Magneto-acoustic protein nanostructures for non-invasive imaging of tissue mechanics in vivo.

Measuring cellular and tissue mechanics inside intact living organisms is essential for interrogating the roles of force in physiological and disease processes. Current agents for studying the mechanobiology of intact, living organisms are limited by poor light penetration and material stability. Magnetomotive ultrasound is an emerging modality for real-time in vivo imaging of tissue mechanics. Nonetheless, it has poor sensitivity and spatiotemporal resolution. Here we describe magneto-gas vesicles (MGVs), protein nanostructures based on gas vesicles and magnetic nanoparticles that produce differential ultrasound signals in response to varying mechanical properties of surrounding tissues. These hybrid nanomaterials significantly improve signal strength and detection sensitivity. Furthermore, MGVs enable non-invasive, long-term and quantitative measurements of mechanical properties within three-dimensional tissues and in vivo fibrosis models. Using MGVs as novel contrast agents, we demonstrate their potential for non-invasive imaging of tissue elasticity, offering insights into mechanobiology and its application to disease diagnosis and treatment.

Nanoscale Magneto-mechanical-genetics of Deep Brain Neurons Reversing Motor Deficits in Parkinsonian Mice.

Here, we introduce the magneto-mechanical-genetic (MMG)-driven wireless deep brain stimulation (DBS) using magnetic nanostructures for therapeutic benefits in the mouse model of Parkinson's disease (PD). Electrical DBS of the subthalamic nucleus (STN) is an effective therapy for mitigating Parkinson's motor symptoms. However, its broader application is hampered by the requirement for implanted electrodes and the lack of anatomical and cellular specificity. Using the nanoscale magnetic force actuators (m-Torquer), which deliver torque force under rotating magnetic fields to activate pre-encoded Piezo1 ion channels on target neurons, our system enables wireless and STN-specific DBS without implants, addressing key unmet challenges in the DBS field. In both late- and early-stage PD mice, MMG-DBS significantly improved locomotor activity and motor balance by 2-fold compared to untreated PD mice. Moreover, MMG-DBS enabled sustained therapeutic effects. This approach provides a non-invasive and implant-free DBS with cellular targeting capability for the effective treatment of Parkinsonian symptoms.

Uniform Synthesis of Bilayer Hydrogen Substituted Graphdiyne for Flexible Piezoresistive Applications.

Graphdiyne (GDY) has garnered significant attention as a cutting-edge 2D material owing to its distinctive electronic, optoelectronic, and mechanical properties, including high mobility, direct bandgap, and remarkable flexibility. One of the key challenges hindering the implementation of this material in flexible applications is its large area and uniform synthesis. The facile growth of centimeter-scale bilayer hydrogen substituted graphdiyne (Bi-HsGDY) on germanium (Ge) substrate is achieved using a low-temperature chemical vapor deposition (CVD) method. This material's field effect transistors (FET) showcase a high carrier mobility of 52.6 cm2 V-1 s-1 and an exceptionally low contact resistance of 10 Ω µm. By transferring the as-grown Bi-HsGDY onto a flexible substrate, a long-distance piezoresistive strain sensor is demonstrated, which exhibits a remarkable gauge factor of 43.34 with a fast response time of ≈275 ms. As a proof of concept, communication by means of Morse code is implemented using a Bi-HsGDY strain sensor. It is believed that these results are anticipated to open new horizons in realizing Bi-HsGDY for innovative flexible device applications.

Statin administration or blocking PCSK9 alleviates airway hyperresponsiveness and lung fibrosis in high-fat diet-induced obese mice.

