Parallel DNA G-quadruplexes (G4) are key regulators of oncogene transcription. The MYC promoter G-quadruplex (MycG4) is a prototype parallel G4 and promising anticancer drug target. However, effects of DNA damage or mutations on their conformational landscape remain elusive. Systematic analysis of mutational effects is challenging because permutating G4-forming sequences creates a vast sequence space inaccessible to most experimental methods. Herein, using a custom G4-DNA microarray, we systematically examine all 2 145 possible single and double mutations of the MYC promoter G4. The results show no single or even double mutation completely prevents MYC G-quadruplex formation, emphasizing its exceptional robustness. Mutated MycG4 sequences can form G-quadruplexes with vacancies or bulges without the need to replace the damaged G-runs. Both length and position of a G-run determine its resilience against mutations. Intriguingly, our results reveal an efficient compensation mechanism for mutations involving nearby redundant G-residues to preserve G4 formation. Moreover, the most disruptive mutations involve two nonadjacent G-runs, which cannot be repaired by a single G-tract but can still be compensated by redundant guanines. These results provide critical insights into G-quadruplex folding, structural resilience, and damage tolerance, with implications for gene regulation and G4-targeted drug design.
Soundscapes in coral reef ecosystems are influenced by species richness and environmental conditions. Shallow coral reef soundscapes have been analyzed in various world regions, but most studies focus on environments exceeding 10 m depth. Additionally, remote locations have received limited attention and often lack recordings that span multiple days. Here, soundscapes were continuously recorded during 24-h periods at two nearby Acropora patches located ∼8 m apart in water depths ∼2 m within fringing reefs on the northwest coast of Moorea, French Polynesia. One patch was degraded from a bleaching event in 2019, whereas the other had greater coral coverage. A diel pattern was observed at both high and low frequencies and exhibited a strong dawn chorus. When comparing sites, the degraded patch exhibited sound levels ∼10 dB lower than the patch with higher coral coverage at frequencies below 2.5 kHz. The magnitude of the local acoustic particle velocity inferred from hydrophone measurements as well as array beamforming confirmed that the soundscapes were distinct with unique acoustic signatures despite proximity. These results provide evidence of measurably distinct soundscapes for close-by coral ecosystems, suggesting differing ecological community structures.
Urbanization-driven environmental change has significant implications for human health and well-being. However, studies have found differing patterns in microbial diversity along urbanization gradients; and it remains unknown whether this reflects methodological limitations or genuine ecological complexities. Resolving these inconsistencies requires innovative, reproducible methods that accurately reflect human contact with environmental microbiota. Measuring microbiota from particulate matter collected from shoe soles has the potential to serve as a simple, effective, and reliable method to assess environmental microbial exposure in large-scale epidemiological studies. Here, we introduce this method for use during outdoor activities and validate the reproducibility of shoe sole dust to reveal changes in microbiota with greenness and other environmental conditions. Through repeated walks on consistent routes along an urbanization gradient in Finland, we show that left and right shoe sole dust from the same walk and same route represent more similar microbial communities compared to different walks and routes. We also found that bacterial biomass and diversity were best predicted by Normalized Difference Vegetation Index (NDVI, as a measure of greenness) immediately surrounding the walking path, whereas fungal communities responded to broader landscape-scale greenness (100m-1km), suggesting that bacteria and fungi are governed by different dispersal processes. Importantly, NDVI explained these differences in diversity more effectively than simple classifications of the path based on its substrate and whether it was in a rural or urban setting. Shoe sole dust sampling offers a straightforward and reproducible approach capable of capturing scale-dependent microbial responses to vegetation, and has the potential to enable more robust epidemiological studies on the health effects of greenness and environmental biodiversity.
