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New Protein Function Characterization for Human

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New Protein Function Characterization for Human Paralog Discovery, Scraping the Bottom of the Genomics Barrel

IIncreasing the number of related protein paralogs is important for fully understanding protein relationships, yet it remains challenging for sequences in the twilight zone. Here, we present an integrated homolog detection framework that combines sequence-based (BLASTp, MMseqs2), structure-based (Foldseek), and embedding-distance-based (PROST) similarity metrics to identify additional paralogs. To characterize functionally related protein pairs, we develop protein-family-specific supervised...

bioRxiv 10d ago

Molecular glue degraders of HuR suppress BRAF-mutant colorectal cancer

Abstract BRAF gain-of-function mutations, particularly BRAF(V600E), affect roughly 10% of all patients with colorectal cancer (CRC), and portend poor prognosis with limited therapeutic interventions. BRAF inhibitors such as encorafenib are ineffective due to MAPK pathway reactivation driven by BRAF dimerization. Combined inhibition of BRAF and EGFR, although approved therapies, results in short survival benefits and frequent treatment resistance and relapse1,2,3.

Nature 20h ago

Diverse binding poses of agonistic neurotoxins on human Na<sub>v</sub>1.6

Abstract Voltage-gated sodium (Nav) channels are key targets of various venomous toxins. Deciphering the binding poses and mechanisms of action of representative toxins will help to dissect the functional mechanism of the channels and facilitate therapeutic development targeting Nav channels1,2. Here we present cryo-electron microscopy (cryo-EM) structures of distinct binding poses of three agonistic peptide toxins on the human Nav1.6–β1 channel complex.

Nature 20h ago

A prognostic human brain network for diffuse midline glioma

Abstract Diffuse midline gliomas (DMGs) are near-universally lethal tumours of the childhood central nervous system1,2. In animal models, DMGs form brain-wide integrated networks through neuron-to-glioma synapses3,4,5,6 and glioma-to-glioma gap junctional coupling3. This extensive connectivity robustly promotes the growth and invasion of DMG3,4,5,6,7,8,9 and other glial malignancies10,11,12 through paracrine mechanisms and direct neuron-to-glioma synapses.

Nature 20h ago

Dead Sea archaea sport reinforced swimming tail for hypersalty waters

Dead Sea archaea sport reinforced swimming tail for hypersalty waters Sadie Harley Scientific Editor Robert Egan Associate Editor Living in the Dead Sea would be a very unpleasant experience for most creatures. With salt concentration above 30% and temperatures ranging from 10–50°C, it takes unique environmental adaptations to survive in such harsh conditions. In a new Nature Communications study, researchers from the Okinawa Institute of Science and Technology (OIST) and the Institute of...

Phys.org 7d ago

SIRT7 regulates dosage compensation and safeguards the female X&#xa0;chromosome

Abstract Sirtuins are deacetylases implicated in stress responses and longevity in mammals1,2. Although their differential impact on disease for the two sexes has been noted3,4,5,6,7, the underlying reasons are unclear. Here, using Sirt7 as a model in mice, we examine the mechanisms leading to sex differences and find that Sirt7−/− female mice have decreased fitness throughout their lifespan.

Nature 20h ago

A first-in-class pulsatile FXR agonist for bile-acid-related liver diseases

Abstract Nuclear receptors are central regulators of metabolism1, yet therapeutic strategies that enforce continuous receptor activation frequently lead to reduced efficacy and unacceptable toxicity. Here we report a first-principles drug design strategy that aligns pharmacokinetics with physiological signalling cycles. We developed linafexor, a potent non-bile-acid agonist of the farnesoid X receptor (FXR)2; it is engineered for rapid systemic clearance, which enables pulsatile receptor...

Nature 20h ago

The Painful Truth About Long Covid

Nothing about long Covid adds up. Consider prevalence rates: How could one study find it affected 3.3 percent of the population of the UK but others an alarming 51 percent of South Americans and 86 percent of Egyptians? Or treatment methods: The BMJ’s systematic review of ways to treat long Covid lists two as supported by moderate evidence, cognitive behavioral therapy and physical exercise.

Wired 9d ago