Rapid advances in industrialisation and informatisation methods have spurred tremendous progress in developing the next generation of manufacturing technology. Today, we are on the cusp of the Fourth ...Industrial Revolution. In 2013, amongst one of 10 'Future Projects' identified by the German government as part of its High-Tech Strategy 2020 Action Plan, the Industry 4.0 project is considered to be a major endeavour for Germany to establish itself as a leader of integrated industry. In 2014, China's State Council unveiled their ten-year national plan, Made-in-China 2025, which was designed to transform China from the world's workshop into a world manufacturing power. Made-in-China 2025 is an initiative to comprehensively upgrade China's industry including the manufacturing sector. In Industry 4.0 and Made-in-China 2025, many applications require a combination of recently emerging new technologies, which is giving rise to the emergence of Industry 4.0. Such technologies originate from different disciplines including cyber-physical Systems, IoT, cloud computing, Industrial Integration, Enterprise Architecture, SOA, Business Process Management, Industrial Information Integration and others. At this present moment, the lack of powerful tools still poses a major obstacle for exploiting the full potential of Industry 4.0. In particular, formal methods and systems methods are crucial for realising Industry 4.0, which poses unique challenges. In this paper, we briefly survey the state of the art in the area of Industry 4.0 as it relates to industries.
Key points
Several distinct strategies produce and conserve heat to maintain the body temperature of mammals, each associated with unique physiologies, with consequences for wellness and disease ...susceptibility
Highly regulated properties of skin offset the total requirement for heat production
We hypothesize that the adipose component of skin is primarily responsible for modulating heat flux; here we evaluate the relative regulation of adipose depots in mouse and human, to test their recruitment to heat production and conservation
We found that insulating mouse dermal white adipose tissue accumulates in response to environmentally and genetically induced cool stress; this layer is one of two adipose depots closely apposed to mouse skin, where the subcutaneous mammary gland fat pads are actively recruited to heat production
In contrast, the body‐wide adipose depot associated with human skin produces heat directly, potentially creating an alternative to the centrally regulated brown adipose tissue
Mammalian skin impacts metabolic efficiency system‐wide, controlling the rate of heat loss and consequent heat production. Here we compare the unique fat depots associated with mouse and human skin, to determine whether they have corresponding functions and regulation. For humans, we assay a skin‐associated fat (SAF) body‐wide depot to distinguish it from the subcutaneous fat pads characteristic of the abdomen and upper limbs. We show that the thickness of SAF is not related to general adiposity; it is much thicker (1.6‐fold) in women than men, and highly subject‐specific. We used molecular and cellular assays of β‐adrenergic‐induced lipolysis and found that dermal white adipose tissue (dWAT) in mice is resistant to lipolysis; in contrast, the body‐wide human SAF depot becomes lipolytic, generating heat in response to β‐adrenergic stimulation. In mice challenged to make more heat to maintain body temperature (either environmentally or genetically), there is a compensatory increase in thickness of dWAT: a corresponding β‐adrenergic stimulation of human skin adipose (in vivo or in explant) depletes adipocyte lipid content. We summarize the regulation of skin‐associated adipocytes by age, sex and adiposity, for both species. We conclude that the body‐wide dWAT depot of mice shows unique regulation that enables it to be deployed for heat preservation; combined with the actively lipolytic subcutaneous mammary fat pads they enable thermal defence. The adipose tissue that covers human subjects produces heat directly, providing an alternative to the brown adipose tissues.
Metal–organic framework (MOF) materials provide an excellent platform to fabricate single-atom catalysts due to their structural diversity, intrinsic porosity, and designable functionality. However, ...the unambiguous identification of atomically dispersed metal sites and the elucidation of their role in catalysis are challenging due to limited methods of characterization and lack of direct structural information. Here, we report a comprehensive investigation of the structure and the role of atomically dispersed copper sites in UiO-66 for the catalytic reduction of NO2 at ambient temperature. The atomic dispersion of copper sites on UiO-66 is confirmed by high-angle annular dark-field scanning transmission electron microscopy, electron paramagnetic resonance spectroscopy, and inelastic neutron scattering, and their location is identified by neutron powder diffraction and solid-state nuclear magnetic resonance spectroscopy. The Cu/UiO-66 catalyst exhibits superior catalytic performance for the reduction of NO2 at 25 °C without the use of reductants. A selectivity of 88% for the formation of N2 at a 97% conversion of NO2 with a lifetime of >50 h and an unprecedented turnover frequency of 6.1 h–1 is achieved under nonthermal plasma activation. In situ and operando infrared, solid-state NMR, and EPR spectroscopy reveal the critical role of copper sites in the adsorption and activation of NO2 molecules, with the formation of {Cu(I)···NO} and {Cu···NO2} adducts promoting the conversion of NO2 to N2. This study will inspire the further design and study of new efficient single-atom catalysts for NO2 abatement via detailed unravelling of their role in catalysis.
