Cholangiocyte organoids to study drug-induced injury.

BACKGROUND: Drug induced bile duct injury is a frequently observed clinical problem leading to a wide range of pathological features. During the past decades, several agents have been identified with various postulated mechanisms of bile duct damage, however, mostly still poorly understood. METHODS: Here, we investigated the mechanisms of chlorpromazine (CPZ) induced bile duct injury using advanced in vitro cholangiocyte cultures. Intrahepatic cholangiocyte organoids (ICOs) were driven into mature cholangiocyte like cells (CLCs), which were exposed to CPZ under cholestatic or non-cholestatic conditions through the addition of a bile acid cocktail. RESULTS: CPZ caused loss of monolayer integrity by reducing expression levels of tight junction protein 1 (TJP1), E-cadherin 1 (CDH1) and lysyl oxidase homolog 2 (LOXL2). Loss of zonula occuludens-1 (ZO-1) and E-cadherin was confirmed by immunostaining after exposure to CPZ and rhodamine-123 leakage further confirmed disruption of the cholangiocyte barrier function. Furthermore, oxidative stress seemed to play a major role in the early damage response by CPZ. The drug also decreased expression of three main basolateral bile acid transporters, ABCC3 (ATP binding cassette subfamily C member 3), SLC51A/B (solute carrier family 51 subunit alpha/beta) and multidrug resistance transporter ABCB1 (ATP binding cassette subfamily B member 1), thereby contributing to bile acid accumulation. CPZ did not induce an inflammatory response by itself, but addition of TNFα revealed a synergistic effect. CONCLUSION: These results show that ICOs present a model to identify toxic drugs affecting the bile ducts while providing mechanistic insights into hepatotoxicity.

Solution Blow Spinning of the Benzimidazole-Containing Aramid Nanofibers for Separators of Lithium-Ion Batteries.

Nanofibers based on high-performance polymers are much highlighted in recent studies toward advanced lithium-ion batteries. Herein, we demonstrate one scalable poly(ethylene oxide) (PEO)-assisted solution blow spinning strategy for the preparation of heterocyclic aramid (HA) nanofibers of poly(p-phenylene-benzimidazole-terephthalamide). The incorporation of PEO is essential to improve the spinnability of the HA solution achieved directly through the low-temperature-solution copolymerization process. Additionally, the flexible PEO with a strong H-bonding affinity is also utilized as the molecular zipper to adjust the pore size of the nanofiber membrane during the post-treatment process. The obtained membrane combines the good wettability of PEO to the liquid electrolytes, with outstanding mechanical strength, modulus, toughness, and environmental resistance of HA. The nonwoven separator membranes with a porosity of 83.6% exhibited excellent comprehensive performance, which could be seen not only on the high tensile strength (68.2 MPa), modulus (3.0 GPa), and toughness but also on the high thermal stability (Td > 405 °C) and flame retardancy, as well as the high electrolyte uptake (302.4%). The ion conductivity of the porous separators reached 0.83 mS/cm, with the bulk resistance dropping to 1/4 of the reference polypropylene separator. In the assembly of the Li/LiFePO4 half battery, the HA separators displayed improved discharge specific capacity and high retention in both rate capability and cycling tests, providing the potential industrial preparation for advanced lithium-ion batteries.

Lens-free auto-focusing imaging algorithm for the ultra-broadband light source.

Auto-focusing is an essential task for lens-free holographic microscopy, which has developed many methods for high precision or fast refocusing. In this work, we derive the relationship among intensity derivation, the derivative of spectral distribution, as well as the distribution of the object, and propose a new auto-focusing criterion, the Robert critical function with axial difference (RCAD), to enhance the accuracy of distance estimation for lens-free imaging with the ultra-broadband light source. This method consists of three steps: image acquisition and preprocessing, axial-difference calculation, and distance estimation with sharpness analysis. The simulations and experiments demonstrate that the accuracy of this metric on auto-focusing with the ultra-broadband spectrum can effectively assist in determining the off-focus distance. The experiments are conducted in an ultra-broad-spectrum on-chip system, where the samples including the resolution target and the cross-section of the Tilia stem are employed to maximize the applicability of this method. We believe that the RCAD criterion is expected to be a useful auxiliary tool for lens-free on-chip microscopes with ultra-broadband spectrum illumination.

Non-invasive quantification of the brain [18F]FDG-PET using inferred blood input function learned from total-body data with physical constraint.

