Specific Defects Research Articles

A very simple synthesis of defect-rich PdAg nanosponges for highly selective hydrogenation of furfural

Furfuryl alcohol (FA) is an important chemical and has extensive applications in varied fields. To realize the highly selective hydrogenation of furfural (FF) to produce FA, the key is the preparation of the catalysts with excellent performance. Herein, a very simple wet chemical method is developed for the one-step preparation of PdAg nanosponges (NSs). Specifically, with Pd(OAc)2 and AgNO3 as precursors, and ethylene glycol (EG) as both solvent and reducing agent, PdAg NSs can be grown and assembled at mild temperature of 40 °C. Throughout the reaction, no any surfactants and additional reducing agents are applied. The as-prepared PdAg NSs possess 3D self-supported alloy structures, “clean” surface, abundant pores, high specific surface area and rich defects. In the FF hydrogenation reaction at 60 °C under 1.5 MPa H2 pressure in the mixed solvent of ethanol and water (1 : 4 in volume ratio), the self-supported PdAg-1 NSs (1 : 1 in Pd/Ag molar ratio) exhibit superior catalytic performance than other PdAg NSs, pure Pd sample and commercial Pd/C (10%). With PdAg-1 NSs as catalyst in the absence of support, 100% FF can be converted and the selectivity toward FA is as high as 97.1% at 36.0 h of reaction. After 4 cycles, PdAg-1 NSs still maintain the high catalytic activity in FF hydrogenation and high selectivity toward FA, which may originate from the 3D self-supported structures, high specific surface area, “clean” surface, rich defects and electronic synergistic effect between Pd and Ag. This simple fabrication of PdAg NSs introduces new ideas for the synthesis of other nanostructured bi- and multi-metallic catalysts for highly selective FF hydrogenation to FA and other advanced applications.

A conserved Plasmodium nuclear protein is critical for late liver stage development

Malaria, caused by Plasmodium parasites, imposes a significant health burden and live-attenuated parasites are being pursued as vaccines. Here, we report on the creation of a genetically attenuated parasite by the deletion of Plasmodium LINUP, encoding a liver stage nuclear protein. In the rodent parasite Plasmodium yoelii, LINUP expression was restricted to liver stage nuclei after the onset of liver stage schizogony. Compared to wildtype P. yoelii, P. yoelii LINUP gene deletion parasites (linup—) exhibited no phenotype in blood stages and mosquito stages but suffered developmental arrest late in liver stage schizogony with a pronounced defect in exo-erythrocytic merozoite formation. This defect caused severe attenuation of the liver stage-to-blood stage transition and immunization of mice with linup— parasites conferred robust protection against infectious sporozoite challenge. LINUP gene deletion in the human parasite Plasmodium falciparum also caused a severe defect in late liver stage differentiation. Importantly, P. falciparum linup— liver stages completely failed to transition from the liver stage to a viable blood stage infection in a humanized mouse model. These results suggest that P. falciparum LINUP is an ideal target for late liver stage attenuation that can be incorporated into a late liver stage-arresting replication competent whole parasite vaccine.

Exploring RNA therapeutics for urea cycle disorders.

RNA has triggered a significant shift in modern medicine, providing a promising way to revolutionize disease treatment methods. Different therapeutic RNA modalities have shown promise to replace, supplement, correct, suppress, or eliminate the expression of a targeted gene. Currently, there are 22 RNA-based drugs approved for clinical use, including the COVID-19 mRNA vaccines, whose unprecedented worldwide success has meant a definitive boost in the RNA research field. Urea cycle disorders (UCD), liver diseases with high mortality and morbidity, may benefit from the progress achieved, as different genetic payloads have been successfully targeted to liver using viral vectors, N-acetylgalactosamine (GalNAc) conjugations or lipid nanoparticles (LNP). This review explores the potential of RNA-based medicines for UCD and the ongoing development of applications targeting specific gene defects, enzymes, or transporters taking part in the urea cycle. Notably, LNP-formulated mRNA therapy has been assayed preclinically for citrullinemia type I (CTLN1), adolescent and adult citrin deficiency, argininosuccinic aciduria, arginase deficiency and ornithine transcarbamylase deficiency, in the latter case has progressed to the clinical trials phase.

