Three-dimensional genome architecture persists in a 52,000-year-old woolly mammoth skin sample.

Analyses of ancient DNA typically involve sequencing the surviving short oligonucleotides and aligning to genome assemblies from related, modern species. Here, we report that skin from a female woolly mammoth (†Mammuthus primigenius) that died 52,000 years ago retained its ancient genome architecture. We use PaleoHi-C to map chromatin contacts and assemble its genome, yielding 28 chromosome-length scaffolds. Chromosome territories, compartments, loops, Barr bodies, and inactive X chromosome (Xi) superdomains persist. The active and inactive genome compartments in mammoth skin more closely resemble Asian elephant skin than other elephant tissues. Our analyses uncover new biology. Differences in compartmentalization reveal genes whose transcription was potentially altered in mammoths vs. elephants. Mammoth Xi has a tetradic architecture, not bipartite like human and mouse. We hypothesize that, shortly after this mammoth's death, the sample spontaneously freeze-dried in the Siberian cold, leading to a glass transition that preserved subfossils of ancient chromosomes at nanometer scale.

High-volume surgeons decrease operating time in robot-assisted radical prostatectomy: results in 1229 patients.

BACKGROUND: The aim is to evaluate factors impacting operating time (OT) during robot-assisted radical prostatectomy (RARP) with or without extended pelvic lymph node dissection (ePLND) for prostate cancer. METHODS: Overall, 1289 patients underwent RARP from January 2013 to December 2021. ePLND was performed in 825 cases. Factors potentially associated with OT variations were assessed. Three low-volume (LVS) and two high-volume surgeons (HVS) performed the procedures. A linear regression model was computed to assess associations with OT variations. RESULTS: When RARP was performed by HVS an OT decrease was observed independently by significant clinical (Body Mass Index [BMI]; prostate volume [PV]) and anatomical/perioperative features (prostate weight [PW]; intraoperative blood loss [BL]) both in clinical (change in OT: -42.979 minutes; 95% CI: -51.789; -34.169; P<0.0001) and anatomical/perioperative models (change in OT: -40.020 minutes; 95% CI: -48.494; -31.587; P<0.0001). A decreased OT was observed in clinical (change in OT: -27.656 minutes; 95% CI: -33.449; -21.864; P<0.0001) and anatomical/perioperative (change in OT: -24.935 minutes; 95% CI: -30.562; -19.308; P<0.0001) models also in case of RARP with ePLND performed by HVS, independently by BMI, PV, PSA as well as for PW, seminal vesicle invasion, positive surgical margins, and BL. CONCLUSIONS: In a tertiary academic referral center, OT decreased when RARP was performed by HVS, independently of adverse clinical and anatomical/perioperative factors. Available OT loads can be planned to optimize waiting lists, teaching tasks, operative costs, and surgeon's volume.

Single-layer versus double-layer renorrhaphy technique during robot-assisted partial nephrectomy: impact on perioperative outcomes, complications, and functional outcomes.

BACKGROUND: The debate between single-layer and double-layer renorrhaphy techniques during robot-assisted partial nephrectomy (RPN) represents a subject of ongoing discourse. The present analysis aims to compare the perioperative and functional outcomes of single- versus double-layer renorrhaphy during RPN. METHODS: Study data were retrieved from prospectively maintained institutional database (Jan2018-May2023). Study population was divided into two groups according to the number of layers (single vs. double) used for renorrhaphy. Baseline and perioperative data were compared. Postoperative surgical outcomes included type and grade of complications as classified according to Clavien-Dindo. Serum creatinine and estimated glomerular filtration rate were used to measure renal function. RESULTS: Three hundred seventeen patients were included in the analysis: 209 received single-layer closure, while 108 underwent double-layer renorrhaphy. Baseline characteristics were not statistically different between the groups. Comparable low incidence of intraoperative complications was observed between the cohorts (P=0.5). No difference was found in terms of mean (95% CI) Hb level drop postoperation (single-layer: 1.6 g/dL [1.5-1.7] vs. double-layer: 1.4 g/dL [1.2-1.5], P=0.3). Overall and "major" rate of complications were 16% and 3%, respectively, with no difference observed in terms of any grade (P=0.2) and major complications (P=0.7). Postoperative renal function was not statistically different between the treatment modalities. At logistic regression analyses, no difference in terms of probability of overall (OR 0.82 [0.63-1.88]) and major (OR 0.94 [0.77-6.44]) complications for the number of suture layers was observed. CONCLUSIONS: Single-layer and double-layer renorrhaphy demonstrated comparable perioperative and functional outcomes within the setting of the present study.