Early clinical results of chimeric antigen receptor (CAR) T cell therapy targeting B cell maturation antigen (BCMA) for multiple myeloma (MM) appear promising, but relapses associated with residual ...low-to-negative BCMA-expressing MM cells have been reported, necessitating identification of additional targets. The orphan G protein-coupled receptor, class C group 5 member D (
), normally expressed only in the hair follicle, was previously identified as expressed by mRNA in marrow aspirates from patients with MM, but confirmation of protein expression remained elusive. Using quantitative immunofluorescence, we determined that GPRC5D protein is expressed on CD138
MM cells from primary marrow samples with a distribution that was similar to, but independent of, BCMA. Panning a human B cell-derived phage display library identified seven GPRC5D-specific single-chain variable fragments (scFvs). Incorporation of these into multiple CAR formats yielded 42 different constructs, which were screened for antigen-specific and antigen-independent (tonic) signaling using a Nur77-based reporter system. Nur77 reporter screen results were confirmed in vivo using a marrow-tropic MM xenograft in mice. CAR T cells incorporating GPRC5D-targeted scFv clone 109 eradicated MM and enabled long-term survival, including in a BCMA antigen escape model. GPRC5D(109) is specific for GPRC5D and resulted in MM cell line and primary MM cytotoxicity, cytokine release, and in vivo activity comparable to anti-BCMA CAR T cells. Murine and cynomolgus cross-reactive CAR T cells did not cause alopecia or other signs of GPRC5D-mediated toxicity in these species. Thus, GPRC5D(109) CAR T cell therapy shows potential for the treatment of advanced MM irrespective of previous BCMA-targeted therapy.
Lebrikizumab (LEB), a high-affinity monoclonal antibody targeting interleukin (IL)-13, demonstrated efficacy and safety in patients with moderate-to-severe atopic dermatitis (AD) during 16 weeks of ...monotherapy in a phase 2b trial, and two 52-week phase 3 trials.
To evaluate efficacy and safety of LEB combined with low- to mid-potency topical corticosteroids (TCS) in patients with moderate-to-severe AD.
The ADhere trial was a 16-week randomized, double-blinded, placebo (PBO)-controlled, multicenter, phase 3 clinical trial conducted from February 3, 2020, to September 16, 2021. The study was conducted at 54 outpatient sites across Germany, Poland, Canada, and the US and included adolescent (aged ≥12 to <18 years weighing ≥40 kg) and adult patients with moderate-to-severe AD. The treatment allocation ratio was 2:1 (LEB:PBO).
Overall, 211 patients were randomized to subcutaneous LEB (loading dose of 500 mg at baseline and week 2, followed by 250 mg every 2 weeks Q2W thereafter) or PBO Q2W in combination with TCS for 16 weeks.
Efficacy analyses at week 16 included proportions of patients achieving Investigator's Global Assessment score of 0 or 1 (IGA 0,1) with 2 or more points improvement from baseline, and 75% improvement in the Eczema Area and Severity Index (EASI-75). Key secondary end points included evaluation of itch, itch interference on sleep, and quality of life. Safety assessments included monitoring adverse events (AEs).
The mean (SD) age of patients was 37.2 (19.3) years, 103 (48.8%) patients were women, 31 (14.7%) patients were Asian, and 28 (13.3%) patients were Black/African American. At week 16, IGA (0,1) was achieved by 145 (41.2%) patients in the LEB+TCS group vs 66 (22.1%) receiving PBO+TCS (P = .01); corresponding proportions of patients achieving EASI-75 were 69.5% vs 42.2% (P < .001). The LEB+TCS group showed statistically significant improvements in all key secondary end points. Most treatment-emergent adverse events (TEAEs) were nonserious, mild or moderate in severity, and did not lead to study discontinuation. The TEAEs frequently reported in the LEB+TCS group included conjunctivitis (7 4.8%), headache (7 4.8%), hypertension (4 2.8%), injection site reactions (4 2.8%), and herpes infection (5 3.4%) vs 1.5% or less patient-reported frequencies in the PBO+TCS group. Similar frequencies of patient-reported serious AEs following LEB+TCS (n = 2, 1.4%) and PBO+TCS (n = 1, 1.5%).