BACKGROUND: Obesity is associated with airway hyperresponsiveness and lung fibrosis, which may reduce the effectiveness of standard asthma treatment in individuals suffering from both conditions. Statins and proprotein convertase subtilisin/kexin-9 inhibitors not only reduce serum cholesterol, free fatty acids but also diminish renin-angiotensin system activity and exhibit anti-inflammatory effects. These mechanisms may play a role in mitigating lung pathologies associated with obesity. METHODS: Male C57BL/6 mice were induced to develop obesity through high-fat diet for 16 weeks. Conditional TGF-ß1 transgenic mice were fed a normal diet. These mice were given either atorvastatin or proprotein convertase subtilisin/kexin-9 inhibitor (alirocumab), and the impact on airway hyperresponsiveness and lung pathologies was assessed. RESULTS: High-fat diet-induced obesity enhanced airway hyperresponsiveness, lung fibrosis, macrophages in bronchoalveolar lavage fluid, and pro-inflammatory mediators in the lung. These lipid-lowering agents attenuated airway hyperresponsiveness, macrophages in BALF, lung fibrosis, serum leptin, free fatty acids, TGF-ß1, IL-1ß, IL-6, and IL-17a in the lung. Furthermore, the increased RAS, NLRP3 inflammasome, and cholecystokinin in lung tissue of obese mice were reduced with statin or alirocumab. These agents also suppressed the pro-inflammatory immune responses and lung fibrosis in TGF-ß1 over-expressed transgenic mice with normal diet. CONCLUSIONS: Lipid-lowering treatment has the potential to alleviate obesity-induced airway hyperresponsiveness and lung fibrosis by inhibiting the NLRP3 inflammasome, RAS and cholecystokinin activity.

The impact of macro- and micro-steatosis on the outcomes of patients who undergo liver transplant: Analysis of the UNOS-STAR database.

BACKGROUND AND AIMS: The presence of steatosis in a donor liver and its relation to post-transplantation outcomes are not well defined. This study evaluates the effect of the presence and severity of micro- and macro-steatosis of a donor graft on post-transplantation outcomes. METHODS: The UNOS-STAR registry (2005-2019) was used to select patients who received a liver transplant graft with hepatic steatosis. The study cohort was stratified by the presence of macro- or micro-vesicular steatosis, and further stratified by histologic grade of steatosis. The primary endpoints of all-cause mortality and graft failure were compared using sequential Cox regression analysis. Analysis of specific causes of mortality was further performed. RESULTS: There were 9184 with no macro-steatosis (control), 150 with grade 3 macro-steatosis, 822 with grade 2 macro-steatosis and 12 585 with grade 1 macro-steatosis. There were 10 320 without micro-steatosis (control), 478 with grade 3 micro-steatosis, 1539 with grade 2 micro-steatosis and 10 404 with grade 1 micro-steatosis. There was no significant difference in all-cause mortality or graft failure among recipients who received a donor organ with any evidence of macro- or micro-steatosis, compared to those receiving non-steatotic grafts. There was increased mortality due to cardiac arrest among recipients of a grade 2 macro-steatosis donor organ. CONCLUSION: This study shows no significant difference in all-cause mortality or graft failure among recipients who received a donor liver with any degree of micro- or macro-steatosis. Further analysis identified increased mortality due to specific aetiologies among recipients receiving donor organs with varying grades of macro- and micro-steatosis.

Hydrogel Magnetomechanical Actuator Nanoparticles for Wireless Remote Control of Mechanosignaling In Vivo.

As a new enabling nanotechnology tool for wireless, target-specific, and long-distance stimulation of mechanoreceptors in vivo, here we present a hydrogel magnetomechanical actuator (h-MMA) nanoparticle. To allow both deep-tissue penetration of input signals and efficient force generation, h-MMA integrates a two-step transduction mechanism that converts magnetic anisotropic energy to thermal energy within its magnetic core (i.e., Zn0.4Fe2.6O4 nanoparticle cluster) and then to mechanical energy to induce the surrounding polymer (i.e., pNiPMAm) shell contraction, finally delivering forces to activate targeted mechanoreceptors. We show that h-MMAs enable on-demand modulation of Notch signaling in both fluorescence reporter cell lines and a xenograft mouse model, demonstrating its utility as a powerful in vivo perturbation approach for mechanobiology interrogation in a minimally invasive and untethered manner.

Controlled Bipolar Doping of One-Dimensional van der Waals Nb2Pd3Se8.

