Sensors and Sensing Devices Utilizing Electrorheological Fluids and Magnetorheological Materials-A Review.

This paper comprehensively reviews sensors and sensing devices developed or/and proposed so far utilizing two smart materials: electrorheological fluids (ERFs) and magnetorheological materials (MRMs) whose rheological characteristics such as stiffness and damping can be controlled by external stimuli; an electrical voltage for ERFs and a magnetic field for MRMs, respectively. In this review article, the MRMs are classified into magnetorheological fluids (MRF), magnetorheological elastomers (MRE) and magnetorheological plastomers (MRP). To easily understand the history of sensing research using these two smart materials, the order of this review article is organized in a chronological manner of ERF sensors, MRF sensors, MRE sensors and MRP sensors. Among many sensors fabricated from each smart material, one or two sensors or sensing devices are adopted to discuss the sensing configuration, working principle and specifications such as accuracy and sensitivity. Some sensors adopted in this article include force sensors, tactile devices, strain sensors, wearable bending sensors, magnetometers, display devices and flux measurement sensors. After briefly describing what has been reviewed in a conclusion, several challenging future works, which should be undertaken for the practical applications of sensors or/and sensing devices, are discussed in terms of response time and new technologies integrating with artificial intelligence neural networks in which several parameters affecting the sensor signals can be precisely and optimally tuned. It is sure that this review article is very helpful to potential readers who are interested in creative sensors using not only the proposed smart materials but also different types of smart materials such as shape memory alloys and active polymers.

Association of midlife body-weight variability and cycles with earlier dementia onset: a nationwide cohort study.

BACKGROUND: Given the rising awareness of health-related lifestyle modifications, the impact of changes in body weight (BW) on cognitive function and dementia generates significant concern. This study aimed to investigate the association between BW changes and dementia in a middle-aged Korean population. METHODS: A retrospective, population-based longitudinal study was conducted utilizing data from the National Health Insurance Service (NHIS) database. Participants aged 40 years or older in 2011 who underwent at least five health checkups between 2002 and 2011 were followed-up for dementia until 2020. A total of 3,635,988 dementia-free Korean aged < 65 at baseline were examined. We analyzed the association between BW variability independent of the mean (VIM) with BW cycle, defined as either an upward or a downward direction of BW, and the risk of incident dementia. RESULTS: The results showed an increased risk of dementia in the highest quartile of VIM quartile (hazard ratio [HR] 1.52, 95% confidence interval [CI] 1.47-1.58) compared to the lowest quartile of VIM. Additionally, the results showed an even higher increased risk of dementia in the highest BW cycle (≥ 2 cycles of 10% BW = HR 2.00, 95% CI 1.74-1.29). Notably, the combined concept of VIM with BW cycle showed an even higher dementia risk (highest quartile of VIM with ≥ 2 cycles of 10% BW = HR 2.37, 95% CI 2.05-2.74) compared to the baseline group (lowest quartile of VIM with < 3% BW cycle). CONCLUSIONS: The present study highlights the importance of considering BW changes with BW variability along with the BW cycle to assess dementia risk in detail, providing valuable insights for preventive strategies.

Evaluation of haematological parameters in haemolytic anaemia caused by tick-borne pathogens in grazing cattle.

BACKGROUND: No tick-borne pathogens (TBPs) causing haemolytic anaemia in cattle have been reported, except Theileria orientalis and complete blood count (CBC) profile is the only haematological parameter to determine the severity of regenerative haemolytic anaemia. OBJECTIVES: To identify the causative agents of TBP-induced haemolytic anaemia and determine haematological parameters that indicate haemolytic anaemia in grazing cattle. METHODS: Eighty-two Korean indigenous cattle (Hanwoo) were divided into two groups: grazing (n = 67) and indoor (n = 15) groups. CBC and serum biochemistry were performed. PCR was conducted using whole blood-extracted DNA to investigate the prevalence of TBPs. RESULTS: TBP-induced haemolytic anaemia was observed in the grazing group. In grazing cattle, co-infection (43.3%, 29/67) was most frequently detected, followed by T. orientalis (37.6%, 25/67) and Anaplasma phagocytophilum infections (1.5%, 1/67). In indoor cattle, only co-infection (20%, 3/15) was identified. Grazing cattle exhibited regenerative haemolytic anaemia with marked monocytosis, mild neutropenia, and thrombocytopenia. According to grazing frequency, the 1st-time grazing group had more severe anaemia than the 2nd-time grazing group. Elevations in indirect bilirubin and L-lactate due to haemolytic anaemia were identified, and correlations with the respective markers were determined in co-infected grazing cattle. CONCLUSIONS: Quantitative evaluation of haematocrit, mean corpuscular volume, and reticulocytes (markers of regenerative haemolytic anaemia in cattle) was performed for the first time. Our results show that, in addition to T. orientalis, A. phagocytophilum is strongly associated with anaemia. The correlation between haemolytic anaemia severity and haematological parameters (indirect bilirubin, reticulocytes, and L-lactate) was confirmed.

