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Glycolytic enzymes are challenging drug targets due to their highly conserved active sites and phosphorylated substrates. Here, the authors identify fast acting allosteric inhibitors of Trypanosoma brucei phosphofructokinase that block trypanosome glycolysis and provide cure evidence in murine model.

An effective and scalable cure strategy is a top priority for the HIV research field; this Review discusses recent advances, knowledge gaps, and priority research areas for the next 5 years.

Targeting two distinct steps of the transcription process yields synergistic antibiotics that kill non-replicating Mycobacterium tuberculosis and reduce drug resistance.

Translation of evidence about dementia risk into effective public health policy is a challenge. In this Consensus Statement, Demnitz-King and colleagues present 56 policy recommendations for dementia prevention, providing policymakers with a foundation for designing and implementing evidence-based dementia prevention strategies, prioritizing clear communication, targeted intervention and sustained research investment.

Understanding the mechanisms underlying the survival of drug tolerant persister cells following chemotherapy remains elusive. Here, multi-omics analysis and experimental approaches show that the germ-cell-specific H3K4 methyltransferase PRDM9 promotes metabolic rewiring in glioblastoma stem cells.

This study highlights a unique drug target for trypanosomatid parasitic protozoa and a new chemical tool for investigating the function of their divergent kinetochores.

In this Review, the authors describe and discuss how advances in artificial intelligence, genomics, radiomics and cytology can be integrated into decision-making processes to improve the management of bladder cancer.

The bicyclic azetidines, a class of potent, well-tolerated antimalarial compounds that is active against multiple stages of the Plasmodium life-cycle, has been discovered following screens against libraries of compounds reminiscent of natural products.

Can a pile of cardboard tubes and boxes help to fight Huntington's Disease? Apparently so, at least if you happen to be a mouse, reports Jeremy Thomson.

One of the main hurdles to curing HIV infection are viral reservoirs. Here, the authors develop a trispecific antibody and demonstrate its ability to simultaneously activate and target latently HIV−1 infected cells for elimination by T cells as an alternative strategy for HIV cure.

Heterozygous mutations in the mechanoenzyme dynamin (DNM2) manifest as either a myopathy or a peripheral neuropathy. Here, the authors show antagonistic effects of these mutations and combining them, in mice, mitigates the phenotypic manifestations observed in individual mutants.

CCR5 is a co-receptor for many transmitted HIV strains. Here, the authors show that biweekly injection of the CCR5-specific antibody Leronlimab protects rhesus macaques against infection following repeated intrarectal challenges of a CCR5-tropic SHIV.

Could the presence of a patent foramen ovale be associated with the occurrence of migraine headaches? In this the first of two Viewpoints on patent foramen ovales, Jeremy Orr and Jonathan Tobis discuss the possibility that the majority of migraine headache could be treated by closing this patent foramen ovale passageway though the heart.

An activator of DNA polymerase γ restores function to disease-causing mutant variants and demonstrates a potential route to treatments for inherited mitochondrial disorders involving POLG mutations.

Rich and colleagues show that glioblastoma stem cells have increased global protein translation, which is achieved via the tRNA modifier YRDC. They show that targeting it or reducing its substrate threonine suppresses tumor growth.

Secondary lymphedema is a debilitating disease with no cure. Here the authors show that topical application of an FDA-approved anti-T cell drug tacrolimus potently prevents development and alleviates pathologic changes of established lymphedema in mice, suggesting a new treatment for human patients.

Only praziquantel is available for treating schistosomiasis, a disease affecting >200 million people. Here, the authors identify compounds active against schistosome infections meeting the criteria for lead progression indicated by WHO with better activity against juvenile worms than praziquantel.

A way of life.

PIEZO1 is a mechanosensitive ion channel. Here, authors identify PIEZO1 human mutations in Prune Belly Syndrome. At a single molecule level these mutations exhibit loss-of-function characteristics.

Genomic analyses of localized, non-indolent prostate cancer identify recurrent aberrations that can predict relapse, and also highlight differences between early prostate cancer and metastatic, castration-resistant disease.

Combination of TCR or CAR T cells expressing the engineered CD47 variant 47_E with anti-CD47 antibody therapy results in synergistic antitumour efficacy due to T cell resistance to clearance by macrophages, while maintaining macrophage recruitment into the tumour microenvironment.

Assessment of more than 400,000 people over the age of 40 demonstrates that homozygosity for a CCR5 variant that prevents HIV-1 infection comes at the cost of increased rates of mortality.

Cryo-electron structures of the hepatitis B virus receptor NTCP show a distinct membrane topology compared with other SLC10 proteins, but a common bile acid transport mechanism that is shared with related mammalian and bacterial proteins.

Analyses of 2,658 whole genomes across 38 types of cancer identify the contribution of non-coding point mutations and structural variants to driving cancer.

Pharmacotyping analyses of large cohorts of pediatric acute lymphoblastic leukemia identify correlations between drug sensitivities and clinical outcomes across different genomic subtypes.