Tailoring the electrical properties of one-dimensional (1D) van der Waals (vdW) materials is desirable for their applications toward electronic devices by exploiting their unique characteristics. However, 1D vdW materials have not been extensively investigated for modulation of their electrical properties. Here we control doping levels and types of 1D vdW Nb2Pd3Se8 over a wide energy range by immersion in AuCl3 or ß-nicotinamide adenine dinucleotide (NADH) solutions, respectively. Through spectroscopic analyses and electrical characterizations, we confirm that the charges were effectively transferred to Nb2Pd3Se8, and the dopant concentration was adjusted to the immersion time. Furthermore, we make the axial p-n junction of 1D Nb2Pd3Se8 by a selective area p-doping using the AuCl3 solution, which exhibits rectifying behavior with an Iforward/Ireverse of 81 and an ideality factor of 1.2. Our findings could pave the way to more practical and functional electronic devices based on 1D vdW materials.

Removable complete denture with a metal base: Integration of digital design and conventional fabrication techniques.

OBJECTIVE: Digitally-designed removable complete dentures are typically composed of a resin denture base without a metal framework. However, metal denture bases are preferable as resin bases are more susceptible to fracture. Therefore, this article introduces a unique technique that integrates computer-aided design (CAD) and conventional resin processing for the fabrication of removable complete dentures with a metal framework. CLINICAL CONSIDERATIONS: A maxillary complete denture with a metal base and a mandibular implant-retained overdenture reinforced with a metal framework were fabricated. The dentures were designed using CAD software and a tooth library. The denture bases were milled from wax disks, and artificial teeth were placed to complete the wax dentures. The metal frameworks were also designed using CAD software and produced via casting of printed resin patterns. Finally, conventional denture processing techniques were applied to obtain dentures with metal frameworks. CONCLUSIONS: A digitally designed, removable complete denture with a metal base can be successfully fabricated using the described technique, which merges digital design and conventional methods. This article demonstrates the feasibility and potential advantages of this innovative approach in denture fabrication. CLINICAL SIGNIFICANCE: The presented technique provides the following advantages: digital design features, precise space above implant overdenture attachments for a metal framework, convenience of esthetic evaluation with printed trial dentures, long-term data storage and duplication, reliable bond between the artificial teeth and denture base, and enhanced strength of the removable complete denture due to the metal reinforcement.

Particulate matter10-induced airway inflammation and fibrosis can be regulated by chitinase-1 suppression.

BACKGROUND: Particulate matter10 (PM10) can induce airway inflammation and fibrosis. Recently, chitinase-1 has been shown to play key roles in inflammation and fibrosis. We aimed to investigate the effects of chitinase-1 inhibitor in PM10-treated murine mice models. METHODS: In female BALB/c mice, PM10 was intranasally administered six times over 3 weeks, and ovalbumin (OVA) was intraperitoneally injected and then intranasally administered. Chitinase-1 inhibitor (CPX) 6 times over 3 weeks or dexamethasone 3 times in the last week were intraperitoneally administered. Two days after the last challenges, mice were euthanized. Messenger RNA sequencing using lung homogenates was conducted to evaluate signaling pathways. RESULTS: PM10 and/or OVA-induced airway inflammation and fibrosis murine models were established. CPX and dexamethasone ameliorated PM10 or PM10/OVA-induced airway hyper-responsiveness, airway inflammation, and fibrosis. CPX and dexamethasone also reduced levels of various inflammatory markers in lung homogenates. PM10 and OVA also induced changes in mRNA expression across an extreme range of genes. CPX and dexamethasone decreased levels of mRNA expression especially associated with inflammation and immune regulation. They also significantly regulated asthma and asthma-related pathways, including the JACK-STAT signaling pathway. CONCLUSIONS: Chitinase-1 suppression by CPX can regulate PM10- and OVA-induced and aggravated airway inflammation and fibrosis via an asthma-related signaling pathway.

Distinct Nitrification Rates and Nitrifiers in Needleleaf and Evergreen Broadleaf Forest Soils.

