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ObjectivePancreatic ductal adenocarcinoma (PDAC) displays a remarkable propensity towards therapy resistance. However, molecular epigenetic and transcriptional mechanisms enabling this are poorly understood. In this study, we aimed to identify novel mechanistic approaches to overcome or prevent resistance in PDAC.DesignWe used in vitro and in vivo models of resistant PDAC and integrated epigenomic, transcriptomic, nascent RNA and chromatin topology data. We identified a JunD-driven subgroup of enhancers, called interactive hubs (iHUBs), which mediate transcriptional reprogramming and chemoresistance in PDAC.ResultsiHUBs display characteristics typical for active enhancers (H3K27ac enrichment) in both therapy sensitive and resistant states but exhibit increased interactions and production of enhancer RNA (eRNA) in the resistant state. Notably, deletion of individual iHUBs was sufficient to decrease transcription of target genes and sensitise resistant cells to chemotherapy. Overlapping motif analysis and transcriptional profiling identified the activator protein 1 (AP1) transcription factor JunD as a master transcription factor of these enhancers. JunD depletion decreased iHUB interaction frequency and transcription of target genes. Moreover, targeting either eRNA production or signaling pathways upstream of iHUB activation using clinically tested small molecule inhibitors decreased eRNA production and interaction frequency, and restored chemotherapy responsiveness in vitro and in vivo. Representative iHUB target genes were found to be more expressed in patients with poor response to chemotherapy compared with responsive patients.ConclusionOur findings identify an important role for a subgroup of highly connected enhancers (iHUBs) in regulating chemotherapy response and demonstrate targetability in sensitisation to chemotherapy.

Data on the prevalence and associated risk factors of naturally occurring haemoplasmosis in owned cats in Malaysia is limited. Being the most pathogenic of the three known feline haemoplasma species, Mycoplasma haemofelis (Mhf) infection was analysed from 2016 to 2019 to determine the periodical prevalence and associated risk factors in Northeastern Malaysia - Kelantan. Archived patient data of 77 clinically ill cats suspected of having M. haemofelis infection were reviewed in this study. Out of the 77 suspected cases, 53 (68.8%) were clinically diagnosed with haemoplasmosis amongst which 46 (59.7%) of the subpopulation were further confirmed with polymerase chain reaction (PCR). Risk factors for M. haemofelis infection (age, breed, ectoparasitism, household condition, roaming status, and sex) were analysed. There was no significant association of breed, ectoparasitism, household condition (number of cats) and occurrence of clinical signs with feline mycoplasmosis. Young, male and roamer cats were more likely to be diagnosed of mycoplasmosis than other categories of cats in this study. There was also a significant association between cats infected with 'Candidatus Mycoplasma haemominutum' with M. haemofelis. Thus, the coinfection of these two haemoplasma species is not uncommon. This study indicates that infection by M. haemofelis in anaemic cats is a common find in client-owned cats from Northeastern Malaysia. As the natural mode of transmission of haemoplasma infection remain unestablished, information in this study may highlight the importance of this disease and contribute to effective prevention and control strategies to minimize feline infectious anaemia (FIA) caused by M. haemofelis.

A thermoelectric generator (TEG) cell is a solid-state semi-conductor capable of converting thermal energy directly into electrical energy. Studies on specific designs for TEG modules are needed for an effective industrial waste heat recovery. Typical TEG systems apply direct heating or cooling without being assisted by heat transfer devices which makes it difficult to maintain high temperature difference between TEG cells surfaces for higher electrical power generation. To suit the TEG system with the industrial condition, a waste heat recovery (WHR) module was developed consisting of a Bismuth Telluride TEG cell and another module consisting of two TEG cells in a stacked configuration. The TEG cells were sandwiched between two copper blocks and connected to two plate-finned heat sinks and eight heat pipes. The two modules were tested on a dedicated test bench to study its performance based on an industrial WHR setup. The hot stream waste heat temperature was constant at 80 ℃ while the cooling air streams were set based on ambient conditions between 22 ℃ to 30 °C. The maximum power performance (MPP) varied from 10 mW to 153 mW where the effect of cooling is very significant on the power outputs. Under forced cooling condition, the MPP generated from the double stacking TEG configuration is significantly higher compared to single cell configuration, by approximately 250%.

