Under the conditions of oxidative gold catalysis, exposure of ethylene to aryl silanes and alcohols generates products of 1,2-oxyarylation. This provides a rare example of a process that allows ...catalytic differential 1,2-difunctionalization of this feedstock chemical.
Three-coordinate bipyridyl complexes of gold, (κ2-bipy)Au(η2-C2H4)NTf2, are readily accessed by direct reaction of 2,2′-bipyridine (bipy), or its derivatives, with the homoleptic gold ethylene ...complex Au(C2H4)3NTf2. The cheap and readily available bipyridyl ligands facilitate oxidative addition of aryl iodides to the Au(I) center to give (κ2-bipy)Au(Ar)INTf2, which undergo first aryl-zinc transmetalation and second C–C reductive elimination to produce biaryl products. The products of each distinct step have been characterized. Computational techniques are used to probe the mechanism of the oxidative addition step, offering insight into both the origin of the reversibility of this process and the observation that electron-rich aryl iodides add faster than electron-poor substrates. Thus, for the first time, all steps that are characteristic of a conventional intermolecular Pd(0)-catalyzed biaryl synthesis are demonstrated from a common monometallic Au complex and in the absence of directing groups.
Chronic low-grade inflammation is a hallmark of obesity and thought to contribute to the development of obesity-related insulin resistance. Toll-like receptor 4 (Tlr4) is a key mediator of ...pro-inflammatory responses. Mice lacking Tlr4s are protected from diet-induced insulin resistance and inflammation; however, which Tlr4-expressing cells mediate this effect is unknown. Here we show that mice deficient in hepatocyte Tlr4 (Tlr4LKO) exhibit improved glucose tolerance, enhanced insulin sensitivity and ameliorated hepatic steatosis despite the development of obesity after a high-fat diet (HFD) challenge. Furthermore, Tlr4LKO mice have reduced macrophage content in white adipose tissue, as well as decreased tissue and circulating inflammatory markers. In contrast, the loss of Tlr4 activity in myeloid cells has little effect on insulin sensitivity. Collectively, these data indicate that the activation of Tlr4 on hepatocytes contributes to obesity-associated inflammation and insulin resistance, and suggest that targeting hepatocyte Tlr4 might be a useful therapeutic strategy for the treatment of type 2 diabetes.
Charcot-Marie-Tooth disease type 1A (CMT1A), the most common inherited demyelinating peripheral neuropathy, is caused by PMP22 gene duplication. Over-expression of wild-type PMP22 in Schwann cells ...destabilizes the myelin sheath, leading to demyelination and ultimately to secondary axonal loss and disability. No treatments currently exist that modify the disease course. The most direct route to CMT1A therapy will involve reducing PMP22 to normal levels. To accomplish this, we developed a gene therapy strategy to reduce PMP22 using novel artificial microRNAs targeting human and mouse PMP22/Pmp22 mRNAs. Our lead therapeutic microRNA, miR871, was packaged into an AAV9 vector and delivered by lumbar intrathecal injection into C61-het mice, a model of CMT1A. AAV9-miR871 efficiently transduced Schwann cells in C61-het peripheral nerves and reduced human and mouse PMP22/Pmp22 mRNA and protein levels. Treatment at early and late stages of the disease significantly improved multiple functional outcome measures and nerve conduction velocities. Furthermore, myelin pathology in lumbar roots and femoral motor nerves was ameliorated. Treated mice also showed reductions in circulating biomarkers of CMT1A. Taken together, our data demonstrate that AAV9-miR871-driven silencing of PMP22 rescues a CMT1A model and provides proof of principle for treating CMT1A using a translatable gene therapy approach.