Preliminary report of Mycoplasma Wenoynii and Candidatus Mycoplasma haemobos infection in Korean native cattle.

BACKGROUND: Hemotropic mycoplasmas or hemoplasmas are bacteria that attach to the erythrocyte surface and cause bovine hemoplasmosis. Two species, Mycoplasma wenyonii and Candidatus Mycoplasma haemobos, have been identified and shown to be distributed worldwide. However, there is currently no information available on hemoplasmas in cattle in the Republic of Korea. The aim of this study was to investigate the presence of hemoplasmas in Korean native cattle and to evaluate the association between hemoplasma infection and anemia. METHODS: One farm was selected, at which blood samples were collected from 104 Korean native cattle [grazing cattle (n = 89) and housed cattle (n = 15)]. Hemoplasmas were detected via polymerase chain reaction analysis and complete blood counts were also performed. RESULTS: The overall prevalence of hemoplasmas was 34% (35/104); 20.2% (21/104) for M. wenyonii, 3.8% (4/104) for C. M. haemobos, and 9.6% (10/104) for co-infection. Candidatus Mycoplasma haemobos was detected only in grazing cattle. Of red blood cell (RBC) parameters, C. M. haemobos-infected cattle had lower RBC and hematocrit, and higher mean cell volume than hemoplasma-negative cattle, although none of these differences were statistically significant. This is the first study to report the occurrence of M. wenyonii and C. M. haemobos. Mycoplasma wenyonii is more prevalent than C. M. haemobos in Korean native cattle. The results did not show an association between hemoplasma infection and anemia. CONCLUSIONS: Considering the infection rate of hemoplasmas shown in this study, further studies, such as on the pathogenicity and clinical significance of hemoplasmas are necessary.

Revealing the Loss Mechanism of Chemically-Induced Hot Electron Transport.

Hot electrons are crucial for unraveling the intrinsic relationship between chemical reactions and charge transfer in heterogeneous catalysis. Significant research focused on real-time detection of reaction-driven hot electron flow (chemicurrent) to elucidate the energy conversion mechanisms, but it remains elusive because carrier generation contributes to only part of the entire process. Here, a theoretical model for quantifying the chemicurrent yield is presented by clarifying the contributions of hot carrier losses from the internal emission and multiple reflections. The experimental chemicurrent yield verifies our model with a reliable mean free path of hot electrons, emphasizing the importance of comprehensive consideration of the transport process besides hot electron generation. Moreover, Pt nanoparticles (NPs)-decorated Au/TiO2 is examined, showing the role of NPs-induced carrier losses in the performance of catalytic nanodiodes. These findings are expected to contribute to understanding the hot electron detection efficiency and designing nanodiodes with enhanced hot carrier flow and catalytic activity.

Scoping review protocol of post-traumatic growth (PTG) in Korean cancer survivors.

