Heterobicyclic inhibitors of transforming growth factor beta receptor I (TGFßRI).

The TGFß-TGFßR signaling pathway has been reported to play a protective role in the later stages of tumorigenesis via increasing immunosuppressive Treg cells and facilitating the epithelial to mesenchymal transition (EMT). Therefore, inhibition of TGFßR has the potential to enhance antitumor immunity. Herein we disclose the identification and optimization of novel heterobicyclic inhibitors of TGFßRI that demonstrate potent inhibition of SMAD phosphorylation. Application of structure-based drug design to the novel pyrrolotriazine chemotype resulted in improved binding affinity (Ki apparent = 0.14 nM), long residence time (T1/2 > 120 min) and significantly improved potency in the PSMAD cellular assay (IC50 = 24 nM). Several analogs inhibited phosphorylation of SMAD both in vitro and in vivo. Additionally, inhibition of TGFß-stimulated phospho-SMAD was observed in primary human T cells.

Impact of bathymetry on Indian Ocean circulation in a nested regional ocean model.

The Regional Indian Ocean model based on Modular Ocean Model (MOM4p1) was used to understand the importance of a realistic representation of bathymetry on Ocean General Circulation. The model has 1/4° uniform horizontal resolution and is forced with Coordinated Ocean-Ice Reference Experiments (CORE-II) inter-annual forcing with two simulations named BLND (realistic bathymetry) and OM3 (smoothed bathymetry), which only differ in the representation of bathymetry for the years 1992-2005. We also used recent reanalysis products from ORAS5 and SODA3 and ADCP observation to compare the subsurface currents. We show that by the inclusion of realistic bathymetry, there is a significant improvement in the upper ocean salinity, temperature, and currents, particularly near the coast. The salinity and temperature of the upper ocean are very close to the observed value near the coast. The bias in the salinity and temperature was reduced to half in BLND simulation compared to OM3, which led to a more realistic East India Coastal Current (EICC). We show the first evidence of a basin-wide cyclonic gyre over the Bay of Bengal at 1000 m depth during spring, which is just opposite to that of a basin-wide anti-cyclonic gyre at the surface. We found the presence of poleward EICC during spring at 1000 m and 2000 m depth, which is opposite to that of the surface. The presence of this deeper EICC structure is completely absent during fall. We show the presence of a boundary current along the coast of Andaman and Nicobar Island at a depth of 2000 m. The observed Wyrtki Jet (WJ) magnitude and spatial structure are most realistically reproduced in BLND simulation as compared to OM3 simulations. Both ORAS5 and SODA reanalysis products underestimate the WJ magnitude. The presence of the Maldives Islands is responsible for the westward extent of Equatorial Under Current (EUC). The presence of Maldives also creates wakes on the leeward side in the EUC zonal current. During fall, EUC is better defined in the eastern Equatorial Indian Ocean and lies at a depth of between 50 and 100 m, unlike its spring counterpart, in which its core is located slightly deeper, between 100 and 150 m depth. During peak summer months, June-July, a strong eastward zonal jet is present at 1000 m depth, similar to Wyrtki Jet (WJ). Inter-monsoon Jets, i.e., spring and fall jets, are also seen but are in the opposite direction, i.e., westward, unlike eastward in WJ.

Quantifying the role of antecedent Southwestern Indian Ocean capacitance on the summer monsoon rainfall variability over homogeneous regions of India.

The role of ocean variability is at a focal point in improving the weather and climate forecasts at different spatial and temporal scales. We study the effect of antecedent southwestern Indian Ocean mean sea level anomaly (MSLA) and sea surface temperature anomalies (SSTA) as a proxy to upper ocean heat capacitance on all India summer monsoon rainfall (AISMR) during 1993-2019. SSTA and MSLA over the southwestern Indian Ocean (SWIO) have been influenced by El Niño-Southern Oscillation (ENSO), the impact of ENSO-induced SWIO variability was low on rainfall variability over several homogeneous regions. Rainfall over northeast (NE) and North India (EI) has been modulated by ENSO-induced SSTA and MSLA over SWIO, thus effecting the total AISMR magnitude. The ENSO-induced changes in heat capacitance (SSTA and MSLA) over SWIO during antecedent months has less impact on west coast of India, central India and North India (NI) rainfall variability. The long-term trend in pre-monsoonal SSTA and MSLA over SWIO shows decreasing rainfall trend over NI, NE, and EI in the recent time. Furthermore, the cooler (warmer) anomaly over the western Indian Ocean affects rainfall variability adversely (favourably) due to the reversal of the wind pattern during the pre-monsoon period. While SSTA and MSLA are increasing in the SWIO, large-scale variability of these parameters during preceding winter and pre-monsoon months combined with surface winds could impact the inter-annual AISMR variability over homogeneous regions of India. Similarly, from an oceanic perspective, the antecedent heat capacitance over SWIO on an inter-annual time scale has been the key to the extreme monsoon rainfall variability.