Research on niche specialization in the microbial communities of ammonia oxidizers is important for assessing the consequences of vegetation shift on nitrogen (N) cycling. In this study, soils were sampled from three tree stands (needleleaf, mixed, and evergreen broadleaf) from the Hannam experimental forest in South Korea in spring (May 2019), summer (August 2019), autumn (November 2019), and winter (January 2020). Quantitative polymerase chain reaction (qPCR) and high-throughput sequencing were used to measure the abundance and community structure of various nitrifiers: ammonia-oxidizing archaea and bacteria (AOA and AOB, respectively) as well as complete ammonia oxidizers (comammox). Nitrification rates and total ammonia oxidizer abundance were significantly higher in needleleaf forest soil than those in other forest stands, and they were lowest in evergreen broadleaf forest soil. Comammox clade B was most abundant in needleleaf and evergreen broadleaf forest soils, while AOA were significantly more abundant in mixed forest soil. The abundances of comammox clade B and AOA were negatively correlated with dissolved organic carbon. Phylogenetic analysis showed that NT-alpha and NS-gamma-2.3.2 were the most abundant AOA lineages in all the samples. The seasonal of AOA, AOB, and comammox varied with the sites, suggesting the need to examine the combinations of environmental factors when considering the effects of seasonal changes in the environment. Overall, the results suggest that potential vegetation shifts in forest ecosystems might affect nitrification activities by regulating the abundance and community structure of ammonia oxidizers.

Attenuation of Methane Oxidation by Nitrogen Availability in Arctic Tundra Soils.

CH4 emission in the Arctic has large uncertainty due to the lack of mechanistic understanding of the processes. CH4 oxidation in Arctic soil plays a critical role in the process, whereby removal of up to 90% of CH4 produced in soils by methanotrophs can occur before it reaches the atmosphere. Previous studies have reported on the importance of rising temperatures in CH4 oxidation, but because the Arctic is typically an N-limited system, fewer studies on the effects of inorganic nitrogen (N) have been reported. However, climate change and an increase of available N caused by anthropogenic activities have recently been reported, which may cause a drastic change in CH4 oxidation in Arctic soils. In this study, we demonstrate that excessive levels of available N in soil cause an increase in net CH4 emissions via the reduction of CH4 oxidation in surface soil in the Arctic tundra. In vitro experiments suggested that N in the form of NO3- is responsible for the decrease in CH4 oxidation via influencing soil bacterial and methanotrophic communities. The findings of our meta-analysis suggest that CH4 oxidation in the boreal biome is more susceptible to the addition of N than in other biomes. We provide evidence that CH4 emissions in Arctic tundra can be enhanced by an increase of available N, with profound implications for modeling CH4 dynamics in Arctic regions.

Abutment margin levels and residual cement occurrence in cement-retained implant restorations: An observational study.

OBJECTIVES: To evaluate the association between different vertical levels of the abutment margin and residual cement prevalence in cement-retained implant restorations with customized abutments. METHODS: One hundred and nine single-unit cement-retained implant restorations with a screw-access channel were included. The crowns were intraorally cemented on the abutments, and excess cement was removed. The abutment-crown complex was unscrewed, and the abutment-crown complex and peri-implant tissue were photographed. Residual cement presence was recorded by dividing the abutment-crown complex and peri-implant tissue into four quadrants: mesial, distal, buccal, and lingual. The prevalence of residual cement was compared according to the height of the custom abutment margin of the corresponding quadrant. A multilevel model was used for statistical analysis (α = .05). RESULTS: Cement remnants were discovered on 72.48% of the dental implants. When the restoration quadrants were compared, cement remnants were present on 51.38%, 39.45%, 20.18%, and 17.43% of the mesial, distal, buccal, and lingual surfaces, respectively (p < .01). Regarding the abutment margin level, cement residues were found in 60.22% and 61.4% of the 0.5 mm subgingival and ≥1 mm subgingival margin groups, respectively, which were significantly more than those in the supragingival (23.65%) and equigingival (26.59%) margin groups (p < .01). After adjustment for confounding factors, the adjusted odds ratio (with 95% confidence interval) for residual cement in the subgingival margin groups was 3.664 (1.71, 7.852) when compared to the supragingival and equigingival margin groups. CONCLUSIONS: The risk of residual cement occurrence was 3.66-fold higher with a subgingival abutment margin than with supragingival and equigingival abutment margins.

Magnetogenetics with Piezo1 Mechanosensitive Ion Channel for CRISPR Gene Editing.