Retinoic acid receptor-related orphan receptor beta (RORβ) is a transcription factor expressed in the central nervous system, retina, and bone that regulates circadian rhythms, retinal neurogenesis, and inflammatory signaling. Despite these critical functions, the mechanisms governing RORβ stability remain poorly understood. Here, we identify a post-translational regulatory axis in which the lysine acetyltransferase p300 and the NAD⁺-dependent deacetylase SIRT1 control RORβ stability and transcriptional activity. p300-mediated acetylation increases RORβ abundance, while SIRT1 modulates turnover through both catalytic and non-catalytic scaffolding mechanisms. K176 acetylation in the hinge primes UBC9/PIAS1-mediated SUMOylation at nearby K179, marking RORβ for proteasomal degradation and reducing transcriptional output, providing a mechanistic framework for targeting RORβ in neurological and retinal disorders, and bone homeostasis. p300 acetylates RORβ at eight lysines; SIRT1 reverses this via catalytic activityK176 acetylation primes UBC9/PIAS1-mediated SUMOylation at nearby K179SUMOylated RORβ undergoes proteasomal degradation leading to reduced RORβ-mediated transcriptional outputp300 displaces ubiquitin E3 ligases from RORβ; SIRT1 activation reduces PIAS1 association. O'Leary et al. define a post-translational circuit in which p300 acetylates K176 within the RORβ hinge domain, priming SUMOylation at nearby K179 preferentially by UBC9/PIAS1. SUMOylated RORβ is targeted for proteasomal degradation with diminished transcriptional activity, while SIRT1 deacetylase activity antagonizes this pathway via both catalytic activity and protein-protein interactions to stabilize active RORβ.Graphical Abstract.
Soybean (Glycine max) is an important model crop for studying plant functional genes, such as the NAC transcription factor (TF) gene family. The NAC transcription factor (TF) family is one of the largest plant-specific TF families and plays critical roles in plant growth, development, and stress responses. In this study, we performed a pan-genome-wide analysis of NAC genes using 29 soybean genomes. A total of 5051 NAC genes were identified and clustered into 245 orthologous gene groups (OGGs), including 58 core, 88 soft-core, 32 shell, and 67 cloud groups. Based on phylogenetic relationships, the representative NAC OGGs were assigned to 18 subfamilies, 17 of which contained soybean NAC genes. Gene duplication analysis indicated that whole-genome duplication (WGD)/segmental duplication was the predominant driver of NAC family expansion, accounting for 90.88% of duplication events. Approximately 39.30% of NAC genes carried at least one intact transposable element (TE) within 2 kb upstream or downstream regions. NAC genes with copy number variation (CNV) harbored more nearby TEs than non-CNV genes (1.54 vs. 1.31 TEs per gene), and dispensable NAC genes contained more nearby TEs than core NAC genes (1.59 vs. 1.33 TEs per gene). These results indicate a significant association between local TE abundance and NAC gene CNV or dispensability. Selection pressure analysis showed that dispensable NAC genes had higher Ka, Ks, and Ka/Ks values than core genes, suggesting relatively relaxed evolutionary constraints. Expression profiling across six tissues revealed distinct transcriptional patterns among NAC subfamilies. Structurally conserved subfamilies generally showed broader expression, whereas structurally divergent subfamilies displayed greater expression variability. Regulatory network and Gene Ontology (GO) enrichment analyses suggested that conserved subfamilies were mainly associated with stress responses, while divergent subfamilies were related to cell wall regulation, signal transduction, and ion homeostasis. Further analysis of Wm82 drought RNA-seq data prioritized several putative drought-responsive NAC candidates, including Glyma.16G043200, Glyma.06G248900, Glyma.07G050600, Glyma.12G206900, and Glyma.18G261300. Overall, these findings elucidate the mechanisms of expansion and the functional divergence of the NAC gene family at the soybean pan-genome level, providing a theoretical basis for understanding NAC gene evolution and facilitating future crop improvement.