INTRODUCTION: Cancer, a life-threatening chronic disease, is the leading cause of death in Korea, accounting for 27% of all deaths in 2020. Due to advancements in medical technology and early detection of cancer in Korea, the 5-year relative survival rate reached 70.7% (2015-2019), highlighting remarkable progress over the past decades. Although cancer has been seen as a traumatic event, cancer survivors also go through a subjective process of self-maturation, which is called post-traumatic growth (PTG). Because research on PTG among Korean cancer survivors has not been systematically synthesised, a scoping review on this topic will provide a better understanding of the positive psychological changes that occur as a patient moves through the illness trajectory of cancer from a Korean cultural perspective. The purpose of this study was to describe the protocol of a scoping review regarding PTG in Korean cancer survivors. METHODS AND ANALYSIS: The scoping review framework suggested by Arksey and O'Malley and the manual refined by the Joanna Briggs Institute for scoping reviews will be used with the six framework guidelines developed by Levac et al. Searched databases will include Ovid-MEDLINE, PubMed, Embase, CINAHL, Cochrane Library and PsycInfo, as well as Korean databases, examining all articles published between 2012 and 2023 in Korean or English on PTG in Korean cancer survivors. Extracted data will be collated, charted and summarised. ETHICS AND DISSEMINATION: Because the scoping review methodology undertakes a secondary analysis of collected data from previous research studies, this study does not require ethical approval. The results of this scoping review will be disseminated through presentations at conferences and publication in a scientific journal.

In vitro and in vivo anti-pigmentation effects of 2-mercaptobenzimidazoles as nanomolar tyrosinase inhibitors on mammalian cells and zebrafish embryos: Preparation of pigment-free zebrafish embryos.

Recently, 10 2-mercaptobenzo[d]imidazole (2-MBI) compounds (1-10) were synthesized. Although all 2-MBI compounds are tyrosinase inhibitors that inhibit mushroom tyrosinase at extremely low concentrations (IC50 values: 20-740 nM) and effectively inhibit the browning of apples, to our knowledge, no studies have determined whether 2-MBI compounds inhibit mammalian tyrosinase. Mammalian tyrosinase is different from mushroom tyrosinase in its distribution within the cell and has structural characteristics that are different from mushroom tyrosinase in amino acid sequence and in the presence of a quaternary structure. Thus, the effect of the 10 2-MBI compounds on mammalian tyrosinase activity was investigated in B16F10 cells. Six compounds (1-6) exhibited stronger intracellular tyrosinase inhibition than that of kojic acid and phenylthiourea (PTU), which are known to be the most potent tyrosinase inhibitors; their strong tyrosinase inhibitory activity robustly inhibited intracellular melanin production in B16F10 cells. None of the tested 2-MBI compounds exhibited appreciable cytotoxicity in HaCaT and B16F10 cells. To confirm the anti-melanogenic efficacy of the 2-MBI compounds in vivo, a zebrafish embryo model was used. At concentrations 100 times lower than kojic acid, most 2-MBI compounds demonstrated much stronger depigmentation efficacy than that of kojic acid, and three 2-MBI compounds (2-4) showed depigmentation activity similar to or more potent than that of PTU, resulting in nearly pigment-free zebrafish embryos. These results suggest that 2-MBI compounds may be potential therapeutic agents for hyperpigmentation-related disorders.

Thiazol-4(5H)-one analogs as potent tyrosinase inhibitors: Synthesis, tyrosinase inhibition, antimelanogenic effect, antioxidant activity, and in silico docking simulation.

As the ß-phenyl-α,ß-unsaturated carbonyl (PUSC) structure was previously identified to play a key role in tyrosinase inhibition, 14 analogs with a PUSC structure built on a thiazol-4(5H)-one scaffold were synthesized using Knoevenagel condensation to serve as potential tyrosinase inhibitors. Through mushroom tyrosinase inhibition experiments, two analogs 9 and 11 were identified as potent tyrosinase inhibitors, with 11 exhibiting an IC50 value of 0.4 ± 0.01 µM, which indicates its 26-fold greater potency than kojic acid. Kinetic studies using Lineweaver-Burk plots revealed that 9 and 11 are competitive and mixed-type inhibitors, respectively; these kinetic results were supported by docking simulations. According to the B16F10 cell-based experiments, 9 and 11 inhibited melanogenesis more effectively than kojic acid due to their potent cellular tyrosinase inhibitory activity. In addition, analogs 9 and 11 exhibited moderate-to-strong antioxidant capacity, scavenging ABTS+, DPPH, and ROS radicals. In particular, analog 12 with a catechol moiety exhibited very strong ROS-scavenging activity, similar to Trolox. These results suggest that analogs 9 and 11, which exhibit potent tyrosinase inhibitory activity in mushroom and mammalian cells and anti-melanogenic effects in B16F10 cells, are promising antibrowning agents for crops and skin lightening agents for hyperpigmentation-related diseases.

