Lifeboat Foundation

Targeted protein degradation (TPD) is an emerging therapeutic modality and has attracted great attention from academia and industry^1,2. The prototypical TPD agents, molecular glues (MGs) and proteolysis targeting chimeras (PROTACs), can lead to temporal proteasomal degradation of the protein-of-interest (POI). PROTACs are small heterobifunctional molecules integrating an E3-ligase binder and a POI binding moiety through a synthetic linker construct. The PROTACs technology has been applied to degrade numerous pathological proteins and a rich pipeline is currently progressing into preclinical and early clinical trials^3,4,5. However, overcoming PK/PD issues towards clinical compounds is demanding due to the intrinsically high molecular weight and related physicochemical properties⁶. On the other hand, MGs are small molecules with beneficial ‘drug-like’ physicochemical properties binding to an E3 ligase, and, similarly to PROTACs, leading to neosubstrate proteasomal degradation. Their mechanism of action is however less predictable; their often hydrophobic surface-exposed portions of the MGs seem to change the hydrophobic surface area of the E3 ligase and thereby leading to neosubstrate ubiquitination and degradation^7,8. MGs have already proven their validity as marketed drugs, as there are several approved drugs or clinical compounds working by an MG mechanism (Fig. 1A), for example, the IKZF1/3 degrader thalidomide and its analogs pomalidomide and lenalidomide⁸, and the RBM39 degrader indisulam⁹. Thalidomide analogs induce selective ubiquitination and degradation of two lymphoid transcription factors, IKZF1 and IKZF3, by the CRBN-CRL4 ubiquitin ligase¹⁰. Additionally, CSNK1A1 (CK1α) was recently discovered as a lenalidomide-specific neo-substrate¹¹. Interestingly, modification of pomalidomide or lenalidomide can have a profound impact on the degradation potency and degradation profiles. For example, CC-220 (Fig. 1A) showed 10-fold more potency in the cells than lenalidomide, and CC-885 (Fig. 1A) was found to induce degradation of the substrate GSPT1^12,13. Both MGs and PROTACs are emerging drug modalities providing interesting features over classical pharmacology-driven drugs by their ability to drive the destruction of proteins that have multiple functions, thereby potentially overcoming resistance mechanisms and providing new pharmacology. While PROTACs can be developed highly rationally, MGs are discovered rather serendipitously requiring synthesis and testing of large series of compounds^14,15. Additionally, the discovery of MGs and PROTACs is done in a sequential, often mmol scale synthesis which is time-consuming and expensive.

In this work, to address current shortcomings in MGs discovery, we use the direct-to-biology (D2B) approach and combined the automated, high throughput miniaturized synthesis with cell-based phenotypic screening (Fig. 1B). The I.DOT (Immediate Drop on Demand Technology, a pressure-based nano dispensing technology) is employed to accelerate the synthesis of diverse MGs libraries on nano scale^{16,17,18,19,20,21}. In a subsequent cell-based phenotypic screening cascade, the compounds are tested in the thalidomide and analog sensitive MM.1S multiple myeloma cell line which reportedly is used for MGs screening²². In this D2B screening platform, the crude compounds are directly screened on cells without further chromatographic purification or clean up. Then, the 19 best compounds are selected for re-synthesis on mmol scale followed by purification and fully characterized.

The delivery of drugs to specific target tissues and cells in the brain poses a significant challenge in brain therapeutics, primarily due to limited understanding of how nanoparticle (NP) properties influence drug biodistribution and off-target organ accumulation. This study addresses the limitations of previous research by using various predictive models based on collection of large data sets of 403 data points incorporating both numerical and categorical features. Machine learning techniques and comprehensive literature data analysis were used to develop models for predicting NP delivery to the brain. Furthermore, the physicochemical properties of loaded drugs and NPs were analyzed through a systematic analysis of pharmacodynamic parameters such as plasma area under the curve. The analysis employed various linear models, with a particular emphasis on linear mixed-effect models (LMEMs) that demonstrated exceptional accuracy. The model was validated via the preparation and administration of two distinct NP formulations via the intranasal and intravenous routes. Among the various modeling approaches, LMEMs exhibited superior performance in capturing underlying patterns. Factors such as the release rate and molecular weight had a negative impact on brain targeting. The model also suggests a slightly positive impact on brain targeting when the drug is a P-glycoprotein substrate.

Optogenetics has revolutionized neuroscience understanding by allowing spatiotemporal control over cell-type specific neurons in neural circuits. However, the sluggish development of noninvasive photon delivery in the brain has limited the clinical application of optogenetics. Focused ultrasound (FUS)-derived mechanoluminescence has emerged as a promising tool for in situ photon emission, but there is not yet a biocompatible liquid-phase mechanoluminescence system for spatiotemporal optogenetics. To achieve noninvasive optogenetics with a high temporal resolution and desirable biocompatibility, we have developed liposome (Lipo@IR780/L012) nanoparticles for FUS-triggered mechanoluminescence in brain photon delivery. Synchronized and stable blue light emission was generated in solution under FUS irradiation due to the cascade reactions in liposomes.

Researchers at the University of Sussex have discovered the transformative potential of Martian nanomaterials, potentially opening the door to sustainable habitation on the red planet.

