Proceedings of the National Academy of Sciences

Nipah virus (NiV) is a sporadic yet extremely deadly zoonotic pathogen, with reported case fatality rates of 40%-75% in impacted areas. Prolonged incubation, documented relapse, and delayed-onset encephalitis following apparent recovery indicate that NiV dynamics are influenced by intricate temporal processes. However, mechanistic contributions of these processes to epidemic persistence remain poorly understood. In this study, we develop and analyze a delay differential equation model for NiV tr...

Epigenetic clocks estimate biological age from DNA methylation patterns at CpG sites, providing robust predictions of mortality and morbidity risk. "Blue zones"--regions of exceptional longevity--offer a unique opportunity to investigate how biological aging diverges from chronological age. However, standard clocks are typically trained on large, heterogeneous datasets, reflecting average population trends rather than region-specific dynamics. Using data from the Costa Rican Longevity and Health...

In a recent article in Science, Shenhar et al. report that human life span heritability reaches [~]55% after removing "extrinsic" mortality, roughly seven-fold higher than recent large pedigree estimates. This conclusion rests on classifying deaths from infections and accidents as environmental noise independent of genetics. This premise is biologically untenable: susceptibility to severe infection is substantially heritable, with adoptee studies showing relative risks exceeding 5 for infection ...

Human contact network structure fundamentally shapes infectious disease transmission and control. Most COVID-19 epidemic models assumed approximately homogeneous contact patterns, yet real-world networks are highly heterogeneous. We analysed 59,585 daily non-household contact reports from Germanys COVIMOD study (2020-2021) using a novel heavy-tail regression framework. Throughout the pandemic, contact distributions remained strongly heavy-tailed despite substantial non-pharmaceutical interventio...

In the three years since Omicron emergence, SARS-CoV-2 dynamics have exhibited persistent twice-yearly waves in the United States, peaking in late summer and winter, with heterogeneity in timing and intensity across states. This semiannual pattern sharply contrasts with typical annual respiratory pathogen dynamics in the US, yet their underlying mechanisms and whether this pattern will persist remain poorly understood. Here, we tested several hypothesized mechanisms and found that a combination ...

Biological fitness quantifies the efficiency and selective advantage of pathogens and hosts in their bilateral interaction. Key questions--such as how much more infectious an emerging variant is compared with its predecessor, or how much protection vaccination offers relative to no vaccination--require fitness to be measured systematically, in real time, and ideally beyond controlled laboratory settings. We propose an approach that infers biological fitness from mostly non-biological data on inf...

Dengue is one of the worlds highest-burden arboviral diseases. Although classically considered an urban disease, many regions experience a substantial dengue burden in rural areas. The combined influence of long-term climate, short-term weather variation, local built environments, and land-use gradients on dengue dynamics in rural settings remains poorly understood, limiting our ability to predict shifting risk under global change. Here, we investigate these dynamics in Costa Rica to disentangle...

Programmatic decisions regarding surveillance and intervention for trachoma are made at the district level, reflecting an implicit assumption that transmission within districts is sufficiently homogeneous. However, as trachoma transmission declines, residual pockets of transmission may become spatially heterogeneous at sub-district scales. Using cluster-level data from 12 districts in Amhara, Ethiopia (2019-2023), we assess the spatial structure of Pgp3 antibody responses, a sensitive measure of...

Biological ageing begins before birth, with early-life exposures shaping late-life health. These exposures drive health inequities early, yet specific exposures and the composition of the ageing exposome remain largely undefined. This gap may persist as the field lacks agnostic investigations accounting for non-linearity, interactions and subtle signals. We aimed to identify exposures predictive of epigenetic ageing accumulated during childhood and adolescence and explore the composition of the...

BackgroundChikungunya virus (CHIKV) is an Aedes transmitted arbovirus. Demographic changes coupled with the expanding footprint of the mosquito from climate change have the potential to shift the global burden from the virus. MethodsHere we use projections of human demography and Aedes mosquitoes distribution to estimate baseline and future burden from CHIKV under different climate change scenarios in 178 countries. We then estimate the potential of vaccines to mitigate the growing burden. Fin...