The Einstein functions in generalized Puiseux and Taylor series are used as forcing functions in Airy’s inhomogeneous equation, and particular and general solutions are obtained. Comparison are made with solutions obtained using the Nield-Kuznetsov functions’ approach. For each of the Einstein’s functions, the standard Nield-Kuznetsov function of the second kind is expressed in terms of Bessel functions. Computations and graphs in this work were produced using Wolfram Alpha.

Higher derivatives and associated polynomials of the standard Nield-Kuznetsov function of the second kind are investigated in this work. Two approaches are introduced in this work. The first, is the direct method of differentiation and generalization of the nth derivative. This approach is dependent on higher derivatives of the Nield-Kuznetsov function of the first kind. The second is the transform method in which integral transforms associated with the Nield-Kuznetsov function of the second kind are introduce first, and higher derivatives are then obtained. The transform method is independent of the direct higher derivatives of the Nield-Kuznetsov function of the first kind. Both approaches are important in practical and theoretical mathematical analysis, and both give rise to associated Airy polynomials, discussed in this work.

Taylor and Maclaurin series, and polynomial approximations of the Standard Nield-Kuznetsov function of the second kind are obtained in this work. Convergence and error criteria are developed. The obtained series represent alternatives to existing asymptotic and ascending series approximations of this integral function, and are expected to provide an efficient method of computation.

In this work, particular and general solutions to Airy’s inhomogeneous equation are obtained when the forcing function is one of Airy’s functions of the first and second kind, and the standard Nield-Kuznetsov function of the first kind. Particular solutions give rise to special integrals that involve products of Airy’s and Nield-Kuznetsov functions. Evaluation of the resulting integrals is facilitated by expressing their integrands in asymptotic series. Corresponding expressions for the Nield-Kuznetsov function of the second kind are obtained.

In this work, the problem of obtaining particular and general solutions to Airy’s inhomogeneous equation when the forcing function is one of Einstein’s functions is examined. Expressions for the particular solutions provide connections between the Nield-Kuznetsov and Einstein functions. Computations have been carried out using Wolfram Alpha.

Analysis and solution of Airy’s inhomogeneous equation, when its forcing function is the sigmoid neural network activation function, are provided in this work. Relationship between the Nield-Kuznetsov, the Scorer, the sigmoid, the polylogarithm and Airy’s functions are established. Solutions to initial and boundary value problems, when the sigmoid function is involved, are obtained. Computations were carried out using Wolfram Alpha.

Taylor and Maclaurin series and polynomial approximations of the Standard Nield-Kuznetsov function of the first kind are obtained in this work. Convergence and error criteria are developed. The obtained series represent alternatives to the existing asymptotic and ascending series approximations of this integral function, and are expected to provide an efficient method of computation that is valid for all values of the argument.

A fifth-order accurate finite difference scheme for the first derivative in von Mises coordinates is developed in this work. The scheme is tested in the computation of boundary vorticity in the study of two-dimensional flow of a viscous fluid in a curvilinear channel. Results obtained show an improvement in the computed solution over fourth-order accurate scheme

BACKGROUND AND AIMS: Biliary disease is associated with a proliferative/fibrogenic ductular reaction (DR). p300 is an epigenetic regulator that acetylates lysine 27 on histone 3 (H3K27ac) and is activated during fibrosis. Long non-coding RNAs (lncRNAs) are aberrantly expressed in cholangiopathies, but little is known about how they recruit epigenetic complexes and regulate DR. We investigated epigenetic complexes, including transcription factors (TFs) and lncRNAs, contributing to p300-mediated transcription during fibrosis. METHODS: We evaluated p300 in vivo using tamoxifen-inducible, cholangiocyte-selective, p300 knockout (KO) coupled with bile duct ligation (BDL) and Mdr KO mice treated with SGC-CBP30. Primary cholangiocytes and liver tissue were analyzed for expression of Acta2-as1 lncRNA by qPCR and RNA ISH. In vitro, we performed RNA-sequencing in human cholangiocytes with a p300 inhibitor. Cholangiocytes were exposed to lipopolysaccharide (LPS) as an injury model. We confirmed formation of a p300/ELK1 complex by immunoprecipitation (IP). RNA IP examined interactions between ACTA2-AS1 and p300. Chromatin IP assays evaluated p300/ELK1 occupancy and p300-mediated H3K27ac. Organoids were generated from ACTA2-AS1-depleted cholangiocytes. RESULTS: BDL-induced DR and fibrosis were reduced in Krt19-Cre(ERT)/p300(fl/fl) mice. Similarly, Mdr KO mice were protected from DR and fibrosis after SGC-CBP30 treatment. In vitro, depletion of ACTA2-AS1 reduced expression of proliferative/fibrogenic markers, reduced LPS-induced cholangiocyte proliferation, and impaired organoid formation. ACTA2-AS1 regulated transcription by facilitating p300/ELK1 binding to the PDGFB promoter after LPS. Correspondingly, LPS-induced H3K27ac was mediated by p300/ELK1 and was reduced in ACTA2-AS1-depleted cholangiocytes. CONCLUSION: Cholangiocyte-selective p300 KO or p300 inhibition attenuate DR/fibrosis in mice. ACTA2-AS1 influences recruitment of p300/ELK1 to specific promoters to drive H3K27ac and epigenetic activation of proliferative/fibrogenic genes. This suggests that cooperation between epigenetic co-activators and lncRNAs facilitates DR/fibrosis in biliary diseases.