Emergency department overcrowding and ambulance diversion are significant problems worldwide and have become more apparent during the COVID-19 pandemic. In Japan, the Dedicated Emergency Physician (DEP) model has been associated with reduced transport time. However, whether this benefit persists during the pandemic remains unclear. This study analyzed the changes in transport outcomes during the COVID-19 pandemic in Japanese regions with and without DEP hospitals to evaluate the effectiveness of the DEP model and identify factors that could improve transport outcomes. Using nationwide data from January 2015 to December 2021, three target areas were analyzed: Urayasu-Ichikawa (DEP Group 1), Shonan-Fujisawa (DEP Group 2), and Ichinomiya-Toyota (Non-DEP Group 3). DEP Groups 1 and 2 contained DEP hospitals, while Non-DEP Group 3 was selected for its comparable population size and strong pre-pandemic transport performance. To minimize the impact of regional variations in COVID-19 prevalence, this study compared the changes in transportation outcomes before and after the pandemic between the target areas and nearby comparison areas. In total, there were 150,856 transports in Group 1; 186,965 in Group 2; and 516,655 in Group 3. In the target areas of Groups 2 and 3, transport time changes were significantly shorter by 2.016 and 0.606 min, respectively, compared to the comparison areas. Moreover, these areas had significantly lower odds of transportation difficulty (Group 2: odds ratio 0.131, 95% confidence interval 0.110-0.157; Group 3: OR 0.086, 95% CI 0.066-0.112). It was found that the common characteristics of these areas were densely located large-scale hospitals and makeshift buildings for patients with COVID-19, adjacent to large-scale hospitals. These findings suggest that DEP hospitals alone did not guarantee favorable transport outcomes during the pandemic. A sufficient number of large-scale hospitals and nearby temporary facilities may be crucial for maintaining effective emergency transportation during a pandemic.
To evaluate the efficacy and safety of neoadjuvant concurrent chemoradiotherapy (CCRT) utilizing nedaplatin and paclitaxel in patients with locally advanced esophageal squamous cell carcinoma (ESCC). Locally advanced ESCC patients received two cycles of nedaplatin plus paclitaxel or albumin-bound paclitaxel with concurrent radiotherapy (41.4-50.4 Gy) as neoadjuvant treatment. Immunohistochemical profiling was performed on biopsies and surgical specimens. The primary endpoint was the pathological complete response (pCR) rate. Among 49 enrolled patients, 33 underwent surgery, yielding a pCR rate of 30.3%. Overall survival was inferior in resected patients with positive postoperative lymph nodes (HR 3.92, 95% CI 1.30-11.80, p = 0.02, log-rank p = 0.009). Higher FOXP3 expression before (HR 0.14, 95% CI 0.02-1.26, p = 0.08, log-rank p = 0.041) and after (HR 0.23, 95% CI 0.07-0.84, p = 0.03, log-rank p = 0.015) treatment nominally contributed to favorable outcomes. Upregulated TIGIT post-treatment trended toward a poorer prognosis in this surgical cohort (HR 7.10, 95% CI 0.79-63.65, p = 0.08, log-rank p = 0.041). Neoadjuvant nedaplatin and paclitaxel-based CCRT demonstrates encouraging preliminary antitumor efficacy. Tumor microenvironment profiling highlights FOXP3 and TIGIT dynamics as potential prognostic indicators. These hypothesis-generating insights warrant further validation in large-scale, randomized controlled trials. Clinical trial registration: Chinese Clinical Trial Registry (http://www.chictr.org.cn), identifier is ChiCTR1900024628. Date of registration: 19 July 2019. Testing a new combination of chemotherapy and radiotherapy before surgery for esophageal cancer.What did this study look at?This study tested a treatment for people with a common type of esophageal cancer (called esophageal squamous cell carcinoma) that had grown into nearby tissues but had not spread widely. The treatment combined two chemotherapy drugs (nedaplatin and paclitaxel) with radiation therapy, all of which were given before surgery. The goal was to see whether this approach could shrink the cancer enough to allow complete removal during surgery.What did the study find?Out of 49 people who started the treatment, 33 were able to have surgery. Among those 33, about 30.3% had no cancer left in the removed tissue. No one died from surgery complications. The most common serious side effect was a low white blood cell count, which occurred in about 31% of people.What do the immune marker results suggest?We also studied small proteins (immune markers) in cancer samples. People whose tumors had higher levels of a marker called FOXP3 before treatment tended to live longer. Also, people whose tumors showed a decrease in another marker called TIGIT after treatment had better survival. However, these findings need to be confirmed in larger studies.What are the limitations?This study did not compare the new treatment against a standard treatment, and the number of people was small. So the results are promising but not final proof.Trial registration: ChiCTR1900024628, 19 July 2019.