Full quantification of brain PET requires the blood input function (IF), which is traditionally achieved through an invasive and time-consuming arterial catheter procedure, making it unfeasible for clinical routine. This study presents a deep learning based method to estimate the input function (DLIF) for a dynamic brain FDG scan. A long short-term memory combined with a fully connected network was used. The dataset for training was generated from 85 total-body dynamic scans obtained on a uEXPLORER scanner. Time-activity curves from 8 brain regions and the carotid served as the input of the model, and labelled IF was generated from the ascending aorta defined on CT image. We emphasize the goodness-of-fitting of kinetic modeling as an additional physical loss to reduce the bias and the need for large training samples. DLIF was evaluated together with existing methods in terms of RMSE, area under the curve, regional and parametric image quantifications. The results revealed that the proposed model can generate IFs that closer to the reference ones in terms of shape and amplitude compared with the IFs generated using existing methods. All regional kinetic parameters calculated using DLIF agreed with reference values, with the correlation coefficient being 0.961 (0.913) and relative bias being 1.68±8.74% (0.37±4.93%) for Ki (K1). In terms of the visual appearance and quantification, parametric images were also highly identical to the reference images. In conclusion, our experiments indicate that a trained model can infer an image-derived IF from dynamic brain PET data, which enables subsequent reliable kinetic modeling.

The role of dynamic, static, and delayed total-body PET imaging in the detection and differential diagnosis of oncological lesions.

OBJECTIVES: Commercialized total-body PET scanners can provide high-quality images due to its ultra-high sensitivity. We compared the dynamic, regular static, and delayed 18F-fluorodeoxyglucose (FDG) scans to detect lesions in oncologic patients on a total-body PET/CT scanner. MATERIALS & METHODS: In all, 45 patients were scanned continuously for the first 60 min, followed by a delayed acquisition. FDG metabolic rate was calculated from dynamic data using full compartmental modeling, whereas regular static and delayed SUV images were obtained approximately 60- and 145-min post-injection, respectively. The retention index was computed from static and delayed measures for all lesions. Pearson's correlation and Kruskal-Wallis tests were used to compare parameters. RESULTS: The number of lesions was largely identical between the three protocols, except MRFDG and delayed images on total-body PET only detected 4 and 2 more lesions, respectively (85 total). FDG metabolic rate (MRFDG) image-derived contrast-to-noise ratio and target-to-background ratio were significantly higher than those from static standardized uptake value (SUV) images (P < 0.01), but this is not the case for the delayed images (P > 0.05). Dynamic protocol did not significantly differentiate between benign and malignant lesions just like regular SUV, delayed SUV, and retention index. CONCLUSION: The potential quantitative advantages of dynamic imaging may not improve lesion detection and differential diagnosis significantly on a total-body PET/CT scanner. The same conclusion applied to delayed imaging. This suggested the added benefits of complex imaging protocols must be weighed against the complex implementation in the future. CLINICAL RELEVANCE: Total-body PET/CT was known to significantly improve the PET image quality due to its ultra-high sensitivity. However, whether the dynamic and delay imaging on total-body scanner could show additional clinical benefits is largely unknown. Head-to-head comparison between two protocols is relevant to oncological management.

Whole genome sequencing enables new genetic diagnosis for inherited retinal diseases by identifying pathogenic variants.

Inherited retinal diseases (IRDs) are a group of common primary retinal degenerative disorders. Conventional genetic testing strategies, such as panel-based sequencing and whole exome sequencing (WES), can only elucidate the genetic etiology in approximately 60% of IRD patients. Studies have suggested that unsolved IRD cases could be attributed to previously undetected structural variants (SVs) and intronic variants in IRD-related genes. The aim of our study was to obtain a definitive genetic diagnosis by employing whole genome sequencing (WGS) in IRD cases where the causative genes were inconclusive following an initial screening by panel sequencing. A total of 271 unresolved IRD patients and their available family members (n = 646) were screened using WGS to identify pathogenic SVs and intronic variants in 792 known ocular disease genes. Overall, 13% (34/271) of IRD patients received a confirmed genetic diagnosis, among which 7% were exclusively attributed to SVs, 4% to a combination of single nucleotide variants (SNVs) and SVs while another 2% were linked to intronic variants. 22 SVs, 3 deep-intronic variants, and 2 non-canonical splice-site variants across 14 IRD genes were identified in the entire cohort. Notably, all of these detected SVs and intronic variants were novel pathogenic variants. Among those, 74% (20/27) of variants were found in genes causally linked to Retinitis Pigmentosa (RP), with the gene EYS being the most frequently affected by SVs. The identification of SVs and intronic variants through WGS enhances the genetic diagnostic yield of IRDs and broadens the mutational spectrum of known IRD-associated genes.