Regulation of genetic activity in single cells and tissues is pivotal to determine key cellular functions in current biomedicine, yet the conventional biochemical activators lack spatiotemporal precision due to the diffusion-mediated slow kinetics and nonselectivity. Here, we describe a magnetogenetic method for target-specific activation of a clustered regularly interspaced short palindromic repeats (CRISPR) system for the regulation of intracellular proteins. We used magnetomechanical force generated by the magnetic nanostructure to activate pre-encoded Piezo1, the mechanosensitive ion channel, on the target cell. The activated Piezo1 further triggers the intracellular Ca2+ signaling pathway, inducing the pre-encoded genes to express genes of interest (GOIs), which is Cas9 protein for the CRISPR regulation of the target proteins. We demonstrated that this magnetogenetic CRISPR system successfully edits the target genome for both in vitro and pseudo-in vivo environments, providing a versatile magnetic platform for remote gene editing of animals with various size scales.

Color and surface stainability of additively and subtractively manufactured interim restorative materials against mouth rinses.

STATEMENT OF PROBLEM: Interim restorations are often used along with mouth rinses during the healing period following surgical procedures. However, evidence regarding the color and surface properties of digitally fabricated interim restorations after oral rinsing is lacking. PURPOSE: The purpose of this in vitro study was to evaluate whether different mouth rinses could affect the color and surface roughness of milled and printed interim restorations after simulated oral rinsing. MATERIAL AND METHODS: Disk-shaped specimens (Ø15×2 mm; N=180) were fabricated by using conventional (Jet Tooth Shade), milled (Yamahachi PMMA Disk), and printed (NextDent C&B) resin materials. All resin specimens were divided into 3 different groups according to the rinsing material: distilled water, whitening mouth rinse (Listerine Healthy White), and conventional mouth rinse (Listerine Cool Mint). The specimens were further allocated into short- and long-term subgroups, and oral rinsing simulation was performed (n=10). Short-term rinsing simulated the conditions in a usual interim restoration period, and long-term rinsing was performed to evaluate the properties of the interim materials. The color differences (CIEDE2000, ΔE00) between the baseline and each time point were determined by using a spectrophotometer. The surface roughness of the tested specimens was measured by using a confocal laser scanning microscope. Kruskal-Wallis and Friedman tests with nonparametric pairwise comparisons were used to analyze the data (α=.05). RESULTS: On simulation of a 6-month use of the mouth rinse, the color change in the milled resin did not differ from that in the conventional resin (P>.334), but the printed resin showed a significantly greater color change than the other resins (P<.007). The greatest color change with the printed resin was observed when a conventional mouth rinse was used. However, all color changes were below a perceptible threshold of 1.30. When daily rinsing for 14 years was simulated, all resin groups showed a perceptible color change when conventional mouth rinse was used, and the printed resin showed the greatest median ±interquartile range ΔE00 (2.24 ±0.2). In both short- and long-term simulations, the printed resin rinsed with the conventional mouth rinse showed significantly greater roughness than that rinsed with distilled water (P<.009). CONCLUSIONS: The printed resin showed higher stainability than the conventional resin, and the color change was greatest with the conventional mouth rinse. However, in 6 months of daily mouth rinse simulation, all the tested resin materials exhibited imperceptible color change and clinically acceptable surface roughness.

Polymer Dispersed Liquid Crystal Imprinted by Microlens Array for Enhanced Outcoupling Efficiency of Organic Light Emitting Diode.

In this paper, we demonstrate the use of polymer dispersed liquid crystal (PDLC) imprinted with a microlens array (MLA) via solution process to improve the outcoupling efficiency of organic light emitting diodes (OLEDs). The PDLC, well known for its scattering effect, is an excellent technology for improving the outcoupling efficiency of OLEDs. Additionally, we introduce a simple spin-coating process to fabricate PDLC which is adaptable for future solution-processed OLEDs. The MLA-imprinted PDLC applied OLED shows an enhancement factor of 1.22 in outcoupling efficiency which is a 37.5% increase compared to the existing PDLC techniques without changing the electrical properties of the OLED. Through this approach, we can expect the roll-to-roll based extremely flexible OLED, and with further research on pattering PDLC by various templates, higher outcoupling efficiency is achievable through a simple UV irradiation process.

A new index for distinguishing hypereosinophilic syndrome and antineutrophil cytoplasmic antibody-negative eosinophilic granulomatosis with polyangiitis.