Multiple learning signals can shape motor output, including reward and punishment (via value-based reinforcement learning) and sensorimotor error (via motor adaptation). However, it is unclear if action values, learned via reinforcement learning, interact with error-based motor learning. Here, we asked if the learned value of competing motor goals influences how the motor system learns from sensorimotor errors linked to those goals. We designed a paradigm that required participants (N = 85) to learn about the value associated with different movement targets prior to undergoing implicit visuomotor adaptation at or nearby those same targets. We observed two classes of related effects: repulsion and suppression. When adaptation brought the limb toward targets associated with low-value, learning was attenuated compared to when adaptation brought the limb away from targets associated with low-value, indicating a "repelling" effect of low-value actions. Moreover, adaptation was suppressed in all directions when low-value targets were themselves the goal of movement. These findings were asymmetric with respect to valence: we did not observe comparable attraction effects when adaptation brought the limb toward targets associated with high-value, nor did we see overall enhancement of adaptation when targets associated with high-value acted as movement goals. Additional analyses and experiments demonstrated that these effects did not reflect generic biases and were driven by relative rather than absolute goal values. Repulsion and suppression effects were tied to movement directions rather than the targets themselves. These results point to a novel interaction between reinforcement learning and motor memory - a kind of "instrumental-motor transfer." In order to ensure our motor behavior yields our desired outcomes, we must not only learn which actions lead to which outcomes (via reinforcement learning) but also how to precisely execute those actions to achieve the desired outcome (by calibrating our actions via implicit motor adaptation. While it is clear that reinforcement learning and motor adaptation operate at different levels of an action selection hierarchy, it is unclear if they interact. Knowing if and how these processes interact is critical for understanding the fundamental algorithms and various neural circuits underlying real-world motor behavior. Here, we show a novel interaction between the two processes where implicit adaptation is suppressed when adaptation would bring the hand toward a previously punished movement goal.
Background: Infant wheezing is a common respiratory condition with a significant healthcare burden, yet data from the Middle East remain limited. This study aimed to identify predictors of any wheezing and recurrent wheezing during the first year of life in a Saudi Arabian birth cohort. Methods: This retrospective birth cohort study included infants born at King Saud University Medical City, Riyadh, in 2020. Data were collected from electronic medical records and a structured parental questionnaire administered via WhatsApp at 12 months of age, assessing wheezing episodes, parental atopy, household smoking, pets, home humidity, and nearby pollution sources. Any wheezing was defined as ≥1 wheezing episode during the first year, and recurrent wheezing as ≥3 episodes. Variables with p < 0.25 in univariable logistic regression were entered into multivariable models; adjusted odds ratios (aOR) with 95% confidence intervals are reported. Results: Of 594 infants, 135 (22.7%) experienced any wheezing and 85 (14.3%) had recurrent wheezing. NICU admission was independently associated with both any wheezing (aOR 2.65, 95% CI 1.49-4.73; p < 0.001) and recurrent wheezing (aOR 2.34, 95% CI 1.21-4.56; p = 0.012). Parental allergic rhinitis was independently associated with both outcomes (any wheezing: aOR 1.55, 95% CI 1.01-2.37; recurrent wheezing: aOR 1.67, 95% CI 1.00-2.78), while parental eczema was specifically associated with recurrent wheezing (aOR 1.74, 95% CI 1.00-3.03). Conclusions: NICU admission and parental atopy were associated with infant wheezing in this cohort. These findings provide region-specific data from Saudi Arabia but should be regarded as hypothesis-generating and require confirmation in prospective multicentre studies before informing clinical follow-up strategies.
