Fabrication of oxygen-carrying microparticles functionalized with liver ECM-proteins to improve phenotypic three-dimensional in vitro liver assembly, function, and responses.

Oxygen and extracellular matrix (ECM)-derived biopolymers play vital roles in regulating many cellular functions in both the healthy and diseased liver. This study highlights the significance of synergistically tuning the internal microenvironment of three-dimensional (3D) cell aggregates composed of hepatocyte-like cells from the HepG2 human hepatocellular carcinoma cell line and hepatic stellate cells (HSCs) from the LX-2 cell line to enhance oxygen availability and phenotypic ECM ligand presentation for promoting the native metabolic functions of the human liver. First, fluorinated (PFC) chitosan microparticles (MPs) were generated with a microfluidic chip, then their oxygen transport properties were studied using a custom ruthenium-based oxygen sensing approach. Next, to allow for integrin engagements the surfaces of these MPs were functionalized using liver ECM proteins including fibronectin, laminin-111, laminin-511, and laminin-521, then they were used to assemble composite spheriods along with HepG2 cells and HSCs. After in vitro culture, liver-specific functions and cell adhesion patterns were compared between groups and cells showed enhanced liver phenotypic responses to laminin-511 and 521 as evidenced via enhanced E-cadherin and vinculin expression, as well as albumin and urea secretion. Furthermore, hepatocytes and HSCs exhibited more pronounced phenotypic arrangements when cocultured with laminin-511 and 521 modified MPs providing clear evidence that specific ECM proteins have distinctive roles in the phenotypic regulation of liver cells in engineering 3D spheroids. This study advances efforts to create more physiologically relevant organ models allowing for well-defined conditions and phenotypic cell signaling which together improve the relevance of 3D spheroid and organoid models.

A Case for Electron-Astrophysics.

The smallest characteristic scales, at which electron dynamics determines the plasma behaviour, are the next frontier in space and astrophysical plasma research. The analysis of astrophysical processes at these scales lies at the heart of the research theme of electron-astrophysics. Electron scales are the ultimate bottleneck for dissipation of plasma turbulence, which is a fundamental process not understood in the electron-kinetic regime. In addition, plasma electrons often play an important role for the spatial transfer of thermal energy due to the high heat flux associated with their velocity distribution. The regulation of this electron heat flux is likewise not understood. By focussing on these and other fundamental electron processes, the research theme of electron-astrophysics links outstanding science questions of great importance to the fields of space physics, astrophysics, and laboratory plasma physics. In this White Paper, submitted to ESA in response to the Voyage 2050 call, we review a selection of these outstanding questions, discuss their importance, and present a roadmap for answering them through novel space-mission concepts.

Turbulence-Driven Ion Beams in the Magnetospheric Kelvin-Helmholtz Instability.

The description of the local turbulent energy transfer and the high-resolution ion distributions measured by the Magnetospheric Multiscale mission together provide a formidable tool to explore the cross-scale connection between the fluid-scale energy cascade and plasma processes at subion scales. When the small-scale energy transfer is dominated by Alfvénic, correlated velocity, and magnetic field fluctuations, beams of accelerated particles are more likely observed. Here, for the first time, we report observations suggesting the nonlinear wave-particle interaction as one possible mechanism for the energy dissipation in space plasmas.

Differentiation syndrome in acute myeloid leukemia after treatment with azacitidine.

We report a case report of hyperleukocytosis, fever, hypotension, pulmonary and pericardial effusions, and acute kidney injury during initial treatment with azacitidine in a patient with AML-MRC. Collectively, the symptomatology resembled differentiation syndrome. Azacitidine has been previously associated with fever, peripheral edema, and hyperleukocytosis, but its side effect profile has never been described as similar to differentiation syndrome. The patient's deteriorating course quickly turned around after treatment with dexamethasone. This potential reaction, and potential treatment, is important for clinicians to be aware of.

Discovery of Conformationally Constrained ALK2 Inhibitors.

Despite decades of research on new diffuse intrinsic pontine glioma (DIPG) treatments, little or no progress has been made on improving patient outcomes. In this work, we explored novel scaffold modifications of M4K2009, a 3,5-diphenylpyridine ALK2 inhibitor previously reported by our group. Here we disclose the design, synthesis, and evaluation of a first-in-class set of 5- to 7-membered ether-linked and 7-membered amine-linked constrained inhibitors of ALK2. This rigidification strategy led us to the discovery of the ether-linked inhibitors M4K2308 and M4K2281 and the amine-linked inhibitors M4K2304 and M4K2306, each with superior potency against ALK2. Notably, M4K2304 and M4K2306 exhibit exceptional selectivity for ALK2 over ALK5, surpassing the reference compound. Preliminary studies on their in vivo pharmacokinetics, including blood-brain barrier penetration, revealed that these constrained scaffolds have favorable exposure and do open a novel chemical space for further optimization and future evaluation in orthotopic models of DIPG.

Magnetosheath Jet Formation Influenced by Parameters in Solar Wind Structures.

