerance (GmHDA13, GmPHO1, GmERF5, GmNAC06, GmbZIP132, and GmHsp90s) around 166 QEIs were verified in previous studies. Five candidate GEIs were confirmed to be associated with salt stress by at least one haplotype analysis. The elite molecular modules of seven candidate genes with selection signs were extracted from wild soybean, and these genes could be applied to soybean molecular breeding. Two of these genes, Glyma06g04840 and Glyma07g18150, were confirmed by qRT-PCR and are expected to be key players in responding to salt stress. CONCLUSIONS: Around the QTNs and QEIs identified in this study, 16 known genes, 6 candidate genes, and 8 candidate GEIs were found to be associated with soybean salt tolerance, of which Glyma07g18150 was further confirmed by qRT-PCR.

Regional integration policies and urban green innovation: Fresh evidence from urban agglomeration expansion.

Climate change is a non-traditional security crisis affecting the global economy and diplomatic progress. In order to curtail carbon emissions and alleviate the perils of climate change at their roots, urban green innovation (UGI) has emerged as a pivotal technological solution. Using the expansion of the Yangtze River Delta urban agglomeration in China as a case study, this paper develops a quasi-experimental model to analyze the effects of regional integration policies on UGI. The main findings are: (1) Regional integration policies significantly enhance UGI and their impact is more pronounced with the expansion of urban agglomerations; (2) Regional integration policies contribute to the advancement of exploitative green innovation while tending to diminish exploratory green innovation; (3) The green innovation effects (GIEs) created by the expansion of regional integration policies are largely influenced by governmental mechanisms on environmental governance as well as residents' green preferences. Based on these findings, recommendations are put forward to promote UGI from the perspective of policy implementation.

Unveiling the NIMBY effect in construction and demolition waste landfilling: Factors, paths, and solutions.

The construction and operation of the construction and demolition waste (C&DW) landfills often encounter significant opposition from nearby residents, which is called the "not in my backyard" (NIMBY) effect. However, little is known about the formation mechanism of the NIMBY effect in C&DW landfilling, so this research was conducted for this purpose. First, the influencing factors leading to the NIMBY effect were determined based on a literature review and questionnaire survey. Then, the interrelationship and influencing path of critical factors were revealed using expert interviews and Interpretative Structural Modelling. The results shown that 12 factors from four levels (including residents, society, government, and enterprises) caused the NIMBY effect in C&DW landfilling. These factors formed a complex network comprising 18 influencing paths. Notably, policy and responding measures as pivotal bottom-level factors that trigger the NIMBY effect by indirectly impacting residents' rights awareness and shaping public perception towards C&DW landfill operation enterprises through directly affecting personal interest, cognitive bias, distrust, disposal technology, management level, opinion leader, and other intermediate factors, ultimately triggering the NIMBY effect. Moreover, strategies for mitigating or resolving the NIMBY effect were proposed, such as protecting personal reasonable interests, understanding the potential risks of C&DW landfills rationally, reporting the C&DW landfills from an objective perspective, improving policies and promoting public participation, and enhancing supervision of the C&DW landfills. The study added new knowledge to the current public's NIMBY effect in C&DW landfilling. Meanwhile, it also provided a reference for formulating C&DW landfilling policies and selecting landfill sites.

Interplay of IL-17A/IL-17RA signaling with microbial homeostasis in systemic anti-tumoral responses.

Enteric IL-17RA deficiency leads to gut dysbiosis, consequently initiating the proliferation of tumors at remote locations. The deficiency or blockade of enteric IL-17RA induces the secretion of IL-17A by B cells and Th17 cells in response to microbial signals, resulting in a systemic elevation of IL-17A and fostering the growth of remote tumors. This figure was created with BioRender.com.

Framework of compressive sensing and data compression for 4D-STEM.

Four-dimensional Scanning Transmission Electron Microscopy (4D-STEM) is a powerful technique for high-resolution and high-precision materials characterization at multiple length scales, including the characterization of beam-sensitive materials. However, the field of view of 4D-STEM is relatively small, which in absence of live processing is limited by the data size required for storage. Furthermore, the rectilinear scan approach currently employed in 4D-STEM places a resolution- and signal-dependent dose limit for the study of beam sensitive materials. Improving 4D-STEM data and dose efficiency, by keeping the data size manageable while limiting the amount of electron dose, is thus critical for broader applications. Here we introduce a general method for reconstructing 4D-STEM data with subsampling in both real and reciprocal spaces at high fidelity. The approach is first tested on the subsampled datasets created from a full 4D-STEM dataset, and then demonstrated experimentally using random scan in real-space. The same reconstruction algorithm can also be used for compression of 4D-STEM datasets, leading to a large reduction (100 times or more) in data size, while retaining the fine features of 4D-STEM imaging, for crystalline samples.