A collection of popular variable permeability functions is presented and discussed in this work. The functions have been used largely in Brinkman’s equation which governs the flow through a porous domain in the presence of solid, macroscopic boundaries on which the no-slip condition is imposed, and has been used in transition layer modelling. A convenient classification of permeability functions is also provided. The sigmoid logistic function is presented in this work in a modified form that is suitable for variable permeability modelling, and is used in obtaining solution to Poiseuille flow through a Brinkman porous channel.

Flow of a fluid with pressure-dependent viscosity through a composite of two porous layers is considered in this work in an attempt to validate velocity and shear stress continuity conditions at the interface, and are popular in the study of flow over porous layers and through composite layers when viscosity of the fluid is constant. For the current problem, conditions at the interface between the porous layers reflect continuity assumptions of velocity and shear stress, with additional continuity assumptions on pressure and viscosity. Viscosity is assumed to vary continuously and exponentially across the layers as a function of pressure. Analytical solutions are obtained to illustrate the effects of flow and media parameters (Darcy numbers, layer thicknesses, angle of inclination, and viscosity adjustment parameter) on the dynamic behaviour of pressure-dependent viscosity fluids in porous structures. All computations, simulations and graphs in this work have been carried out and obtained using Maple 2020 software package.

Pancreatic ductal adenocarcinoma (PDAC) displays a dismal prognosis due to late diagnosis and high chemoresistance incidence. For advanced disease stages or patients with comorbidities, treatment options are limited to gemcitabine alone or in combination with other drugs. While gemcitabine resistance has been widely attributed to the levels of one of its targets, RRM1, the molecular consequences of gemcitabine resistance in PDAC remain largely elusive. Here we sought to identify genomic, epigenomic, and transcriptomic events associated with gemcitabine resistance in PDAC and their potential clinical relevance. We found that gemcitabine-resistant cells displayed a coamplification of the adjacent RRM1 and STIM1 genes. Interestingly, RRM1, but not STIM1, was required for gemcitabine resistance, while high STIM1 levels caused an increase in cytosolic calcium concentration. Higher STIM1-dependent calcium influx led to an impaired endoplasmic reticulum stress response and a heightened nuclear factor of activated T-cell activity. Importantly, these findings were confirmed in patient and patient-derived xenograft samples. Taken together, our study uncovers previously unknown biologically relevant molecular properties of gemcitabine-resistant tumors, revealing an undescribed function of STIM1 as a rheostat directing the effects of calcium signaling and controlling epigenetic cell fate determination. It further reveals the potential benefit of targeting STIM1-controlled calcium signaling and its downstream effectors in PDAC.Significance:Gemcitabine-resistant and some naïve tumors coamplify RRM1 and STIM1, which elicit gemcitabine resistance and induce a calcium signaling shift, promoting ER stress resistance and activation of NFAT signaling.

Supplementary Tables S4 to S8

Supplementary Figures S1-S10

Supplementary Materials & Methods, Supplementary Tables S1-S3.

