Doping isolated single atoms of a platinum-group metal into the surface of a noble-metal host is sufficient to dramatically improve the activity of the unreactive host yet also facilitates the ...retention of the host’s high reaction selectivity in numerous catalytic reactions. The atomically dispersed highly active sites in these single-atom alloy (SAA) materials are capable of performing facile bond activations allowing for the uptake of species onto the surface and the subsequent spillover of adspecies onto the noble host material, where selective catalysis can be performed. For example, SAAs have been shown to activate C–H bonds at low temperatures without coke formation, as well as selectively hydrogenate unsaturated hydrocarbons with excellent activity. However, to date, only a small subset of SAAs has been synthesized experimentally and it is unclear which metallic combinations may best catalyze which chemical reactions. To shed light on this issue, we have performed a widespread screening study using density functional theory to elucidate the fundamental adsorptive and catalytic properties of 12 SAAs (Ni-, Pd-, Pt-, and Rh-doped Cu(111), Ag(111), and Au(111)). We considered the interaction of these SAAs with a variety of adsorbates often found in catalysis and computed reaction mechanisms for the activation of several catalytically relevant species (H2, CH4, NH3, CH3OH, and CO2) by SAAs. Finally, we discuss the applicability of thermochemical linear scaling and the Brønsted–Evans–Polanyi relationship to SAA systems, demonstrating that SAAs combine weak binding with low activation energies to give enhanced catalytic behavior over their monometallic counterparts. This work will ultimately facilitate the discovery and development of SAAs, serving as a guide to experimentalists and theoreticians alike.
Despite advances in surgical technique and prosthetic technologies, the risks for recurrence and infection are high following the repair of incisional ventral hernias. High-quality data suggest that ...all ventral hernia repairs should be reinforced with prosthetic repair materials. The current standard for reinforced hernia repair is synthetic mesh, which can reduce the risk for recurrence in many patients. However, permanent synthetic mesh can pose a serious clinical problem in the setting of infection. Assessing patients' risk for wound infection and other surgical-site occurrences, therefore, is an outstanding need. To our knowledge, there currently exists no consensus in the literature regarding the accurate assessment of risk of surgical-site occurrences in association with or the appropriate techniques for the repair of incisional ventral hernias. This article proposes a novel hernia grading system based on risk factor characteristics of the patient and the wound. Using this system, surgeons may better assess each patient's risk for surgical-site occurrences and thereby select the appropriate surgical technique, repair material, and overall clinical approach for the patient. A generalized approach and technical considerations for the repair of incisional ventral hernias are outlined, including the appropriate use of component separation and the growing role of biologic repair materials.
Background
There has been recent interest in using pathological complete response (pCR) as a potential surrogate endpoint for long-term outcomes in the neoadjuvant treatment of high-risk, early-stage ...breast cancer.
Methods
We review the clinical trials that have contributed to our understanding of the association between pCR and long-term outcomes, describe the various definitions of pCR, describe patient populations in which pCR may predict long-term benefit, and discuss the implications of pCR on drug development and accelerated approval for neoadjuvant treatment of breast cancer.
Results
Varying definitions of pCR across clinical trials conducted in heterogeneous patient populations make understanding the association of pCR with long-term outcomes challenging. The US Food and Drug Administration established the Collaborative Trials in Neoadjuvant Breast Cancer group to evaluate the potential use of pCR as a regulatory endpoint. The group demonstrated that pCR defined as no residual invasive cancer in the breast and axillary nodes with presence or absence of in situ cancer (ypT0/is ypN0 or ypT0 ypN0) provided a better association with improved outcomes compared to eradication of invasive tumor from the breast alone (ypT0/is).
Conclusion
Even though pCR was not validated as a surrogate endpoint for long-term outcomes, the promising data regarding the strong association of pCR with substantially improved outcomes in individual patients with more aggressive subtypes of breast cancer supported the opening of an accelerated approval pathway for patients with high-risk, early-stage breast cancer.
The investment of nearly 2 decades of clinical investigation into cardiac cell therapy has yet to change cardiovascular practice. Recent insights into the mechanism of cardiac regeneration help ...explain these results and provide important context in which we can develop next-generation therapies. Non-contractile cells such as bone marrow or adult heart derivatives neither engraft long-term nor induce new muscle formation. Correspondingly, these cells offer little functional benefit to infarct patients. In contrast, preclinical data indicate that transplantation of bona fide cardiomyocytes derived from pluripotent stem cells induces direct remuscularization. This new myocardium beats synchronously with the host heart and induces substantial contractile benefits in macaque monkeys, suggesting that regeneration of contractile myocardium is required to fully recover function. Through a review of the preclinical and clinical trials of cardiac cell therapy, distinguishing the primary mechanism of benefit as either contractile or non-contractile helps appreciate the barriers to cardiac repair and establishes a rational path to optimizing therapeutic benefit.
Although we have convincing evidence that attention to auditory stimuli modulates neuronal responses at or before the level of primary auditory cortex (A1), the underlying physiological mechanisms ...are unknown. We found that attending to rhythmic auditory streams resulted in the entrainment of ongoing oscillatory activity reflecting rhythmic excitability fluctuations in A1. Strikingly, although the rhythm of the entrained oscillations in A1 neuronal ensembles reflected the temporal structure of the attended stream, the phase depended on the attended frequency content. Counter-phase entrainment across differently tuned A1 regions resulted in both the amplification and sharpening of responses at attended time points, in essence acting as a spectrotemporal filter mechanism. Our data suggest that selective attention generates a dynamically evolving model of attended auditory stimulus streams in the form of modulatory subthreshold oscillations across tonotopically organized neuronal ensembles in A1 that enhances the representation of attended stimuli.
