Tiny intrinsic time fluctuations could limit ultimate clock precision: Study
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APOE4 to APOE2 allelic switching in mice improves Alzheimer’s disease-related metabolic signatures, neuropathology and cognition
APOE allele switching improves Alzheimer’s in mice.
Type of apolipoprotein E (APOE) allele carried by individuals is a major risk factor in Alzheimer’s disease (AD). For example, compared to individuals carrying two copies of the APOE ε4 allele, ε2 homozygotes have an approximate 99% reduction in late-onset Alzheimer’s disease (AD) risk.
The authors in this study developed a knock-in mouse model that allows for an inducible ‘switch’ between risk and protective alleles (APOE4s2). These mice synthesize E4 at baseline and E2 after tamoxifen administration.
A whole-body allelic switch resulted in a metabolic profile resembling E2/E2 humans and drives AD-relevant alterations in the lipidome and single-cell transcriptome, particularly in astrocytes.
E4 to E2 switching improved cognition, decreased amyloid pathology, lowered gliosis and reduced plaque-associated apolipoprotein E.
Thus, APOE replacement may be a viable strategy for future gene editing approaches to simultaneously reduce multiple AD-associated pathologies. sciencenewshighlights ScienceMission https://sciencemission.com/APOE4-to-APOE2-allelic-switching
New treatment for drug-resistant fungal infections
Infections caused by Cryptococcus are extremely dangerous. The pathogen, which can cause pneuomia-like symptoms, is notoriously drug-resistant, and it often preys on people with weakened immune systems, like cancer patients or those living with HIV. And the same can be said about other fungal pathogens, like Candida auris or Aspergillus fumigatus — both of which, like Cryptococcus, have been declared priority pathogens by the World Health Organization.
Despite the threat, though, doctors have only three treatment options for fungal infections.
The gold standard is a drug class called amphotericin but has major toxic side-effects on humans.
The other two antifungal drug classes that are available — azoles and echinocandins — are much less effective treatment options, especially against Cryptococcus. The author says azoles merely stop fungi from growing rather than outright killing them, while Cryptococcus and other fungi have become totally resistant to echinocandins, rendering them completely ineffective.
“Adjuvants are helper molecules that don’t actually kill pathogens like drugs do, but instead make them extremely susceptible to existing medicine,” explains the author.
Looking for adjuvants that might better sensitize Cryptococcus to existing antifungal drugs, the lab screened vast chemical collection for candidate molecules.
Quickly, the team found a hit: butyrolactol A, a known-but-previously understudied molecule produced by certain Streptomyces bacteria. The researchers found that the molecule could synergize with echinocandin drugs to kill fungi that the drugs alone could not.
Organoid-derived alveolar cells differentiate on a stretchable microfluidic device and show force-dependent susceptibility to
Mechanical strain exacerbates Pseudomonas infection in an organoid-based pneumonia-on-a-chip model.
In this Research Letter, Geraldine Nouailles & team use an advanced human lung-on-a-chip model to show that increased mechanical strain can make the lungs more vulnerable to harmful bacteria such as Pseudomonas aeruginosa.
1Charité — Universitätsmedizin Berlin, Department of Infectious Diseases, Respiratory Medicine and Critical Care, Berlin, Germany.
2Bundeswehr Hospital Berlin, Department of Internal Medicine, Berlin, Germany.
3Universität Leipzig, ScaDS.AI, Institute for Medical Informatics, Statistics, and Epidemiology, Leipzig, Germany.
Specialized transporters relay lipids to cellular targets
In addition to providing energy, lipids are also essential building blocks of our cell membranes. However, despite their importance, they remain poorly understood. A research team has revealed for the first time the secrets of their transport within cells. Each lipid uses a limited number of proteins to move from its place of production to its place of action. The team has also compiled an inventory of the proteins involved in the transport of hundreds of lipids.
These findings, published in the journal Nature, provide a better picture of the functioning of our cells, as well as of many genetic and metabolic disorders, such as diabetes and Alzheimer’s disease.
Biologists brought together more than a hundred transfer proteins with hundreds of different lipids. The aim was to obtain the most comprehensive list possible of the ‘pairs’ formed between each protein and the lipids it can carry.
To do this, two experimental methods were combined. The first, carried out in a test tube, provides a highly controlled environment, while the second, which more closely corresponds to the inside of a cell, allows researchers to verify how these bonds are formed under near-real conditions. This is a world first on such a scale and at such a level of complexity. “The ‘‘couples’’ identified show that transfer proteins are not “buses” capable of transporting most lipids, but private chauffeurs with specific characteristics,” explains the senior author.
Scientists have been able to determine, using advanced mathematical models, how three transfer proteins recognise, among all lipids, those that they actually transport. ScienceMission sciencenewshighlights.
Low-input proteomics identifies vWF as a negative regulator of Tet2 mutant hematopoietic stem cell expansion
Jassinskaja, Bode et al. provide a multi-omics characterization of Tet2-mutated cells, including global proteomics revealing novel roles for extracellular matrix (ECM) molecules in selectively modifying self-renewal divisions. These findings point more broadly to physical and mechanical mediators of self-renewal, implicating integrins and cytokine signaling as extracellular drivers of clonal expansion.
T-DXd/Pertuzumab Earns Type II Application Validation in EU for HER2+ mBC
The EMA has validated a Type II Variation marketing authorization application for T-DXd plus pertuzumab in first-line unresectable or metastatic HER2-positive breast cancer.
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The marketing authorization was based on results from the DESTINY-Breast09 trial assessing T-DXd/pertuzumab in first-line HER2+ metastatic breast cancer.
Virus-Specific T Cells and Response to Checkpoint Inhibitors in PML
Patients with detectable virus-specific T cells before checkpoint inhibitor therapy in PML demonstrated better survival rates and functional recovery than those without.
Question Are pretreatment JC virus-and/or BK virus-specific T cells in the blood associated with the efficacy of immune checkpoint inhibitors (ICIs) in progressive multifocal leukoencephalopathy (PML)?
Findings In this cohort study of 111 patients with PML treated with ICIs, those with detectable virus-specific T cells (n = 21) had significantly higher response rates and longer survival than both T cell–negative patients (n = 22) and those with unknown status (n = 68).
Laser speed in 3D printing tunes atomic structure of high-entropy alloys
Next-generation technology requires next-generation materials that can be tailored to exact mission requirements. Additive manufacturing, or 3D printing, has already revolutionized industries like aerospace engineering by enabling previously unthinkable component designs. However, this technique has been largely limited to pre-existing metallic alloys. This is due to the inherent complexity of the process that leads to far-from-equilibrium microstructures and results in mechanical properties that are hard to predict.
New research on alloy microstructures
In a new study, scientists at Lawrence Livermore National Laboratory and their collaborators demonstrate a method to overcome the challenges of the traditional additive manufacturing process. By adjusting the speed of the laser in a compositionally complex alloy (also called high-entropy alloy), the team discovered a method to guide how the atoms settle as the metal solidifies, controlling the material’s properties directly at the atomic scale.