An evaluation model for city-scale construction and demolition waste management effectiveness: A case study in China.

The growing generation of construction and demolition waste (CDW) has emerged as a prominent challenge on global environmental agendas. However, the effectiveness of CDW management (CDWM) strategies varies among cities. Existing literature predominantly evaluates the effectiveness of CDWM at the project level, offering a localized perspective that fails to capture a city's comprehensive CDWM profile. This localized focus has certain limitations. To fill this gap in city-scale evaluations, this study introduces a novel model for assessing CDWM effectiveness at the municipal level. An empirical investigation was conducted across 11 cities within the Guangdong-Hong Kong-Macao Greater Bay Area (GBA) to operationalize this model. The model defines five distinct levels of CDWM effectiveness. Findings indicate that Hong Kong consistently achieves the highest level (level I), while the majority of cities fall within levels III and IV. This pattern suggests that CDWM effectiveness in the GBA is moderately developed, with uneven progress in CDW management outcomes and supporting systems. Essentially, there is a lack of synchronous development of CDWM results and guarantee systems. The proposed evaluation model enriches existing CDWM research field and offers a framework that may inform future studies in other countries.

One-year results of the Flowdynamics Dense Mesh Stent for residual dissection after proximal repair of stanford type A or type B aortic dissection: a multicenter, prospective, and randomized study.

OBJECTIVE: Negative remodeling of the distal aorta following proximal repair for acute aortic dissection has garnered growing attention. This clinical scenario has spurred the development of techniques and devices. A multicenter, prospective, and randomized controlled study was conducted with the aim of confirming the safety and effectiveness of a newly-designed flowdynamics dense mesh stent for the treatment of residual dissection after proximal repair. METHODS: Patients with nonchronic residual dissection affecting visceral branches were prospectively enrolled at three centers and randomly allocated to either the FDMS group or the control group. Primary endpoints encompassed all-cause and aortic-related mortality, while the patency of branch arteries is indeed a key focal metric. Morphological changes (diameter, area, and volume) were analyzed to demonstrate the therapeutic effect. RESULTS: One hundred twelve patients were recruited in the clinical trial, and 103 patients completed the 12-month follow-up. The rate of freedom from all-cause and aortic-related death in the FDMS group was 94.64 and 100%, respectively. All visceral branches remained patent. The FDMS group exhibited a substantial expansion in TL and a notable shrinkage in FL at the planes below renal arteries (ΔArea TL : FDMS vs. Control, 0.74±0.46 vs. 0.34±0.66 cm 2 , P <0.001; ΔArea FL : FDMS vs. Control, -0.72±1.26 vs. -0.12±0.86 cm, P =0.01) and 5 cm below renal arteries (ΔArea TL : FDMS vs. Control, 1.06±0.75 vs. 0.16±0.63 cm 2 , P <0.001; ΔArea FL : FDMS vs. Control, -0.53±1.43 vs. -0.25±1.00 cm, P =0.27). Meanwhile, the FDMS group demonstrated an increase of 22.55±11.14 cm 3 in TL ( P <0.001) and a corresponding reduction of 21.94±11.77 cm 3 in FL ( P =0.08). CONCLUSIONS: This newly-designed FDMS for endovascular repair of residual dissection following the proximal repair is demonstrated to be safe and effective at 12 months.

Highly modified cephalotane-type diterpenoids from Cephalotaxus fortunei var. alpina and C. sinensis.

Cephalotanes are a rare class of diterpenoids occurring exclusively in Cephalotaxus plants. The intriguing structures and promising biological activities for this unique compound class prompt us to investigate C. fortunei var. alpina and C. sinensis, leading to the isolation of six undescribed cephalotane-type diterpenoids and/or norditerpenoids, ceforloids A-F (1-6). Their structures were elucidated by comprehensive analysis of spectroscopic data, including ECD and single-crystal X-ray diffraction studies, as well as quantum chemical calculations. Compound 1 possesses an unprecedented norditerpenoid skeleton featuring an unusual acetophenone moiety, and originated putatively from a disparate biogenetic pathway. Compounds 4 and 5 incorporate a unique 12,13-p-hydroxybenzylidene acetal motif. Compound 6 is a rare cephalotane-type diterpenoid glycoside. Immunosuppressive assays showed that compounds 2 and 6 exhibited mild suppressive activity against the activated T and B lymphocytes proliferation. These findings not only expanded the structural diversity of this small group of diterpenoids, but also explored their potential as novel structures for the development of immunosuppressive agents.

White adipose tissue, a novel antirheumatic target: Clues from its secretory capability and adipectomy-based therapy.