Investigations of strength and quality of clinched joints using digital image correlation

ABSTRACT This study examines the impact of processing conditions on joint strength and the effectiveness of digital image correlation (DIC) in detecting failure points in clinched joints. Mechanical tests, including single-lap shear and pull-out tests, were conducted using DIC to evaluate joint quality in various clinched configurations. The results showed frequent failures at the neck rejoin in clinched joints between mild steel and aluminum sheets, particularly when thinner sheets were positioned on the punch side and softer materials on the die side. DIC effectively identified defects and failure locations, offering insights into material combinations, sheet positioning, and failure modes. Although DIC was useful in detecting defects in both elastic and destructive regions, its ability to distinguish specific defect types from strain contour maps was limited. The study highlights the need for further research to extend DIC’s application to other mechanical joining systems and advocates for its proactive use in refining designs and manufacturing processes.

Guided bone regeneration improves defect fill and reconstructive outcomes in 3-wall peri-implantitis defects.

This multi-center, randomized clinical trial compared the long-term outcomes of guided bone regeneration (GBR) with open flap debridement (OFD) in treating peri-implantitis-related bony defects with ≥3 osseous walls over 36 months. The study aimed to evaluate the healing potential of GBR using a deproteinized bovine bone mineral (DBBM) graft and native bilayer collagen membrane (NBCM) compared to OFD without the use of graft materials. Sixty-six individuals diagnosed with peri-implantitis were randomly assigned to either GBR (34 patients) or OFD (32 patients). The OFD group served as the control, where inflamed tissue was removed and the implant surface decontaminated using 3% hydrogen peroxide, but no bone graft was placed. The GBR group received DBBM and NBCM for defect reconstruction. Radiographic defect fill (RDF), probing pocket depth (PPD), bleeding on probing (BOP), suppuration (SUP), mucosal recession (MREC), and patient-reported outcomes (PROs) were assessed over the study duration. Post-surgical care included azithromycin, ibuprofen, and chlorhexidine rinses. The study involved baseline assessments, surgical interventions, and follow-ups at 6, 12, and 36 months. Supportive peri-implant therapy was provided every 3 months during the additional 24-month follow-up. Primary outcome was RDF at 36 months. Secondary outcomes included PPD, BOP, SUP, MREC, and PROs. Descriptive statistics and ANCOVA models were used for analysis. At 36 months, GBR resulted in a mean RDF of 2.13 ± 1.26 mm, compared to 1.64 ± 1.54 mm with OFD (p = .18). No significant differences were found in PPD, BOP, SUP, REC, or PROs between the groups. Treatment success (defined as no additional bone loss, PPD ≤ 5 mm, no BOP, and no SUP) was achieved in 46.2% of GBR cases and 20% of OFD cases (p = 0.053). GBR provided improved short-term defect fill and higher treatment success compared to OFD, although the differences were not statistically significant. Both procedures maintained clinical parameters over 36 months, with similar patient satisfaction (PROs) observed for GBR and OFD. The adjunct use of DBBM and NBCM may offer clinical benefits for peri-implantitis cases with specific bony defect morphology.

Investigations on the leak resistance performance and the difference mechanism of composite materials under several typical curing processes

This study aims to investigate the leak resistance of carbon fiber composite products formed by various typical curing processes. Firstly, the leak rates of specimens produced through different curing methods were measured, and the defect were statistically analyzed. After that, the simulation approach was applied to numerically study the impact of these defect characteristics on leak rates was examined from the three factors of porosity, void distribution and void morphology, specimen with prefabricated defects was prepared, and its leak performance were tested to validate the simulation results. Finally, the differences in leak resistance among specimens under different curing processes were analyzed from the perspective of curing defects, and specific defect characteristics contributing to enhanced leak resistance were identified.

Emerging roles of cancer-associated histone mutations in genomic instabilities.

