Summary Background The interleukin-23 pathway is implicated genetically and biologically in the pathogenesis of Crohn's disease. We aimed to assess the efficacy and safety of risankizumab (BI 655066, ...Boehringer Ingelheim, Ingelheim, Germany), a humanised monoclonal antibody targeting the p19 subunit of interleukin-23, in patients with moderately-to-severely active Crohn's disease. Methods In this randomised, double-blind, placebo-controlled phase 2 study, we enrolled patients at 36 referral sites in North America, Europe, and southeast Asia. Eligible patients were aged 18–75 years, with a diagnosis of Crohn's disease for at least 3 months, assessed as moderate-to-severe Crohn's disease at screening, defined as a Crohn's Disease Activity Index (CDAI) of 220–450, with mucosal ulcers in the ileum or colon, or both, and a Crohn's Disease Endoscopic Index of Severity (CDEIS) of at least 7 (≥4 for patients with isolated ileitis) on ileocolonoscopy scored by a masked central reader. Patients were randomised 1:1:1 using an interactive response system to a double-blind investigational product, and stratified by previous exposure to TNF antagonists (yes vs no). Patients received intravenous 200 mg risankizumab, 600 mg risankizumab, or placebo, at weeks 0, 4, and 8. The primary outcome was clinical remission (CDAI <150) at week 12 (intention-to-treat population). Safety was assessed in patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov , number NCT02031276. Findings Between March, 2014, and September, 2015, 213 patients were screened, and 121 patients randomised. At baseline, 113 patients (93%) had been previously treated with at least one tumour necrosis factor (TNF) antagonist (which had failed in 96 79%). At week 12, 25 (31%) of 82 risankizumab patients (pooled 41 patients in 200 mg and 41 patients in 600 mg arms) had clinical remission versus six (15%) of 39 placebo patients (difference vs placebo 15·0%, 95% CI 0·1 to 30·1; p=0·0489). Ten (24%) of 41 patients who received 200 mg risankizumab had clinical remission (9·0%, −8·3 to 26·2; p=0·31) and 15 (37%) of 41 who received the 600 mg dose (20·9%, 2·6 to 39·2; p=0·0252). 95 (79%) patients had adverse events (32 in the placebo group, 32 randomised to 200 mg risankizumab, 31 randomised to 600 mg risankizumab); 18 had severe adverse events (nine, six, three); 12 discontinued (six, five, one); 24 had serious adverse events (12, nine, three). The most common adverse event was nausea and most common serious adverse event was worsening of underlying Crohn's disease. No deaths occurred. Interpretation In this short-term study, risankizumab was more effective than placebo for inducing clinical remission in patients with active Crohn's disease. Therefore, selective blockade of interleukin-23 via inhibition of p19 might be a viable therapeutic approach in Crohn's disease. Funding Boehringer Ingelheim.
Lactobacillus paracasei is a major probiotic and is well known for its anti-inflammatory properties. Thus, we investigated the effects of L. paracasei-derived extracellular vesicles (LpEVs) on ...LPS-induced inflammation in HT29 human colorectal cancer cells and dextran sulfate sodium (DSS)-induced colitis in C57BL/6 mice. ER stress inhibitors (salubrinal or 4-PBA) or CHOP siRNA were utilized to investigate the relationship between LpEV-induced endoplasmic reticulum (ER) stress and the inhibitory effect of LpEVs against LPS-induced inflammation. DSS (2%) was administered to male C57BL/6 mice to induce inflammatory bowel disease, and disease activity was measured by determining colon length, disease activity index, and survival ratio. In in vitro experiments, LpEVs reduced the expression of the LPS-induced pro-inflammatory cytokines IL-1α, IL-1β, IL-2, and TNFα and increased the expression of the anti-inflammatory cytokines IL-10 and TGFβ. LpEVs reduced LPS-induced inflammation in HT29 cells and decreased the activation of inflammation-associated proteins, such as COX-2, iNOS and NFκB, as well as nitric oxide. In in vivo mouse experiments, the oral administration of LpEVs also protected against DSS-induced colitis by reducing weight loss, maintaining colon length, and decreasing the disease activity index (DAI). In addition, LpEVs induced the expression of endoplasmic reticulum (ER) stress-associated proteins, while the inhibition of these proteins blocked the anti-inflammatory effects of LpEVs in LPS-treated HT29 cells, restoring the pro-inflammatory effects of LPS. This study found that LpEVs attenuate LPS-induced inflammation in the intestine through ER stress activation. Our results suggest that LpEVs have a significant effect in maintaining colorectal homeostasis in inflammation-mediated pathogenesis.
Polymers for IR imaging: The preparation of high refractive index polymers (n = 1.75 to 1.86) via the inverse vulcanization of elemental sulfur is reported. High quality imaging in the near (1.5 μm) ...and mid‐IR (3–5 μm) regions using high refractive index polymeric lenses from these sulfur materials was demonstrated.