Tropomyosin (Tpm) is an actin-binding protein that, together with troponin (Tn), mediates Ca2+-regulation of cardiac muscle contraction. Tpm coiled-coil dimers bind each other through overlap junctions between their N- and C-termini, forming a continuous strand along the actin filament. Among the many TPM1 mutations identified in cardiac Tpm (Tpm1.1), few substitute canonical residues with proline, the amino acid most disruptive to coiled-coil structure. We examined properties of recombinant cardiac Tpm with L43P or L57P substitutions in both chains and compared them with wild-type (WT) Tpm using differential scanning calorimetry, viscometry, molecular dynamics (MD) simulations, and an in vitro motility assay. Both mutations markedly destabilized the N-terminal part of the Tpm molecule. In MD simulations, Pro43 and Pro57 disrupted nearby backbone hydrogen bonds, and Pro43 promoted N-terminal unfolding, demonstrating a long-range effect within supercoiled Tpm molecules. Both substitutions strongly reduce Tpm's affinity for F-actin in the absence of Tn. In addition, viscometry showed that the L43P Tpm variant polymerizes less efficiently than WT and L57P Tpm, resulting in a reduced ability to assemble into a continuous strand along an actin filament. The L57P substitution increases maximum sliding velocity of thin filaments in in vitro motility assay and enhances Ca2+ sensitivity of actin-myosin interaction, a feature commonly associated with hypertrophic cardiomyopathy. In contrast, the L43P substitution hinders the formation of fully regulatory-competent thin filaments and severely impairs the Ca2+-regulatory function of reconstructed thin filaments in vitro. Our study reveals distinct mechanisms of pathogenic effects for these two largely similar amino acid substitutions.
Does a conformal manifold imply the existence of exactly marginal operators? We answer this question affirmatively under the assumption that there exists a conformal interface with certain properties connecting nearby conformal field theories. We show that the exactly marginal operator that connects the conformal field theories can be reconstructed from the interface displacement operator. Our construction is model independent and based on the general principles of conformal symmetry.
Laemostenus (Pristonychus) violeta Fidan & Elverici, sp. nov., from Türkiye is described and illustrated. The new species belongs to the terricola species group of the subgenus Pristonychus. It is readily distinguished from congeners by the unique structure of the aedeagus (slender median lobe and distinct apical shape) and the vivid violaceous sheen of the elytra. The species was found in extremely high abundance in the guano-rich dark zone of Singildakli in (Hamambogazi) Cave, Central Anatolia, and was absent from a nearby guano-free cave. Its ecology indicates a guanophilic and troglophilic lifestyle, and it is currently known only from the type locality, suggesting a localized cave endemicity within the group.
The commissioning of medical cyclotrons necessitates a thorough assessment of radioactive waste management systems, operational protocols, and radiological safety. Significant neutron and gamma radiation is generated during cyclotron operation for radionuclide production, which are frequently employed in positron emission tomography (PET) for clinical diagnosis and biological research. This study assesses waste management procedures and radiation risks at the Institute of Nuclear Medical Physics' recently commissioned cyclotron facility. Neutron and gamma dose rates were measured at multiple locations under single-beam (80 μA) and dual-beam (160 μA) operational modes. Calibrated radiation survey meters were used to obtain reliable dose measurements during routine cyclotron operation. While gaseous radionuclides were temporarily housed in the air compression station (ACS) prior to controlled emission through the ventilation stack, liquid radioactive waste was kept in lead-shielded decay tanks to allow controlled radioactive decay prior to disposal. Gamma radiation and stack airflow were continuously monitored to guarantee adherence to workplace safety regulations. Neutron and gamma dose rates within the cyclotron vault increased with beam current, ranging from 45.7 ± 4.2 to 49.0 ± 4.5 mSv h-1 and 50.24 ± 2.56 to 95.51 ± 4.87 mSv h-1, respectively. Effective shielding had been verified by the extremely low radiation levels (≤0.7 μSv h-1) at the vault entrance, console room, and nearby locations. The findings demonstrate that the GE PETtrace Cyclotron facility operates reliably under both single-beam and dual-beam configurations, thereby ensuring robust radiological protection for personnel and the surrounding environment.