Phenolic concentrations and carbon/nitrogen ratio in annual shoots of bilberry (Vaccinium myrtillus) after simulated herbivory.

Herbivory can be reduced by the production of defense compounds (secondary metabolites), but generally defenses are costly, and growth is prioritized over defense. While defense compounds may deter herbivory, nutrients may promote it. In a field study in boreal forest in Norway, we investigated how simulated herbivory affected concentrations of phenolics (generally a defense) and the carbon/nitrogen (C/N) ratio in annual shoots of bilberry (Vaccinium myrtillus), a deciduous clonal dwarf shrub whose vegetative and generative parts provide forage for many boreal forest animals. We measured concentrations of total tannins, individual phenolics, nitrogen and carbon following several types and intensities of herbivory. We identified 22 phenolics: 15 flavonoids, 1 hydroquinone and 6 phenolic acids. After high levels of herbivory, the total tannin concentration and the concentration of these 22 phenolics together (called total phenolic concentration) were significantly lower in bilberry annual shoots than in the control (natural herbivory at low to intermediate levels). Low-intensive herbivory, including severe defoliation, gave no significantly different total tannin or total phenolic concentration compared with the control. Many individual phenolics followed this pattern, while phenolic acids (deterring insect herbivory) showed little response to the treatments: their concentrations were maintained after both low-intensive and severe herbivory. Contrary to our predictions, we found no significant difference in C/N ratio between treatments. Neither the Carbon:Nutrient Balance hypothesis nor the Optimal Defense hypotheses, theories predicting plant resource allocation to secondary compounds, can be used to predict changes in phenolic concentrations (including total tannin concentration) in bilberry annual shoots after herbivory: in this situation, carbon is primarily used for other functions (e.g., maintenance, growth, reproduction) than defense.

ELViM: Exploring Biomolecular Energy Landscapes through Multidimensional Visualization.

Molecular dynamics (MD) simulations provide a powerful means of exploring the dynamic behavior of biomolecular systems at the atomic level. However, analyzing the vast data sets generated by MD simulations poses significant challenges. This article discusses the energy landscape visualization method (ELViM), a multidimensional reduction technique inspired by the energy landscape theory. ELViM transcends one-dimensional representations, offering a comprehensive analysis of the effective conformational phase space without the need for predefined reaction coordinates. We apply the ELViM to study the folding landscape of the antimicrobial peptide Polybia-MP1, showcasing its versatility in capturing complex biomolecular dynamics. Using dissimilarity matrices and a force-scheme approach, the ELViM provides intuitive visualizations, revealing structural correlations and local conformational signatures. The method is demonstrated to be adaptable, robust, and applicable to various biomolecular systems.

A Novel Pan-RAS Inhibitor with a Unique Mechanism of Action Blocks Tumor Growth in Mouse Models of GI Cancer.