Some of Vibrio species is well known as pathogenic bacteria in aquaculture and the marine industry. Its infection is able to generate a massive outbreak and affect the fish population, especially for net caged fish such as seabass. This study was conducted to investigate the prevalence of Vibrio spp. isolated from seabass (Lates calcarifer) in Sri Tujuh Lagoon, Tumpat, Kelantan. Then, to determine the antibiotic resistance in Vibrio isolates. Polymerase chain reaction (PCR) was used to detect Vibrio species using specific primer VR169 and VR744 with estimation base pair size band, 597 bp and further identified by sequencing. On the other hand, antibiotic susceptibility tests were continued by using 13 types of antibiotics; kanamycin (K30), chloramphenicol (C30), neomycin (N10), ampicillin (AMP10), nitrofurantoin (F300), tetracycline (TE30), streptomycin (S10), norfloxacin (NOR10), ciprofloxacin (CIP5), nalidixic acid (NA30), gentamicin (CN10), doxycycline (DO30) and sulfamethoxazole (SXT100). As a result, 14 Vibrio isolates were identified, including Vibrio fluvialis (n=6), Vibrio parahaemolyticus (n=3), Vibrio harveyi (n=2) and each isolate for Vibrio vulnificus, Vibrio alginolyticus and Vibrio spp. The results showed that all isolates were sensitive to most antibiotics except ampicillin, neomycin and streptomycin. The MAR index value was ranging from 0 to 0.31. This study demonstrates the prevalence of Vibrio spp. in seabass and the report on multidrug resistance strains that could be of concern to the fish farmers. In addition, data from this study can be further used in fish disease management plans.

BACKGROUND & AIMS: Loss of AT-rich interactive domain-containing protein 1A (ARID1A) fosters acinar-to-ductal metaplasia (ADM) and pancreatic carcinogenesis by down-regulating transcription programs controlling acinar cell identity. However, how ARID1A reacts to metaplasia-triggering environmental cues remains elusive. Here, we aimed to elucidate the role of ARID1A in controlling ductal pancreatic gene signatures and deciphering hierarchical signaling cues determining ARID1A-dependent chromatin regulation during acinar cell reprogramming. METHODS: Acinar cell explants with differential ARID1A status were subjected to genome-wide expression analyses. The impact of epidermal growth factor receptor (EGFR) signaling, NFATc1 activity, and ARID1A status on acinar reprogramming processes were characterized by ex vivo ADM assays and transgenic mouse models. EGFR-dependent ARID1A chromatin binding was studied by chromatin immunoprecipitation sequencing analysis and cellular fractionation. RESULTS: EGFR signaling interferes with ARID1A-dependent transcription by inducing genome-wide ARID1A displacement, thereby phenocopying ARID1A loss-of-function mutations and inducing a shift toward ADM permissive ductal transcription programs. Moreover, we show that EGFR signaling is required to push ARID1A-deficient acinar cells toward a metaplastic phenotype. Mechanistically, we identified the transcription factor nuclear factor of activated T cells 1 (NFATc1) as the central regulatory hub mediating both EGFR signaling-induced genomic ARID1A displacement and the induction of ADM-promoting gene signatures in the absence of ARID1A. Consequently, pharmacologic inhibition of NFATc1 or its depletion in transgenic mice not only preserves genome-wide ARID1A occupancy, but also attenuates acinar metaplasia led by ARID1A loss. CONCLUSIONS: Our data describe an intimate relationship between environmental signaling and chromatin remodeling in orchestrating cell fate decisions in the pancreas, and illustrate how ARID1A loss influences transcriptional regulation in acinar cell reprogramming.

Background: Intravenous ferric carboxymaltose has been shown to improve symptoms and quality of life in patients with chronic heart failure and iron deficiency. We aimed to evaluate the effect of ferric carboxymaltose, compared with placebo, on outcomes in patients who were stabilised after an episode of acute heart failure. Methods: AFFIRM-AHF was a multicentre, double-blind, randomised trial done at 121 sites in Europe, South America, and Singapore. Eligible patients were aged 18 years or older, were hospitalised for acute heart failure with concomitant iron deficiency (defined as ferritin

Forward finite difference expressions of first-order accuracy for boundary vorticity on a solid boundary are evaluated in this work when the physical coordinates are clustered and mapped using von Mises coordinates. Results show that schemes using in-field grid points do not improve solutions obtained. Results also show that the finer the grid used in the physical domain, and the more clustered it is, improves the boundary vorticity values in the computational domain. The “best” expressions forward finite difference expressions are identified when two, three, four and five grid points are used.