BACKGROUND AND PURPOSE: White adipose tissue (WAT) is involved in rheumatoid arthritis (RA). This study explored its potential as an antirheumatic target. EXPERIMENTAL APPROACH: WAT status of healthy and adjuvant-induced arthritis (AIA) rats were compared. The contribution of WAT to RA pathology was evaluated by pre-adipocyte transplant experiments and by dissecting perirenal fat pads of AIA rats. The impact of RA on WAT was investigated by culturing pre-adipocytes. Proteins differentially expressed in WAT of healthy and AIA rats were identified by the UPLC/MS2 method. These together with PPARγ siRNA and agonist were used to treat pre-adipocytes in vitro. The medium was used for THP-1 monocyte culture. KEY RESULTS: Compared with healthy controls, AIA WAT was smaller but secreted more leptin, eNAMPT, MCP-1, TNF-α, and IL-6. AIA rat pre-adipocytes increased the levels of these adipokines in healthy recipients. RA patients' serum induced a similar secretion change and impaired differentiation of pre-adipocytes. Adipectomy eased AIA-related immune abnormalities and arthritic manifestations. Hepatokines PON1, IGFBP4, and GPIHBP1 were among the differential proteins in high levels in RA blood, and induced inflammatory secretions by pre-adipocytes. GPIHBP1 inhibited PPARγ expression and caused differentiation impairment and inflammatory secretion by pre-adipocytes, a similar outcome to PPARγ-silencing. This endowed the cells with an ability to activate monocytes, which can be abrogated by rosiglitazone. CONCLUSION AND IMPLICATIONS: Certain hepatokines potentiate inflammatory secretions by pre-adipocytes and expedite RA progression by inhibiting PPARγ. Targeting this signalling or abnormal WAT secretion by various approaches may reduce RA severity.

Mid-term results of a prospective study for aortic dissection with a gutter-plugging chimney stent graft.

OBJECTIVES: Our goal was to access early and mid-term outcomes of a gutter-plugging chimney stent graft for treatment of Stanford type B aortic dissections in the clinical trial Prospective Study for Aortic Arch Therapy with stENt-graft for Chimney technology (PATENCY). METHODS: Between October 2018 and March 2022, patients with Stanford type B aortic dissections were treated with the Longuette chimney stent graft in 26 vascular centres. The efficiency and the incidence of adverse events over 12 months were investigated. RESULTS: A total of 150 patients were included. The technical success rate was 99.33% (149/150). The incidence of immediate postoperative endoleak was 5.33% (8/150, type I, n = 6; type II, n = 1; type IV, n = 1) neurologic complications (stroke or spinal cord ischaemia); the 30-day mortality was 0.67% (1/150) and 1.33% (2/150), respectively. During the follow-up period, the median follow-up time was 11.67 (5-16) months. The patent rate of the Longuette graft was 97.87%. Two patients with type I endoleak underwent reintervention. The follow-up rate of the incidence of retrograde A type aortic dissection was 0.67% (1/150). There was no paraplegia, left arm ischaemia or stent migration. CONCLUSIONS: For revascularization of the left subclavian artery, the Longuette chimney stent graft can provide an easily manipulated, safe and effective endovascular treatment. It should be considered a more efficient technique to prevent type Ia endoleak. Longer follow-up and a larger cohort are needed to validate these results. CLINICAL TRIAL REGISTRY NUMBER: NCT03767777.

Dynamic regulation of alternative polyadenylation by PQBP1 during neurogenesis.

Alternative polyadenylation (APA) is a critical post-transcriptional process that generates mRNA isoforms with distinct 3' untranslated regions (3' UTRs), thereby regulating mRNA localization, stability, and translational efficiency. Cell-type-specific APA extensively shapes the diversity of the cellular transcriptome, particularly during cell fate transition. Despite its recognized significance, the precise regulatory mechanisms governing cell-type-specific APA remain unclear. In this study, we uncover PQBP1 as an emerging APA regulator that actively maintains cell-specific APA profiles in neural progenitor cells (NPCs) and delicately manages the equilibrium between NPC proliferation and differentiation. Multi-omics analysis shows that PQBP1 directly interacts with the upstream UGUA elements, impeding the recruitment of the CFIm complex and influencing polyadenylation site selection within genes associated with the cell cycle. Our findings elucidate the molecular mechanism by which PQBP1 orchestrates dynamic APA changes during neurogenesis, providing valuable insights into the precise regulation of cell-type-specific APA and the underlying pathogenic mechanisms in neurodevelopmental disorders.

Oseltamivir (Tamiflu), a Commonly Prescribed Antiviral Drug, Mitigates Hearing Loss in Mice.