In 2019 October Betelgeuse began a decline in V-band brightness that went beyond the minimum expected from its quasi-periodic ∼420 day cycle, becoming the faintest in recorded photometric history. ...Observations obtained in 2019 December with Very Large Telescope/SPHERE have shown that the southern half of the star has become markedly fainter than in 2019 January, indicating that a major change has occurred in, or near, the photosphere. We present Stratospheric Observatory for Infrared Astronomy (SOFIA) Echelon Cross Echelle Spectrograph (EXES) high spectral-resolution observations of Fe ii and S i emission lines from Betelgeuse obtained during the unprecedented 2020 February V-band brightness minimum to investigate potential changes in the circumstellar flow. These spectra are compared to observations obtained in 2015 and 2017 when the V magnitude was typical of brighter phases. We find only very small changes in the gas velocities reflected by either of the line profiles, no significant changes in the flux to continuum ratios, and hence no significant changes in the Fe ii/S i flux ratios. There is evidence that absorption features have appeared in the 2020 continuum. The Alfvén wave-crossing time from the upper photosphere is sufficiently long that one would not expect a change in the large-scale magnetic field to reach the circumstellar Fe ii and S i line-forming regions, 3 < R (R*) < 20. However, the light-crossing time is of order a few hours and a reduction in luminosity may reduce the dust-gas heating rate and O i emission, which has contributions from R > 20R*, where significant circumstellar oxygen-rich dust is observed.
Ponds are among the most biodiverse and ecologically important freshwater habitats globally and may provide a significant opportunity to mitigate anthropogenic pressures and reverse the decline of ...aquatic biodiversity. Ponds also provide important contributions to society through the provision of ecosystem services. Despite the ecological and societal importance of ponds, freshwater research, policy, and conservation have historically focused on larger water bodies, with significant gaps remaining in our understanding and conservation of pond ecosystems. In May 2019, pond researchers and practitioners participated in a workshop to tackle several pond ecology, conservation, and management issues. Nine research themes and 30 research questions were identified during and following the workshop to address knowledge gaps around: (1) pond habitat definition; (2) global and long‐term data availability; (3) anthropogenic stressors; (4) aquatic–terrestrial interactions; (5) succession and disturbance; (6) freshwater connectivity; (7) pond monitoring and technological advances; (8) socio‐economic factors; and (9) conservation, management, and policy. Key areas for the future inclusion of ponds in environmental and conservation policy were also discussed. Addressing gaps in our fundamental understanding of pond ecosystems will facilitate more effective research‐led conservation and management of pondscapes, their inclusion in environmental policy, support the sustainability of ecosystem services, and help address many of the global threats driving the decline in freshwater biodiversity.
Three leading disease causes of age-related visual loss are cataract, age-related macular degeneration (AMD), and glaucoma. Although all 3 eye diseases have been implicated with falls and fracture ...risk, evidence is mixed, with the contribution of different eye diseases being uncertain.
To examine whether people with cataract, AMD, or glaucoma have higher risks of falls or fractures than those without.
This cohort study was a population-based study in England using routinely collected electronic health records from the Clinical Practice Research Datalink (CPRD) GOLD and Aurum primary care databases with linked hospitalization and mortality records from 2007 to 2020. Participants were people with cataract, AMD, or glaucoma matched to comparators (1:5) by age, sex, and general practice. Data were analyzed from May 2021 to June 2023.
For each eye disease, we estimated the risk of falls or fractures using separate multivariable Cox proportional hazards regression models.
Two primary outcomes were incident falls and incident fractures derived from general practice, hospital, and mortality records. Secondary outcomes were incident fractures of specific body sites.
A total of 410 476 people with cataract, 75 622 with AMD, and 90 177 with glaucoma were matched (1:5) to 2 034 194 (no cataract), 375 548 (no AMD), and 448 179 (no glaucoma) comparators. The mean (SD) age was 73.8 (11.0) years, 79.4 (9.4) years, and 69.8 (13.1) years for participants with cataract, AMD, or glaucoma, respectively. Compared with comparators, there was an increased risk of falls in those with cataract (adjusted hazard ratio HR, 1.36; 95% CI, 1.35-1.38), AMD (HR, 1.25; 95% CI, 1.23-1.27), and glaucoma (HR, 1.38; 95% CI, 1.35-1.41). Likewise for fractures, there were increased risks in all eye diseases, with an HR of 1.28 (95% CI, 1.27-1.30) in the cataract cohort, an HR of 1.18 (95% CI, 1.15-1.21) for AMD, and an HR of 1.31 (95% CI, 1.27-1.35) for glaucoma. Site-specific fracture analyses revealed increases in almost all body sites (including hip, spine, forearm, skull or facial bones, pelvis, ribs or sternum, and lower leg fractures) compared with matched comparators.
