Access to Macrocycles with an endo Aryl Ether and an endo Aryl-Aryl Bond, Development and Application

Macrocyclization methodologies allowing access to macrocycles having an endo aryl ether and an endo aryl–aryl bond, especially those based on an intramolecular SNAr reaction and the Suzuki-Miyaura reaction, are summarized. Total synthesis of complestatin, a bis-macrocyclic natural product, featuring these two technologies are presented

Dynamic causal effects evaluation in A/B testing with a reinforcement learning framework

A/B testing, or online experiment is a standard business strategy to compare a new product with an old one in pharmaceutical, technological, and traditional industries. Major challenges arise in online experiments of two-sided marketplace platforms (e.g., Uber) where there is only one unit that receives a sequence of treatments over time. In those experiments, the treatment at a given time impacts current outcome as well as future outcomes. The aim of this article is to introduce a reinforcement learning framework for carrying A/B testing in these experiments, while characterizing the long-term treatment effects. Our proposed testing procedure allows for sequential monitoring and online updating. It is generally applicable to a variety of treatment designs in different industries. In addition, we systematically investigate the theoretical properties (e.g., size and power) of our testing procedure. Finally, we apply our framework to both simulated data and a real-world data example obtained from a technological company to illustrate its advantage over the current practice. A Python implementation of our test is available at https://github.com/callmespring/CausalRL. Supplementary materials for this article are available online

A Reinforcement Learning Framework for Time-Dependent Causal Effects Evaluation in A/B Testing

A/B testing, or online experiment is a standard business strategy to compare a new product with an old one in pharmaceutical, technological, and traditional industries. Major challenges arise in online experiments where there is only one unit that receives a sequence of treatments over time. In those experiments, the treatment at a given time impacts current outcome as well as future outcomes. The aim of this paper is to introduce a reinforcement learning framework for carrying A/B testing, while characterizing the long-term treatment effects. Our proposed testing procedure allows for sequential monitoring and online updating, so it is generally applicable to a variety of treatment designs in different industries. In addition, we systematically investigate the theoretical properties (e.g., asymptotic distribution and power) of our testing procedure. Finally, we apply our framework to both synthetic datasets and a real-world data example obtained from a ride-sharing company to illustrate its usefulness

Bed level changes in the surf zone during post-storm beach recovery

The study of post-storm beach recovery is important for economic development and the protection of life in coastal areas. In this study, field observations were conducted for 21 days in the surf zone of Dongdao Beach, Hailing Island, China, after tropical storm “Cempaka”. Data on depth, wave, Eulerian velocity, sediment, three-dimensional topography of the beach, and high-frequency variations in bed-level elevation were collected. The results showed that the beach experienced medium- to low- to medium-energy waves during field observations and covered two complete astronomical tide cycles. Contrary to the effect of wave energy conditions on beaches under normal wave conditions, a higher wave energy during beach recovery can promote silting and accelerate beach recovery. Tidal water level is an important factor affecting beach restoration, and a smaller tidal range is conducive to beach accretion. In a mixed semidiurnal tide, beach erosion and accretion occurred in the “highest tide” and “sub-highest tide” tidal cycles, respectively, and the combined effect of the two affected the change in the bed level in a mixed semidiurnal tide. After the storm, the hydrodynamic forcing mechanism and self-organization process of the sand bar jointly drove the formation of the topography of the bar channel in the surf zone. After the storm stopped, the spectral energy in free surface elevation was mainly distributed in the very low frequency and decayed rapidly at the infragravity band. The very low-frequency pulsation of the surf zone during recovery is a prominent feature of bed-level elevation, depth, and velocity. This study provides a good case for the study of hydrodynamic and bed level changes in the post-storm surf zone, as well as a reference for future studies of the intrinsic mechanisms post-storm beach recovery processes around the world

A missense mutation in Pitx2 leads to early-onset glaucoma via NRF2-YAP1 axis.

Glaucoma is a leading cause of blindness, affecting 70 million people worldwide. Owing to the similarity in anatomy and physiology between human and mouse eyes and the ability to genetically manipulate mice, mouse models are an invaluable resource for studying mechanisms underlying disease phenotypes and for developing therapeutic strategies. Here, we report the discovery of a new mouse model of early-onset glaucoma that bears a transversion substitution c. G344T, which results in a missense mutation, p. R115L in PITX2. The mutation causes an elevation in intraocular pressure (IOP) and progressive death of retinal ganglion cells (RGC). These ocular phenotypes recapitulate features of pathologies observed in human glaucoma. Increased oxidative stress was evident in the inner retina. We demonstrate that the mutant PITX2 protein was not capable of binding to Nuclear factor-like 2 (NRF2), which regulates Pitx2 expression and nuclear localization, and to YAP1, which is necessary for co-initiation of transcription of downstream targets. PITX2-mediated transcription of several antioxidant genes were also impaired. Treatment with N-Acetyl-L-cysteine exerted a profound neuroprotective effect on glaucoma-associated neuropathies, presumably through inhibition of oxidative stress. Our study demonstrates that a disruption of PITX2 leads to glaucoma optic pathogenesis and provides a novel early-onset glaucoma model that will enable elucidation of mechanisms underlying the disease as well as to serve as a resource to test new therapeutic strategies

Effect of Tanshinone IIA on gut microbiome in diabetes-induced cognitive impairment

Diabetes-induced cognitive impairment (DCI) presents a major public health risk among the aging population. Previous clinical attempts on known therapeutic targets for DCI, such as depleted insulin secretion, insulin resistance, and hyperglycaemia have delivered poor patient outcomes. However, recent evidence has demonstrated that the gut microbiome plays an important role in DCI by modulating cognitive function through the gut–brain crosstalk. The bioactive compound tanshinone IIA (TAN) has shown to improve cognitive and memory function in diabetes mellitus models, though the pharmacological actions are not fully understood. This study aims to investigate the effect and underlying mechanism of TAN in attenuating DCI in relation to regulating the gut microbiome. Metagenomic sequencing analyses were performed on a group of control rats, rats with diabetes induced by a high-fat/high-glucose diet (HFD) and streptozotocin (STZ) (model group) and TAN-treated diabetic rats (TAN group). Cognitive and memory function were assessed by the Morris water maze test, histopathological assessment of brain tissues, and immunoblotting of neurological biomarkers. The fasting blood glucose (FBG) level was monitored throughout the experiments. The levels of serum lipopolysaccharide (LPS) and tumor necrosis factor-α (TNF-α) were measured by enzyme-linked immunoassays to reflect the circulatory inflammation level. The morphology of the colon barrier was observed by histopathological staining. Our study confirmed that TAN reduced the FBG level and improved the cognitive and memory function against HFD- and STZ-induced diabetes. TAN protected the endothelial tight junction in the hippocampus and colon, regulated neuronal biomarkers, and lowered the serum levels of LPS and TNF-α. TAN corrected the reduced abundance of Bacteroidetes in diabetic rats. At the species level, TAN regulated the abundance of B. dorei, Lachnoclostridium sp. YL32 and Clostridiodes difficile. TAN modulated the lipid metabolism and biosynthesis of fatty acids in related pathways as the main functional components. TAN significantly restored the reduced levels of isobutyric acid and butyric acid. Our results supported the use of TAN as a promising therapeutic agent for DCI, in which the underlying mechanism may be associated with gut microbiome regulation