Magnetosheath jets are dynamic pressure enhancements observed in the terrestrial magnetosheath. Their generation mechanisms are currently debated but the majority of jets can be linked to foreshock processes. Recent results showed that jets are less numerous when coronal mass ejections (CMEs) cross the magnetosheath and more numerous when stream interaction regions (SIRs) cross it. Here, we show for the first time how the pronounced substructures of CMEs and SIRs are related to jet production. We distinguish between compression and magnetic ejecta (ME) regions for the CME as well as compression region associated with the stream interface and high-speed streams (HSSs) for the SIR. Based on THEMIS and OMNI data covering 2008-2021, we show the 2D probability distribution of jet occurrence using the cone angle and Alfvén Mach number. We compare this distribution with the values within each solar wind (SW) structure. We find that both high cone angles and low Alfvén Mach numbers within CME-MEs are unfavorable for jet production as they may inhibit a well-defined foreshock region. 1D histograms of all parameters show, which SW parameters govern jet occurrence in each SW structure. In terms of the considered parameters the most favorable conditions for jet generation are found for HSSs due to their associated low cone angles, low densities, and low magnetic field strengths.

Magnetosheath Jet Occurrence Rate in Relation to CMEs and SIRs.

Magnetosheath jets constitute a significant coupling effect between the solar wind (SW) and the magnetosphere of the Earth. In order to investigate the effects and forecasting of these jets, we present the first-ever statistical study of the jet production during large-scale SW structures like coronal mass ejections (CMEs), stream interaction regions (SIRs) and high speed streams (HSSs). Magnetosheath data from Time History of Events and Macroscale Interactions during Substorms (THEMIS) spacecraft between January 2008 and December 2020 serve as measurement source for jet detection. Two different jet definitions were used to rule out statistical biases induced by our jet detection method. For the CME and SIR + HSS lists, we used lists provided by literature and expanded on incomplete lists using OMNI data to cover the time range of May 1996 to December 2020. We find that the number and total time of observed jets decrease when CME-sheaths hit the Earth. The number of jets is lower throughout the passing of the CME-magnetic ejecta (ME) and recovers quickly afterward. On the other hand, the number of jets increases during SIR and HSS phases. We discuss a few possibilities to explain these statistical results.

Targeting ALK2: An Open Science Approach to Developing Therapeutics for the Treatment of Diffuse Intrinsic Pontine Glioma.

Diffuse intrinsic pontine glioma is an aggressive pediatric cancer for which no effective chemotherapeutic drugs exist. Analysis of the genomic landscape of this disease has led to the identification of the serine/threonine kinase ALK2 as a potential target for therapeutic intervention. In this work, we adopted an open science approach to develop a series of potent type I inhibitors of ALK2 which are orally bio-available and brain-penetrant. Initial efforts resulted in the discovery of M4K2009, an analogue of the previously reported ALK2 inhibitor LDN-214117. Although highly selective for ALK2 over the TGF-ßR1 receptor ALK5, M4K2009 is also moderately active against the hERG potassium channel. Varying the substituents of the trimethoxyphenyl moiety gave rise to an equipotent benzamide analogue M4K2149 with reduced off-target affinity for the ion channel. Additional modifications yielded 2-fluoro-6-methoxybenzamide derivatives (26a-c), which possess high inhibitory activity against ALK2, excellent selectivity, and superior pharmacokinetic profiles.

Leveraging an Open Science Drug Discovery Model to Develop CNS-Penetrant ALK2 Inhibitors for the Treatment of Diffuse Intrinsic Pontine Glioma.

There are currently no effective chemotherapeutic drugs approved for the treatment of diffuse intrinsic pontine glioma (DIPG), an aggressive pediatric cancer resident in the pons region of the brainstem. Radiation therapy is beneficial but not curative, with the condition being uniformly fatal. Analysis of the genomic landscape surrounding DIPG has revealed that activin receptor-like kinase-2 (ALK2) constitutes a potential target for therapeutic intervention given its dysregulation in the disease. We adopted an open science approach to develop a series of potent, selective, orally bioavailable, and brain-penetrant ALK2 inhibitors based on the lead compound LDN-214117. Modest structural changes to the C-3, C-4, and C-5 position substituents of the core pyridine ring afforded compounds M4K2009, M4K2117, and M4K2163, each with a superior potency, selectivity, and/or blood-brain barrier (BBB) penetration profile. Robust in vivo pharmacokinetic (PK) properties and tolerability mark these inhibitors as advanced preclinical compounds suitable for further development and evaluation in orthotopic models of DIPG.

Ideation and implementation of an open science drug discovery business model - M4K Pharma.

M4K Pharma was incorporated to launch an open science drug discovery program that relies on regulatory exclusivity as its primary intellectual property and commercial asset, in lieu of patents.In many cases and in key markets, using regulatory exclusivity can provide equivalent commercial protection to patents, while also being compatible with open science. The model is proving attractive to government, foundation and individual funders, who collectively have different expectations for returns on investment compared with biotech, pharmaceutical companies, or venture capital investors.In the absence of these investor-driven requirements for returns, it should be possible to commercialize therapeutics at affordable prices.M4K is piloting this open science business model in a rare paediatric brain tumour, but there is no reason it should not be more widely applicable.