BACKGROUND: It is difficult to differentiate between hypereosinophilic syndrome (HES) and antineutrophil cytoplasmic antibody (ANCA)-negative eosinophilic granulomatosis with polyangiitis (EGPA). OBJECTIVE: We compared laboratory data at diagnosis between Korean patients with HES and ANCA-negative EGPA and investigated independent laboratory predictors suggesting HES. METHODS: We reviewed the medical records of 41 HES patients and 16 ANCA-negative EGPA patients. The cut-offs were extrapolated by the receiver operator characteristic (ROC) curve. The odds ratio (OR) and relative risk (RR) were assessed using the multivariable logistic regression analysis and the chi-square test, respectively. We developed a new equation by assigning a weight to each variable according to the slopes (B) and expressed a decimal as the nearest integer. RESULTS: HES patients had a higher median WBC and eosinophil counts than ANCA-negative EGPA patients. The cutoffs of WBC and eosinophil counts for HES were set at 9,900.0/mm3 and 2,400.0/mm3. In the multivariable analysis, WBC count ≥ 9,900.0/mm3 (B 1.763) and eosinophil count ≥ 2,400.0/mm3 (B 1.515) were significantly associated with HES. An equation was as follows: HES-suggesting laboratory index (HSLI) = 2 × (WBC count ≥ 9,900.0/mm3 (1 = No or 2 = Yes)) + 1.5 × (eosinophil count ≥ 2,400.0/mm3 (1 = No or 2 = Yes)). The cut-off of HSLI for HES was 4.25. Patients with HSLI ≥ 4.25 exhibited a significantly high RR (51.429) for HES, compared to those without. CONCLUSIONS: In conclusion, the cut-off of HSLI derived from WBC and eosinophil counts could be an independent predictor of HES in patients suspected of both HES and ANCA-negative EGPA.

Kasugamycin Is a Novel Chitinase 1 Inhibitor with Strong Antifibrotic Effects on Pulmonary Fibrosis.

Pulmonary fibrosis is a devastating lung disease with few therapeutic options. CHIT1 (chitinase 1), an 18 glycosyl hydrolase family member, contributes to the pathogenesis of pulmonary fibrosis through the regulation of TGF-ß (transforming growth factor-ß) signaling and effector function. Therefore, CHIT1 is a potential therapeutic target for pulmonary fibrosis. This study aimed to identify and characterize a druggable CHIT1 inhibitor with strong antifibrotic activity and minimal toxicity for therapeutic application to pulmonary fibrosis. Extensive screening of small molecule libraries identified the aminoglycoside antibiotic kasugamycin (KSM) as a potent CHIT1 inhibitor. Elevated concentrations of CHIT1 were detected in the lungs of patients with pulmonary fibrosis. In in vivo bleomycin- and TGF-ß-stimulated murine models of pulmonary fibrosis, KSM showed impressive antifibrotic effects in both preventive and therapeutic conditions. In vitro studies also demonstrated that KSM inhibits fibrotic macrophage activation, fibroblast proliferation, and myofibroblast transformation. Null mutation of TGFBRAP1 (TGF-ß-associated protein 1), a recently identified CHIT1 interacting signaling molecule, phenocopied antifibrotic effects of KSM in in vivo lungs and in vitro fibroblasts responses. KSM inhibits the physical association between CHIT1 and TGFBRAP1, suggesting that the antifibrotic effect of KSM is mediated through regulation of TGFBRAP1, at least in part. These studies demonstrate that KSM is a novel CHIT1 inhibitor with a strong antifibrotic effect that can be further developed as an effective and safe therapeutic drug for pulmonary fibrosis.

Upregulation of HLA class II in pancreatic beta cells from organ donors with type 1 diabetes.