Here, we describe a novel pan-RAS inhibitor, ADT-007, that potently inhibited the growth of RAS mutant cancer cells irrespective of the RAS mutation or isozyme. RAS WT cancer cells with activated RAS from upstream mutations were equally sensitive. Conversely, cells from normal tissues or RAS WT cancer cells harboring downstream BRAF mutations were insensitive. Insensitivity to ADT-007 was attributed to low activated RAS levels and metabolic deactivation by UDP-glucuronosyltransferases expressed in normal cells but repressed in RAS mutant cancer cells. Cellular, biochemical, and biophysical experiments show ADT-007 binds nucleotide-free RAS to block GTP activation of RAS and MAPK/AKT signaling. Local administration of ADT-007 strongly inhibited tumor growth in syngeneic immune-competent and xenogeneic immune-deficient mouse models of colorectal and pancreatic cancer while activating innate and adaptive immunity in the tumor immune microenvironment. Oral administration of ADT-007 prodrug inhibited tumor growth, supporting further development of this novel class of pan-RAS inhibitors for treating RAS-driven cancers. SIGNIFICANCE: ADT-007 is a 1 st -in-class pan-RAS inhibitor with ultra-high potency and unique selectivity for cancer cells with mutant or activated RAS capable of circumventing resistance and activating antitumor immunity. Further development of ADT-007 analogs or prodrugs with oral bioavailability as a generalizable monotherapy or combined with immunotherapy is warranted.

Reliability and Time Course of Postexercise Hypotension during Exercise Training among Adults with Hypertension.

Postexercise hypotension (PEH), or the immediate decrease in blood pressure (BP) lasting for 24 h following an exercise bout, is well-established; however, the influence of exercise training on PEH dynamics is unknown. This study investigated the reliability and time course of change of PEH during exercise training among adults with hypertension. PEH responders (n = 10) underwent 12 weeks of aerobic exercise training, 40 min/session at moderate-to-vigorous intensity for 3 d/weeks. Self-measured BP was used to calculate PEH before and for 10 min after each session. The intraclass correlation coefficient (ICC) and Akaike Information Criterion (AIC) determined PEH reliability and goodness-of-fit for each week, respectively. Participants were obese (30.6 ± 4.3 kg∙m-2), middle-aged (57.2 ± 10.5 years), and mostly men (60%) with stage I hypertension (136.5 ± 12.1/83.4 ± 6.7 mmHg). Exercise training adherence was 90.6 ± 11.8% with 32.6 ± 4.2 sessions completed. PEH occurred in 89.7 ± 8.3% of these sessions with BP reductions of 9.3 ± 13.1/3.2 ± 6.8 mmHg. PEH reliability was moderate (ICC ~0.6). AIC analysis revealed a stabilization of maximal systolic and diastolic BP reductions at 3 weeks and 10 weeks, respectively. PEH persisted throughout exercise training at clinically meaningful levels, suggesting that the antihypertensive effects of exercise training may be largely due to PEH. Further studies in larger samples and under ambulatory conditions are needed to confirm these novel findings.

Safety of the yellow fever vaccine in people living with HIV: a longitudinal study exploring post-vaccination viremia and hematological and liver kinetics.

BACKGROUND: Safety data on the yellow fever vaccine 17DD in People Living with HIV (PLWH) are limited. This study explored the occurrence of post-vaccination 17DD viremia and the kinetics of hematological and liver laboratorial parameters in PLWH and HIV-uninfected participants [HIV(-) controls]. METHODS: We conducted a secondary analysis of a longitudinal interventional trial (NCT03132311) study that enrolled PLWH and HIV(-) controls to receive a single 17DD dose and were followed at 5, 30 and 365 days after vaccination in Rio de Janeiro, Brazil. 17DD viremia (obtained throughreal-time PCR and plaque forming units' assays), hematological (neutrophils, lymphocytes and platelets counts) and liver enzymes (ALT and AST) results were assessed at baseline and Days 5 and 30 post-vaccination. Logistic regression models explored factors associated with the odds of having positive 17DD viremia. Linear regression models explored variables associated with hematological and liver enzymes results at Day 5. RESULTS: A total of 202 PLWH with CD4 ≥ 200 cells/µL and 68 HIV(-) controls were included in the analyses. 17DD viremia was found in 20.0 % of the participants and was twice more frequent in PLWH than in HIV(-) controls (22.8% vs. 11.8 %, p-value < 0.001). Neutrophils, lymphocytes and platelets counts dropped at Day 5 and returned to baseline values at Day 30. 17DD viremia was associated with lower nadir of lymphocytes and platelets at Day 5. ALT levels did not increase post-vaccination and were not associated with 17DD viremia. CONCLUSIONS: 17DD was safe and well-tolerated in PLWH with CD4 ≥ 200 cells/µL. Post-vaccination viremia was more frequent in PLWH than in controls. Transient and self-limited decreases in lymphocytes and neutrophils occurred early after vaccination. 17DD viremia was associated with lower lymphocytes and platelets nadir after vaccination. We did not observe elevations in ALT after 17DD vaccination.