Here, Biswas et al. present and characterize a second-generation model of HBV infection in rhesus macaques, showing that extended infection requires suppression of host immunity.

Cancers evolve as they progress under differing selective pressures. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, the authors present the method TrackSig the estimates evolutionary trajectories of somatic mutational processes from single bulk tumour data.

New antimalarials are urgently needed. Here, the authors identify Open Source Malaria compound, OSMS-106, as a reaction hijacking inhibitor of the malaria parasite protein synthesis machinery, with potential use for treatment and prophylaxis.

Streptococcus pyogenes causes ~750 million infections and more than 500,000 deaths each year. In this study, human volunteers were challenged with S. pyogenes and participants that developed pharyngitis had elevated levels of cytokines, and increased migration and activation of immune cells.

Empirically based models of disease progression in familial frontotemporal dementia reveal the relative ordering of clinical, neuroimaging, and fluid biomarker changes and facilitate novel clinical trial designs

In a randomized placebo-controlled trial in rural Niger, biannual azithromycin distribution to children 1-59 months reduced all-cause mortality. Based on serology, Arzika et al. here report a reduction of Campylobacter infection, supporting one mechanism for the intervention’s impact on mortality.

Exome sequencing and copy number analysis are used to define genomic aberrations in early sporadic pancreatic ductal adenocarcinoma; among the findings are mutations in genes involved in chromatin modification and DNA damage repair, and frequent and diverse somatic aberrations in genes known as embryonic regulators of axon guidance.

In a phase 2 trial, the combination of gemcitabine, cisplatin and anti-PD-1 led to a clinical complete response in 43% of patients with muscle-invasive bladder cancer, which facilitated bladder sparing and was associated with long-term bladder-intact metastasis-free survival.

Glioblastoma stem cells might be dependent on cues from aberrant vascular niches that mimic the normal neural stem cell niche. What are the implications of these findings for treatment of this disease?

A portable magnetic-resonance sensor accurately grades liver steatosis and fibrosis in living mice and human liver samples.

Recurrent urinary tract infections occur in ~ 25% of women. Here, Beatson and colleagues use whole genome sequencing to track the dynamics of an E. coli ST131 clone in a single patient over a 5-year period. This study provides unique insights into pathogen evolution during recurrent urinary infection.

Malaria case numbers are rising globally and there is a vital need for new medicines that overcome the emergence of drug resistance. This Review describes the current landscape of small-molecule antimalarial therapies and the methods used to discover them as well as perspectives on approaches to find new targets and treatments.

Pepstatin is a known inhibitor of malarial proteases, but its activity varies between sources. Here, Istvanet al. identify a pepstatin ester as the active component of pepstatin preparations and show that this prodrug is activated by a Plasmodiumesterase, mutation of which can confer resistance to pepstatin and other compounds.

Brain cancer encompasses a diverse range of complex malignancies, many of which are associated with a poor prognosis and require more effective treatments. In this Position Paper, an international panel of clinicians and laboratory-based scientists convened by Cancer Research UK identify and discuss seven challenges that must be overcome if we are to cure all patients with a brain tumour.

The Tuberculosis Drug Accelerator, an experiment designed to facilitate collaboration in tuberculosis drug discovery by breaking down barriers among competing labs and institutions, has reached a 10-year landmark. We review the consortium’s achievements, advantages and limitations and advocate for the application of similar models to other diseases.

Abeysundara, Rasnitsyn, Fong et al. report that the presence of leptomeningeal metastatic tumour cells leads to the recruitment and remodelling of fibroblasts, which, in turn, facilitate the colonization and outgrowth of medulloblastoma cells in the leptomeninges.

Malaria is a mosquito-transmitted infection that affects more than 200 million people worldwide, with the highest morbidity and mortality in Africa. Elimination, through vector control approaches and chemoprevention, is within reach, but is threatened by the emergence of drug-resistant strains of mosquitoes and Plasmodium spp., the infectious parasite.

Precisely tuning the genetic response to environmental stimuli is a key step in engineering synthetic biology systems. Here, the authors profile 8269 IPTG-induced promoters to deconstruct the relationship between sequence architecture and gene expression.

Tracking single molecule movements is a challenging task, but highly desired for applications and fundamental studies. Here the authors reconstruct the sub-angstrom relative movements of a molecule interacting with a metal adatom, by measuring its vibrational spectrum in a self-assembled monolayer, continuously modified by the adatom in a nanoparticle-on-mirror construct.

The Movember global Landscape Analysis Committee (LAC) was established to act as an independent group of experts across urology, medical oncology, radiation oncology, radiology, pathology, translational research, health economics and patient advocacy to identify the highest priority research needs across the prostate cancer biomedical research domain. Findings from the landscape analysis illustrate the research priorities in prostate cancer and will enable Movember to focus on specific needs, with particular investment in research to reduce disease progression and improve therapies for advanced prostate cancer.

Circulating tumour DNA profiling in early-stage non-small-cell lung cancer can be used to track single-nucleotide variants in plasma to predict lung cancer relapse and identify tumour subclones involved in the metastatic process.