The Multidomain Metaverse Cancer Care Digital Platform: Development and Usability Study.

BACKGROUND: As cancer treatment methods have diversified and the importance of self-management, which lowers the dependence rate on direct hospital visits, has increased, effective cancer care education and management for health professionals and patients have become necessary. The metaverse is in the spotlight as a means of digital health that allows users to engage in cancer care education and management beyond physical constraints. However, it is difficult to find a multipurpose medical metaverse that can not only be used in the field but also complements current cancer care. OBJECTIVE: This study aimed to develop an integrated metaverse cancer care platform, Dr. Meta, and examine its usability. METHODS: We conducted a multicenter, cross-sectional survey between November and December 2021. A descriptive analysis was performed to examine users' experiences with Dr. Meta. In addition, a supplementary open-ended question was used to ask users for their suggestions and improvements regarding the platform. RESULTS: Responses from 70 Korean participants (male: n=19, 27% and female: n=51, 73%) were analyzed. More than half (n=37, 54%) of the participants were satisfied with Dr. Meta; they responded that it was an interesting and immersive platform (n=50, 72%). Less than half perceived no discomfort when using Dr. Meta (n=34, 49%) and no difficulty in wearing and operating the device (n=30, 43%). Furthermore, more than half (n=50, 72%) of the participants reported that Dr. Meta would help provide non-face-to-face and noncontact services. More than half also wanted to continue using this platform in the future (n=41, 59%) and recommended it to others (n=42, 60%). CONCLUSIONS: We developed a multidomain metaverse cancer care platform that can support both health professionals and patients in non-face-to-face cancer care. The platform was uniquely disseminated and implemented in multiple regional hospitals and showed the potential to perform successful cancer care.

A Novel Tactile Sensing System Utilizing Magnetorheological Structures for Dynamic Contraction and Relaxation Motions.

It is well known that the rheological properties of magnetorheological (MR) material change under a magnetic field. So far, most works on MR materials have been oriented toward actuating characteristics instead of sensing functions. In this work, to realize dynamic tactile motion, a spherical MR structure was designed as a sensor, incorporating a magnetic circuit core to provide maximum dynamic motion. After manufacturing a prototype (sample), a sinusoidal magnetic field of varying exciting frequency and magnitude was applied to the sample, and the dynamic contraction and relaxation motion depending on the exciting magnetic field was observed. Among the test results, when 10% deformation occurred, the instantaneous force generated was from 2.8 N to 8.8 N, and the force when relaxed was from 1.2 N to 3.5 N. It is also shown that the repulsive force within this range can be implemented using an acceptable input current. The special tactile sensing structure proposed in this work can be used as a sensor to measure the field-dependent viscoelastic properties of human tissues such as stomach, liver, and overall body. In addition, it could be usefully applied to robot surgery, because it can mimic the dynamic motions of various human organs under various surgical conditions.

Device updates in pediatric and neonatal ECMO.

Since the early use of extracorporeal life support (ECLS), new innovations and technological advancements have augmented the ability to use this technology in children and neonates. Cannulae have been re-designed to maintain structure and allow for single cannula venovenous (VV) ECLS in smaller patients. Circuit technology, including pumps and tubing, has evolved to permit smaller priming volumes and lower flow rates with fewer thrombotic or hemolytic complications. New oxygenator developments also improve efficiency of gas exchange. This paper serves as an overview of recent device developments in ECLS delivery to pediatric and neonatal patients.

Design of High-Performance Organic Nonlinear Optical and Terahertz Crystals by Controlling the van der Waals Volume.

In the development of new organic crystals for nonlinear optical and terahertz (THz) applications, it is very challenging to achieve the essentially required non-centrosymmetric molecular arrangement. Moreover, the resulting crystal structure is mostly unpredictable due to highly dipolar molecular components with complex functional substituents. In this work, new organic salt crystals with top-level macroscopic optical nonlinearity by controlling the van der Waals volume (VvdW ), rather than by trial and error, are logically designed. When the VvdW of molecular ionic components varies, the corresponding crystal symmetry shows an observable trend: change from centrosymmetric to non-centrosymmetric and back to centrosymmetric. All non-centrosymmetric crystals exhibit an isomorphic P1 crystal structure with an excellent macroscopic second-order nonlinear optical response. Apart from the top-level macroscopic optical nonlinearity, new organic crystals introducing highly electronegative fluorinated substituents with strong secondary bonding ability show excellent performance in efficient and broadband THz wave generation, high crystal density, high thermal stability, and good bulk crystal growth ability.