Transition metal dichalcogenides (TMDs) have attracted significant interest as gas‐sensing materials due to their unique crystal structure and surface. However, there are still issues when it comes ...to expanding the types of sensing gases for the TMD gas sensors. To extend gas‐sensing selectivity for the TMD gas sensors in this study, a monolayer (ML) 2D metal–organic framework (MOF) is introduced on top of the PtSe2 gas sensor, thereby tuning the major sensing analyte of PtSe2 from NO2 to H2S. Density functional theory calculations elucidate that the metal species of ML MOFs are attributed to the tuned selectivity of the analytes, based on the difference in binding energies. It is also demonstrated that ML MOF maintained the high responsivity of the pristine PtSe2 even at a low concentration of gas (200 ppb). This is further confirmed through the molecular dynamics simulations, which reveal that the ML feature of the ML MOF is highly essential to preserve the intrinsic ultra‐low limit detection properties of pristine PtSe2.
The monolayer 2D metal–organic framework is introduced to tune the gas‐sensing selectivity of PtSe2, one of the most promising gas‐sensing materials in transition metal dichalcogenides. The tuning mechanism is revealed by density functional theory calculations. The monolayer metal–organic framework also preserves ultra‐low detection limit of PtSe2, and it is elucidated by molecular dynamics simulation.
Thiopurine therapy, commonly used in autoimmune conditions, can be complicated by life-threatening leukopenia. This leukopenia is associated with genetic variation in TPMT (encoding thiopurine ...S-methyltransferase). Despite a lower frequency of TPMT mutations in Asians, the incidence of thiopurine-induced leukopenia is higher in Asians than in individuals of European descent. Here we performed an Immunochip-based 2-stage association study in 978 Korean subjects with Crohn's disease treated with thiopurines. We identified a nonsynonymous SNP in NUDT15 (encoding p.Arg139Cys) that was strongly associated with thiopurine-induced early leukopenia (odds ratio (OR) = 35.6; P(combined) = 4.88 × 10(-94)). In Koreans, this variant demonstrated sensitivity and specificity of 89.4% and 93.2%, respectively, for thiopurine-induced early leukopenia (in comparison to 12.1% and 97.6% for TPMT variants). Although rare, this SNP was also strongly associated with thiopurine-induced leukopenia in subjects with inflammatory bowel disease of European descent (OR = 9.50; P = 4.64 × 10(-4)). Thus, NUDT15 is a pharmacogenetic determinant for thiopurine-induced leukopenia in diverse populations.
Little is known about the long-term natural history of
complex lung disease (MAC-LD) in untreated patients with stable course.The aim of this study was to investigate the natural course of untreated ...stable MAC-LD, with a focus on factors associated with clinical deterioration, spontaneous sputum conversion and prognosis.Of 488 patients diagnosed with MAC-LD between 1998 and 2011, 305 patients (62.5%) showed progressive MAC-LD resulting in treatment initiation within 3 years of diagnosis and 115 patients (23.6%) exhibited stable MAC-LD for at least 3 years with a median follow-up duration of 5.6 years. Patients with stable MAC-LD were more likely to have higher body mass index and less systemic symptoms at initial diagnosis compared with patients with progressive MAC-LD, while positive sputum acid-fast bacilli smear, fibrocavitary type and more extensive disease in radiological findings were more associated with progressive MAC-LD. Of the untreated patients with stable MAC-LD, 51.6% underwent spontaneous sputum conversion, with younger age, higher body mass index and negative sputum acid-fast bacilli smear at initial diagnosis found to be predictors of this occurrence.Advanced age, fibrocavitary type and abnormal pulmonary function were negative prognostic factors for survival in patients with stable MAC-LD.
Acute kidney injury (AKI) is a major risk factor in the development of chronic kidney disease (CKD). However, the mechanisms linking AKI to CKD remain unclear. We examined the alteration of ...macrophage phenotypes during an extended recovery period following ischemia/reperfusion injury (IRI) and determine their roles in the development of fibrosis.
The left renal pedicle of mice was clamped for 40 min. To deplete monocyte/macrophage, liposome clodronate was injected or CD11b-DTR and CD11c-DTR transgenic mice were used.
Throughout the phase of IRI recovery, M2-phenotype macrophages made up the predominant macrophage subset. On day 28, renal fibrosis was clearly shown with increased type IV collagen and TGF-β. The depletion of macrophages induced by the liposome clodronate injection improved renal fibrosis with a reduction of kidney IL-6, type IV collagen, and TGF-β levels. Additionally, the adoptive transfer of the M2c macrophages partially reversed the beneficial effect of macrophage depletion, whereas the adoptive transfer of the M1 macrophages did not. M2 macrophages isolated from the kidneys during the recovery phase expressed 2.5 fold higher levels of TGF-β than the M1 macrophages. The injection of the diphtheria toxin into CD11b or CD11c-DTR transgenic mice resulted in lesser depletion or no change in M2 macrophages and had little impact on renal fibrosis.
Although M2 macrophages are known to be indispensible for short-term recovery, they are thought to be main culprit in the development of renal fibrosis following IRI.