Hearing loss affects up to 10% of all people worldwide, but currently there is only one FDA-approved drug for its prevention in a subgroup of cisplatin-treated pediatric patients. Here, we performed an unbiased screen of 1,300 FDA-approved drugs for protection against cisplatin-induced cell death in an inner ear cell line, and identified oseltamivir phosphate (brand name Tamiflu), a common influenza antiviral drug, as a top candidate. Oseltamivir phosphate was found to be otoprotective by oral delivery in multiple established cisplatin and noise exposure mouse models. The drug conferred permanent hearing protection of 15-25 dB SPL for both female and male mice. Oseltamivir treatment reduced in mice outer hair cells death after cisplatin treatment and mitigated cochlear synaptopathy after noise exposure. A potential binding protein, ERK1/2, associated with inflammation, was shown to be activated with cisplatin treatment and reduced by oseltamivir cotreatment in cochlear explants. Importantly, the number of infiltrating immune cells to the cochleae in mice post noise exposure, were significantly reduced with oseltamivir treatment, suggesting an anti-inflammatory mechanism of action. Our results support oseltamivir, a widespread drug for influenza with low side effects, as a promising otoprotective therapeutic candidate in both cisplatin chemotherapy and traumatic noise exposure.

In silico transcriptome screens identify epidermal growth factor receptor inhibitors as therapeutics for noise-induced hearing loss.

Noise-induced hearing loss (NIHL) is a common sensorineural hearing impairment that lacks U.S. Food and Drug Administration-approved drugs. To fill the gap in effective screening models, we used an in silico transcriptome-based drug screening approach, identifying 22 biological pathways and 64 potential small molecule treatments for NIHL. Two of these, afatinib and zorifertinib [epidermal growth factor receptor (EGFR) inhibitors], showed efficacy in zebrafish and mouse models. Further tests with EGFR knockout mice and EGF-morpholino zebrafish confirmed their protective role against NIHL. Molecular studies in mice highlighted EGFR's crucial involvement in NIHL and the protective effect of zorifertinib. When given orally, zorifertinib was found in the perilymph with favorable pharmacokinetics. In addition, zorifertinib combined with AZD5438 (a cyclin-dependent kinase 2 inhibitor) synergistically prevented NIHL in zebrafish. Our results underscore the potential for in silico transcriptome-based drug screening in diseases lacking efficient models and suggest EGFR inhibitors as potential treatments for NIHL, meriting clinical trials.

An orbital strategy for regulating the Jahn-Teller effect.

The Jahn-Teller effect (JTE) arising from lattice-electron coupling is a fascinating phenomenon that profoundly affects important physical properties in a number of transition-metal compounds. Controlling JT distortions and their corresponding electronic structures is highly desirable to tailor the functionalities of materials. Here, we propose a local coordinate strategy to regulate the JTE through quantifying occupancy in the [Formula: see text] and [Formula: see text] orbitals of Mn and scrutinizing the symmetries of the ligand oxygen atoms in MnO6 octahedra in LiMn2O4 and Li0.5Mn2O4. The effectiveness of such a strategy has been demonstrated by constructing P2-type NaLi x Mn1 - x O2 oxides with different Li/Mn ordering schemes. In addition, this strategy is also tenable for most 3d transition-metal compounds in spinel and perovskite frameworks, indicating the universality of local coordinate strategy and the tunability of the lattice-orbital coupling in transition-metal oxides. This work demonstrates a useful strategy to regulate JT distortion and provides useful guidelines for future design of functional materials with specific physical properties.

Piplartine attenuates aminoglycoside-induced TRPV1 activity and protects from hearing loss in mice.

Hearing loss is a major health concern in our society, affecting more than 400 million people worldwide. Among the causes, aminoglycoside therapy can result in permanent hearing loss in 40% to 60% of patients receiving treatment, and despite these high numbers, no drug for preventing or treating this type of hearing loss has yet been approved by the US Food and Drug Administration. We have previously conducted high-throughput screenings of bioactive compounds, using zebrafish as our discovery platform, and identified piplartine as a potential therapeutic molecule. In the present study, we expanded this work and characterized piplartine's physicochemical and therapeutic properties. We showed that piplartine had a wide therapeutic window and neither induced nephrotoxicity in vivo in zebrafish nor interfered with aminoglycoside antibacterial activity. In addition, a fluorescence-based assay demonstrated that piplartine did not inhibit cytochrome C activity in microsomes. Coadministration of piplartine protected from kanamycin-induced hair cell loss in zebrafish and protected hearing function, outer hair cells, and presynaptic ribbons in a mouse model of kanamycin ototoxicity. Last, we investigated piplartine's mechanism of action by phospho-omics, immunoblotting, immunohistochemistry, and molecular dynamics experiments. We found an up-regulation of AKT1 signaling in the cochleas of mice cotreated with piplartine. Piplartine treatment normalized kanamycin-induced up-regulation of TRPV1 expression and modulated the gating properties of this receptor. Because aminoglycoside entrance to the inner ear is, in part, mediated by TRPV1, these results suggested that by regulating TRPV1 expression, piplartine blocked aminoglycoside's entrance, thereby preventing the long-term deleterious effects of aminoglycoside accumulation in the inner ear compartment.