BackgroundThe Most Favored Nation (MFN) policy is a mechanism that incorporates foreign prices to determine the maximum allowable net price for any branded drug within US government-funded healthcare. Two proposed rules, the Global Benchmark for Efficient Drug Pricing ("GLOBE") (90 Fed. Reg. 60,244) for Medicare Part B and the Guarding US Medicare Against Rising Drug Costs ("GUARD") (90 Fed. Reg. 60,338) for Medicare Part D, invoke the Center for Medicare and Medicaid Innovation Centers payment ...

A recent randomized clinical trial in non-small cell lung cancer1 confirms what numerous observational studies have reported time of day (ToD) may dramatically influence treatment outcomes in cancer patients. In this recent trial median overall survival (OS) decreased from 28 months in the early ToD arm to 16.8 months in the late ToD arm. We raise the concern that clinical trial outcomes may be influenced by seemingly minor biases in treatment time across arms. We also suggest that by measuring ...

Pathogenic organisms are typically thought to be constrained by a tradeoff between the rate and duration of transmission, an assumption that underpins a considerable body of evolutionary theory. Here we test for a transmission-duration tradeoff using detailed historical malaria infection data from an era prior to widespread use of antibiotics when humans were deliberately infected with malaria parasites as treatment for neurosyphilis (malariatherapy). These time series follow individual human in...

1The timeliness of infectious disease surveillance systems largely determines the speed at which mitigation interventions may be implemented. However, it is unclear how surveillance timeliness evolves during a pandemic with changing government policies, testing tools, and population-level infection and immunity landscapes. Here, we adapt an agent-based model for COVID-19 transmission to explore the timeliness of the surveillance signals obtained from polymerase chain reaction (PCR) and rapid ant...

The COVID-19 pandemic led to substantial life expectancy losses globally. Historically, life expectancy reversals have been followed by rapid returns to previous trajectories, but whether this is true for the COVID-19 pandemic is still unknown. We update life expectancy estimates through 2024 for 34 high-income countries and quantify annual and cumulative life expectancy "deficits" by comparing observed life expectancy with counterfactuals based on pre-pandemic trends. Five years after the pande...

Mitochondria are semi-autonomous organelles whose generation and maintenance demand precise expression, processing, and assembly of >1,000 proteins encoded across two genomes. To explore this cooperativity, we performed multiomic analyses on >200 cell lines harboring mitochondrial gene perturbations, generating >26M molecular measurements. Our data reveal that mitochondrial proteome homeostasis is heavily influenced by post-transcriptional processes. Through nearest neighbor analyses, we reveal ...

Large-scale epidemics are consistently associated with increased psychological distress and substantial changes in human mobility, yet the relationship between mental health responses and effective population mobility remains overlooked. During the COVID-19 pandemic, non-pharmaceutical interventions (NPIs) such as lockdowns and travel restrictions altered daily movement patterns while simultaneously affecting psychological well-being. Importantly, formal policy stringency alone does not fully ca...

Methods that analyze single-cell RNA-seq+ATAC-seq multiome data have shown promise in linking enhancers to target genes by correlating chromatin accessibility with gene expression across cells. However, correlations among ATAC-seq peaks may induce non-causal tagging peak-gene links (analogous to tagging associations in GWAS); indeed, we confirm that tagging effects induced by peak co-accessibility are pervasive in peak-gene linking. We defined two scores for each ATAC-seq peak: co-accessibility ...

BackgroundImmune checkpoint inhibition has transformed cancer therapy; however, many patients fail to respond to single-agent blockade, and combination strategies are often limited by toxicity. Central nervous system tumors exploit multiple immunosuppressive pathways, including the CD200 and PD-1/PD-L1 axis to evade anti-tumor immunity and support tumor aggressiveness. MethodsWe investigated ARL200, a peptide ligand targeting the CD200 activation receptor (CD200AR) using in vitro immune assays,...

Background: Human-to-human transmission of pathogens fundamentally depends on interactions among infectious and susceptible individuals, yet traditional population-scale models often overlook the stochastic, behaviour-driven, and highly heterogeneous nature of these interactions. Methods: Here, we develop a large-scale actor-based model capturing early epidemic dynamics of a novel respiratory pathogen on dynamic contact networks. We build these networks upon explicitly integrating detailed demog...