Epigenetic mechanisms often fuel the quick evolution of cancer cells from normal cells. Mutations or aberrant expressions in the enzymes of DNA methylation, histone post-translational modifications, and chromatin remodellers have been extensively investigated in cancer pathogenesis; however, cancer-associated histone mutants have gained momentum in recent decades. Next-generation sequencing of cancer cells has identified somatic recurrent mutations in all the histones (H3, H4, H2A, H2B, and H1) with different frequencies for various tumour types. Importantly, the well-characterised H3K27M, H3G34R/V, and H3K36M mutations are termed as oncohistone mutants because of their wide roles, from defects in cellular differentiation, transcriptional dysregulation, and perturbed epigenomic profiles to genomic instabilities. Mechanistically, these histone mutants impart their effects on histone modifications and/or on irregular distributions of chromatin complexes. Recent studies have identified the crucial roles of the H3K27M and H3G34R/V mutants in the DNA damage response pathway, but their impacts on chemotherapy and tumour progression remain elusive. In this review, we summarise the recent developments in their functions toward genomic instabilities and tumour progression. Finally, we discuss how such a mechanistic understanding can be harnessed toward the potential treatment of tumours harbouring the H3K27M, H3G34R/V, and H3K36M mutations.

Laminin-α2 chain deficiency in skeletal muscle causes dysregulation of multiple cellular mechanisms.

LAMA2, coding for the laminin-α2 chain, is a crucial ECM component, particularly abundant in skeletal muscle. Mutations in LAMA2 trigger the often-lethal LAMA2-congenital muscular dystrophy (LAMA2-CMD). Various phenotypes have been linked to LAMA2-CMD; nevertheless, the precise mechanisms that malfunction during disease onset in utero remain unknown. We generated Lama2-deficient C2C12 cells and found that Lama2-deficient myoblasts display proliferation, differentiation, and fusion defects, DNA damage, oxidative stress, and mitochondrial dysfunction. Moreover, fetal myoblasts isolated from the dy W mouse model of LAMA2-CMD display impaired differentiation and fusion in vitro. We also showed that disease onset during fetal development is characterized by a significant down-regulation of gene expression in muscle fibers, causing pronounced effects on cytoskeletal organization, muscle differentiation, and altered DNA repair and oxidative stress responses. Together, our findings provide unique insights into the critical importance of the laminin-α2 chain for muscle differentiation and muscle cell homeostasis.

Direct mitochondrial import of lactate supports resilient carbohydrate oxidation.

Lactate is the highest turnover circulating metabolite in mammals. While traditionally viewed as a waste product, lactate is an important energy source for many organs, but first must be oxidized to pyruvate for entry into the tricarboxylic acid cycle (TCA cycle). This reaction is thought to occur in the cytosol, with pyruvate subsequently transported into mitochondria via the mitochondrial pyruvate carrier (MPC). Using 13 C stable isotope tracing, we demonstrated that lactate is oxidized in the myocardial tissue of mice even when the MPC is genetically deleted. This MPC-independent lactate import and mitochondrial oxidation is dependent upon the monocarboxylate transporter 1 (MCT1/ Slc16a1 ). Mitochondria isolated from the myocardium without MCT1 exhibit a specific defect in mitochondrial lactate, but not pyruvate, metabolism. The import and subsequent mitochondrial oxidation of lactate by mitochondrial lactate dehydrogenase (LDH) acts as an electron shuttle, generating sufficient NADH to support respiration even when the TCA cycle is disrupted. In response to diverse cardiac insults, animals with hearts lacking MCT1 undergo rapid progression to heart failure with reduced ejection fraction. Thus, the mitochondrial import and oxidation of lactate enables carbohydrate entry into the TCA cycle to sustain cardiac energetics and maintain myocardial structure and function under stress conditions.