Polar fluid through a porous structure is considered in an attempt to derive expressions for its effective viscosity under Poiseuille flow. Expressions for the velocity field and micro-rotation are obtained and compared with the corresponding expressions for flow in free space in order to illustrate the effects of the porous medium parameters on the traversing fluid. This work might be of applicability in the study of lubrication problems in configurations involving porous linings, and in the study of the effects of viscosity changes on oil well yield.

In this work, we consider flow of a fluid with pressure-dependent viscosity down an inclined porous plane with variable permeability that is incorporated in the pressure-dependent drag coefficient. We provide a solution to a recently developed flow model, and study the effects of flow and domain parameters (viscosity control parameter, permeability proportionality constant, and angle of inclination) on the flow characteristics. Suitability of a variable permeability model that considers permeability proportional to the flow velocity is investigated. Results show that large values of the permeability proportionality constant have little or no effects on flow characteristics.

Coupled parallel flow of fluid with pressure-dependent viscosity through an inclined channel underlain by a porous layer of variable permeability and variable thickness is initiated in this work. Conditions at the interface between the channel and the porous layer reflect continuity assumptions of velocity, shear stress, pressure and viscosity. Viscosity is assumed to vary in terms of a continuous pressure function that is valid throughout the channel and the porous layer. Model equations are cast in a form where the pressure as an independent variable and solutions are obtained to illustrate the effects of flow and media parameters on the dynamics behaviour of pressure-dependent viscosity fluid. A permeability and a viscosity adjustable control parameters are introduced to avoid unrealistic values of permeability and viscosity. This work could serve as a model for flow over a mushy zone.

In this article, we discuss a class of functions known as the Nield-Kuznetsov functions, introduced over the past decade. These functions arise in the solutions to inhomogeneous Airy’s and Weber’s equations. Derivations of these functions are provided, together with their methods of computations

Inhomogeneous Airy’s and Generalized Airy’s equations with initial and boundary date are considered in this work. Solutions are obtained for constant and variable forcing functions, and general solutions are expressed in terms of Standard and Generalized Nield-Kuznetsov functions of the first- and second-kinds. Series representations of these functions and their efficient computation methodologies are presented with examples.

Equations governing the flow of a fluid with pressure-dependent viscosity through an isotropic porous structure are derived using the method of intrinsic volume averaging. Viscosity of the fluid is assumed to be a variable function of pressure, and the effects of the porous microstructure are modelled and included in the pressure-dependent drag coefficient. Five friction factors relating to five different microstructures are used in this work

BACKGROUND/AIMS: Although T-cell intrinsic expression of G9a has been associated with murine intestinal inflammation, mechanistic insight into the role of this methyltransferase in human T-cell differentiation is ill defined, and manipulation of G9a function for therapeutic use against inflammatory disorders is unexplored. METHODS: Human naive T cells were isolated from peripheral blood and differentiated in vitro in the presence of a G9a inhibitor (UNC0642) before being characterized via the transcriptome (RNA sequencing), chromatin accessibility (assay for transposase-accessible chromatin by sequencing), protein expression (cytometry by time of flight, flow cytometry), metabolism (mitochondrial stress test, ultrahigh performance liquid chromatography–tandem mas spectroscopy) and function (T-cell suppression assay). The in vivo role of G9a was assessed using 3 murine models. RESULTS: We discovered that pharmacologic inhibition of G9a enzymatic function in human CD4 T cells led to spontaneous generation of FOXP3(+) T cells (G9a-inibitors–T regulatory cells [Tregs]) in vitro that faithfully reproduce human Tregs, functionally and phenotypically. Mechanistically, G9a inhibition altered the transcriptional regulation of genes involved in lipid biosynthesis in T cells, resulting in increased intracellular cholesterol. Metabolomic profiling of G9a-inibitors–Tregs confirmed elevated lipid pathways that support Treg development through oxidative phosphorylation and enhanced lipid membrane composition. Pharmacologic G9a inhibition promoted Treg expansion in vivo upon antigen (gliadin) stimulation and ameliorated acute trinitrobenzene sulfonic acid–induced colitis secondary to tissue-specific Treg development. Finally, Tregs lacking G9a expression (G9a-knockout Tregs) remain functional chronically and can rescue T-cell transfer–induced colitis. CONCLUSION: G9a inhibition promotes cholesterol metabolism in T cells, favoring a metabolic profile that facilitates Treg development in vitro and in vivo. Our data support the potential use of G9a inhibitors in the treatment of immune-mediated conditions including inflammatory bowel disease.