Synthesis of Bench-stable Polycyclic Organophosphorus Heterocycles via Staudinger-type Annulations of ortho-Azidophenols.

The formation of a five- or six-membered ring is known to stabilize unstable molecular structures such as hemiacetals. This idea can also be extended to stabilize other high-coordinated p-block element species. Herein, we synthesized two novel polycyclic organophosphorus heterocycles via Staudinger-type annulations. Reactions of either ortho-phosphinoarenesulfonyl fluorides 1 or ortho-phosphinobenzoic acid methyl esters 4 with ortho-azidophenols 2 gave rise to penta-coordinated P(V) heterocycles, benzo-benzo-1,2,3-thiazaphospholo-1,3,2-oxazaphosphole (B-B-TAP-OAP) 3 and benzo-benzo-1,2-azaphospholo-1,3,2-oxazaphosphol-12-one (B-B-AP-OAP) 5 in satisfactory yields. It is remarkable that heterocycles 3 and 5 are both bench-stable and exhibit considerable stability in a 10 % aqueous tetrahydrofuran solution. Preliminary computational studies disclosed that the formation of nitrogen gas is the key driving force for the annulations. In addition, the formation of a strong Si-F bond is another contributor to the annulation of 1 and 2.

PCT, IL-6, and IL-10 facilitate early diagnosis and pathogen classifications in bloodstream infection.

BACKGROUND: In the diagnosis of bloodstream infection (BSI), various inflammatory markers such as C-reactive protein (CRP), procalcitonin (PCT), interleukins (IL), white blood cell count (WBC), neutrophil percentage (NE%), platelet count (PLT), and erythrocyte sedimentation rate (ESR) have been extensively utilized. However, their specific roles in distinguishing BSI from local bacterial infection (LBI) and in classifying BSI pathogens remain uncertain. METHODS: A historical cohort study was conducted, involving the enrollment of 505 patients with BSI and 102 patients with LBI. To validate the reliability of the clinical data obtained from this cohort, mouse models of BSI were utilized. RESULTS: Our findings revealed that patients with BSI had significantly higher levels of inflammatory markers, including CRP, PCT, IL-6, IL-10, WBC, NE%, and ESR, compared to those with LBI (p < 0.05). The receiver operating characteristic (ROC) curve analysis demonstrated that CRP, PCT, IL-6, IL-10, ESR and NE% exhibited excellent diagnostic efficacy for BSI. Additionally, we observed significant differences in CRP, PCT, IL-6, and IL-10 levels between patients with BSI caused by Gram-positive bacteria (GP-BSI) and Gram-negative bacteria (GN-BSI), but no significant variations were found among specific bacterial species. Furthermore, our study also found that CRP, PCT, and IL-10 have good discriminatory ability for vancomycin-resistant Enterococcus (VRE), but they show no significant diagnostic efficacy for other multidrug-resistant organisms (MDROs) such as carbapenem-resistant Enterobacteriaceae (CRE), carbapenem-resistant Pseudomonas aeruginosa (CRPA), and methicillin-resistant Staphylococcus aureus (MRSA). In our mouse model experiments, we observed a remarkable increase in PCT, IL-6, and IL-10 levels in mice with GN-BSI compared to those with GP-BSI. CONCLUSION: Our study has confirmed that PCT, IL-6, and IL-10 are efficient biomarkers for distinguishing between BSI and LBI. Furthermore, they can be utilized to classify BSI pathogens and differentiate between VRE and vancomycin-susceptible Enterococcus. These findings are extremely valuable for clinicians as they enable timely initiation of empiric antibiotic therapies and ultimately lead to improved clinical outcomes for patients with BSI.

Choroidal Vessel and Stromal Volumetric Analysis After Photodynamic Therapy or Focal Laser for Central Serous Chorioretinopathy.