Autophagy controls neuronal differentiation by regulating the WNT-DVL signaling pathway

ABSTRACT Macroautophagy/autophagy dysregulation is associated with various neurological diseases, including Vici syndrome. We aimed to determine the role of autophagy in early brain development. We generated neurons from human embryonic stem cells and developed a Vici syndrome model by introducing a loss-of-function mutation in the EPG5 gene. Autophagy-related genes were upregulated at the neuronal progenitor cell stage. Inhibition of autolysosome formation with bafilomycin A1 treatment at the neuronal progenitor cell stage delayed neuronal differentiation. Notably, WNT (Wnt family member) signaling may be part of the underlying mechanism, which is negatively regulated by autophagy-mediated DVL2 (disheveled segment polarity protein 2) degradation. Disruption of autolysosome formation may lead to failure in the downregulation of WNT signaling, delaying neuronal differentiation. EPG5 mutations disturbed autolysosome formation, subsequently inducing defects in progenitor cell differentiation and cortical layer generation in organoids. Disrupted autophagy leads to smaller organoids, recapitulating Vici syndrome-associated microcephaly, and validating the disease relevance of our study. Abbreviations: BafA1: bafilomycin A1; co-IP: co-immunoprecipitation; DVL2: dishevelled segment polarity protein 2; EPG5: ectopic P-granules 5 autophagy tethering factor; gRNA, guide RNA; hESC: human embryonic stem cells; KO: knockout; mDA, midbrain dopamine; NIM: neural induction media; NPC: neuronal progenitor cell; qPCR: quantitative polymerase chain reaction; UPS: ubiquitin-proteasome system; WNT: Wnt family member; WT: wild type.

Jag1 insufficiency alters liver fibrosis via T cell and hepatocyte differentiation defects.

Fibrosis contributes to tissue repair, but excessive fibrosis disrupts organ function. Alagille syndrome (ALGS, caused by mutations in JAGGED1) results in liver disease and characteristic fibrosis. Here, we show that Jag1Ndr/Ndr mice, a model for ALGS, recapitulate ALGS-like fibrosis. Single-cell RNA-seq and multi-color flow cytometry of the liver revealed immature hepatocytes and paradoxically low intrahepatic T cell infiltration despite cholestasis in Jag1Ndr/Ndr mice. Thymic and splenic regulatory T cells (Tregs) were enriched and Jag1Ndr/Ndr lymphocyte immune and fibrotic capacity was tested with adoptive transfer into Rag1-/- mice, challenged with dextran sulfate sodium (DSS) or bile duct ligation (BDL). Transplanted Jag1Ndr/Ndr lymphocytes were less inflammatory with fewer activated T cells than Jag1+/+ lymphocytes in response to DSS. Cholestasis induced by BDL in Rag1-/- mice with Jag1Ndr/Ndr lymphocytes resulted in periportal Treg accumulation and three-fold less periportal fibrosis than in Rag1-/- mice with Jag1+/+ lymphocytes. Finally, the Jag1Ndr/Ndr hepatocyte expression profile and Treg overrepresentation were corroborated in patients' liver samples. Jag1-dependent hepatic and immune defects thus interact to determine the fibrotic process in ALGS.

Short interbirth interval and adverse pregnancy outcomes: a Bayesian network approach

BackgroundInterbirth interval (IBI), the time between consecutive births, has been tied to perinatal outcomes. ObjectiveTo analyze adverse perinatal events following short IBI in a large South American sample. Study designObservational, retrospective, hospital-based study including malformed and nonmalformed live- and stillbirths. Outcomes were preterm birth (PTB), low birth weight (LBW), and specific birth defects. Logistic regressions were used to evaluate the risk of selected variables for short IBI and for adverse outcomes after short IBI, adjusting by confounders. Bayesian networks exhibited relationships among short IBI, outcomes, and variables. ResultsShort IBI rate was 2%–3%. Maternal age and a previous abortion were the main confounders. A significant high risk for short IBI was found in mothers ≤19 years while mothers ≥30 were at low risk, mediated by a previous abortion. The risk of short IBI, adjusted by confounders, was significant for LBW but not for PTB. An unadjusted risk of short IBI was observed for gastroschisis, which disappeared after adjusting for confounders. Maternal age ≤19 and previous abortion were directly related with gastroschisis; the relationship between gastroschisis and short IBI occurred through any of these two variables. A direct relationship between gastroschisis and maternal age ≥30 was observed. ConclusionsOnly young mothers were directly related with short IBI. In older mothers, a short IBI mainly occurred after a previous abortion. Short IBI was a risk factor only for LBW. The PTB and gastroschisis relationship with short IBI was indirect, mediated by young maternal age and/or a previous abortion.