In this randomized phase 3 clinical trial, LEB+TCS was associated with improved outcomes in adolescents and adults with moderate-to-severe AD compared with TCS alone, and safety was consistent with previously reported AD trials.
ClinicalTrials.gov Identifier: NCT04250337.
Since its conditional approval in 2012, bedaquiline (BDQ) has been a valuable tool for treatment of drug-resistant tuberculosis. More recently, a novel short-course regimen combining BDQ with ...pretomanid and linezolid won approval to treat highly drug-resistant tuberculosis. Clinical reports of emerging BDQ resistance have identified mutations in
that derepress the expression of the MmpL5/MmpS5 efflux transporter as the most common cause. Because the effect of these mutations on bacterial susceptibility to BDQ is relatively small (e.g., 2 to 8× MIC shift), increasing the BDQ dose would increase antibacterial activity but also pose potential safety concerns, including QTc prolongation. Substitution of BDQ with another diarylquinoline with superior potency and/or safety has the potential to overcome these limitations. TBAJ-587 has greater
potency than BDQ, including against
mutants, and may offer a larger safety margin. Using a mouse model of tuberculosis and different doses of BDQ and TBAJ-587, we found that against wild-type
H37Rv and an isogenic
mutant, TBAJ-587 has greater efficacy against both strains than BDQ, whether alone or in combination with pretomanid and either linezolid or moxifloxacin and pyrazinamide. TBAJ-587 also reduced the emergence of resistance to diarylquinolines and pretomanid.
Novel regimens combining bedaquiline and pretomanid with either linezolid (BPaL regimen) or moxifloxacin and pyrazinamide (BPaMZ regimen) shorten the treatment duration needed to cure tuberculosis ...(TB) in BALB/c mice compared to that of the first-line regimen and have yielded promising results in initial clinical trials. However, the independent contribution of the investigational new drug pretomanid to the efficacy of BPaMZ has not been examined, and its contribution to BPaL has been examined only over the first 2 months of treatment. In the present study, the addition of pretomanid to BL increased bactericidal activity, prevented emergence of bedaquiline resistance, and shortened the duration needed to prevent relapse with drug-susceptible isolates by at least 2 months in BALB/c mice. Addition of pretomanid to bedaquiline, moxifloxacin, and pyrazinamide (BMZ) resulted in a 1-log
greater CFU reduction after 1 month of treatment and/or reduced the number of mice relapsing in each of 2 experiments in BALB/c mice and in immunocompromised nude mice. Bedaquiline-resistant isolates were found at relapse in only one BMZ-treated nude mouse. Treatment of infection with a pyrazinamide-resistant mutant in BALB/c mice with BPaMZ prevented selection of bedaquiline-resistant mutants and reduced the proportion of mice relapsing compared to that for BMZ treatment alone. Among severely ill C3HeB/FeJ mice with caseous pneumonia and cavitation, BPaMZ increased median survival (≥60 versus 21 days) and reduced median lung CFU by 2.4 log
at 1 month compared to the level for BMZ. In conclusion, in 3 different mouse models, pretomanid contributed significantly to the efficacy of the BPaMZ and BPaL regimens, including restricting the selection of bedaquiline-resistant mutants.
