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Uncovering hidden enhancers through unbiased in vivo testing
Abstract Chromatin signatures are widely used to identify tissue-specific in vivo enhancers, but their sensitivity and specificity remains unclear. Here we show that many developmental enhancers remain undetectable using currently available chromatin data. In an initial comparison of over 1200 developmental enhancers with tissue-matched chromatin data, 14% ( n = 285) lacked canonical enhancer-associated chromatin signatures. To further assess the prevalence of enhancers missed by chromatin profiling approaches, we used a high-throughput transgenic enhancer assay to screen the regulatory landscapes of two key developmental genes at 5 kb resolution, spanning 1.3 Mb of mouse sequence in total. We observed that 23 of 88 (26%) in vivo enhancers discovered by this approach lacked enhancer-associated chromatin signatures in the respective tissue. Our findings suggest the existence of tens of thousands of enhancers that remain undiscovered by currently available chromatin data, underscoring the continued need for expanding resources for enhancer discovery.
“It’s like a book in the palm of my hand”: Adapting the Safe Delivery App for Papua New Guinea to improve quality of maternal and newborn care
Background Health workers in many low- and middle-income countries are not adequately trained to provide quality antenatal and intrapartum care. The freely available Safe Delivery App (the App) provides health care professionals with direct and instant access to evidence-based, up-to-date clinical guidelines equipping them with an on-the-job reference guide, even in the most remote areas. In this paper we describe the uptake and acceptability and the process to align the App in Papua New Guinea (PNG). Methods Between June 2022 and December 2024, quantitative and qualitative methods were used to explore the usage and acceptability of the App among health care workers in PNG, re-designing images and aligning clinical content with PNG national clinical guidelines. Dissemination of the App took place through formal and informal networks, including a training of trainers’ program in one province. Results The App was seen as an acceptable and useful tool among midwives and nurses working clinically, particularly those in remote areas and midwifery educators. There was an increase in the use of the App, from 354 registered users in 2022 to 1304 in 2024. The majority of users were midwives and nurses, working in primary health care facilities and nursing and midwifery establishments. Participants reported that the App has led to changes in practice, supporting and encouraging staff to follow evidence-based guidelines, improving their clinical management. Conclusion The Safe Delivery App is seen as a useful tool, supporting clinical practice, knowledge and skills, providing users with more confidence in their ability to provide quality maternal and newborn health care. Wider implementation of the App across PNG may be a potential way to support health care workers in the remote settings, providing up to date evidence based clinical guidance in the absence of skilled midwives and doctors.
Human cytomegalovirus induces neuronal gene expression through IE1 for viral maturation
Presymptomatic microRNA-based biomarker signatures for the prognosis of localized radiation injury in mice
The threat of nuclear or radiological events requires early diagnostic tools for radiation induced health effects. Localized radiation injuries (LRI) are severe outcomes of such events, characterized by a latent presymptomatic phase followed by symptom onset ranging from erythema and edema to ulceration and tissue necrosis. Early diagnosis is crucial for effective triage and adapted treatment, potentially through minimally invasive biomarkers including circulating microRNAs (miRNAs), which have been correlated with tissue injuries and radiation exposure, suggesting their potential in diagnosing LRI. In this study, we sought to identify early miRNA signatures for LRI severity prognosis before clinical symptoms appear. Using a mouse model of hindlimb irradiation at 0, 20, 40, or 80 Gy previously shown to lead to localized injuries of different severities, we performed broad-spectrum plasma miRNA profiling at two latency stages (day 1 and 7 post-irradiation). The identified candidate miRNAs were then challenged using two independent mouse cohorts to refine miRNA signatures. Through sparse partial least square discriminant analysis (sPLS-DA), signatures of 14 and 16 plasma miRNAs segregated animals according to dose groups at day 1 and day 7, respectively. Interestingly, these signatures shared 9 miRNAs, including miR-19a-3p, miR-93-5p, miR-140-3p, previously associated with inflammation, radiation response and tissue damage. In addition, the Bayesian latent variable modeling confirmed significant correlations between these prognostic miRNA signatures and day 14 clinical and functional outcomes from unrelated mice. This study identified plasma miRNA signatures that might be used throughout the latency phase for the prognosis of LRI severity. These results suggest miRNA profiling could be a powerful tool for early LRI diagnosis, thereby improving patient management and treatment outcomes in radiological emergency situations.
