1,2,3,5-Tetrakis(carbazol-9-yl)-4,6-dicyanobenzene (4CzIPN) is a typical donor-acceptor fluorophore, with carbazolyl as an electron donor and dicyanobenzene as an electron acceptor. It has emerged as ...a powerful organophotocatalyst since 2016. Excellent redox window, good chemical stability and broad applicability make 4CzIPN an attractive metal-free photocatalyst. In this review, the recent advances of the application of 4CzIPN as a photoredox catalyst in the past three years (2016-2018) for various organic reactions are summarized.
In this review, the recent advances of the application of 1,2,3,5-tetrakis(carbazol-9-yl)-4,6-dicyanobenzene (4CzIPN) as a photoredox catalyst in the past three years (2016-2018) for various organic reactions are summarized.
Constructing efficient cell factories for product synthesis is frequently hampered by competing pathways and/or insufficient precursor supply. This is particularly evident in the case of triterpenoid ...biosynthesis in
, where squalene biosynthesis is tightly coupled to cytosolic biosynthesis of sterols essential for cell viability. Here, we addressed this problem by reconstructing the complete squalene biosynthetic pathway, starting from acetyl-CoA, in the peroxisome, thus harnessing peroxisomal acetyl-CoA pool and sequestering squalene synthesis in this organelle from competing cytosolic reactions. This strategy led to increasing the squalene levels by 1,300-fold relatively to native cytosolic synthesis. Subsequent enhancement of the peroxisomal acetyl-CoA supply by two independent approaches, 1) converting cellular lipid pool to peroxisomal acetyl-CoA and 2) establishing an orthogonal acetyl-CoA shortcut from CO
-derived acetate in the peroxisome, further significantly improved local squalene accumulation. Using these approaches, we constructed squalene-producing strains capable of yielding 32.8 g/L from glucose, and 31.6 g/L from acetate by employing a cofeeding strategy, in bioreactor fermentations. Our findings provide a feasible strategy for protecting intermediate metabolites that can be claimed by multiple reactions by engineering peroxisomes in
as microfactories for the production of such intermediates and in particular acetyl-CoA-derived metabolites.
Carbapenems are considered as last-resort antibiotics for the treatment of infections caused by multidrug-resistant Gram-negative bacteria. With the increasing use of carbapenems in clinical ...practice, the emergence of carbapenem-resistant pathogens now poses a great threat to human health. Currently, antibiotic options for the treatment of carbapenem-resistant
(CRE) are very limited, with polymyxins, tigecycline, fosfomycin, and aminoglycosides as the mainstays of therapy. The need for new and effective anti-CRE therapies is urgent. Here, we describe the current understanding of issues related to CRE and review combination therapeutic strategies for CRE infections, including high-dose tigecycline, high-dose prolonged-infusion of carbapenem, and double carbapenem therapy. We also review the newly available antibiotics which have potential in the future treatment of CRE infections: ceftazidime/avibactam, which is active against KPC and OXA-48 producers; meropenem/vaborbactam, which is active against KPC producers; plazomicin, which is a next-generation aminoglycoside with
activity against CRE; and eravacycline, which is a tetracycline class antibacterial with
activity against CRE. Although direct evidence for CRE treatment is still lacking and the development of resistance is a concern, these new antibiotics provide additional therapeutic options for CRE infections. Finally, we review other potential anti-CRE antibiotics in development: imipenem/relebactam and cefiderocol. Currently, high-dose and combination strategies that may include the new β-lactam/β-lactamase inhibitors should be considered in severe CRE infections to maximize treatment success. In the future, when more treatment options are available, therapy for CRE infections should be individualized and based on molecular phenotypes of resistance, susceptibility profiles, disease severity, and patient characteristics. More high-quality studies are needed to guide effective treatment for infections caused by CRE.
The sigma-1 receptor (Sig-1R) is an endoplasmic reticulum (ER) protein that resides specifically in the mitochondria-associated endoplasmic reticulum (ER) membrane (MAM), an interface between ER and ...mitochondria. In addition to being able to translocate to the plasma membrane (PM) to interact with ion channels and other receptors, Sig-1R also occurs at the nuclear envelope, where it recruits chromatin-remodeling factors to affect the transcription of genes. Sig-1Rs have also been reported to interact with other membranous or soluble proteins at other loci, including the cytosol, and to be involved in several central nervous system (CNS) diseases. Here, we propose that Sig-1R is a pluripotent modulator with resultant multiple functional manifestations in living systems.