Surface-modified composites of metal–organic framework and wood-derived carbon for high-performance supercapacitors

The renewable nature, high carbon content, and unique hierarchical structure of wood-derived carbon make it an optimal self-supporting electrode for energy storage. However, the limitations in specific surface area and electrical conductivity defects pose challenges to achieving satisfactory charge storage in wood-derived carbon electrodes. Therefore, exploring diverse and effective surface strategies is crucial for enhancing the electrochemical energy storage performance. Herein, a decoration technique for enhancing aesthetic appeal involves applying a metal–organic framework (Ni/Co-MOF) containing nickel and cobalt onto the inner walls of wood tracheids. The sequential modification steps include carbonization, oxidation activation, and acid-etching. The Ni/NiO/CoO-CW-4 electrode, made by acid-etching carbonized wood (CW) doped with nickel, nickel oxide, and cobalt oxide for 4 h, has excellent surface area and pore size distribution, high graphitization degree, and exceptional conductivity. Furthermore, surface modification optimizes the surface chemistry and phase composition, resulting in a 0.8 mm thick Ni/NiO/CoO-CW-4 electrode with an exceptionally high areal capacitance of 16.76 F cm−2 at 5 mA cm−2. Meanwhile, the fabricated solid-state supercapacitor achieves an impressive energy density of 0.67 mWh cm−2 (8.38 mWh cm−3) at 2.5 mW cm−2 (31.25 mW cm−3), surpassing representative modified wood-based carbon electrodes by approximately 2–7 times. Additionally, the supercapacitor demonstrates exceptional stability, maintaining 96.21 % of capacitance even over 10,000 cycles. The parameters presented here demonstrate a significant improvement compared to those typically observed in most modified wood-derived carbon-based supercapacitors, effectively addressing common issues of low energy density and suboptimal cycling performance with wood carbon composites.

Griscelli syndrome: a diagnostic challenge of a rare disease: a case report

Introduction: Griscelli syndrome (GS) is a rare autosomal recessive genetic disorder that primarily manifests as hair and skin hypopigmentation, with three types differentiated by their specific genetic defects as well as by their clinical features. Clinically, GS type 1 is characterized by early neurological alterations, while GS type 2 is characterized by immunodeficiency and could present with neurological symptoms, and type 3 is characterized by a chromosomal anomaly without a specific clinical profile besides hypopigmentation. This article details the challenges faced in the diagnosis of a patient with GS who presents with neurological symptoms followed by immunological deficits. Case presentation: A 7-month-old female presented with complaints of developmental delay following an otitis media infection. Upon examination, she exhibited signs of psychomotor developmental regression and had pale bronze skin and silvery-gray hair, as well as hepatosplenomegaly. The examination of her hair shaft revealed a pattern consistent with GS. During her hospitalization, the patient developed an intermittent fever and signs of hemophagocytic lymphohistiocytosis (HLH). She subsequently developed recurrent seizures treated with phenytoin and Aciclovir. Shortly she succumbed to respiratory distress syndrome and multisystem failure. Discussion: The presence of HLH confirms the type of GS. However, in some cases, the HLH criteria could not be fulfilled, presenting a diagnostic challenge. Conclusion: The genetic examination is the only way to differentiate GS type 1 from type 2. However, when it is not available, the presence of specific symptoms and features may assist in the classification. Furthermore, treatments should be administered when GS type 2 is suspected since they have the potential to improve life quality through treating HLH, delaying and altering the neurological symptoms.