Physical and chemical niche of human growth plate for polarized bone development
Automatic modulation classification for interrupted sampling proximity detector signals using time–frequency reconstruction network and polynomial chirplet transform
Mendelian randomization analysis: The causal relationship between C-reactive protein and amyloidosis and between C-reactive protein and atherosclerosis
Background A number of studies have shown that elevated CRP is linked to AS and reduced CRP is linked to amyloidosis. However, the exact mechanism explaining this connection is not known. Methods We used genomic pooled data from the Genome-Wide Association Study (GWAS) in a two-sample, two-way Mendelian randomization (MR) analysis study. Methods used included inverse variance weighting (IVW), weighted median (WM), MR-Egger method, Cochran’s Q, MR-PRESSO, MR-Egger intercept test, and leave-one-out sensitivity analysis. To investigate the specific causal relationship between C-reactive protein and amyloidosis and between C-reactive protein and atherosclerosis (coronary, cerebral, aortic, and peripheral atherosclerosis). The study procedure was performed with the STROBE-MR checklist. Results There was a inverse association between C-reactive protein and amyloidosis and an positive causal relationship between C-reactive protein and aortic atherosclerosis. The development of aortic atherosclerosis was positively correlated with C-reactive protein levels (IVW:p = 0.003, OR=1.203,95% CI:1.066–1.358). Whereas amyloidosis onset was associated with reduced C-reactive protein levels (IVW:p = 0.022, OR=0.582,95% CI:0.366–0.924). Reverse Mendelian randomization analysis found no evidence of reverse causality. Conclusion We verified the existence of a negative association between C-reactive protein and amyloidosis and a positive association between C-reactive protein and atherosclerosis by Mendelian randomization, which may provide some reference value for subsequent studies and treatment in the clinic.
Amorphous polymers separate small organic molecules with switchable selective states
AAGP integrates physicochemical and compositional features for machine learning-based prediction of anti-aging peptides
Assessment of change and persistence of youth psychosocial status reported by youth and their guardians during the COVID-19 pandemic: A MyHEARTSMAP study
Background The pediatric mental health crisis pre-dated the COVID 19 pandemic with rates of mental health visits to pediatric emergency departments steadily increasing for the last decade. The COVID-19 pandemic has profoundly impacted children and adolescents and understanding the trajectory of their psychosocial status is important for appropriate resource allocation and policy planning. Methods MyHEARTSMAP is a digital self-assessment mental health evaluation that examines four major psychosocial domains: psychiatry, social, function, and youth health. Children and adolescents throughout British Columbia, and their guardians, completed the baseline assessment between August 2020 and July 2021 (51.8% completed by guardian only, 40.2% youth and guardians, 7.9% youth only). Both children and their guardians repeated the MyHEARTSMAP evaluation three-months after their baseline. Patient demographics and psychosocial concerns were statistically described and compared between baseline and follow-up. A logistic regression model assessed the influence of baseline scores and demographic factors on follow-up severity. Results 241 of 424 participants (56.8%) completed both the baseline and three-month follow-up. The majority of participants reported no change overtime across the psychosocial domains. Both improvement and decline occurred in each domain, with a greater proportion of psychosocial states improving rather than worsening, for all domains. Higher severity of psychosocial concerns reported at baseline indicated a greater likelihood of psychosocial concerns at 3-month follow-up for psychiatric, social and function concerns. Demographic, pandemic, and support service variables were not associated with psychosocial trajectories. Conclusions The severity of youth mental health concerns in British Columbia remained consistent through three-month follow up, despite the changing nature of the COVID-19 pandemic during this period. Greater persistence of psychosocial concerns with increased severity highlights the need for early intervention to prevent worsening mental health. Community support is needed for youth experiencing mental health concerns to address mild psychosocial concerns before presentation at the emergency department.
