A new “digital twin” framework shows that 2 out of 9 FDA-approved drugs have the potential to treat preterm labor. The twin model virtually replicated how human immune cells that contribute to labor onset react to each therapy. The work spotlights a form of folic acid and a combination of aspirin plus the acid reflux treatment lansoprazole as the best candidates to postpone birth. Clinical trials to address pregnancy complications, such as preterm labor, must overcome ethical quagmires and underfunding. These difficulties have led to a paucity of prenatal interventions. In a related Focus, Adrienne Scott adds: “The therapeutic gap in treating pregnancy complications reflects not only scientific challenges but also restrictive regulations and a history of tragic failures in treating pregnant people.” Digital twin models offer a safe way to repair this gap. Now, Jakob Einhaus and colleagues present a framework called Simulated Immunome Modeling of Clinical Outcomes (SIMCO), applying it to evaluate the potential of 9 FDA-approved, low-risk drugs as interventions for preterm labor. The drugs were chlorthalidone, maprotiline, metformin, lansoprazole, pravastatin, rifabutin, salicylic acid (aspirin), salicylic acid with lansoprazole, and 5-methyltetrahydrofolate (folic acid). Einhaus et al. first established the drugs’ impact on in vitro cells from blood samples from pregnant and non-pregnant people. Then, they used another set of untreated cell samples from 11 pregnant people to connect gestational age at delivery with molecular immune activity (8 non-pregnant people served as controls). By integrating the data from both experiments, SIMCO’s digital twins could replicate how each drug altered labor-related immune cell activity. Tetrahydrofolate and salicylic acid, alongside lansoprazole, showed the most potential to delay the beginning of labor. The 7 other drugs were counterproductive at first, speeding up labor onset before slowing it.

Reduced activity in the brain’s beta waves may be a neural marker for schizophrenia, according to research involving 25 patients. Hsi Wei and colleagues found that these brain waves (which are associated with predicting what happens next) fluctuated less when patients received stimuli and undertook tasks, compared with neural activity in a control cohort of 25 volunteers. This phenomenon correlated with speech distortion and clinical severity. Identifying neural markers of schizophrenia offers a way to connect brain biology with clinical symptoms. Here, Wei et al. have discovered that the extent of change in event-related brain responses (in the beta-band frequency of 15 to 30 Hertz) in the brain’s inferior frontal gyrus could be a marker for schizophrenia. Employing magnetoencephalography, the team monitored brain activity in 25 patients and 25 participant controls as they encountered audio and visual stimuli and undertook sensorimotor tasks. The beta-band activities in the brains of patients changed less in both settings, and reduced beta-band modulation also corresponded with increased clinical severity and disorganized speech in the patients. “This work provides important preliminary support for an account of perceptual and expressive dysfunction in psychosis,” the authors write, noting that beta-band dynamics may signal a potential for targeted interventions.

By applying a unique molecular “scaffold,” researchers have created a broad-spectrum antifungal drug that homes in on a key fungal compound without disrupting the host’s cholesterol – a frequent side effect of current therapies. The compound’s selectivity could help avoid the toxic side effects that have plagued antifungal therapy regimens and frustrated clinicians for decades. To deal with fungal infections, clinicians often turn to a drug called amphotericin B, which is considered the gold-standard for a wide range of different fungal pathogens. The drug has reigned supreme for more than 50 years, but it comes with dangerous side effects such as kidney and blood toxicity. These side effects arise because the drug targets a fungal compound called ergosterol, which shares many structural features with mammalian cholesterol. As a result, amphotericin B frequently disrupts cholesterol biology, constraining its clinical utility. To uncouple ergosterol and cholesterol, Wei Liu and colleagues engineered a new antifungal named mandimycin M16, which they built on a molecular framework they called a 5 +1 polyene scaffold. The scaffold design enables the drug to more specifically target fungal ergosterol through the C5-C8 diene system, which is absent in cholesterol. M16 neutralized 11 priority threat fungal pathogens in vitro – including multidrug-resistant strains – without binding to cholesterol. It also outperformed amphotericin B in several mouse models of systemic Candida infections without causing kidney injury. “M16 provides a mechanistic and structural foundation for designing next-generation antifungal drugs […] offering a pathway toward antifungal agents that address the therapeutic gaps left by current treatments,” Liu et al. write.