SALL2 regulates neural differentiation of mouse embryonic stem cells through Tuba1a

The spalt (Sal) gene family has four members (Sall1-4) in vertebrates, all of which play pivotal roles in various biological processes and diseases. However, the expression and function of SALL2 in development are still less clear. Here, we first charted SALL2 protein expression pattern during mouse embryo development by immunofluorescence, which revealed its dominant expression in the developing nervous system. With the establishment of Sall2 deficient mouse embryonic stem cells (ESCs), the in vitro neural differentiation system was leveraged to interrogate the function of SALL2, which showed impaired neural differentiation of Sall2 knockout (KO) ESCs. Furthermore, neural stem cells (NSCs) could not be derived from Sall2 KO ESCs and the generation of neural tube organoids (NTOs) was greatly inhibited in the absence of SALL2. Meanwhile, transgenic expression of E1 isoform of SALL2 restored the defects of neural differentiation in Sall2 KO ESCs. By chromatin immunoprecipitation sequencing (ChIP-seq), Tuba1a was identified as downstream target of SALL2, whose function in neural differentiation was confirmed by rescuing neural phenotypes of Sall2 KO ESCs when overexpressed. In sum, by elucidating SALL2 expression dynamics during early mouse development and mechanistically characterizing its indispensable role in neural differentiation, this study offers insights into SALL2’s function in human nervous system development, associated pathologies stemming from its mutations and relevant therapeutic strategy.

Fabric Defect Detection Using Transfer Learning

Transfer learning in fabric defect detection involves utilizing pre-trained deep learning models on a large dataset, typically from a different domain, and fine-tuning them on a smaller dataset that is specific to fabric defects. By leveraging transfer learning, the limitations of limited annotated data for fabric defect detection can be overcome by utilizing the knowledge gained from a more extensive and diverse dataset. The pre-trained model's learned features are adjusted to recognize specific fabric defect patterns, resulting in more accurate and efficient defect detection. This approach reduces the reliance on a massive labelled dataset for training, which is particularly beneficial in industrial applications where obtaining a vast amount of annotated fabric defect images may be challenging. Ultimately, transfer learning enhances the model's ability to generalize and detect fabric defects with higher precision, thereby contributing to improved quality control in textile manufacturing processes.

Single-cell transcriptomics reveals e-cigarette vapor-induced airway epithelial remodeling and injury

BackgroundIn recent years, e-cigarettes have been used as alternatives among adult smokers. However, the impact of e-cigarette use on human bronchial epithelial (HBE) cells remains controversial.MethodsWe collected primary HBE cells of healthy nonsmokers and chronic obstructive pulmonary disease (COPD) smokers, and analyzed the impact of e- cigarette vapor extract (ECE) or cigarette smoke extract (CSE) on HBE cell differentiation and injury by single-cell RNA sequencing, immunostaining, HE staining, qPCR and ELISA. We obtained serum and sputum from healthy non- smokers, smokers and e-cigarette users, and analyzed cell injury markers and mucin proteins.ResultsECE treatment led to a distinct differentiation program of ciliated cells and unique patterns of their cell–cell communications compared with CSE. ECE treatment caused increased Notch signaling strength in a ciliated cell subpopulation, and HBE cell remodeling and injury including hypoplasia of ciliated cells and club cells, and shorter cilia. ECE-induced hypoplasia of ciliated cells and shorter cilia were ameliorated by the Notch signaling inhibition.ConclusionsThis study reveals distinct characteristics in e-cigarette vapor-induced airway epithelial remodeling, pointing to Notch signaling pathway as a potential targeted intervention for e-cigarette vapor-caused ciliated cell differentiation defects and cilia injury. In addition, a decrease in SCGB1A1 proteins is associated with e- cigarette users, indicating a potential lung injury marker for e-cigarette users.

Enhanced anti-cancer efficacy of arginine deaminase expressed by tumor-seeking Salmonella Gallinarum.