Bacterial d-3-hydroxybutyrate dehydrogenases (HBDHs) catalyze the conversion between d-3-hydroxybutyrate and acetoacetate with NAD as the cofactor but not with NAD 2'-phosphate (NADP). However, HBDHs of the early-branched eukaryotic genus Trypanosoma utilize both NAD and NADP (T. brucei) or exclusively NADP (T. cruzi). Here we reveal that NADP specificity of T. cruzi HBDH arises from stabilization of the flexible β2αB loop by the 2'-phosphate interaction. Stabilization of this loop by a nearby C64Y mutation enables T. cruzi HBDH to use NAD in addition to NADP; thus, the Cys/Tyr residue is critical for determining cofactor specificity in trypanosomal HBDHs, suggesting that most trypanosomal HBDHs use both NAD and NADP except for T. cruzi HBDH. Furthermore, Arg42 within the β2αB loop interacts with the adenine ring of NADP by ideal CH-π interactions, while the R42F mutant switches to non-ideal π-π interactions, increasing kcat ∼10-fold and KM ∼40-fold. Collectively, we identified the β2αB loop stability and sequence as key determinants of NAD(P) co-factor specificity and kinetics in HBDHs.
In the Ni-based hydrogen electrode of a solid oxide cell (SOC), Ni coarsening is an important degradation mechanism and could be enhanced by NiH diffusing on the Ni particle surfaces. In this work, the average lifetime and diffusion distance of NiH on Ni(111) are computed using density-functional theory and kinetic Monte Carlo methods. It is found that NiH is extremely short-lived and, thus, cannot promote coarsening in the SOC. Also, the diffusion of Ni on Ni(111) is shown to be at most slightly accelerated by H along NiH dissociation paths involving the movement of Ni with a nearby H. Based on this result, coarsening is not likely to be dramatically accelerated by the diffusion of Ni with H on Ni(111). However, support is provided for the experimental procedure of measuring the product of surface coverage and single-species diffusivity of Ni on Ni(111) in a hydrogen-rich atmosphere.
Karst tiankengs-giant enclosed sinkholes-harbor humid, shaded forests that may buffer climate stress yet isolate populations. Here, we generated a near telomere-to-telomere genome assembly for the endangered karst tree Magnolia aromatica and resequenced 26 populations across tiankeng interiors and surrounding habitats in southwest China. Population genomics resolved four lineages and indicated a history of divergence with gene flow constrained by strong dispersal barriers. At the lineage scale, tiankeng-associated populations exhibited intermediate genomic diversity and mutation load relative to non-tiankeng lineages. At fine spatial scales, however, tiankeng-interior populations showed reduced diversity and elevated deleterious burden compared with nearby exterior populations, consistent with demographic isolation and strong genetic drift. We detected lineage-specific selection signals in genes related to photosynthesis and carbon fixation, and shading experiments revealed that seedlings exhibited high mortality under strong light but survived and grew well under deep shade. Forecasts combining species distribution models, genomic offset, and mutation-load prediction identified future risk hotspots near barriers and suggested that genomic erosion may compound climate vulnerability in parts of the range. Together, these results indicate that karst tiankengs can function as nested microrefugia that promote persistence while constraining connectivity and long-term evolutionary potential, with important implications for conserving edaphic specialists under climate change.
