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Category: biotech/medical – Page 206

DNA-reading AI reconstructs ancestry in minutes, matching top statistical methods

Researchers at the University of Oregon have developed an artificial intelligence tool that can read genetic code the way large language models like ChatGPT read text. Scanning the genome for biological mutation patterns, the computer model traces pairs of genes back in time to their last common ancestor.

It’s the first language model designed for population genetics, said Andrew Kern, a computational biologist in the UO College of Arts and Sciences. As described in a paper published April 10 in the Proceedings of the National Academy of Sciences, the AI tool offers scientists a fast and flexible alternative to classical methods for reconstructing evolutionary history.

In practice, it can help researchers like Kern understand when disease-resistance genes emerged in a population, for example, or when species evolved key traits.

No more guesswork in drug design—atomic-resolution method exposes what trial and error keep missing

Drug discovery still too often relies on expensive trial and error. Researchers from ICTER show there is another way—building molecules step by step and observing their behavior at atomic resolution. This approach could significantly speed up the development of new therapies while reducing side effects.

The starting point of the study, published in Diabetology by Vineeta Kaushik, Saurav Karmakar, and Humberto Fernandes, is aldose reductase (AR)—an enzyme that has long been at the center of research into diabetic complications. Under conditions of chronic hyperglycemia, the so-called polyol pathway becomes overactive, converting glucose into sorbitol. Its accumulation leads to osmotic stress, redox imbalance, and ultimately cellular damage.

This mechanism is directly linked to complications such as diabetic retinopathy, neuropathy, and nephropathy. Inhibiting aldose reductase, therefore, appears to be an obvious therapeutic strategy. Yet despite decades of research, no drug has successfully combined strong efficacy with a favorable safety profile.

This New “Sound Laser” Could Measure Gravity With Stunning Precision

A new sound-based laser could measure gravity with unprecedented precision and reshape navigation technology.

Since their introduction in the 1960s, lasers have fueled major advances in science and everyday technology, from supermarket scanners to eye surgery. Traditional lasers operate by controlling photons, which are particles of light. Over the past two decades, researchers have expanded this concept to other particles, including phonons, which represent tiny units of vibration or sound. Learning to control phonons could unlock new capabilities, including access to unusual quantum effects such as entanglement.

Squeezed Phonon Laser Advances Precision.

A common parasite in the brain is far more active than we thought

A parasite carried by billions isn’t dormant at all—it’s running a secret survival operation inside the brain.

A common parasite long thought to lie dormant is actually much more active and complex. Researchers found that Toxoplasma gondii cysts contain multiple parasite subtypes, not just one sleeping form. Some are primed to reactivate and cause disease, which helps explain why infections are so hard to treat. The discovery could reshape efforts to develop drugs that finally eliminate the parasite for good.

Physical exercise protects against Toxoplasma gondii infection-induced muscle atrophy and microvascular rarefaction

FNDC5/irisin detection was performed by a sandwich ELISA reaction using DuoSet® ELISA Development Systems kit (R&D Systems), according to manufacturer’s instructions. Blood samples were collected at 10 or 40 dpi, allowed to sit for at least 1 h, and then centrifuged for 10 min at 224 g in a refrigerated centrifuge (4 °C) to isolate the serum. Samples were stored at −80 °C until irisin detection.

Serum samples were assayed for TNF-α, INF-γ, IL-2, IL-4, IL-6, IL-10, and IL-17a using a Cytometric Bead Array (CBA) Th1/ Th2/ Th17 kit (BD Biosciences), according to the manufacturer’s instructions. Data were acquired using a Cytoflex S (Beckman Coulter) flow cytometer. After data acquisition, dedicated software (FCAP Array, BD Biosciences) was used to analyze the results by gating bead populations, calculating MFI values, generating standard curves, and determining analyte concentrations. These analyses were performed at the Flow Cytometry Facility of the Instituto Oswaldo Cruz (Fiocruz).

T. gondii infection was quantified using RT-qPCR with bag1 and enolase2 primers to detect bradyzoite and tachyzoite forms, respectively, according to49. Ct values were compared to a standard curve amplification, derived from known T. gondii RNA concentrations. The standard curve was constructed with six 10-fold dilutions, starting with 6.0 × 106 parasites for either bradyzoites or tachyzoites. Primer sequences are available in Table 2.

An ultrasound-scanning in vivo light source

Beautifully executed paper on putting mechanoluminescent nanoparticles into blood circulation of mice which express optogenetic channels. Focused ultrasound can then trigger targeted light emission and control of neural activity in the brain and elsewhere.

A deep-tissue light source made from mechanoluminescent transducers stimulated by focused ultrasound enables wide imaging of live animal vasculature, and modulation of neuronal activity and behaviour.

One missing metabolic step can turn cancer’s DNA-copying machinery into a lethal weakness

Loss of an enzyme necessary for a process called lipoylation disrupts the way cancer cells copy their DNA, increasing their vulnerability to a class of anticancer drugs known as PARP inhibitors, a study led by UT Southwestern Medical Center researchers shows.

The findings, published in Science Advances, reveal a previously unrecognized mechanism to protect DNA replication and genome stability that could lead to new treatments for some cancers.

“This study shows that metabolism doesn’t just fuel cancer cells—it also directly shapes how DNA is copied and protected. This helps explain why inhibiting lipoylation could make tumors especially sensitive to PARP inhibitors,” said Yuanyuan “Faith” Zhang, M.D., Ph.D., Assistant Professor of Radiation Oncology and a member of the Experimental Therapeutics Research Program in the Harold C. Simmons Comprehensive Cancer Center at UT Southwestern. Dr. Zhang co-led the study with first author Zengfu Shang, Ph.D., Assistant Professor of Radiation Oncology in the Zhang Lab.

