Epigenetic biomarkers of aging (the "epigenetic clock") have the potential to address puzzling findings surrounding mortality rates and incidence of cardio-metabolic disease such as: (1) women ...consistently exhibiting lower mortality than men despite having higher levels of morbidity; (2) racial/ethnic groups having different mortality rates even after adjusting for socioeconomic differences; (3) the black/white mortality cross-over effect in late adulthood; and (4) Hispanics in the United States having a longer life expectancy than Caucasians despite having a higher burden of traditional cardio-metabolic risk factors.
We analyzed blood, saliva, and brain samples from seven different racial/ethnic groups. We assessed the intrinsic epigenetic age acceleration of blood (independent of blood cell counts) and the extrinsic epigenetic aging rates of blood (dependent on blood cell counts and tracks the age of the immune system). In blood, Hispanics and Tsimane Amerindians have lower intrinsic but higher extrinsic epigenetic aging rates than Caucasians. African-Americans have lower extrinsic epigenetic aging rates than Caucasians and Hispanics but no differences were found for the intrinsic measure. Men have higher epigenetic aging rates than women in blood, saliva, and brain tissue.
Epigenetic aging rates are significantly associated with sex, race/ethnicity, and to a lesser extent with CHD risk factors, but not with incident CHD outcomes. These results may help elucidate lower than expected mortality rates observed in Hispanics, older African-Americans, and women.
State-of-the-art compact antennas rely on electromagnetic wave resonance, which leads to antenna sizes that are comparable to the electromagnetic wavelength. As a result, antennas typically have a ...size greater than one-tenth of the wavelength, and further miniaturization of antennas has been an open challenge for decades. Here we report on acoustically actuated nanomechanical magnetoelectric (ME) antennas with a suspended ferromagnetic/piezoelectric thin-film heterostructure. These ME antennas receive and transmit electromagnetic waves through the ME effect at their acoustic resonance frequencies. The bulk acoustic waves in ME antennas stimulate magnetization oscillations of the ferromagnetic thin film, which results in the radiation of electromagnetic waves. Vice versa, these antennas sense the magnetic fields of electromagnetic waves, giving a piezoelectric voltage output. The ME antennas (with sizes as small as one-thousandth of a wavelength) demonstrates 1-2 orders of magnitude miniaturization over state-of-the-art compact antennas without performance degradation. These ME antennas have potential implications for portable wireless communication systems.The miniaturization of antennas beyond a wavelength is limited by designs which rely on electromagnetic resonances. Here, Nan et al. have developed acoustically actuated antennas that couple the acoustic resonance of the antenna with the electromagnetic wave, reducing the antenna footprint by up to 100.
Algorithms for comparing protein structure are frequently used for function annotation. By searching for subtle similarities among very different proteins, these algorithms can identify remote ...homologs with similar biological functions. In contrast, few comparison algorithms focus on specificity annotation, where the identification of subtle differences among very similar proteins can assist in finding small structural variations that create differences in binding specificity. Few specificity annotation methods consider electrostatic fields, which play a critical role in molecular recognition. To fill this gap, this paper describes VASP-E (Volumetric Analysis of Surface Properties with Electrostatics), a novel volumetric comparison tool based on the electrostatic comparison of protein-ligand and protein-protein binding sites. VASP-E exploits the central observation that three dimensional solids can be used to fully represent and compare both electrostatic isopotentials and molecular surfaces. With this integrated