Epigenetic modulation with nanosatellite triggers tumoricidal immunity for hepatocellular carcinoma treatment
A quasi-experimental study on a co-production- and school-based psychosocial well-being program in Hong Kong
Modeling the effects of treatment adherence challenges on the transmission dynamics of hepatitis C virus
Infectious disease modeling is crucial for predicting disease progression over time and helps guide decision makers in public health policy. Hepatitis C virus (HCV) prevalence is still increasing in Zimbabwe, a low-middle-income country (LMIC), despite the availability of effective treatments, and the reasons for this increase are not well understood. Our study employed a mathematical model to explain the impact of poor treatment adherence on HCV transmission dynamics in Zimbabwe. We computed the basic reproduction number (ℛ0), a vital metric of disease spread. Equilibrium states of the model were determined, and their stability was investigated. The study demonstrated that an adherence level exceeding 52% causes the reproduction number to drop below 1, curtailing further spread. Our HCV model indicates that variations in re-susceptibility minimally impact outcomes, suggesting that re-susceptibility can often be excluded in such analyses. Our model unraveled the synergistic impact of simultaneously enhancing the recovery rate of acutely infected individuals and treatment adherence on reducing ℛ0. The study underlines the pressing need for stronger health interventions, including patient education, financial assistance, and rigorous monitoring, to improve treatment adherence. These interventions are paramount in curbing HCV proliferation, particularly in LMICs like Zimbabwe, and can serve as a template for similar settings globally.
Time-varying stimuli that prolong IKK activation promote nuclear remodeling and mechanistic switching of NF-κB dynamics
Abstract Temporal properties of molecules within signaling networks, such as sub-cellular changes in protein abundance, encode information that mediate cellular responses to stimuli. How dynamic signals relay and process information is a critical gap in understanding cellular behaviors. In this work, we investigate transmission of information about changing extracellular cytokine concentrations from receptor-level supramolecular assemblies of IKK kinases downstream to the NF-κB transcription factor. In a custom robot-controlled microfluidic cell culture, we simultaneously measure input-output encoding of IKK-NF-κB in dual fluorescent-reporter cells. When compared with single cytokine pulses, dose-conserving pulse trains prolong IKK assemblies and lead to disproportionately enhanced retention of nuclear NF-κB. Using particle swarm optimization, we demonstrate that a mechanistic model does not recapitulate this emergent property. By contrast, invoking mechanisms for NF-κB-dependent chromatin remodeling to the model recapitulates experiments, showing how temporal dosing that prolongs IKK assemblies facilitates switching to permissive chromatin that sequesters nuclear NF-κB. Remarkably, using simulations to resolve single-cell receptor data accurately predicts same-cell NF-κB time courses for more than 80% of our single cell trajectories. Our data and simulations therefore suggest that cell-to-cell heterogeneity in cytokine responses are predominantly due to mechanisms at the level receptor-associated protein complexes.