Purpose: To utilize volumetric analysis to quantify volumetric changes in choroidal vessels and stroma after photodynamic therapy (PDT) and focal laser photocoagulation (PC) for central serous chorioretinopathy (CSCR). Methods: This retrospective, comparative study included 58 eyes (58 patients) with CSCR (PC, 33 eyes; PDT, 25 eyes) followed up with swept-source optical coherence tomography at 3 months after treatment. Three-dimensional (3D) choroidal vessel and stromal volumes in each area of the central 1.5-mm-diameter circle, the torus-shaped area with 6-mm-diameter circle excluding the area of the central 1.5-mm-diameter circle, and the treated area of the Early Treatment Diabetic Retinopathy Study (ETDRS) grid centered at the fovea were analyzed using a deep learning-based method. Changes in volume at baseline and 1 and 3 months after treatment were compared. Results: The mean patient age was 49.3 ± 10.5 years. In the central 1.5-mm-diameter circle, the mean vessel and stromal volume rates significantly decreased after the treatment in both the PDT and PC groups (P = 0.00029 and P = 0.0014, respectively), and significant differences between the PDT and PC groups of continuous variables within times were observed in both volumes (P = 0.024 and P = 0.037, respectively). In the torus-shaped area and treated area, the PDT and PC groups both showed similar decreases in vessel and stromal volume over time. Conclusions: In the 3D optical coherence tomography volumetric analysis, both PDT and focal PC reduced choroid vessel volume in eyes with CSCR. Translational Relevance: This new finding is useful in elucidating the pathogenesis and healing mechanisms of CSCR.

Nanowired delivery of dl-3-n-butylphthalide with antibodies to alpha synuclein potentiated neuroprotection in Parkinson's disease with emotional stress.

Stress is one of the most serious consequences of life leading to several chronic diseases and neurodegeneration. Recent studies show that emotional stress and other kinds of anxiety and depression adversely affects Parkinson's disease symptoms. However, the details of how stress affects Parkinson's disease is still not well known. Traumatic brain injury, stroke, diabetes, post-traumatic stress disorders are well known to modify the disease precipitation, progression and persistence. However, show stress could influence Parkinson's disease is still not well known. The present investigation we examine the role of immobilization stress influencing Parkinson's disease brain pathology in model experiments. In ore previous report we found that mild traumatic brain injury exacerbate Parkinson's disease brain pathology and nanodelivery of dl-3-n-butylphthalide either alone or together with mesenchymal stem cells significantly attenuated Parkinson's disease brain pathology. In this chapter we discuss the role of stress in exacerbating Parkinson's disease pathology and nanowired delivery of dl-3-n-butylphthalide together with monoclonal antibodies to alpha synuclein (ASNC) is able to induce significant neuroprotection. The possible mechanisms of dl-3-n-butylphthalide and ASNC induced neuroprotection and suitable clinical therapeutic strategy is discussed.

Extended and adjustable field-of-view of variable interscan time analysis by ammonite-scanning swept-source optical coherence tomography angiography.

A novel scanning protocol, ammonite scan, is proposed for widefield optical coherence tomography angiography (OCTA) and relative retinal blood flow velocity imaging in the human retina using variable interscan time analysis (VISTA). A repeated circle scan using a 400 kHz swept-source was employed to achieve an interscan time of 1.28 ms. The center of the repeated circular scan continuously moved spirally towards the peripheral region, ensuring an extended and adjustable scan range while preserving the short interscan time. Image artifacts due to eye movement were eliminated via extra motion-correction processing using data redundancy. The relative blood flow velocity in superficial and deep plexus layers was calculated from the VISTA image, and their ratio was used to explore the microvascular flow parameter in the healthy human eye.

Co-administration of dl-3-n-butylphthalide and neprilysin is neuroprotective in Alzheimer disease associated with mild traumatic brain injury.

dl-3-n-Butylphthalide is a potent synthetic Chinese celery extract that is highly efficient in inducing neuroprotection in concussive head injury (CHI), Parkinson's disease, Alzheimer's disease, stroke as well as depression, dementia, anxiety and other neurological diseases. Thus, there are reasons to believe that dl-3-n-butylphthalide could effectively prevent Alzheimer's disease brain pathology. Military personnel during combat operation or veterans are often the victims of brain injury that is a major risk factor for developing Alzheimer's disease in their later lives. In our laboratory we have shown that CHI exacerbates Alzheimer's disease brain pathology and reduces the amyloid beta peptide (AßP) inactivating enzyme neprilysin. We have used TiO2 nanowired-dl-3-n-butylphthalide in attenuating Parkinson's disease brain pathology exacerbated by CHI. Nanodelivery of dl-3-n-butylphthalide appears to be more potent as compared to the conventional delivery of the compound. Thus, it would be interesting to examine the effects of nanowired dl-3-n-butylphthalide together with nanowired delivery of neprilysin in Alzheimer's disease model on brain pathology. In this investigation we found that nanowired delivery of dl-3-n-butylphthalide together with nanowired neprilysin significantly attenuated brain pathology in Alzheimer's disease model with CHI, not reported earlier. The possible mechanism and clinical significance is discussed based on the current literature.