The sigma-1 receptor (Sig-1R) is a chaperone that resides mainly at the mitochondrion-associated endoplasmic reticulum (ER) membrane (called the MAMs) and acts as a dynamic pluripotent modulator in ...living systems. At the MAM, the Sig-1R is known to play a role in regulating the Ca
signaling between ER and mitochondria and in maintaining the structural integrity of the MAM. The MAM serves as bridges between ER and mitochondria regulating multiple functions such as Ca
transfer, energy exchange, lipid synthesis and transports, and protein folding that are pivotal to cell survival and defense. Recently, emerging evidences indicate that the MAM is critical in maintaining neuronal homeostasis. Thus, given the specific localization of the Sig-1R at the MAM, we highlight and propose that the direct or indirect regulations of the Sig-1R on mitochondrial functions may relate to neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD) and amyotrophic lateral sclerosis (ALS). In addition, the promising use of Sig-1R ligands to rescue mitochondrial dysfunction-induced neurodegeneration is addressed.
The primary analysis of the ICARIA-MM study showed significant improvement in progression-free survival with addition of isatuximab to pomalidomide–dexamethasone in relapsed and refractory multiple ...myeloma. Here, we report a prespecified updated overall survival analysis at 24 months after the primary analysis.
In this randomised, multicentre, open-label, phase 3 study adult patients (aged ≥18 years) with relapsed and refractory multiple myeloma who had received at least two previous lines of therapy, including lenalidomide and a proteasome inhibitor, and had an Eastern Cooperative Oncology Group performance status of 0–2 were recruited from 102 hospitals in 24 countries across Europe, North America, and the Asia-Pacific regions. Patients were excluded if they had anti-CD38 refractory disease or previously received pomalidomide. Patients were randomly assigned (1:1), using an interactive response technology with permuted blocked randomisation (block size of four) and stratified by number of previous treatment lines (2–3 vs >3) and aged (<75 vs ≥75 years), to isatuximab–pomalidomide–dexamethasone (isatuximab group) or pomalidomide–dexamethasone (control group). In the isatuximab group, intravenous isatuximab 10 mg/kg was administered on days 1, 8, 15, and 22 of the first 4-week cycle, and then on days 1 and 15 of subsequent cycles. Both groups received oral pomalidomide 4 mg on days 1–21 of each cycle, and weekly oral or intravenous dexamethasone 40 mg (20 mg if aged ≥75 years) on days 1, 8, 15, and 22 of each cycle. Treatment was continued until disease progression, unacceptable toxicity, or withdrawal of consent. Here' we report a prespecified second interim analysis of overall survival (time from randomisation to any-cause death), a key secondary endpoint, in the intention-to-treat population (ie, all patients who provided informed consent and allocated a randomisation number) at 24 months after the primary analysis. Safety was assessed in all patients who received at least one dose or part dose of study treatment. The prespecified stopping boundary for the overall survival analysis was when the derived p value was equal to or less than 0·0181. This study is registered with ClinicalTrials.gov, NCT02990338, and is active, but not recruiting.
Between Jan 10, 2017, and Feb 2, 2018, 387 patients were screened and 307 randomly assigned to either the isatuximab (n=154) or control group (n=153). Median follow-up at data cutoff (Oct 1, 2020) was 35·3 months (IQR 33·5–37·4). Median overall survival was 24·6 months (95% CI 20·3–31·3) in the isatuximab group and 17·7 months (14·4–26·2) in the control group (hazard ratio 0·76 95% CI 0·57–1·01; one-sided log-rank p=0·028, not crossing prespecified stopping boundary). The most common grade 3 or worse treatment-emergent adverse events in the isatuximab group versus the control group were neutropenia (76 50% of 152 patients vs 52 35% of 149 patients), pneumonia (35 23% vs 31 21%), and thrombocytopenia (20 13% vs 18 12%). Serious treatment-emergent adverse events were observed in 111 (73%) patients in the isatuximab group and 90 (60%) patients in the control group. Two (1%) treatment-related deaths occurred in the isatuximab group (one due to sepsis and one due to cerebellar infarction) and two (1%) occurred in the control group (one due to pneumonia and one due to urinary tract infection).
Addition of isatuximab plus pomalidomide–dexamethasone resulted in a 6·9-month difference in median overall survival compared with pomalidomide–dexamethasone and is a new standard of care for lenalidomide-refractory and proteasome inhibitor-refractory or relapsed multiple myeloma. Final overall survival analysis follow-up is ongoing.
Sanofi.
A wideband circular patch antenna (CPA) is proposed and fabricated in this article. Based on the cavity mode theory of circular patch, four resonant modes of quasi-TM 01 , quasi-TM 02 , quasi-TM 03 , ...and quasi-TM 04 are merged together to obtain a wide passband through cutting slots and adding short pins on the driven patch. In order to generate low stopband radiation nulls, two circles of defected ground structures (DGSs) are designed. Meanwhile, a stacked patch is added above the driven patch to obtain an upper edge radiation null. The experimental results achieve the 10 dB impedance bandwidth of 30.3% from 5.3 to 7.19 GHz with an overall size of <inline-formula> <tex-math notation="LaTeX">1.84\,\,\lambda _{0} \times 1.84\lambda _{0} \times 0.05 \lambda _{0} </tex-math></inline-formula> (<inline-formula> <tex-math notation="LaTeX">\lambda _{0} </tex-math></inline-formula> is the free space wavelength at 6 GHz). Without any extra filtering circuit, the proposed antenna obtains the sharp band edge with a stopband suppression level of 15.7 dB. The out-of-roundness of the radiation pattern in the H-plane is less than 2.7 dB in passband. With good performance in wideband, omnidirectivity, low profile, and high stopband suppression, the proposed antenna has great application prospects in the high-integration microwave systems of large unmanned aerial vehicles.