AIMS/HYPOTHESIS: We aimed to characterise and quantify the expression of HLA class II (HLA-II) in human pancreatic tissue sections and to analyse its induction in human islets. METHODS: We immunostained human pancreatic tissue sections from non-diabetic (n = 5), autoantibody positive (Aab+; n = 5), and type 1 diabetic (n = 5) donors, obtained from the Network of Pancreatic Organ Donors (nPOD), with HLA-II, CD68 and insulin. Each tissue section was acquired with a widefield slide scanner and then analysed with QuPath software. In total, we analysed 7415 islets that contained 338,480 cells. Widefield microscopy was further complemented by high resolution imaging of 301 randomly selected islets, acquired using a Zeiss laser scanning confocal (LSM880) to confirm our findings. Selected beta cells were acquired in enhanced resolution using LSM880 with an Airyscan detector. Further, we cultured healthy isolated human islets and reaggregated human islet microtissues with varying concentrations of proinflammatory cytokines (IFN-γ, TNF-α and IL-1ß). After proinflammatory cytokine culture, islet function was measured by glucose-stimulated insulin secretion, and HLA-I and HLA-II expression was subsequently evaluated with immunostaining or RNA sequencing. RESULTS: Insulin-containing islets (ICIs) of donors with type 1 diabetes had a higher percentage of HLA-II positive area (24.31%) compared with type 1 diabetic insulin-deficient islets (IDIs, 0.67%), non-diabetic (3.80%), and Aab+ (2.31%) donors. In ICIs of type 1 diabetic donors, 45.89% of the total insulin signal co-localised with HLA-II, and 27.65% of the islet beta cells expressed both HLA-II and insulin, while in non-diabetic and Aab+ donors 0.96% and 0.59% of the islet beta cells, respectively, expressed both markers. In the beta cells of donors with type 1 diabetes, HLA-II was mostly present in the cell cytoplasm, co-localising with insulin. In the experiments with human isolated islets and reaggregated human islets, we observed changes in insulin secretion upon stimulation with proinflammatory cytokines, as well as higher expression of HLA-II and HLA-I when compared with controls cultured with media, and an upregulation of HLA-I and HLA-II RNA transcripts. CONCLUSIONS/INTERPRETATION: After a long-standing controversy, we provide definitive evidence that HLA-II can be expressed by pancreatic beta cells from patients with type 1 diabetes. Furthermore, this upregulation can be induced in vitro in healthy isolated human islets or reaggregated human islets by treatment with proinflammatory cytokines. Our findings support a role for HLA-II in type 1 diabetes pathogenesis since HLA-II expressing beta cells can potentially become a direct target of autoreactive CD4+ lymphocytes.

Novel High Current-Carrying Quasi-1D Material: Nb2 PdS6.

A quasi-one-dimensional van der Waals metallic nanowire Nb2 PdS6 is synthesized, and its electrical characteristics are analyzed. The chemical vapor transport method is applied to produce centimeter-scale Nb2 PdS6 crystals with needle-like structures and X-ray diffraction (XRD) confirms their high crystallinity. Scanning transmission electron microscopy reveals the crystal orientation and atomic arrangement of the specific region with atomic resolution. The electrical properties are examined by delaminating bulk Nb2 PdS6 crystals into a few nanometer-scale wires onto 100 nm-SiO2 /Si substrates using a mechanical exfoliation process. Ohmic behavior is confirmed at the low-field measurements regardless of their thickness variation, and 4.64 nm-thick Nb2 PdS6 shows a breakdown current density (JBD ) of 52 MA cm-2 when the high electrical field is delivered. Moreover, with further exfoliation down to a single atomic chain, the JBD of Nb2 PdS6 is predicted to have a value of 527 MA cm-2 . The breakdown of Nb2 PdS6 proceeds due to the Joule heating mechanism, and the Nb2 PdS6 nanowires are well fitted to the 1D thermal dissipating model.

Non-contact long-range magnetic stimulation of mechanosensitive ion channels in freely moving animals.

Among physical stimulation modalities, magnetism has clear advantages, such as deep penetration and untethered interventions in biological subjects. However, some of the working principles and effectiveness of existing magnetic neurostimulation approaches have been challenged, leaving questions to be answered. Here we introduce m-Torquer, a magnetic toolkit that mimics magnetoreception in nature. It comprises a nanoscale magnetic torque actuator and a circular magnet array, which deliver piconewton-scale forces to cells over a working range of ~70 cm. With m-Torquer, stimulation of neurons expressing bona fide mechanosensitive ion channel Piezo1 enables consistent and reproducible neuromodulation in freely moving mice. With its long working distance and cellular targeting capability, m-Torquer provides versatility in its use, which can range from single cells to in vivo systems, with the potential application in large animals such as primates.