Tau-PET abnormality as a biomarker for Alzheimer's disease staging and early detection: a topological perspective.

Alzheimer's disease can be detected early through biomarkers such as tau positron emission tomography (PET) imaging, which shows abnormal protein accumulations in the brain. The standardized uptake value ratio (SUVR) is often used to quantify tau-PET imaging, but topological information from multiple brain regions is also linked to tau pathology. Here a new method was developed to investigate the correlations between brain regions using subject-level tau networks. Participants with cognitive normal (74), early mild cognitive impairment (35), late mild cognitive impairment (32), and Alzheimer's disease (40) were included. The abnormality network from each scan was constructed to extract topological features, and 7 functional clusters were further analyzed for connectivity strengths. Results showed that the proposed method performed better than conventional SUVR measures for disease staging and prodromal sign detection. For example, when to differ healthy subjects with and without amyloid deposition, topological biomarker is significant with P < 0.01, SUVR is not with P > 0.05. Functionally significant clusters, i.e. medial temporal lobe, default mode network, and visual-related regions, were identified as critical hubs vulnerable to early disease conversion before mild cognitive impairment. These findings were replicated in an independent data cohort, demonstrating the potential to monitor the early sign and progression of Alzheimer's disease from a topological perspective for individual.

Chondrocyte-laden gelatin/sodium alginate hydrogel integrating 3D printed PU scaffold for auricular cartilage reconstruction.

Clinically, modified autologous rib cartilage grafts and commercial implants are commonly used for intraoperative repair of auricular cartilage defects caused by injuries. However, scaffold implantation is often accompanied by various complications including absorption and collapse, resulting in undesirable clinical outcomes. Three-dimensional printed auricular cartilage scaffolds have the advantage of individual design and biofunctionality, which attracted tremendous attention in this field. In this study, to better simulate the mechanical properties of auricular cartilage, we tested PU treated by ultrasonication and high temperature for 30 min (PU-30) or 60 min (PU-60). The results indicated that the compression modulus of PU-30 was 2.21-2.48 MPa, which similar to that of natural auricular cartilage (2.22-7.23 MPa) and was chosen for subsequent experiments. And the pores of treated PU were filled with a gelatin/sodium alginate hydrogel loaded with chondrocytes. In vivo analysis using a rabbit model confirmed that implanted PU-30 scaffold filled with chondrocytes contained hydrogel successfully integrated with normal auricular cartilage, and that new cartilage was generated at the scaffold-tissue interface by histological examination. These findings illustrate that this engineered scaffold represents a potential strategy for repair of ear cartilage damage in clinical.

An RNA-informed dosage sensitivity map reflects the intrinsic functional nature of genes.

Understanding dosage sensitivity or why Mendelian diseases have dominant vs. recessive modes of inheritance is crucial for uncovering the etiology of human disease. Previous knowledge of dosage sensitivity is mainly based on observations of rare loss-of-function mutations or copy number changes, which are underpowered due to ultra rareness of such variants. Thus, the functional underpinnings of dosage constraint remain elusive. In this study, we aim to systematically quantify dosage perturbations from cis-regulatory variants in the general population to yield a tissue-specific dosage constraint map of genes and further explore their underlying functional logic. We reveal an inherent divergence of dosage constraints in genes by functional categories with signaling genes (transcription factors, protein kinases, ion channels, and cellular machinery) being dosage sensitive, while effector genes (transporters, metabolic enzymes, cytokines, and receptors) are generally dosage resilient. Instead of being a metric of functional dispensability, we show that dosage constraint reflects underlying homeostatic constraints arising from negative feedback. Finally, we employ machine learning to integrate DNA and RNA metrics to generate a comprehensive, tissue-specific map of dosage sensitivity (MoDs) for autosomal genes.