Public involvement in chronic respiratory diseases research: A qualitative study of patients', carers' and citizens' perspectives.

INTRODUCTION: Patient and public involvement (PPI) initiatives involving patients with chronic respiratory disease (CRD) are rare. Therefore, this study aimed to explore the perspectives of patients with CRD, carers and interested citizens regarding the relevance and need for a PPI network and suggestions for its implementation. METHODS: A qualitative study based on focus groups was conducted. Recruitment occurred through invitations on social media platforms and to patients who have participated in previous asthma studies of the team. Three focus groups were conducted, via video conference, using a semi-structured guide. Thematic analysis was performed by two independent researchers and discussed with the extended team. RESULTS: Fifteen patients with CRD, one carer and one interested citizen (13 females, median 36 (range: 18-72) years) participated. All participants acknowledged the importance of implementing a collaborative network and demonstrated interest in being integrated. Participants acknowledged the importance of their involvement in several phases of the research cycle. The main aim identified for this network was to facilitate communication between patients and researchers. Participants regarded the integration of patients, carers, researchers and healthcare professionals from different scientific areas as relevant. The use of digital platforms to attract members and support the work, together with group dynamics and regular meetings, were some of the most relevant practical considerations for implementing the network. The identified facilitators for their engagement were sharing experiences, researchers' and healthcare professionals' support and feedback and schedule flexibility. The identified barriers included the amount of time dedicated, low health/digital literacy and the potential detachment of nondiagnosed patients or those with low symptom impact in daily life. CONCLUSION: Patients, carers and citizens acknowledged the relevance of implementing a collaborative network and demonstrated interest in active participation in every stage of the health research cycle. A deeper knowledge of the barriers and facilitators identified in this study could support implementing these initiatives in Portugal. PATIENT OR PUBLIC CONTRIBUTION: This study was designed by a research team that included one patient with asthma and one carer. They were specifically involved in building the study protocol and the interview guide. They also gave feedback regarding the electronic consent form and the short sociodemographic questionnaire created, namely by removing noncontributing words or phrases and rewording expressions. The lay summary was written by another patient with asthma. All participants of this study were invited to implement and integrate the ConectAR network-a collaborative network of research in respiratory health. PUBLIC SUMMARY: In Portugal, chronic respiratory patients do not have an active role as 'coinvestigators'. This study aimed to acknowledge if patients and citizens considered a patient and public involvement network useful, whose main purpose would be to facilitate communication between patients and researchers. A study based on online group interviews was carried out with patients with chronic respiratory diseases and interested citizens, both recruited on social media platforms. Participants considered that bringing together patients, carers, researchers and healthcare professionals is valuable because sharing different experiences and perspectives may help patients to improve their daily lives and increase research quality. In conclusion, patients agree that implementing a collaborative network with researchers and healthcare professionals and participating in the health research cycle is quite preponderant. Acknowledging what can help and deter this network may be beneficial to implementing this type of initiative in Portugal.