How agriculture emerged in East Asia and the demographic and social dynamics associated with this transition remain incompletely understood. Here, we present genome-wide data from eleven individuals from the Xinglong site in northern China, directly dated to ∼9,000-5,000 cal. before present (BP), together with stable carbon and nitrogen isotope compositions from bone collagen. Genetic analyses show that these individuals share a homogeneous genetic profile with the nearby Yumin individual, indicating a shared regional ancestry profile consistent with population interactions across the Mongolian Plateau during the Early Holocene, and that this profile persisted for at least 1,500 years (9,000-7,500 cal. BP) at Xinglong. This long-term regional demic stability provides a backdrop for a transition toward millet cultivation, as suggested by isotopic and macrofossil evidence dated to ∼7,500 cal. BP. Between 7,500 and 5,500 cal. BP, early millet-associated populations across northern China exhibit heterogeneous genetic structures, suggesting that early millet-associated populations in northern China were genetically heterogeneous and did not derive from a single homogeneous population. By 5,500 cal. BP, individuals from Xinglong show admixture with Middle Neolithic Yellow River millet farmers while retaining affinities with earlier Xinglong and Baikal-related ancestries. Co-buried individuals from residential burials dated to ∼9,000 and ∼7,500 cal. BP, respectively, both show first-degree kinship, suggesting possible continuity in biologically kin-based residential burial practices. Together, these findings suggest that dietary change was not necessarily accompanied by major demographic replacement or by a genetically detectable shift in kin-based residential burial practices at Xinglong.
The continuous and automated monitoring of animal activity with sensors can help to refine and improve the quality of animal experiments. The aim of this study was to develop a system for real-time automated multi-species monitoring of individual animal activity in research trials ("RAMSMART"), to test this system in terms of battery life and data completeness, and to demonstrate its added value. We used lightweight commercially available accelerometers with edge computing and uploaded self-written firmware to these accelerometers to calculate the vectorial dynamic body acceleration (VeDBA). The accelerometer is attached, for example, to an animal's ear tag. It then collects raw acceleration data (at a user-defined sampling frequency), calculates the mean VeDBA across a certain period (based on a user-defined updating interval) and creates a data packet with the VeDBA, which is then broadcasted (at a user-defined broadcasting frequency) through Bluetooth Low Energy to a nearby receiving device, e.g., a laptop. On this receiving device, data are stored in a SQLite database and regularly copied to a shared drive to enable (near) real-time visualization of results from outside animal facilities. Battery life depended on the sampling frequency, the updating interval and the broadcasting frequency. For example, when the sampling frequency was kept constant at 12.5 Hz, and the broadcasting frequency at 4 Hz, an updating interval of 1 second or 1 minute resulted in a battery life of 15.9 days (± 1.0 days) or 47.7 days (± 1.9 days), respectively. To avoid missing data, a sufficiently high broadcasting frequency was needed and the distance between sensor and receiver should be limited (preferably to < 20 m), or a multiple receiver set-up could be used. We showcased RAMSMART in three infectious disease trials in pigs, sheep and calves, connecting the VeDBA with other clinical symptoms, and demonstrating the added value of this system for early detection of deviations in activity. RAMSMART provides a low-invasive, affordable, re-usable, generalizable and plug-and-play approach for routine and long-term real-time automated activity monitoring based on acceleration data of (particularly livestock) animals in research trials. The source code and documentation of RAMSMART are openly available.
Spatial enhancer connectivity is fundamental to proper gene regulation. Enhancer dysregulation has emerged as a hallmark of cancers, including T-cell acute lymphoblastic leukemias (T-ALL). T-ALL are aggressive malignancies characterized by marked transcriptional heterogeneity driven by distinct stages of developmental arrest and diverse noncoding alterations. How these cancers co-opt nuclear architecture to rewire enhancer connectivity remains poorly understood. Here, we report that the LDB1 chromatin architectural complex is an essential mediator of enhancer-oncogene looping that sustains oncogenic transcriptional programs across multiple T-ALL subtypes. Integrating bulk and single-cell transcriptomic data from patients with T-ALL and healthy hematopoietic controls, we show that the LDB1-dependent regulatory circuitry defines the molecular identities of distinct T-ALL subtypes while restricting plasticity toward alternative cell states. LDB1 loss dismantles chromatin looping among cell state-defining enhancers liberating them to form promiscuous interactions with nearby genes. This enhancer rewiring stimulates expression of key metabolic genes, creating a mevalonate pathway dependency exploitable with statin treatment. Our study establishes LDB1 as a central executor of T-ALL regulatory circuitry and more broadly illustrates chromatin rewiring as a source of targetable dependencies in cancer.