Using resources and techniques currently applied on the International Space Station and by NASA, Dr. Conor Boland, a Lecturer in Materials Physics at the University of Sussex, led a research group that investigated the potential of nanomaterials—incredibly tiny components thousands of times smaller than a human hair —for clean energy production and building materials on Mars.

Taking what was considered a waste product by NASA and applying only sustainable production methods, including water-based chemistry and low-energy processes, the researchers have successfully identified electrical properties within gypsum nanomaterials—opening the door to potential clean energy and sustainable technology production on Mars.

On the pursuit for anyons (Majoranas) in the context of the latest progress on multiple platforms.

Already, the graphene efforts have offered “a breath of fresh air” to the community, Alicea says. “It’s one of the most promising avenues that I’ve seen in a while.” Since leaving Microsoft, Zaletel has shifted his focus to graphene. “It’s clear that this is just where you should do it now,” he says.

But not everyone believes they will have enough control over the free-moving quasiparticles in the graphene system to scale up to an array of qubits—or that they can create big enough gaps to keep out intruders. Manipulating the quarter-charge quasiparticles in graphene is much more complicated than moving the Majoranas at the ends of nanowires, Kouwenhoven says. “It’s super interesting for physics, but for a quantum computer I don’t see it.”

Continue reading “A ghostly quasiparticle rooted in a century-old Italian mystery could unlock quantum computing’s potential” »

Researchers in China have produced a phenomenon known as the giant skyrmion topological Hall effect in a two-dimensional material using only a small amount of current to manipulate the skyrmions responsible for it. The finding, which a team at Huazhong University of Science and Technology in Hubei observed in a ferromagnetic crystal discovered in 2022, comes about thanks to an electronic spin interaction known to stabilize skyrmions. Since the effect was apparent at a wide range of temperatures, including room temperature, it could prove useful for developing two-dimensional topological and spintronic devices such as racetrack memory, logic gates and spin nano-oscillators.

Skyrmions are quasiparticles with a vortex-like structure, and they exist in many materials, notably magnetic thin films and multilayers. They are robust to external perturbations, and at just tens of nanometres across, they are much smaller than the magnetic domains used to encode data in today’s hard disks. That makes them ideal building blocks for future data storage technologies such as “racetrack” memories.

Skyrmions can generally be identified in a material by spotting unusual features (for example, abnormal resistivity) in the Hall effect, which occurs when electrons flow through a conductor in the presence of an applied magnetic field. The magnetic field exerts a sideways force on the electrons, leading to a voltage difference in the conductor that is proportional to the strength of the field. If the conductor has an internal magnetic field or magnetic spin texture, like a skyrmion does, this also affects the electrons. In these circumstances, the Hall effect is known as the skyrmion topological Hall effect (THE).

Johns Hopkins researchers have identified minuscule particles that supercharge therapeutic cancer vaccines, which train the immune system to attack tumors. These new lipid nanoparticles—tiny structures made of fat—not only stimulate a two-pronged immune system response that enhances the body’s ability to fight cancer but also make vaccines more effective in targeting tumors.

“This research marks a pivotal turning point in our understanding of how lipid nanoparticles can be harnessed to optimize anticancer immunity,” said Hai-Quan Mao, director of Johns Hopkins’ Institute for NanoBioTechnology and professor in the Whiting School of Engineering’s Department of Materials Science and Engineering. “Our findings unlock new avenues for enhancing the efficacy of RNA-based treatments for cancer and infectious diseases.”

The team’s results appear in Nature Biomedical Engineering.

A nitrogen-vacancy (NV) center is a defect in the crystal structure of diamond, where a nitrogen atom replaces a carbon atom in the diamond lattice and a neighboring site in the lattice is vacant. This and other fluorescent defects in diamond, known as color centers, have attracted researchers’ attention owing to their quantum properties, such as single-photon emission at room temperature and with long coherence time. Their many applications include quantum information encoding and processing, and cell marking in biological studies.

Microfabrication in diamond is technically difficult, and nanodiamonds with color centers have been embedded in custom-designed structures as a way of integrating these quantum emitters into photonic devices. A study conducted at the University of São Paulo’s São Carlos Institute of Physics (IFSC-USP) in Brazil has established a method for this, as described in an article published in the journal Nanomaterials.

“We demonstrated a method of embedding fluorescent nanodiamonds in microstructures designed for this purpose, using two-photon polymerization [2PP],” Cleber Mendonça, a professor at IFSC-USP and last author of the article, told Agência FAPESP. “We studied the ideal concentration of nanodiamond in the photoresist to achieve structures with at least one fluorescent NV center and good structural and optical quality.” The photoresist is a light-sensitive material used in the fabrication process to transfer nanoscale patterns to the substrate.

Detection efficiency is 1,000 times higher than conventional ion detectors due to high sensitivity.

An international research team led by quantum physicist Markus Arndt (University of Vienna) has achieved a breakthrough in the detection of protein ions: Due to their high energy sensitivity, superconducting nanowire detectors achieve almost 100% quantum efficiency and exceed the detection efficiency of conventional ion detectors at low energies by a factor of up to a 1,000. In contrast to conventional detectors, they can also distinguish macromolecules by their impact energy. This allows for more sensitive detection of proteins and it provides additional information in mass spectrometry. The results of this study were recently published in the journal Science Advances.

Advancements in Mass Spectrometry.