New Frontier

ABSTRACT The agricultural innovation systems (AIS) approach holds promise for researchers seeking to gain deeper understanding of how actors, norms, and knowledge interact and drive improvements in the agricultural sector in developing countries. However, use of the AIS framework in empirical research is limited and conceptual and operational frameworks are needed. In this paper we have created a conceptual framework for how innovation platforms (IPs), a unique type of multistakeholder meetings, contribute to the AIS approach by fostering innovation, networking, and performance. The conceptual framework is then applied to a case study of the Feed the Future Innovation Lab for Livestock Systems (LSIL). Findings from the case study analysis showed the meetings fostered innovative thinking, strengthened networks, and shared knowledge among actors. While the generalisability of the case is limited, the study demonstrates how future research could use the conceptual framework for advancing knowledge around AIS and IP meetings.

The association between the triglyceride-glucose (TyG) index and impaired fasting glucose (IFG) in elderly individuals remains uncertain. Our study aimed to explore the association between the TyG index and the risk of future IFG in this population. This retrospective cohort study included 17,746 elderly individuals over 60. In this population, Cox regression models proportional to hazards, along with smooth curve fitting and cubic spline functions, were employed to examine the association between the baseline TyG index and the risk of IFG. Subgroup analyses and sensitivity were also performed to ensure the robustness of the study findings. After adjusting for covariates, a positive association between the TyG index and the risk of IFG was found (HR = 1.43, 95% CI 1.27–1.60, P < 0.0001). The likelihood of IFG rose steadily as the TyG index quartiles (from Q1 to Q4) increased, with Q4 demonstrating a 62% elevated risk compared to Q1 (adjusted HR = 1.62, 95% CI 1.37–1.90). Additionally, we found the association between TyG index and risk of IFG was a linear. Sensitivity and subgroup analyses confirmed the stability of the results. Our study observed a linear association between the TyG index and the development of IFG in elderly Chinese individuals. Recognizing this association can help clinicians identify high-risk individuals and implement targeted interventions to reduce their risk of progressing to diabetes.

Abstract We have previously described a novel compound, BTM-3566, that exhibits robust single agent activity in xenograft and PDX models of DLBCL. BTM-3566 is effective on all types of DLBCL, independent of cell of origin (COO) or genotype. Drug activity depends on activation of the mitochondrial protease OMA1 followed by activation of HRI and induction of the ATF4 ISR. To ascertain whether ATF4 ISR induction occurs in vivo, we determined the pharmacokinetics (PK) and pharmacodynamic (PD) responses of BTM-3566 in mouse xenograft models of DLBCL using the double hit lymphoma SU-DHL-10. To establish PK parameters, tumor bearing mice were dosed orally for 1 or 5 consecutive days with 20 mg/kg BTM-3566 and blood sampled over 28 hours. Plasma levels of BTM-3566 were determined and analyzed using a non-compartment model. Half-life in blood plasma was 5.4 and 4.5 hours on days 1 and 5 respectively. Total exposure (AUCinf) was 524164 and 429485 hr*nM on day 1 and day 5 respectively. Drug AUCinf in tumor after a single oral dose of BTM-3566 was 151260 hr*nM. Free drug was estimated to be above the free IC90 for approximately 16 hours post-dose in both plasma and tumor. PD responses to BTM-3566 treatment were determined by measuring biomarkers of the therapeutic cascade: OPA1 cleavage is used as a surrogate for target engagement and activation of OMA1; increased phosphorylation of eIF2α represents pathway activation; induction of ATF4 regulated transcripts and the decrease in the anti-apoptotic protein MCL1 represent pathway effect. A single 20/mg/kg dose of BTM-3566 on day 1 resulted in cleavage of OPA1 by 0.5 hour, with maximal cleavage seen by 12 hours. Phosho-eIF2α was observed by 0.5 hours, peaking at 6 hours. Induction of the ATF4 transcripts ATF4, DDIT3, TRIB3, and CDKN1A was observed within 2 hours with a maximum at 6-12 hours followed by a reduction in transcript levels. MCL1 protein levels were reduced consistent with suppression of translation and protein turnover. By day 5, repeat dosing shows evidence of cumulative pathway effects: OPA1 is extensively cleaved; despite generally depressed levels, phosphorylation of eIF2α remains dynamic and MCL1 levels are markedly suppressed. Induction of ATF4 transcripts, however, follow largely the same kinetics as seen on day 1. The data suggests that in vivo anti-tumor activity of BTM-3566 is associated with activation of the mitochondrial protease OMA1 and induction of the ATF4 ISR. Robust tumor regression is correlated with both blood plasma levels of BTM-3566 and induction of the ATF4 ISR pathway. The data support the use of both ATF4 transcripts and OPA1 cleavage as robust PD markers of target engagement and pathway effect in human clinical trials. An Investigational New Drug application for BTM3566 in B-cell malignancies has been approved with initiation of first in human clinical trials planned for spring 2023. Citation Format: Azadeh Bagherzadeh, Jennifer Baker, Charlotte Bennett, Mi-Young Lee, Natalia Pacheco, Bhavisha Patel, Kevin Stewart, Jon Travers, Michael Stocum, Todd Hembrough, Matthew Kostura. Pharmacokinetics and pharmacodynamics of the novel OMA1 activator BTM 3566 in a mouse model of diffuse large B-cell lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2803.