Anti-Browning Effect of 2-Mercaptobenzo[d]imidazole Analogs with Antioxidant Activity on Freshly-Cut Apple Slices and Their Highly Potent Tyrosinase Inhibitory Activity.

Ten 2-mercaptobenzimidazole (2-MBI) analogs were synthesized as potential tyrosinase inhibitors because mercapto-containing compounds can bind to copper ions at the active site of tyrosinase to inhibit enzyme activity. Nine 2-MBI analogs showed sub-micromolar IC50 values for mushroom tyrosinase monophenolase activity; analog 4 was 280-fold more potent than kojic acid, and in diphenolase activity, 6 was 970-fold more potent than kojic acid. The inhibition mode of the 2-MBI analogs was investigated using kinetic studies supported by docking simulations. Benzimidazoles without the 2-mercapto substituent of the 2-MBI analogs lost their tyrosinase inhibitory activity, implying that the 2-mercapto substituent plays an important role in tyrosinase inhibition. The 2-MBI analogs exerted potent antioxidant effects against 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid (ABTS), 2,2-diphenyl-1-picrylhydrazyl (DPPH), and reactive oxygen species (ROS). The results obtained from apple slices and human embryonic kidney cells (HEK-293) suggest that most 2-MBI analogs are sufficiently safe candidates to delay the browning of apple slices effectively. Thus, these results support the potential use of 2-MBI analogs as anti-browning agents in foods such as mushrooms, vegetables, and fruits.

Identification and molecular mechanism of novel 5-alkenyl-2-benzylaminothiazol-4(5H)-one analogs as anti-melanogenic and antioxidant agents.

Mushroom tyrosinase is a tetramer, whereas mammalian tyrosinase is a monomeric glycoprotein. In addition, the amino acid sequence of mushroom tyrosinases differs from that of mammalian tyrosinases. MHY2081 exhibits potent inhibitory activity against both mushroom and mammalian tyrosinases. Accordingly, based on the MHY2081 structure, 5-alkenyl-2-benzylaminothiazol-4(5H)-one analogs were designed as a novel anti-tyrosinase agent and synthesized using 2-((3,4-dimethoxybenzyl)amino)thiazol-4(5H)-one (16), a key intermediate obtained via the rearrangement of a benzylamino group. Compounds 6 and 9 (IC50 = 1.5-4.6 µM) exhibited higher mushroom tyrosinase inhibitory activity than kojic acid (IC50 = 20-21 µM) in the presence of l-tyrosine and/or l-dopa. Based on kinetic analysis using Lineweaver-Burk plots, 6 was a mixed inhibitor, whereas 9 was a competitive inhibitor, and docking simulation results supported that these compounds could bind to the active site of mushroom tyrosinase. Using B16F10 mammalian cells, we demonstrated that these compounds inhibited melanogenesis more potently than kojic acid, and their anti-melanogenic effects could be attributed to tyrosinase inhibition. All synthesized compounds could scavenge reactive oxygen species (ROS), with five compounds exhibiting mild-to-strong ABTS+ and DPPH radical-scavenging abilities. Compounds 6 and 9 were potent tyrosinase inhibitors with strong antioxidant activities against ROS, ABTS+, and DPPH radicals. Moreover, the compounds significantly suppressed tyrosinase expression in a dose-dependent manner. Collectively, these results suggest that the novel 5-alkenyl-2-benzylaminothiazol-4(5H)-one analogs, especially 6 and 9, are potential anti-melanogenic agents with antioxidant activity.

Co-expression of HLA-E and HLA-G on genetically modified porcine endothelial cells attenuates human NK cell-mediated degranulation.

