Poly(A)-binding protein is an ataxin-2 chaperone that regulates biomolecular condensates.

Biomolecular condensation underlies the biogenesis of an expanding array of membraneless assemblies, including stress granules (SGs), which form under a variety of cellular stresses. Advances have been made in understanding the molecular grammar of a few scaffold proteins that make up these phases, but how the partitioning of hundreds of SG proteins is regulated remains largely unresolved. While investigating the rules that govern the condensation of ataxin-2, an SG protein implicated in neurodegenerative disease, we unexpectedly identified a short 14 aa sequence that acts as a condensation switch and is conserved across the eukaryote lineage. We identify poly(A)-binding proteins as unconventional RNA-dependent chaperones that control this regulatory switch. Our results uncover a hierarchy of cis and trans interactions that fine-tune ataxin-2 condensation and reveal an unexpected molecular function for ancient poly(A)-binding proteins as regulators of biomolecular condensate proteins. These findings may inspire approaches to therapeutically target aberrant phases in disease.

Feasibility and Methodology of a Pilot Free Blood Pressure Monitoring and Follow-Up Program at Two Free Clinics.

BACKGROUND: Hypertension affects approximately 1 in 2 adults in the US. Home blood pressure (BP) monitoring programs are effective in the diagnosis and management of hypertension. Free clinics serve as an integral safety net for millions of uninsured and economically disadvantaged patients in the US. The feasibility and effects of a free home BP monitoring and follow-up program in a free clinic setting is not well characterized. METHODS: This was a prospective study of the implementation of a pilot BP monitoring and follow-up program between March 2021 and August 2023 at 2 free clinics in the San Francisco Bay Area. A total of 78 hypertensive patients were enrolled in the program and given a free BP monitor. We surveyed via telephone the change in systolic and diastolic BPs and BP monitor use and comfort at 3 weeks. Volunteers in clinic roles involved in the BP monitoring program were surveyed to assess their time spent and perceptions of the program. RESULTS: Of the 78 patients, 37 provided responses to the 3-week survey. A total of 36 of 37 (97%) patients reported using their BP monitor. A total of 35 patients reported using it at least once a week (95%), with the majority reporting at least four uses a week (68%). A total of 36 patients (97%) planned on continuing to use their BP monitor. At 3 weeks, the mean systolic and diastolic BP changed by -6.40 mmHg (95% CI, -10.8 to -2.01 mmHg; P = .00577) and -2.72 mmHg (95% CI, -5.62 to 0.188 mmHg; P = .0657), respectively. The time commitment for this program ranged from 130 ± 51 min for program leaders to 16 ± 14 min per week for patient-facing roles. All volunteer roles (patient-facing, phone follow-up, program leaders) expressed that they had a clear understanding of their responsibilities in the program (median 4 on Likert scale, IQR 3-5). CONCLUSION: Home BP monitoring and follow-up is feasible to implement in free clinics, resulting in high rates of patient engagement among respondents. Our findings suggest that home BP monitoring and follow-up programs may be beneficial in vulnerable patient populations.

Aberrant phase separation is a common killing strategy of positively charged peptides in biology and human disease.

Positively charged repeat peptides are emerging as key players in neurodegenerative diseases. These peptides can perturb diverse cellular pathways but a unifying framework for how such promiscuous toxicity arises has remained elusive. We used mass-spectrometry-based proteomics to define the protein targets of these neurotoxic peptides and found that they all share similar sequence features that drive their aberrant condensation with these positively charged peptides. We trained a machine learning algorithm to detect such sequence features and unexpectedly discovered that this mode of toxicity is not limited to human repeat expansion disorders but has evolved countless times across the tree of life in the form of cationic antimicrobial and venom peptides. We demonstrate that an excess in positive charge is necessary and sufficient for this killer activity, which we name 'polycation poisoning'. These findings reveal an ancient and conserved mechanism and inform ways to leverage its design rules for new generations of bioactive peptides.