We examined the high pressure behavior of stannous oxalate via Raman and X-ray absorption spectroscopy (XAS) inside a diamond anvil cell. Phase transitions were observed to occur near 2.6 and 15 GPa which were reversible upon decompression to ambient conditions. When further pressurized above 15 GPa, the colorless material sustains irreversible chemical alterations and becomes bright red colored - darkening at higher pressures. Another irreversible phase transition occurred above 20 GPa. Concomitant with color change of the sample, we observed a softening of the ν(C-C) modes of the C2O42- anion via Raman spectroscopy. We performed a separate XAS experiment which indicates that the Sn2+ cation undergoes a partial reduction of the 2+ oxidation state with pressure which persists when the sample was depressurized to ambient conditions. Thus, electron density within the C-C bond in the oxalate anion appears to migrate toward the tin cation with pressure. This observation suggests that pressure can offer a very controllable means to vary cation-anion and unit cell dimensions (and thus the electric interactions causing electron movement) and thus the pressure-induced synthesis of novel materials.

The structure of the plasma membrane affects its function. Changes in membrane fluidity with concomitant effects on membrane protein activities and cellular communication often accompany the transition from a healthy to a diseased state. Although deliberate modulation of membrane fluidity with drugs has not been exploited to date, the latest data suggest the "druggability" of the membrane. Azelaic acid esters (azelates) modulate plasma membrane fluidity and exhibit a broad range of immunomodulatory effects in vitro and in vivo. Azelates represent a new class of drugs, membrane active immunomodulators (MAIMs), which use the entire plasma membrane as the target, altering the dynamics of an innate feedback regulated homeostatic system, adaptive membrane fluidity modulation (AMFM). A review of the literature data spanning >200 years supports the notion that molecules in the MAIMs category including known drugs do exert immunomodulatory effects that have been either neglected or dismissed as off-target effects.

It is generally recognized that no one cell culture system can be universally applied to all cell types commonly used for biopharmaceutical manufacture. The analogous concept that no single cell type may be useful for the expression of all biopharmaceutical products may also gain credence in the biotechnology community. It may be that like specialized bioreactors, there will come to exist a variety of cell types that will be used for the production of different types of biopharmaceutical products. In addition, it may not be enough in the future just to demonstrate the stability of expression of the amino acid backbone of the protein only; the carbohydrate portion of the molecule may become the subject of real scrutiny. Questions such as how the carbohydrate side chain affects the performance of the molecule in vivo are being asked of more DNA constructs. The next question becomes, how can we control the expression of carbohydrate moieties on the molecule? Such questions are in the future of the biotech manufacturing field. Aside from those examples mentioned above dealing with the insertion of receptors, other more subtle attempts at modifying cellular metabolism are taking place. It was reported at a recent meeting that the sialyltransferase gene was inserted into a CHO line which did not normally express this enzyme (116). The transfected line was capable of expressing the transferase and, more importantly, the enzyme functioned correctly in sialylating glycoproteins. Other very complex relationships exist between the substratum and the cell that could have very direct consequences on culture maintenance. For example, researchers recently published results indicating that collagenase synthesis and secretion is stimulated in rabbit fibroblasts by autocrine factors. They determined that these autocrine proteins had sequence homology to serum amyloid-A and beta-2-microglobulin. It may be that using serum supplements in the medium in those systems that couple fibroblast and collagen substratum may not be prudent, especially for long-term culture. The traditional selection of a cell type for expressing heterologous proteins has generally been limited to the more "common" cell types such as CHO cells, C127 cells, and myeloma cells. In many cases these cell types were selected because there was a great deal of preexisting literature on the cell type (i.e., "cookbook" methods of transfection for the cell) or the cell was simply being carried in the lab at the time the effort was made to express a biopharmaceutical product.(ABSTRACT TRUNCATED AT 400 WORDS)

Metal-organic composites are of great interest for a wide range of applications. The control of their structure remains a challenge, one of the problems being a complex interplay of covalent and supramolecular interactions. This paper describes the self-assembly, thermal stability and phase transitions of ordered structures of silver atoms and thiol molecules spanning from the molecular to the mesoscopic scale. Building blocks of molecularly defined clusters formed from 44 silver atoms, each particle coated by a monolayer of 30 thiol ligands, are used as ideal building blocks. By changing solvent and temperature it is possible to tune the self-assembled 3D crystals of pristine nanoparticles or, conversely, 2D layered structures, with alternated stacks of Ag atoms and thiol monolayers. The study investigates morphological, chemical and structural stability of these materials between 25 and 300 °C in situ and ex situ at the nanoscale by combining optical and electronic spectroscopic and scattering techniques, scanning probe microscopies and density-functional theory (DFT) calculations. The proposed wet-chemistry approach is relatively cheap, easy to implement, and scalable, allowing the fabricated materials with tuned properties using the same building blocks.