Sinus tachycardia (ST) is ubiquitous, but its presence outside of normal physiological triggers in otherwise healthy individuals remains a commonly encountered phenomenon in medical practice. In many cases, ST can be readily explained by a current medical condition that precipitates an increase in the sinus rate, but ST at rest without physiological triggers may also represent a spectrum of normal. In other cases, ST may not have an easily explainable cause but may represent serious underlying pathology and can be associated with intolerable symptoms. The classification of ST, consideration of possible etiologies, as well as the decisions of when and how to intervene can be difficult. ST can be classified as secondary to a specific, usually treatable, medical condition (eg, pulmonary embolism, anemia, infection, or hyperthyroidism) or be related to several incompletely defined conditions (eg, inappropriate ST, postural tachycardia syndrome, mast cell disorder, or post-COVID syndrome). While cardiologists and cardiac electrophysiologists often evaluate patients with symptoms associated with persistent or paroxysmal ST, an optimal approach remains uncertain. Due to the many possible conditions associated with ST, and an overlap in medical specialists who see these patients, the inclusion of experts in different fields is essential for a more comprehensive understanding. This article is unique in that it was composed by international experts in Neurology, Psychology, Autonomic Medicine, Allergy and Immunology, Exercise Physiology, Pulmonology and Critical Care Medicine, Endocrinology, Cardiology, and Cardiac Electrophysiology in the hope that it will facilitate a more complete understanding and thereby result in the better care of patients with ST.

Objectives: To determine the efficacy of a deep-learning (DL) tool in assisting dentists in detecting apical radiolucencies on periapical radiographs. Methods: Sixty-eight intraoral periapical radiographs with CBCT-proven presence or absence of apical radiolucencies were selected to serve as the testing subset. Eight readers examined the subset, denoted the positions of apical radiolucencies, and used a 5-point confidence scale to score each radiolucency. The same subset was assessed by readers under two conditions: with and without Denti.AI DL tool predictions. For the two sessions, the performance of the readers was compared. The comparison was performed with the alternate free response receiver operating characteristic (AFROC) methodology. Results: Localization of lesion accuracy (AFROC-AUC), specificity and sensitivity (by lesion) detection demonstrated improvements in the DL aided session in comparison with the unaided reading session. Subgroup performance analysis revealed an increase in sensitivity for small radiolucencies and in radiolucencies located apical to endodontically treated teeth.. Conclusion: The study revealed that the DL technology (Denti.AI) enhances dental professionals' abilities to detect apical radiolucencies on intraoral radiographs. Advances in knowledge: DL tools have the potential to improve diagnostic efficacy of dentists in identifying apical radiolucencies on periapical radiographs.

Equations governing the flow of a fluid-particle mixture with variable viscosity through a porous structure are developed. Method of intrinsic volume averaging is used to average Saffman’s dusty gas equations. A modelling flexibility is offered in this work by introducing a dust-phase partial pressure in the governing equations, interpreted as the pressure necessary to maintain a uniform particle distribution in the flow field. Viscosity of the fluid-particle mixture is assumed to be variable, with variations in viscosity being due to fluid pressure. Particles are assumed spherical and Stokes’ coefficient of resistance is expressed in terms of the pressure-dependent fluid viscosity. Both Darcy resistance and the Forchheimer micro-inertial effects are accounted for in the developed model