Diode Characteristics in Magnetic Domain Wall Devices via Geometrical Pinning for Neuromorphic Computing.

Neuromorphic computing (NC) is considered a potential vehicle for implementing energy-efficient artificial intelligence. To realize NC, several technologies are being investigated. Among them, the spin-orbit torque (SOT)-driven domain wall (DW) devices are one of the potential candidates. Researchers have proposed different device designs to achieve neurons and synapses, the building blocks of NC. However, the experimental realization of DW device-based NC is only at the primeval stage. Here, we have studied pine-tree DW devices, based on the Laplace pressure on the elastic DWs, for achieving synaptic functionalities and diode-like characteristics. We demonstrate an asymmetric pinning strength for DW motion in two opposite directions to show the potential of these devices as DW diodes. We have used micromagnetic simulations to understand the experimental findings and to estimate the Laplace pressure for various design parameters. The study provides a strategy to fabricate a multifunctional DW device, exhibiting synaptic properties and diode characteristics.

Dihydrooxazine oxides as key intermediates in organocatalytic Michael additions of aldehydes to nitroalkenes.

Pause and play: dihydrooxazine oxides are stable intermediates that are protonated directly, without the intermediacy of the zwitterions, in organocatalytic Michael additions of aldehydes and nitroalkenes (see scheme, R=alkyl). Protonation of these species explains both the role of the acid co-catalyst in these reactions, and the observed stereochemistry when the reaction is conducted with α-alkylnitroalkenes.

Discovery of BMS-986260, a Potent, Selective, and Orally Bioavailable TGFßR1 Inhibitor as an Immuno-oncology Agent.

Novel imidazole-based TGFßR1 inhibitors were identified and optimized for potency, selectivity, and pharmacokinetic and physicochemical characteristics. Herein, we report the discovery, optimization, and evaluation of a potent, selective, and orally bioavailable TGFßR1 inhibitor, 10 (BMS-986260). This compound demonstrated functional activity in multiple TGFß-dependent cellular assays, excellent kinome selectivity, favorable pharmacokinetic properties, and curative in vivo efficacy in combination with anti-PD-1 antibody in murine colorectal cancer (CRC) models. Since daily dosing of TGFßR1 inhibitors is known to cause class-based cardiovascular (CV) toxicities in preclinical species, a dosing holiday schedule in the anti-PD-1 combination efficacy studies was explored. An intermittent dosing regimen of 3 days on and 4 days off allowed mitigation of CV toxicities in one month dog and rat toxicology studies and also provided similar efficacy as once daily dosing.

A multiple gap plasma cathode electron gun and its electron beam analysis in self and trigger breakdown modes.

In the present paper, a pseudospark discharge based multiple gap plasma cathode electron gun is reported which has been operated separately in self and trigger breakdown modes using two different gases, namely, argon and hydrogen. The beam current and beam energy have been analyzed using a concentric ring diagnostic arrangement. Two distinct electron beams are clearly seen with hollow cathode and conductive phases. The hollow cathode phase has been observed for ∼50 ns where the obtained electron beam is having low beam current density and high energy. While in conductive phase it is high current density and low energy electron beam. It is inferred that in the hollow cathode phase the beam energy is more for the self breakdown case whereas the current density is more for the trigger breakdown case. The tailor made operation of the hollow cathode phase electron beam can play an important role in microwave generation. Up to 30% variation in the electron beam energy has been achieved keeping the same gas and by varying the breakdown mode operations. Also, up to 32% variation in the beam current density has been achieved for the trigger breakdown mode at optimized trigger position by varying the gas type.