Natural killer (NK) cells play an important role in immune rejection in solid organ transplantation. To mitigate human NK cell activation in xenotransplantation, introducing inhibitory ligands on xenografts via genetic engineering of pigs may protect the graft from human NK cell-mediated cytotoxicity and ultimately improve xenograft survival. In this study, non-classical HLA class I molecules HLA-E and HLA-G were introduced in an immortalized porcine liver endothelial cell line with disruption of five genes (GGTA1, CMAH, ß4galNT2, SLA-I α chain, and ß-2 microglobulin) encoding three major carbohydrate xenoantigens (αGal, Neu5Gc, and Sda) and swine leukocyte antigen class I (SLA-I) molecules. Expression of HLA-E and/or HLA-G on pig cells were confirmed by flow cytometry. Endogenous HLA-G molecules as well as exogenous HLA-G VL9 peptide could dramatically enhance HLA-E expression on transfected pig cells. We found that co-expression of HLA-E and HLA-G on porcine cells led to a significant reduction in human NK cell activation compared to the cells expressing HLA-E or HLA-G alone and the parental cell line. NK cell activation was assessed by analysis of CD107a expression in CD3-CD56+ population gated from human peripheral blood mononuclear cells. CD107a is a sensitive marker of NK cell activation and correlates with NK cell degranulation and cytotoxicity. HLA-E and/or HLA-G on pig cells did not show reactivity to human sera IgG and IgM antibodies. This in vitro study demonstrated that co-expression of HLA-E and HLA-G on genetically modified porcine endothelial cells provided a superior inhibition in human xenoreactive NK cells, which may guide further genetic engineering of pigs to prevent human NK cell mediated rejection.

A Discrete-Finite Element Analysis Model Based on Almen Intensity Test for Evaluation of Real Shot Peening Residual Stress.

In this study, a combined discrete-finite element model based on the Almen intensity measurement test was proposed to evaluate the real shot peening residual stress. The discrete element analysis was utilized to simulate the random behavior of numerous shot balls, while the finite element analysis was employed to quantitatively predict the residual stress induced by shot peening. Moreover, the Almen intensity, an essential factor in the actual shot peening process, was taken into account. Initially, an Almen strip analysis model was established, and the multi-random impact analysis was performed to validate the good agreement between the analytical Almen curve and experimental Almen curve. Subsequently, the unit cell discrete-finite element analysis model was expanded for predicting the peening residual stress, incorporating the Almen intensity. The analysis results showed a significant correlation between the predicted peening residual stress and the XRD (X-ray diffraction) experimental residual stress. Therefore, it was confirmed that the proposed discrete-finite element random impact analysis model in this study could serve as an effective analytical technique capable of substituting for the actual shot peening process.

Oil-gated isoporous membrane with micro-apertures for controllable pressure-induced passive flow regulator.

The pressure-driven liquid flow controller is one of the key components in diverse applications including microfluidic systems, biomedical drug injection devices, and pressurized water supply systems. Electric feedback loop based flow controllers are fine-tunable but expensive and complex. The conventional safety valves based on spring force are simple and low cost, but their diverse application is limited due to their fixed pressure range, size, and shape. Herein, we propose a simple and controllable liquid-flowing system combining a closed liquid reservoir and an oil-gated isoporous membrane (OGIM). The ultra-thin and flexible OGIM acts as an immediately responsive and precisely controlled gas valve to maintain internal pneumatic pressure as designed to induce constant liquid flow. The oil filling apertures act as a gate for gas flow depending on the applied pressure and the threshold (gating) pressure of the gate is determined by the surface tension of the oil and the gate diameter. It is confirmed that the gating pressure is precisely controlled by varying the gate diameter, which agrees with the theoretically estimated pressures. Based on stably maintained pressure due to the function of OGIM, the constant liquid flow rate is achieved even with the high gas flow rate.

Development of Scaffold-Free Three-Dimensional Cholangiocyte Organoids to Study the Progression of Primary Sclerosing Cholangitis.