► Selective attention results in a spatiotemporal modulation of excitability in A1 ► Subthreshold neuronal activity models attended auditory streams via entrainment ► Entrained neuronal oscillations across A1 act as a spectrotemporal filter mechanism ► Oscillatory entrainment modulates and stabilizes responses to attended stimuli
The study by Lakatos et al. shows that the spatiotemporal pattern of excitability fluctuations across neuronal ensembles in primary auditory cortex models both the temporal structure and spectral content of attended stimuli, which results in an enhancement and stabilization of their sensory representation.
Apixaban is an oral, direct factor Xa inhibitor that inhibits both free and clot-bound factor Xa, and has been approved for clinical use in several thromboembolic disorders, including reduction of ...stroke risk in non-valvular atrial fibrillation, thromboprophylaxis following hip or knee replacement surgery, the treatment of deep vein thrombosis or pulmonary embolism, and prevention of recurrent deep vein thrombosis and pulmonary embolism. The absolute oral bioavailability of apixaban is ~ 50%. Food does not have a clinically meaningful impact on the bioavailability. Apixaban exposure increases dose proportionally for oral doses up to 10 mg. Apixaban is rapidly absorbed, with maximum concentration occurring 3–4 h after oral administration, and has a half-life of approximately 12 h. Elimination occurs via multiple pathways including metabolism, biliary excretion, and direct intestinal excretion, with approximately 27% of total apixaban clearance occurring via renal excretion. The pharmacokinetics of apixaban are consistent across a broad range of patients, and apixaban has limited clinically relevant interactions with most commonly prescribed medications, allowing for fixed dosages without the need for therapeutic drug monitoring. The pharmacodynamic effect of apixaban is closely correlated with apixaban plasma concentration. This review provides a summary of the pharmacokinetic, pharmacodynamic, biopharmaceutical, and drug–drug interaction profiles of apixaban. Additionally, the population-pharmacokinetic analyses of apixaban in both healthy subjects and in the target patient populations are discussed.
Our knowledge of pluripotent stem cell (PSC) biology has advanced to the point where we now can generate most cells of the human body in the laboratory. PSC-derived cardiomyocytes can be generated ...routinely with high yield and purity for disease research and drug development, and these cells are now gradually entering the clinical research phase for the testing of heart regeneration therapies. However, a major hurdle for their applications is the immature state of these cardiomyocytes. In this Review, we describe the structural and functional properties of cardiomyocytes and present the current approaches to mature PSC-derived cardiomyocytes. To date, the greatest success in maturation of PSC-derived cardiomyocytes has been with transplantation into the heart in animal models and the engineering of 3D heart tissues with electromechanical conditioning. In conventional 2D cell culture, biophysical stimuli such as mechanical loading, electrical stimulation and nanotopology cues all induce substantial maturation, particularly of the contractile cytoskeleton. Metabolism has emerged as a potent means to control maturation with unexpected effects on electrical and mechanical function. Different interventions induce distinct facets of maturation, suggesting that activating multiple signalling networks might lead to increased maturation. Despite considerable progress, we are still far from being able to generate PSC-derived cardiomyocytes with adult-like phenotypes in vitro. Future progress will come from identifying the developmental drivers of maturation and leveraging them to create more mature cardiomyocytes for research and regenerative medicine.
Abstract A-to-I RNA editing, the deamination of adenosine (A) to inosine (I) that occurs in regions of RNA with double-stranded character, is catalyzed by a family of Adenosine Deaminases Acting on ...RNA (ADARs). In mammals there are three ADAR genes. Two encode proteins that possess demonstrated deaminase activity: ADAR1, which is interferon-inducible, and ADAR2 which is constitutively expressed. ADAR3, by contrast, has not yet been shown to be an active enzyme. The specificity of the ADAR1 and ADAR2 deaminases ranges from highly site-selective to non-selective, dependent on the duplex structure of the substrate RNA. A-to-I editing is a form of nucleotide substitution editing, because I is decoded as guanosine (G) instead of A by ribosomes during translation and by polymerases during RNA-dependent RNA replication. Additionally, A-to-I editing can alter RNA structure stability as I:U mismatches are less stable than A:U base pairs. Both viral and cellular RNAs are edited by ADARs. A-to-I editing is of broad physiologic significance. Among the outcomes of A-to-I editing are biochemical changes that affect how viruses interact with their hosts, changes that can lead to either enhanced or reduced virus growth and persistence depending upon the specific virus.
A novel coronavirus now known as SARS-CoV-2 emerged in late 2019, possibly following a zoonotic crossover from a coronavirus present in bats. This virus was identified as the pathogen responsible for ...the severe respiratory disease, coronavirus disease-19 (COVID-19), which as of May 2023, has killed an estimated 6.9 million people globally according to the World Health Organization. The interferon (IFN) response, a cornerstone of antiviral innate immunity, plays a key role in determining the outcome of infection by SARS-CoV-2. This review considers evidence that SARS-CoV-2 infection leads to IFN production; that virus replication is sensitive to IFN antiviral action; molecular mechanisms by which the SARS-CoV-2 virus antagonizes IFN action; and how genetic variability of SARS-CoV-2 and the human host affects the IFN response at the level of IFN production or action or both. Taken together, the current understanding suggests that deficiency of an effective IFN response is an important determinant underlying some cases of critical COVID-19 disease and that IFNλ and IFNα/β have potential as therapeutics for the treatment of SARS-CoV-2 infection.
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