Safety of the yellow fever vaccine in people living with HIV: a longitudinal study exploring post-vaccination viremia and hematological and liver kinetics

ABSTRACT Background: Safety data on the yellow fever vaccine 17DD in People Living with HIV (PLWH) are limited. This study explored the occurrence of post-vaccination 17DD viremia and the kinetics of hematological and liver laboratorial parameters in PLWH and HIV-uninfected participants [HIV(-) controls]. Methods: We conducted a secondary analysis of a longitudinal interventional trial (NCT03132311) study that enrolled PLWH and HIV(-) controls to receive a single 17DD dose and were followed at 5, 30 and 365 days after vaccination in Rio de Janeiro, Brazil. 17DD viremia (obtained throughreal-time PCR and plaque forming units' assays), hematological (neutrophils, lymphocytes and platelets counts) and liver enzymes (ALT and AST) results were assessed at baseline and Days 5 and 30 post-vaccination. Logistic regression models explored factors associated with the odds of having positive 17DD viremia. Linear regression models explored variables associated with hematological and liver enzymes results at Day 5. Results: A total of 202 PLWH with CD4 > 200 cells/μL and 68 HIV(-) controls were included in the analyses. 17DD viremia was found in 20.0 % of the participants and was twice more frequent in PLWH than in HIV(-) controls (22.8% vs. 11.8 %, p-value < 0.001). Neutrophils, lymphocytes and platelets counts dropped at Day 5 and returned to baseline values at Day 30. 17DD viremia was associated with lower nadir of lymphocytes and platelets at Day 5. ALT levels did not increase post-vaccination and were not associated with 17DD viremia. Conclusions: 17DD was safe and well-tolerated in PLWH with CD4 > 200 cells/μL. Post-vaccination viremia was more frequent in PLWH than in controls. Transient and self-limited decreases in lymphocytes and neutrophils occurred early after vaccination. 17DD viremia was associated with lower lymphocytes and platelets nadir after vaccination. We did not observe elevations in ALT after 17DD vaccination.

A Review of the Metal Additive Manufacturing Processes.

Metal additive manufacturing (AM) is a layer-by-layer process that makes the direct manufacturing of various industrial parts possible. This method facilitates the design and fabrication of complex industrial, advanced, and fine parts that are used in different industry sectors, such as aerospace, medicine, turbines, and jewelry, where the utilization of other fabrication techniques is difficult or impossible. This method is advantageous in terms of dimensional accuracy and fabrication speed. However, the parts fabricated by this method may suffer from faults such as anisotropy, micro-porosity, and defective joints. Metals like titanium, aluminum, stainless steels, superalloys, etc., have been used-in the form of powder or wire-as feed materials in the additive manufacturing of various parts. The main criterion that distinguishes different additive manufacturing processes from each other is the deposition method. With regard to this criterion, AM processes can be divided into four classes: local melting, sintering, sheet forming, and electrochemical methods. Parameters affecting the properties of the additive-manufactured part and the defects associated with an AM process determine the method by which a certain part should be manufactured. This study is a survey of different additive manufacturing processes, their mechanisms, capabilities, shortcomings, and the general properties of the parts manufactured by them.

Distinctive Electric Properties of Group 14 Oxides: SiO2, SiO, and SnO2.

The oxides of group 14 have been widely used in numerous applications in glass, ceramics, optics, pharmaceuticals, and food industries and semiconductors, photovoltaics, thermoelectrics, sensors, and energy storage, namely, batteries. Herein, we simulate and experimentally determine by scanning kelvin probe (SKP) the work functions of three oxides, SiO2, SiO, and SnO2, which were found to be very similar. Electrical properties such as electronic band structure, electron localization function, and carrier mobility were also simulated for the three crystalline oxides, amorphous SiO, and surfaces. The most exciting results were obtained for SiO and seem to show Poole-Frankel emissions or trap-assisted tunneling and propagation of surface plasmon polariton (SPP) with nucleation of solitons on the surface of the Aluminum. These phenomena and proposed models may also describe other oxide-metal heterojunctions and plasmonic and metamaterials devices. The SiO2 was demonstrated to be a stable insulator interacting less with the metals composing the cell than SnO2 and much less than SiO, configuring a typical Cu/SiO2/Al cell potential well. Its surface charge carrier mobility is small, as expected for an insulator. The highest charge carrier mobility at the lowest conduction band energy is the SnO2's and the most symmetrical the SiO's with a similar number of electron holes at the conduction and valence bands, respectively. The SnO2 shows it may perform as an n-type semiconductor.