representation, VASP-E is able to dissect the electrostatic environments of protein-ligand and protein-protein binding interfaces, identifying individual amino acids that have an electrostatic influence on binding specificity. VASP-E was used to examine a nonredundant subset of the serine and cysteine proteases as well as the barnase-barstar and Rap1a-raf complexes. Based on amino acids established by various experimental studies to have an electrostatic influence on binding specificity, VASP-E identified electrostatically influential amino acids with 100% precision and 83.3% recall. We also show that VASP-E can accurately classify closely related ligand binding cavities into groups with different binding preferences. These results suggest that VASP-E should prove a useful tool for the characterization of specific binding and the engineering of binding preferences in proteins.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Identification of microRNA expression quantitative trait loci (miR-eQTL) can yield insights into regulatory mechanisms of microRNA transcription, and can help elucidate the role of microRNA as ...mediators of complex traits. Here we present a miR-eQTL mapping study of whole blood from 5,239 individuals, and identify 5,269 cis-miR-eQTLs for 76 mature microRNAs. Forty-nine per cent of cis-miR-eQTLs are located 300-500 kb upstream of their associated intergenic microRNAs, suggesting that distal regulatory elements may affect the interindividual variability in microRNA expression levels. We find that cis-miR-eQTLs are highly enriched for cis-mRNA-eQTLs and regulatory single nucleotide polymorphisms. Among 243 cis-miR-eQTLs that were reported to be associated with complex traits in prior genome-wide association studies, many cis-miR-eQTLs miRNAs display differential expression in relation to the corresponding trait (for example, rs7115089, miR-125b-5p and high-density lipoprotein cholesterol). Our study provides a roadmap for understanding the genetic basis of miRNA expression, and sheds light on miRNA involvement in a variety of complex traits.
Introduction
Despite its high lifetime prevalence rate and the elevated disability caused by posttraumatic stress disorder (PTSD), treatments exhibit modest efficacy. In consideration of the abnormal ...connectivity between the dorsolateral prefrontal cortex (DLPFC) and amygdala in PTSD, several randomized controlled trials (RCTs) addressing the efficacy of different noninvasive brain stimulation (NIBS) modalities for PTSD management have been undertaken. However, previous RCTs have reported inconsistent results. The current network meta‐analysis (NMA) aimed to compare the efficacy and acceptability of various NIBS protocols in PTSD management.
Methods
We systematically searched ClinicalKey, Cochrane Central Register of Controlled Trials, Embase, ProQuest, PubMed, ScienceDirect, Web of Science, and ClinicalTrials.gov to identify relevant RCTs. The targeted RCTs was those comparing the efficacy of NIBS interventions, such as transcranial direct current stimulation (tDCS), repetitive transcranial magnetic stimulation (rTMS), and transcutaneous cervical vagal nerve stimulation, in patients with PTSD. The NMA was conducted using a frequentist model. The primary outcomes were changes in the overall severity of PTSD and acceptability (to be specific, rates of dropouts for any reason).
Results
We identified 14 RCTs that enrolled 686 participants. The NMA demonstrated that among the investigated NIBS types, high‐frequency rTMS over bilateral DLPFCs was associated with the greatest reduction in overall PTSD severity. Further, in comparison with the sham controls, excitatory stimulation over the right DLPFC with/without excitatory stimulation over left DLPFC were associated with significant reductions in PTSD‐related symptoms, including depression and anxiety symptoms, and overall PTSD severity.
Conclusions
This NMA demonstrated that excitatory stimulation over the right DLPFC with or without excitatory stimulation over left DLPFC were associated with significant reductions in PTSD‐related symptoms.