The sigma-1 receptor (Sig-1R) chaperone at the endoplasmic reticulum (ER) plays important roles in cellular regulation. Here we found a new function of Sig-1R, in that it translocates from the ER to ...the nuclear envelope (NE) to recruit chromatin-remodeling molecules and regulate the gene transcription thereof. Sig-1Rs mainly reside at the ER-mitochondrion interface. However, on stimulation by agonists such as cocaine, Sig-1Rs translocate from ER to the NE, where Sig-1Rs bind NE protein emerin and recruit chromatin-remodeling molecules, including lamin A/C, barrier-to-autointegration factor (BAF), and histone deacetylase (HDAC), to form a complex with the gene repressor specific protein 3 (Sp3). Knockdown of Sig-1Rs attenuates the complex formation. Cocaine was found to suppress the gene expression of monoamine oxidase B (MAOB) in the brain of wild-type but not Sig-1R knockout mouse. A single dose of cocaine (20 mg/kg) in rats suppresses the level of MAOB at nuclear accumbens without affecting the level of dopamine transporter. Daily injections of cocaine in rats caused behavioral sensitization. Withdrawal from cocaine in cocaine-sensitized rats induced an apparent time-dependent rebound of the MAOB protein level to about 200% over control on day 14 after withdrawal. Treatment of cocaine-withdrawn rats with the MAOB inhibitor deprenyl completely alleviated the behavioral sensitization to cocaine. Our results demonstrate a role of Sig-1R in transcriptional regulation and suggest cocaine may work through this newly discovered genomic action to achieve its addictive action. Results also suggest the MAOB inhibitor deprenyl as a therapeutic agent to block certain actions of cocaine during withdrawal.
Sarcopenic obesity (SO), which refers to the coexistence of sarcopenia and obesity. It can lead to physical disability, morbidity, and even mortality. This systematic review and meta-analysis aimed ...to estimate the global prevalence of SO in older adults.
We searched PubMed, Embase, and Web of Science for studies reporting the prevalence of SO from inception to December 2020. Two researchers independently screened the literature, evaluated study quality, and extracted data. A random-effects model was used to pool the estimates for the prevalence of SO. Subgroup analysis, sensitivity analysis, and meta-regression analysis were conducted. Publication bias was assessed using a funnel plot and the Egger test. All statistical analyses were performed using Stata 15.0 software.
This review included 50 studies, we found that the global prevalence of SO in older adults was 11%. Subgroup analyses showed that the prevalence of SO was higher among studies using diagnostic criteria of muscle mass alone (15%) to diagnose sarcopenia, using dual-energy X-ray absorptiometry (15%) to assess muscle mass, and those focused on age ≥ 75 years old (23%), hospitalized (16%), South Americans (21%) and North Americans (19%). There were no significant differences in the prevalence of SO among studies using body fat percentage (10%), body mass index (13%), waist circumference (16%) to diagnose obesity and in female (14%), male (10%) patients. Sensitivity analysis showed that none of the studies affected the overall pooled results. Meta-regression analysis found that publication year, geographical region, study setting, and the diagnostic criteria of sarcopenia were sources of heterogeneity.
This meta-analysis indicated SO affects more than one in ten older adults globally. Therefore, we should attach importance to the screening and early diagnosis of SO in older adults, then selecting appropriate interventions to reduce the occurrence of it and various adverse outcomes in this demographic.
When two antennas working in different frequency bands are placed in proximity, they suffer from strong cross-band interactions that degrade their radiation performance and reduce the isolation ...between them. This paper presents holistic methods to simultaneously suppress cross-band scattering and coupling. Specifically, we develop a systematic solution to suppress the scattering of low-band (LB) antennas to high-band (HB) radiation as well as the scattering of HB antennas to LB radiation using three new techniques. This leads to much reduced cross-band coupling between the LB and HB antennas. The proposed methods are applied to a "1 LB + 1 HB" dual-band array configuration with only one LB cross-dipole and one HB cross-dipole placed side-by-side to exclude the effects of the array topology. The robustness of the proposed methods is comprehensively verified for different scenarios by simulations and experiments. Furthermore, the methods are evaluated in a "1 LB + 4 HB" array configuration. In addition to effectively suppressing cross-band scattering and coupling, the proposed methods also demonstrated a significant reduction in in-band coupling between adjacent HB antennas.
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