Biospectroscopy screening and molecular fingerprinting of gastric cancer cases from biofluids by vibrational spectroscopy allied with chemometrics
Characterization of an unusual carlavirus-like RNA from papaya (Carica papaya) lacking essential genes
We report the characterization of a novel carlavirus-like RNA, provisionally named papaya defective virus 1 (PapDfV1), identified through high-throughput sequencing of papaya latex RNA. PapDfV1 contains two open reading frames (ORFs): ORF 1 encodes a 211.1 kDa replicase with 96% sequence identity to Zhejiang betaflexivirus 2 (ZhBV2), while ORF 2 exhibits a chimeric structure with regions homologous to two distinct ORFs of ZhBV2. Notably, PapDfV1 harbors a 2.1 kb deletion spanning the downstream portion of triple gene block (TGB) 1, the entirety of TGB2 and TGB3, capsid protein (CP), and the upstream region of the nucleic acid binding protein (NABP). Phylogenetic analysis of the replicase sequence grouped PapDfV1 with ZhBV2 and three Chinese isolates of cowpea mild mottle virus (CPMMV), two of which share the terminal regions 5’-GGAAAAACAGAA and CCTGGTTTT-3’. Mechanical inoculation and agroinfiltration failed to infect PapDfV1 in papaya, Nicotiana benthamiana, and common bean, whereas a ZhBV2 construct successfully infected soybean, common bean, and N. occidentalis. Detection of PapDfV1 in total and double-stranded RNA from leaf tissue of a 2-year-old papaya plant indicates that its replication and movement may depend on host proteins expressed in mature papaya plants or be facilitated by co-infection with unknown papaya viruses. These findings contribute to the growing body of knowledge on the existence and evolution of non-canonical virus-like RNA sequences lacking CP and other genes typically involved in virus movement.
Light in, sound keys out: photoacoustic PUFs from stochastic nanocomposites
Abstract We present a concept of physically unclonable functions utilizing the photoacoustic effect to generate structurally random, inference-resistant cryptographic keys. The system consists of a CuO/SnO₂ nanoparticle composite, where CuO acts as a visible-range absorber and SnO₂ serves as a non-absorbing dispersive matrix. Nanosecond laser pulses induce localized heating and acoustic wave emission, providing spatially heterogeneous photoacoustic signals that are digitized into binary matrices. Evaluations across ten devices yielded a bit uniformity of 49.54%, inter-device Hamming distance of 49.69%, entropy of 0.983, and bit aliasing of 49.38%—all approaching ideal values for secure key generation. Machine learning attacks using logistic regression and support vector machines failed to infer underlying patterns, with prediction accuracies of 53.53% and 52.54%. The device maintains cryptographic performance after transfer to diverse substrates, including human skin, highlighting its mechanical adaptability. This subsurface, light-to-sound-based approach offers a scalable platform for secure authentication on flexible or opaque surfaces.
Analysis of temperature field evolution in ground freezing construction of twin tunnels in a coastal urban area
Feeding ecology and activity patterns of Hippopotamus amphibious in the Dhidhessa Wildlife Sanctuary, Southwestern Ethiopia
Understanding the dietary composition and activity patterns of hippopotamuses (Hippopotamus amphibious) is critical for assessing their ecological role within their habitat. This study investigated the feeding habits and behavioral rhythms of common hippopotamuses in the Dhidhessa Wildlife Sanctuary (DWS), Ethiopia, from 2022 to 2023. Dietary data were collected through direct observation of fresh feeding signs and fecal analysis, while activity patterns were recorded via continuous focal sampling of adult males and females at 30-minute intervals. Hippopotamuses allocated 30.1% of their time to resting, followed by movement (23.7%). Vocalizations (barking) constituted 53.1% of recorded behaviors, while yawning accounted for 46.9%. Males exhibited significantly more resting behavior than females. Peak feeding and movement occurred during early morning and late afternoon, whereas resting peaked at midday. Both sexes displayed higher frequencies of barking and yawning in the afternoon. Dietary analysis identified 34 plant species from 12 families consumed by hippos. Poaceae dominated their diet (60%), while Combretaceae contributed the least (0.5%). Typha latifolia was the most frequently consumed species (9.4%), followed by Eriochloa fatmensis (8.7%). Seasonal variation was evident, with 76.7% of foraging occurring in the wet season compared to 23.3% in the dry season. Twenty-one forage species were available year-round. These findings highlight the importance of seasonal resource availability and temporal activity shifts in hippopotamus ecology. Conservation strategies in DWS should prioritize habitat management to ensure sustainable ecosystem functionality.