A phase 2, double-blind, placebo-controlled trial evaluated apremilast efficacy, safety, and pharmacodynamics in adults with moderate to severe atopic dermatitis. Patients were randomly assigned to ...receive placebo, apremilast 30 mg twice daily (APR30), or apremilast 40 mg twice daily (APR40) for 12 weeks. During weeks 12–24, all patients received APR30 or APR40. A biopsy substudy evaluated atopic dermatitis-related biomarkers. Among 185 randomly assigned intent-to-treat patients at week 12, a dose-response relationship was observed; APR40 (n = 63), but not APR30 (n = 58), led to statistically significant improvements (vs. placebo, n = 64) in Eczema Area and Severity Index (mean standard deviation percent change from baseline = −31.6% 44.6 vs. −11.0% 71.2, P < 0.04; primary endpoint). mRNA expression of T helper type 17/T helper type 22-related markers (IL-17A, IL-22, and S100A7/A8; P < 0.05) showed the highest reductions with APR40, with minimal changes in other immune axes. Safety with APR30 was largely consistent with apremilast’s known profile (common adverse events: nausea, diarrhea, headache, and nasopharyngitis). With APR40, adverse events were more frequent, and cellulitis occurred (n = 6). An independent safety monitoring committee discontinued the APR40 dosage. APR40 showed modest efficacy and decreased atopic dermatitis-related biomarkers in moderate to severe atopic dermatitis patients. Adverse events, including cellulitis, were more frequent with APR40, which was discontinued during the trial. Clinical Trial Registration Number: NCT02087943 (clinicaltrials.gov).
Undersizing mitral annuloplasty (UMA) is a frequently used surgical repair technique to correct ischemic mitral regurgitation in patients with heart failure. In this study, we sought to test the ...hypothesis that downsizing the mitral annulus can adversely affect the shape and mechanics of the left ventricle inhibiting its functional recovery.
Eighteen farm swine that underwent an inferolateral myocardial infarction and developed ischemic mitral regurgitation of >2+ severity after 2 months were assigned as follows: 9 swine received an undersized mitral annuloplasty, 6 received papillary muscle approximation (PMA), and 3 animals did not receive any other intervention. Animals lived another 3 months and cardiac magnetic resonance imaging was performed before termination to assess ventricle mechanics and function.
Ejection fraction was comparable between the 2 repair groups before surgery, but was significantly lower in UMA at 38.89% ± 7.91% versus 50.83% ± 9.04% in the PMA group (P = .0397). Animals receiving UMA had lower regional peak fractional shortening and reduced systolic and diastolic radial velocities compared with PMA and in some regions were lower than sham. Animals that underwent UMA had higher circumferential strain than sham, but lower than PMA. UMA animals have lower longitudinal strain compared to sham group and lower LV torsion than PMA.
Undersizing the mitral annulus with an annuloplasty ring can restore valvular competence, but unphysiologically impair ventricle mechanics. Mitral valve repair strategies should focus not only on restoring valve competence, but preserving ventricle mechanics.
Top row, Schematic representation of experimental design of this study. Bottom row, Key findings from this study that demonstrate the deleterious effect of undersizing mitral annuloplasty on left ventricle mechanics compared with papillary muscle approximation alone. Display omitted
Buruli ulcer is treatable with antibiotics. An 8-week course of rifampin (RIF) and either streptomycin (STR) or clarithromycin (CLR) cures over 90% of patients. However, STR requires injections and ...may be toxic, and CLR shares an adverse drug-drug interaction with RIF and may be poorly tolerated. Studies in a mouse footpad infection model showed that increasing the dose of RIF or using the long-acting rifamycin rifapentine (RPT), in combination with clofazimine (CFZ), a relatively well-tolerated antibiotic, can shorten treatment to 4 weeks. CFZ is reduced by a component of the electron transport chain (ETC) to produce reactive oxygen species toxic to bacteria. Synergistic activity of CFZ with other ETC-targeting drugs, the ATP synthase inhibitor bedaquiline (BDQ) and the
:
oxidase inhibitor Q203 (now named telacebec), was recently described against
Recognizing that
mutants lacking the alternative
oxidase are hypersusceptible to Q203 and that
is a natural
oxidase-deficient mutant, we tested the
susceptibility of
to Q203 and evaluated the treatment-shortening potential of novel 3- and 4-drug regimens combining RPT, CFZ, Q203, and/or BDQ in a mouse footpad model. The MIC of Q203 was extremely low (0.000075 to 0.00015 μg/ml). Footpad swelling decreased more rapidly in mice treated with Q203-containing regimens than in mice treated with RIF and STR (RIF+STR) and RPT and CFZ (RPT+CFZ). Nearly all footpads were culture negative after only 2 weeks of treatment with regimens containing RPT, CFZ, and Q203. No relapse was detected after only 2 weeks of treatment in mice treated with any of the Q203-containing regimens. In contrast, 15% of mice receiving RIF+STR for 4 weeks relapsed. We conclude that it may be possible to cure patients with Buruli ulcer in 14 days or less using Q203-containing regimens rather than currently recommended 56-day regimens.
PDF