Primary sclerosing cholangitis (PSC) is a chronic fibroinflammatory disease of the biliary tract characterized by cellular senescence and periportal fibrogenesis. Specific disease features that are cell intrinsic and either genetically or epigenetically mediated remain unclear due in part to a lack of appropriate, patient‐specific, in vitro models. Recently, our group developed systems to create induced pluripotent stem cell (iPSC)‐derived cholangiocytes (iDCs) and biliary epithelial organoids (cholangioids). We use these models to investigate whether PSC cholangiocytes are intrinsically predisposed to cellular senescence. Skin fibroblasts from healthy controls and subjects with PSC were reprogrammed to pluripotency, differentiated to cholangiocytes, and subsequently grown in three‐dimensional matrigel‐based culture to induce formation of cholangioids. RNA sequencing (RNA‐seq) on iDCs showed significant differences in gene expression patterns, including enrichment of pathways associated with cell cycle, senescence, and hepatic fibrosis, that correlate with PSC. These pathways also overlapped with RNA‐seq analysis on isolated cholangiocytes from subjects with PSC. Exome sequencing on the subjects with PSC revealed genetic variants of unknown significance in the genes identified in these pathways. Three‐dimensional culture revealed smaller size, lack of a central lumen, and increased cellular senescence in PSC‐derived cholangioids. Congruent with this, PSC‐derived iDCs showed increased secretion of the extracellular matrix molecule fibronectin as well as the inflammatory cytokines interleukin‐6, and chemokine (C‐C motif) ligand 2. Conditioned media (CM) from PSC‐derived iDCs more potently activated hepatic stellate cells compared to control CM. Conclusion: We demonstrated efficient generation of iDCs and cholangioids from patients with PSC that show disease‐specific features. PSC cholangiocytes are intrinsically predisposed to cellular senescence. These features are unmasked following biliary differentiation of pluripotent stem cells and have functional consequences in epithelial organoids., Biliary differentiation of Induced Pluripotent Stem Cells from subjects with Primary Sclerosing Cholangitis unmasks their senescence phenotype and ability to activate hepatic stellate cells.

In this article, we discuss a class of functions known as the Nield-Kuznetsov functions, introduced over the past decade. These functions arise in the solutions to inhomogeneous Airy’s and Weber’s equations. Derivations of these functions are provided, together with their methods of computations

Gravity-driven flow through an inclined channel over a semi-infinite porous layer is considered in order to obtain a modification to the usual Beavers and Joseph slip condition that is suitable for this type of flow. Expressions for the velocity, shear stress, volumetric flow rates, and pressure distribution across the channel are obtained together with an expression for the interfacial velocity. In the absence of values for the slip parameter when the flow is over a Forchheimer porous layer, this work provides a relationship between the slip parameters of the Darcy and Forchheimer layers. Expressions for the interfacial velocities in both cases are obtained. This original work is intended to provide baseline analysis and a benchmark with which more sophisticated types of flow, over porous layers in an inclined domain can be compared.

Penelitian ini bertujuan untuk mengetahui dan memahami batasan perlindungan hukum bagi anak yang dapat dipertanggungjawabkan sebagai pelaku kejahatan dan mengetahui dan memahami faktor-faktor yang mempengaruhi pertimbangan perlindungan hukum bagi anak yang dapat dipertanggungjawabkan sebagai pelaku kejahatan. Penelitian ini menggunakan pendekatan yuridis normatif. Adapun metode analisis dilakukan dengan cara mengidentifikasi secara sistematis, dipolarisasi, dikategorisasi dan dikelompokkan sesuai dengan alur pembahasan dalam penelitian ini. Berdasarkan uraian hasil dan pembahasan, maka dapat disimpulkan bahwa batasan perlindungan hukum bagi anak yang dapat dipertanggungjawabkan sebagai pelaku kejahatan yakni umur 12 tahun ke bawah, anak yang berumur 12 tahun ke atas atau berusia belum berusia 14 tahun dikenakan sanksi pidana berupa tindakan (tindakan dalam artian yuridis). Sanksi pidana penjara adalah alternatif terakhir bagi anak pelaku kejahatan, berbeda dengan orang dewasa. Adapun faktor-faktor yang mempengaruhi perlindungan hukum bagi anak yang dapat dipertanggungjawabkan sebagai pelaku kejahatan, yaitu aspek sosiologis serta kriminilogis. Aspek kriminologis terdiri dari tiga sub yang penting, yaitu ekonomi, lingkungan, dan keluarga. Selain itu, adapun terkait konsep diversi yang dipertajam dengan konsep restoratif justice belum saatnya menjadi ius constitutum di Indonesia, oleh karena kejahatan yang ada di Indonesia merupakan kejahatan yang masif dan sistematis.