Ultrafast MRI uncovers brain signal direction: New scan may help decode autism, Alzheimer’s and hallucinations

Researchers at the Champalimaud Foundation in Lisbon have for the first time managed to identify with an imaging technique whether nervous impulses in the brain of rats are flowing in a “bottom-up” (feedforward), carrying information about visual input, or a “top-down” (feedback) direction, carrying information about expectations or predictions on a given task or about the perception of the world around us. Their results, published in Nature Communications, could have important implications for understanding changes in the brains of people with hallucinations, Alzheimer’s, schizophrenia, autism, and other conditions.

Joana Carvalho, first author of the new study, who at the time was working in the Preclinical MRI lab led by senior author Noam Shemesh (she has since become a group leader at Coimbra University), “came up with the ideas, did the experiments and analyzed the results. I just brought the MRI expertise,” says Shemesh good-humoredly. Co-author Koen V. Haak from Tilburg University (Netherlands) gave assistance with the computational models and the others helped with the experiments.

The team showed that spontaneous feedforward and feedback nervous impulses in these rodents (the brain never sleeps) each have a unique, distinct signature, which can be detected by using a method they developed, called uFLARE (UltraFast Layer-Resolved Encoding), a neuroimaging technique designed to map brain activity with unprecedented high temporal and spatial resolutions.

In Silico Analysis of the Chikungunya Virus and SARS-CoV-2 Macrodomain

The chikungunya virus (ChikV) was first isolated during an arthritic disease outbreak in Tanzania in 1952 [1, 2]. ChikV is a mosquito-borne virus that belongs to the Alphavirus genus of the Togaviridae family. ChikV infections have emerged as a global health risk with approximately 16.9 million cases per year [3]. Major symptoms of ChikV infection include severe fever, rashes, and joint pain. Chronic arthritis-like symptoms may persist and can be debilitating [4, 5]. ChikV, a positive-sense RNA virus, encodes 5 structural proteins and 4 nonstructural proteins (NSP1 to NSP4) [6]. Nonstructural protein 3 (NSP3) consists of a conserved macrodomain (Mac1) at the N-terminus, a poorly conserved hypervariable domain, and a central zinc-binding domain known as the alphavirus unique domain [7]. The macrodomain fold is highly conserved across evolution, having been identified in bacteria, algae, and eukaryotes [8, 9]. It has been suggested that ChikV Mac1 suppresses the host immune response through its adenosine diphosphate ribosyl (ADP-ribosyl) hydrolase activity [10], which removes ADP-ribose posttranslational modifications from target host proteins by hydrolyzing mono-ADP-ribosylated aspartate and glutamate residues. Mac1 has therefore emerged as a promising antiviral drug target [10], supported by evidence suggesting that it is a key determinant of ChikV virulence in mice. Despite their therapeutic potential, efforts to identify ChikV inhibitors have had limited success. A fragment screen of ~14,000 compounds identified only weak inhibitors (e.g., 2-pyrimidone-4-carboxylic acid scaffold, with one of the compounds showing IC50 of 23 μM) [11]. Another computational docking and simulation study screened 820 compounds and predicted that natural compounds from plants, including apigetrin, baicalin, baloxavir, luteoloside, rutaecarpine, and amentoflavone [12], are Mac1 inhibitors. The predicted binding affinity of baicalin was −10.8 kcal/mol against ChikV Mac1. Another study identified N-[2-(5-methoxy-1 H-indol-3-yl) ethyl]-2-oxo-1,2-dihydroquinoline-4-carboxamide through virtual screening of 245,532 natural compounds, followed by in vitro validation using a microscale thermophoresis binding assay (binding constant [Kd] of 1.066 × 10−6 ± 0.95 μM) and in vivo inhibition of ChikV replication [13].

Similar to ChikV, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) NSP3 contains 3 tandem macrodomains, with Mac1 serving as the catalytically active macrodomain that binds and hydrolyzes mono-ADP-ribose on posttranslationally modified target host proteins [14,15]. SARS-CoV-2 Mac1 is essential for viral pathogenesis and represents a promising drug target [16,17]. In contrast to ChikV Mac1, it has proven amenable to inhibitor development. An early crystallographic screen of approximately 2,600 compounds revealed 234 fragment structures bound to SARS-CoV-2 Mac1 [18]. Using these hits, several optimized inhibitors were designed, followed by another round of crystallographic screening [19]. Among the resulting top inhibitors was AVI-4206, a potent inhibitor with an IC50 of 20 nM that is effective in an animal model of SARS-CoV-2 infection [20]. Other studies have identified additional promising scaffolds, including 2-amide-3-methylester thiophene scaffold derivatives that bind SARS-CoV-2 Mac1 (IC50 = 1.5 μM) and inhibit viral replication [21], synthetic analogs of ADP-ribose that bind SARS-CoV-2 Mac1 with nanomolar affinity [22], and pyrrolo-pyrimidine-based compounds that inhibit viral replication in SARS-CoV-2 [23].

The structural similarity between ChikV Mac1 and SARS-CoV-2 Mac1 [24] has not translated into similar druggability. One strategy to improve ligand-binding affinity is to exploit the presence of water molecules in the binding site by designing inhibitors that effectively use them to form bridging interactions that strengthen binding to the protein [25]. This strategy is particularly relevant for Mac1 ADP-ribose-binding sites, which are large, solvent exposed, and known to maintain an extensive network of ordered water molecules upon ADP binding. In SARS-CoV-2 Mac1, ADP-ribose forms several water-mediated interactions, resulting in the water network in the ADP-ribose-binding site reorganizing upon ligand binding [18,26].

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