Van der Waals (vdW) heterostructures have drawn much interest over the last decade owing to their absence of dangling bonds and their intriguing low‐dimensional properties. The emergence of 2D ...materials has enabled the achievement of significant progress in both the discovery of physical phenomena and the realization of superior devices. In this work, the group IV metal chalcogenide 2D‐layered Ge4Se9 is introduced as a new selection of insulating vdW material. 2D‐layered Ge4Se9 is synthesized with a rectangular shape using the metalcorganic chemical vapor deposition system using a liquid germanium precursor at 240 °C. By stacking the Ge4Se9 and MoS2, vdW heterostructure devices are fabricated with a giant memory window of 129 V by sweeping back gate range of ±80 V. The gate‐independent decay time reveals that the large hysteresis is induced by the interfacial charge transfer, which originates from the low band offset. Moreover, repeatable conductance changes are observed over the 2250 pulses with low non‐linearity values of 0.26 and 0.95 for potentiation and depression curves, respectively. The energy consumption of the MoS2/Ge4Se9 device is about 15 fJ for operating energy and the learning accuracy of image classification reaches 88.3%, which further proves the great potential of artificial synapses.
Ge4Se9, a new insulating 2D‐layered material, is synthesized using metal–organic chemical vapor deposition at 240 °C with low‐reactive precursors. The 2D‐layered Ge4Se9 forms a low band offset with MoS2, exhibiting a large memory window with linear gate‐tunability. As an artificial synapse, the MoS2/Ge4Se9 heterostructure exhibits synaptic updates with low non‐linearity of 0.26 and low energy consumption of 15 fJ.
Herein, we fabricate nanofiber membranes by electrospinning with poly (vinylidene fluoride-co-hexafluoropropene) and then coated with TiO2 nanoparticles using electrospraying (hereafter E-TiO2), to ...demonstrate a simple way for membrane regeneration during real seawater desalination by membrane distillation (MD). Coupled with a ferrate pretreatment followed by dissolved air floatation (F-DAF), MD achieved enhanced fouling control and membrane regeneration. In this present study, we report the characteristics of the fabricated membrane, effects of pretreatment, membrane performance, and fouling mitigation for 5-day real seawater desalination. Compared with a commercial PVDF membrane, E-TiO2 membrane had increased anti-fouling and anti-wetting properties that could efficiently be recovered by simple physical water flushing. Fouled fabricated membranes showed recoverable super-hydrophobicity after 30 mins of simple water flushing (contract angle recovered from 131.4° ± 2.2° to 151.3° ± 1.2°). Additionally, in-situ ferrate generated from NaOCl and Fe(III) reduced the algal organic matter (AOM) in seawater and subsequently reduced membrane fouling. Membrane distillation coupled with F-DAF system has proven its potential to be applied in long-term seawater desalination by controlling AOM and membrane fouling mitigation and has shown its high performance as a facile technology.
•Salt rejection of 99.9% with high flux was achieved during the 5-day desalination•E-TiO2 electrospun membrane demonstrated persistent superhydrophobicity with anti-fouling function.•Ferrate with DAF-coagulation pre-treatment shows high AOM removal•In situ and non-invasive OCT monitored fouling development in real time.•Superhydrophobicity of TiO2 membrane was recovered by simple water flushing.
2D MoS2 has gained attention for the post‐silicon material owing to its atomically thin nature and dangling bond‐free surface. The bi‐layer MoS2 is considered a promising material for electronic ...devices due to its better electrical properties than monolayer MoS2. However, the uniform growth of bi‐layer MoS2 is still challenging. Herein, the uniform growth of bi‐layer MoS2 is demonstrated using gas‐phase alkali metal‐assisted metal–organic chemical vapor deposition (GAA‐MOCVD). Thanks to enhanced metal reactant diffusion length in GAA‐MOCVD, the uniform growth of bi‐layer MoS2 film is achieved even at fast nucleation kinetics for a shorter growth time compared to previously reported MOCVD. The bi‐layer MoS2 field‐effect transistors (FETs) show superior electrical properties such as sheet conductance and electron mobility than monolayer MoS2 FETs. The electron mobility of bi‐layer MoS2 FETs with bismuth contacts reaches a maximum of 92.35 cm2 V−1 s−1. Using the partially grown epitaxial bi‐layer (PGEB) MoS2, it is demonstrated that a photodetector showed a near‐infrared photoresponse with a low dark current that is advantageous for both monolayer and bi‐layer applications. The potential expansion of the growth technique to layer‐by‐layer growth can result in boosted performance across a wide spectrum of electronic and optoelectronic devices employing MoS2.
The GAA‐MOCVD is introduced to realize the epitaxial growth of one additional layer on monolayer MoS2, resulting in bi‐layer MoS2 film with spatial homogeneity and high‐quality, which is challenging to achieve in conventional MOCVD techniques using powder alkali metals. The FETs fabricated by bi‐layer MoS2 films exhibit superior electrical properties including sheet conductance, electron mobility, and on/off ratio.
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