Trial registration: PROSPERO CRD42023391562.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Biologics and biosimilars are medicines made from living cells that treat common and serious diseases such as cancer, diabetes, rheumatoid arthritis, and other inflammatory diseases. They are highly ...targeted, efficacious, and represent an increasingly important part of physicians’ armamentaria in the combat against these medical conditions. Yet they are extremely expensive, costing on average $10,000–$30,000 per year and exceed $500,000 for the most expensive biologics. The advent of biosimilar drugs, or high similar copies of biologics, was supposed to help reduce costs, but thus far the cost of treatment with biologics or biosimilars has not fallen sharply in the USA. We argue that a primary hurdle is the extent of patent protection for the reference biologics that impedes greater numbers of biosimilars entering into the market. To date, of the 12 biosimilars approved for marketing by the US Food and Drug Administration (FDA), only five are commercially available. All but one of the remaining biosimilars are withheld from commercialization due to patent disputes. We argue that the market for biologics and biosimilars will become price competitive only if more biosimilars are available to patients. To this end, the process to eliminate marginally inventive patents held by the reference drug makers must be streamlined and improved. In this perspective article, we suggest actions to improve the pre-FDA approval patent resolution process known as the patent dance, the streamlined patent invalidation process known as Inter Partes Reviews, and the process of granting patents.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, VSZLJ, ZAGLJ
•We study efficiency of response to health signals from mandatory checkups.•Regression discontinuity analysis of diabetes thresholds reveals heterogeneous effects.•Among the general population, ...utilization increases but no evidence of improved health.•For high risks, medical care increases and health outcomes improve, cost-effectively.•Health signals can improve welfare if thresholds are appropriate and follow-up care well targeted.
We investigate the marginal value of information in the context of health signals that people receive after checkups. Although underlying health status is similar for individuals just below and above a clinical threshold, treatments differ according to the checkup signals they receive. For the general population, whereas health warnings about diabetes increase healthcare utilization, health outcomes do not improve. However, among high-risk individuals, outcomes do improve, and improved health is worth its cost. These results indicate that the marginal value of health information depends on setting appropriate thresholds for health warnings and targeting individuals most likely to benefit from follow-up medical care.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Many algorithms that compare protein structures can reveal similarities that suggest related biological functions, even at great evolutionary distances. Proteins with related function often exhibit ...differences in binding specificity, but few algorithms identify structural variations that effect specificity. To address this problem, we describe the Volumetric Analysis of Surface Properties (VASP), a novel volumetric analysis tool for the comparison of binding sites in aligned protein structures. VASP uses solid volumes to represent protein shape and the shape of surface cavities, clefts and tunnels that are defined with other methods. Our approach, inspired by techniques from constructive solid geometry, enables the isolation of volumetrically conserved and variable regions within three dimensionally superposed volumes. We applied VASP to compute a comparative volumetric analysis of the ligand binding sites formed by members of the steroidogenic acute regulatory protein (StAR)-related lipid transfer (START) domains and the serine proteases. Within both families, VASP isolated individual amino acids that create structural differences between ligand binding cavities that are known to influence differences in binding specificity. Also, VASP isolated cavity subregions that differ between ligand binding cavities which are essential for differences in binding specificity. As such, VASP should prove a valuable tool in the study of protein-ligand binding specificity.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The maturation of machine learning and technologies that generate high dimensional data have led to the growth in the number of predictive models, such as the "epigenetic clock". While powerful, ...machine learning algorithms run a high risk of overfitting, particularly when training data is limited, as is often the case with high-dimensional data ("large
, small
"). Making independent validation a requirement of "algorithmic biomarker" development would bring greater clarity to the field by more efficiently identifying prediction or classification models to prioritize for further validation and characterization. Reproducibility has been a mainstay in science, but only recently received attention in defining its various aspects and how to apply these principles to machine learning models. The goal of this paper is merely to serve as a call-to-arms for greater rigor and attention paid to newly developed models for prediction or classification.
The geometry of cavities in the surfaces of proteins facilitates a variety of biochemical functions. To better understand the biochemical nature of protein cavities, the shape, size, chemical ...properties, and evolutionary nature of functional and nonfunctional surface cavities have been exhaustively surveyed in protein structures. The rigidity of surface cavities, however, is not immediately available as a characteristic of structure data, and is thus more difficult to examine. Using rigidity analysis for assessing and analyzing molecular rigidity, this paper performs the first survey of the relationships between cavity properties, such as size and residue content, and how they correspond to cavity rigidity. Our survey measured a variety of rigidity metrics on 120,323 cavities from 12,785 sequentially non-redundant protein chains. We used VASP-E, a volume-based algorithm for analyzing cavity geometry. Our results suggest that rigidity properties of protein cavities are dependent on cavity surface area.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
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