Prevalence of lipoprotein(a) measurement in patients with or at risk of cardiovascular disease.

INTRODUCTION: Lipoprotein(a) [Lp(a)] is a genetically determined independent risk factor for atherosclerotic cardiovascular disease (ASCVD) and calcific aortic valve disease. Despite recommendations from professional societies in the cardiovascular field, the awareness of elevated Lp(a) as a risk factor and screening for Lp(a) are suspected to be low. METHODS: We conducted a retrospective, observational case control study of patient charts from January 1, 2017 to June 19, 2022. The primary aims were 1) to describe the proportion of patients at the healthcare network's primary care and cardiology clinics that met Lp(a) screening criteria and were tested; and 2) to describe the proportion of patients throughout the entire healthcare network that had Lp(a) measured. RESULTS: Of the 2,412,020 patient charts in the health network, only 5,942 (0.25 %) had Lp(a) measured. Of the 84,581 patients in primary care or cardiology clinics who met screening criteria, only 1,311 (1.55 %) had Lp(a) measured. Patients with Lp(a) measured were more likely to be younger, non-Hispanic/Latinx, had a lipid panel measured, a cardiac computed tomography (CT) imaging study, and higher low-density lipoprotein-cholesterol. Patients with ASCVD, heart failure, ischemic heart disease, aortic stenosis, peripheral vascular disease, or a stroke did not feature highly among patients who received Lp(a) testing. Having an abnormal or risk-enhancing Lp(a) level was associated with being female and/or being Black/African American. CONCLUSIONS: Despite increased awareness of Lp(a) and its contribution to cardiovascular disease there exists a paucity of testing. Increased Lp(a) testing can identify patients who have an increased cardiovascular risk underestimated by other metrics.

Impact of Sex on Cardiovascular Adaptations to Exercise: JACC Review Topic of the Week.

Routine exercise leads to cardiovascular adaptations that differ based on sex. Use of cardiac testing to screen athletes has driven research to define how these sex-based adaptations manifest on the electrocardiogram and cardiac imaging. Importantly, sex-based differences in cardiovascular structure and outcomes in athletes often parallel findings in the general population, underscoring the importance of understanding their mechanisms. Substantial gaps exist in the understanding of why cardiovascular adaptations and outcomes related to exercise differ by sex because of underrepresentation of female participants in research. As female sports participation rates have increased dramatically over several decades, it also remains unknown if differences observed in older athletes reflect biological mechanisms vs less lifetime access to sports in females. In this review, we will assess the effect of sex on cardiovascular adaptations and outcomes related to exercise, identify the impact of sex hormones on exercise performance, and highlight key areas for future research.

Immunogenicity and reactogenicity of yellow fever vaccine in people with HIV.

OBJECTIVE: To evaluate immunogenicity and reactogenicity of yellow fever (YF) vaccine in people with HIV (PWH) compared to HIV-uninfected controls. DESIGN: In this longitudinal interventional trial (NCT03132311), PWH with CD4 + cell count ≥200 cells/µl and controls, aged 18-59, without a previous history of YF vaccination received a single standard dose of YF vaccine (17DD) and were followed at Days 5, 30 and Year 1. METHODS: YF-neutralization titers were measured at Days 0, 30 and Year 1 and geometric mean titers (GMT) were calculated. Adverse events (AE) and YF virus detection were measured at Days 5 and 30. Linear regression evaluated factors associated with YF-neutralization titers. RESULTS: Two hundred and eighteen PWH and 82 controls were included. At baseline, all PWH were using antiretroviral therapy; 92.6% had undetectable HIV viral load (VL) and median CD4 + cell count was 630 cells/µl [interquartile range (IQR) 463-888]. YF vaccine was safe and there were no serious AEs. At Day 30, seroconversion was observed in 98.6% of PWH [95% confidence interval (CI): 95.6-99.6] and in 100% of controls (95% CI: 93.9-100); at Year 1, 94.0% of PWH (95% CI: 89.6-96.7) and 98.4% of controls (95% CI 90.3-99.9) were seropositive. PWH had lower GMTs than controls at Day 30 and Year 1. Baseline VL >1000 copies/ml, low CD4 + cell count and low CD4 + /CD8 + ratio were associated with lower YF-neutralization titers. CONCLUSIONS: YF vaccine is safe in PWH with CD4 + cell count ≥200 cells/µl. YF vaccine immunogenicity is impaired in PWH, particularly among those with high VL, low CD4 + cell count and low CD4 + /CD8 + ratio at vaccination and YF-neutralization titers decays over time.