Chemodivergent Staudinger Reactions of Secondary Phosphine Oxides and Application to the Total Synthesis of LL-D05139ß Potassium Salt.

Unprecedented Staudinger reaction modes of secondary phosphine oxides (SPO) and organic azides are herein disclosed. By the application of various additives, selective nitrogen atom exclusion from the azide group has been achieved. Chlorotrimethylsilane mediates a stereoretentive Staudinger reaction with a 2-N exclusion which provides a valuable method for the synthesis of phosphinic amides and can be considered complementary to the stereoinvertive Atherton-Todd reaction. Alternatively, a 1-N exclusion pathway is promoted by acetic acid to provide the corresponding diazo compound. The effectiveness of this protocol has been further demonstrated by the total synthesis of the diazo-containing natural product LL-D05139ß, which was prepared as a potassium salt for the first time in 6 steps and 26.5 % overall yield.

Scalable Production of Catecholamine-Densified MXene Coatings for Electromagnetic Shielding and Infrared Stealth.

Processing transition metal carbides/nitrides (MXenes) inks into large-area functional coatings expects promising potential for electromagnetic interference (EMI) shielding and infrared stealth. However, the coating performances, especially for scalable fabrication techniques, are greatly constrained by the flake size and stacking manner of MXene. Herein, the large-area production of highly densified and oriented MXene coatings is demonstrated by engineering interfacial interactions of small MXene flakes with catecholamine molecules. The catecholamine molecules can micro-crosslink MXene nanosheets, significantly improving the ink's rheological properties. It favors the shear-induced sheet arrangement and inhibition of structural defects in the blade coating process, making it possible to achieve high orientation and densification of MXene assembly by either large-area coating or patterned printing. Interestingly, the MXene/catecholamine coating exhibits high conductivity of up to 12 247 S cm-1 and ultrahigh specific EMI shielding effectiveness of 2.0 ×10 5  dB cm2 g-1 , obviously superior to most of the reported MXene materials. Furthermore, the regularly assembled structure also endows the MXene coatings with low infrared emissivities for infrared stealth applications. Therefore, MXene/catecholamine coatings with ultraefficient EMI shielding and low infrared emissivity prove the feasibility of applications in aerospace, military, and wearable devices.

Tertiary Amine-Mediated Reductions of Phosphine Oxides to Phosphines.

The reduction of phosphine oxides without the use of highly reactive reductants represents a safer and more sustainable solution for recycling of organophosphorus compounds. Herein, we disclose an N,N,N',N'-tetramethylethylenediamine (TMEDA)-mediated reduction via an unusual intermolecular hydride transfer. Mechanistic studies suggest that TMEDA serves as a hydride donor, while the P(V) halophosphonium salt acts as the hydride acceptor. This methodology provides a scalable and efficient protocol to reduce phosphine oxides under mild conditions.

Co-administration of Nanowired DL-3-n-Butylphthalide (DL-NBP) Together with Mesenchymal Stem Cells, Monoclonal Antibodies to Alpha Synuclein and TDP-43 (TAR DNA-Binding Protein 43) Enhance Superior Neuroprotection in Parkinson's Disease Following Concussive Head Injury.

dl-3-n-butylphthalide (dl-NBP) is one of the potent antioxidant compounds that induces profound neuroprotection in stroke and traumatic brain injury. Our previous studies show that dl-NBP reduces brain pathology in Parkinson's disease (PD) following its nanowired delivery together with mesenchymal stem cells (MSCs) exacerbated by concussive head injury (CHI). CHI alone elevates alpha synuclein (ASNC) in brain or cerebrospinal fluid (CSF) associated with elevated TAR DNA-binding protein 43 (TDP-43). TDP-43 protein is also responsible for the pathologies of PD. Thus, it is likely that exacerbation of brain pathology in PD following brain injury may be thwarted using nanowired delivery of monoclonal antibodies (mAb) to ASNC and/or TDP-43. In this review, the co-administration of dl-NBP with MSCs and mAb to ASNC and/or TDP-43 using nanowired delivery in PD and CHI-induced brain pathology is discussed based on our own investigations. Our observations show that co-administration of TiO2 nanowired dl-NBP with MSCs and mAb to ASNC with TDP-43 induced superior neuroprotection in CHI induced exacerbation of brain pathology in PD, not reported earlier.