The results of this study support recognition that people with 1 or more of these eye diseases are at increased risk of both falls and fractures. They may benefit from improved advice, access, and referrals to falls prevention services.
Ovarian cancer is the sixth leading cause of cancer-related death in women, and both occurrence and mortality are increased in women over the age of 60. There are documented age-related changes in ...the ovarian cancer microenvironment that have been shown to create a permissive metastatic niche, including the formation of advanced glycation end products, or AGEs, that form crosslinks between collagen molecules. Small molecules that disrupt AGEs, known as AGE breakers, have been examined in other diseases, but their efficacy in ovarian cancer has not been evaluated. The goal of this pilot study is to target age-related changes in the tumor microenvironment with the long-term aim of improving response to therapy in older patients. Here, we show that AGE breakers have the potential to change the omental collagen structure and modulate the peritoneal immune landscape, suggesting a potential use for AGE breakers in the treatment of ovarian cancer.
Summary
Concerns about the future availability and continuity of metal supplies have triggered research efforts to define and assess metal criticality. In this study, we apply a comprehensive ...methodology to the elements of the geological zinc, tin, and lead family: zinc (Zn); germanium (Ge); cadmium (Cd); indium (In); tin (Sn); and lead (Pb). Zn, Sn, and Pb have played important roles in various technological sectors for centuries, whereas Ge, Cd, and In are by‐product metals that are increasingly utilized in emerging and strategic technologies. Criticality assessments are made on national (i.e., the United States) and global levels for 2008. The results are presented with uncertainty estimates in three‐dimensional “criticality space,” comprised of supply risk (SR), environmental implications, and vulnerability to supply restriction (VSR) axes. SR is the highest for In for both the medium (i.e., five to ten years) and long term (i.e., a few decades). Pb and Zn have the lowest SR for the medium term and Pb the lowest SR for the long term. In and Ge production have the highest environmental burdens, mainly as a result of emissions from Zn smelting and subsequent metals purification and recovery from Zn leaching residues. VSR is highest for Pb at the global and national levels.
Corticosteroid injections are commonly used to treat thumb carpometacarpal arthritis in adults. We aimed to define the timing of surgery following an initial corticosteroid injection and identify ...patient-specific factors that influence the likelihood of repeat injection or surgery.
We performed a retrospective analysis of all patients who underwent a first-time corticosteroid injection for carpometacarpal arthritis between 2009 and 2017. Demographic information, radiographic classification, additional nonsurgical therapies, complications, and outcomes were collected. Primary outcomes were repeat injection and surgical reconstruction. Kaplan-Meier survival analysis was used to characterize the timing of surgical intervention and Cox regression modeling was used to identify predictors of subsequent intervention.
Two-hundred thirty-nine patients (average age, 62.9 years) were identified, of which 141 (59.0%) had a repeat injection and 90 (37.6%) underwent surgery. There were no patient-specific characteristics associated with repeat injection. Eaton stage III/IV arthritis at initial presentation, current smoking status, and prior ipsilateral hand surgery were associated with an increased likelihood of surgery. By Kaplan-Meier analyses, 87.7% of patients who presented with Eaton III/IV arthritis did not have surgery within a year and 66.7% of these patients did not have surgery within 5 years.
In this retrospective observational cohort study with 10-year follow-up from a 4-surgeon practice, advanced radiographic arthritis, current smoking status, and a history of ipsilateral hand surgery were patient-specific factors that predicted progression to surgery following injection. Of patients who presented with advanced radiographic arthritis, one-third underwent surgery within 5 years of initial injection. Although injection efficacy and causality cannot be inferred based on an observational longitudinal analysis, these data identify patient-specific factors that may have an impact on surgical decision-making and a potential timeframe for future intervention.
Prognostic IV.
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