Organoids are novel in vitro models to study intercellular cross talk between the different types of cells in disease pathophysiology. To better understand the underlying mechanisms driving the progression of primary sclerosing cholangitis (PSC), scaffold-free multicellular three-dimensional cholangiocyte organoids (3D-CHOs) were developed using primary liver cells derived from normal subjects and patients with PSC. Human liver samples from healthy donors and patients with PSC were used to isolate primary cholangiocytes [epithelial cell adhesion molecule (EpCam)+/ cytokeratin-19+], liver endothelial cells (CD31+), and hepatic stellate cells (HSCs; CD31-/CD68-/desmin+/vitamin A+). 3D-CHOs were formed using cholangiocytes, HSCs, and liver endothelial cells, and kept viable for up to 1 month. Isolated primary cell lines and 3D-CHOs were further characterized by immunofluorescence, quantitative RT-PCR, and transmission electron microscopy. Transcription profiles for cholangiocytes (SOX9, CFTR, EpCAM, AE, SCT, and SCTR), fibrosis (ACTA2, COL1A1, DESMIN, and TGFß1), angiogenesis (PECAM, VEGF, CDH5, and vWF), and inflammation (IL-6 and TNF-α) confirmed PSC phenotypes of 3D-CHOs. Because cholangiocytes develop a neuroendocrine phenotype and express neuromodulators, confocal immunofluorescence was used to demonstrate localization of the neurokinin-1 receptor within cytokeratin-19+ cholangiocytes and desmin+ HSCs. Moreover, 3D-CHOs from patients with PSC confirmed PSC phenotypes with up-regulated neurokinin-1 receptor, tachykinin precursor 1, and down-regulated membrane metalloendopeptidase. Scaffold-free multicellular 3D-CHOs showed superiority as an in vitro model in mimicking PSC in vivo phenotypes compared with two-dimensional cell culture, which can be used in PSC disease-related research.

Higgsino Dark Matter Confronts 14 Years of Fermi γ-Ray Data.

Thermal Higgsino dark matter (DM), with mass around 1 TeV, is a well-motivated, minimal DM scenario that arises in supersymmetric extensions of the standard model. Higgsinos may naturally be the lightest superpartners in split-supersymmetry models that decouple the scalar superpartners while keeping Higgsinos and gauginos close to the TeV scale. Higgsino DM may annihilate today to give continuum γ-ray emission at energies less than a TeV in addition to a linelike signature at energies equal to the mass. Previous searches for Higgsino DM, for example with the H.E.S.S. γ-ray telescope, have not reached the necessary sensitivity to probe the Higgsino annihilation cross section. In this work we make use of 14 years of data from the Fermi Large Area Telescope at energies above ∼10 GeV to search for the continuum emission near the Galactic Center from Higgsino annihilation. We interpret our results using DM profiles from Milky Way analog galaxies in the FIRE-2 hydrodynamic cosmological simulations. We set the strongest constraints to date on Higgsino-like DM. Our results show a mild, ∼2σ preference for Higgsino DM with a mass near the thermal Higgsino mass and, depending on the DM density profile, the expected cross section.

CRISPR Interference-Based Inhibition of MAB_0055c Expression Alters Drug Sensitivity in Mycobacterium abscessus.

There is an unmet medical need for effective treatments against Mycobacterium abscessus infections. Although advanced molecular genetic tools to validate drug targets and resistance of M. abscessus exist, the practical design and construction of plasmids are relatively laborious and time-consuming. Thus, for this purpose, we used CRISPR interference (CRISPRi) combined with catalytically deactivated Cas9 to inhibit the gene expression of a predicted LysR-type transcriptional regulator gene, MAB_0055c, in M. abscessus and evaluated its contribution to the development of drug resistance. Our results showed that silencing the MAB_0055c gene lead to increased rifamycin susceptibility depending on the hydroquinone moiety. These results demonstrate that CRISPRi is an excellent approach for studying drug resistance in M. abscessus. IMPORTANCE In this study, we utilized CRISPR interference (CRISPRi) to specifically target the MAB_0055c gene in M. abscessus, a bacterium that causes difficult-to-treat infections. The study found that silencing the gene lead to increased rifabutin and rifalazil susceptibility. This study is the first to establish a link between the predicted LysR-type transcriptional regulator gene and antibiotic resistance in mycobacteria. These findings underscore the potential of using CRISPRi as a tool for elucidating resistance mechanisms, essential drug targets, and drug mechanisms of action, which could pave the way for more effective treatments for M. abscessus infections. The results of this study could have important implications for the development of new therapeutic options for this challenging-to-treat bacterial infection.