Amino acid deprivation, particularly of nonessential amino acids that can be synthesized by normal cells but not by cancer cells with specific defects in the biosynthesis pathway, has emerged as a potential strategy in cancer therapeutics. In normal cells, arginine is synthesized from citrulline in two steps via two enzymes: argininosuccinate synthetase (ASS1) and argininosuccinate lyase. Several cancer cells exhibit arginine auxotrophy due to the loss or down-regulation of ASS1. These cells undergo starvation-induced cell death in the presence of arginine-degrading enzymes such as arginine deaminase (ADI). Thus, ADI has emerged as a potential therapeutic in cancer therapy. However, the use of ADI has two major disadvantages: ADI of bacterial origin is strongly antigenic in mammals, and ADI has a short circulation half-life (∼5 h). In this study, we engineered tumor-targeting Salmonella Gallinarum to express and secrete ADI and deployed this strain into mice implanted with ASS1-defective mouse colorectal cancer (CT26) through an intravenous route. A notable antitumor effect was observed, suggesting that the disadvantages were overcome as ADI was expressed constitutively by tumor-targeting bacteria. A combination with chloroquine, which inhibits the induction of autophagy, further enhanced the effect. Anti-cancer effect of Salmonella Gallinarum expressing an arginine deiminase (ADI) on arginine-dependent tumors in situ.

NEMF mutations in mice illustrate how Importin-β specific nuclear transport defects recapitulate neurodegenerative disease hallmarks.

Pathological disruption of Nucleocytoplasmic Transport (NCT), such as the mis-localization of nuclear pore complex proteins (Nups), nuclear transport receptors, Ran-GTPase, and RanGAP1, are seen in both animal models and in familial and sporadic forms of amyotrophic lateral sclerosis (ALS), frontal temporal dementia and frontal temporal lobar degeneration (FTD\FTLD), and Alzheimer's and Alzheimer's Related Dementias (AD/ADRD). However, the question of whether these alterations represent a primary cause, or a downstream consequence of disease is unclear, and what upstream factors may account for these defects are unknown. Here, we report four key findings that shed light on the upstream causal role of Importin-β-specific nuclear transport defects in disease onset. First, taking advantage of two novel mouse models of NEMF neurodegeneration (NemfR86S and NemfR487G) that recapitulate many cellular and biochemical aspects of neurodegenerative diseases, we find an Importin-β-specific nuclear import block. Second, we observe cytoplasmic mis-localization and aggregation of multiple proteins implicated in the pathogenesis of ALS/FTD and AD/ADRD, including TDP43, Importin-β, RanGap1, and Ran. These findings are further supported by a pathological interaction between Importin-β and the mutant NEMFR86S protein in cytoplasmic accumulations. Third, we identify similar transcriptional dysregulation in key genes associated with neurodegenerative disease. Lastly, we show that even transient pharmaceutical inhibition of Importin-β in both mouse and human neuronal and non-neuronal cells induces key proteinopathies and transcriptional alterations seen in our mouse models and in neurodegeneration. Our convergent results between mouse and human neuronal and non-neuronal cellular biology provide mechanistic evidence that many of the mis-localized proteins and dysregulated transcriptional events seen in multiple neurodegenerative diseases may in fact arise primarily from a primary upstream defect in Importin- β nuclear import. These findings have critical implications for investigating how sporadic forms of neurodegeneration may arise from presently unidentified genetic and environmental perturbations in Importin-β function.

Incorporation of specific defects through ion bombardment for better ferroelectrics

AbstractIncorporating specific defects into complex oxides facilitates the exploration of exotic phenomena and novel functionalities based on the intricate coupling between the defects and lattice/charge. However, methods for maximizing the density of specific defects while enhancing the desired properties have been rarely explored. In this study, the effect of N+ ion bombardment‐driven specific defects on the properties of bismuth ferrite (BFO) thin films was investigated. Furthermore, atomic structure characterization and computational processing revealed the displacement and orientation of the Fe atoms, which are linearly related to the degree of polarization. The ion bombardment introduced deep‐level trap states within the lattice, leading to a significant reduction in the leakage current and improved insulation performance of the films. By precisely engineering the defect content through N+ ion bombardment, the pure BFO thin films with remarkable and stable ferroelectric properties (remnant polarization, Pr = ∼116.8 µC·cm−2; leakage current, J = ∼1.5 × 10−8 A·cm−2) were fabricated. This innovative defect engineering‐based approach enables the customization and optimization of local ferroelectric order parameters, thereby establishing a solid foundation for designing functionalities across various functional material systems.