Thermal monitoring of a Cryosol in a high marine terrace (Half Moon Island, Maritime Antarctica).

Active layer and permafrost are important indicators of climate changes in periglacial areas of Antarctica, and the soil thermal regime of Maritime Antarctica is sensitive to the current warming trend. This research aimed to characterize the active layer thermal regime of a patterned ground located at an upper marine terrace in Half Moon Island, during 2015-2018. Temperature and moisture sensors were installed at different soil depths, combined with air temperature, collecting hourly data. Statistical analysis was applied to describe the soil thermal regime and estimate active layer thickness. The thermal regime of the studied soil was typical of periglacial environment, with high variability in temperature and water content in the summer, resulting in frequent freeze-thaw cycles. We detected dominant freezing conditions, whereas soil temperatures increased, and the period of high soil moisture content lasted longer over the years. Active layer thickness varied between the years, reaching a maximum depth in 2018. Permafrost degradation affects soil drainage and triggers erosion in the upper marine terrace, where permafrost occurrence is unlikely. Longer monitoring periods are necessary for a detailed understanding on how current climatic and geomorphic conditions affect the unstable permafrost of low-lying areas of Antarctica (marine terraces).

The role of predation risk in structuring life-history traits of crucian carp (Carassius carassius) in a series of small boreal lakes.

Predation is a major evolutionary force determining life-history traits in prey by direct and indirect mechanisms. This study focuses on life-history trait variation in crucian carp (Carassius carassius), a species well known for developing a deep body as an inducible morphological defence against predation risk. Here, the authors tested variation in growth and reproductive traits in 15 crucian carp populations in lakes along a predation risk gradient represented by increasingly efficient predator communities. Lakes were located in south-eastern Norway and were sampled in summer 2018 and 2019. The authors expected crucian carp to attain higher growth rate, larger size, and later age at maturity with increasing predation risk. In the absence of predators, they expected high adult mortality, early maturity and increased reproductive effort caused by strong intraspecific competition. They found that the life-history traits of crucian carp were clearly related to the presence of piscivores: with increasing predation risk, fish grew in body length and depth and attained larger asymptotic length and size at maturity. This growth was evident at young age, especially in productive lakes with pike, and it suggests that fish quickly outgrew the predation window by reaching a size refuge. Contrary to the authors' predictions, populations had similar age at maturity. High-predation lakes also presented low density of crucian carp. This suggests that fish from predator lakes may experience high levels of resource availability due to reduced intraspecific competition. Predation regulated life-history traits in crucian carp populations, where larger size, higher longevity and size at maturity were observed in lakes with large gaped predators.

Control of Arterial Hypertension by the AhR Blocker CH-223191: A Chronopharmacological Study in Chronic Intermittent Hypoxia Conditions.

Chronic intermittent hypoxia (CIH) is a major contributor to the development of hypertension (HTN) in obstructive sleep apnea (OSA). OSA subjects frequently display a non-dipping pattern of blood pressure (BP) and resistant HTN. After discovering that AHR-CYP1A1 axis is a druggable target in CIH-HTN, we hypothesized that CH-223191 could control BP in both active and inactive periods of the animals, recovering the BP dipping profile in CIH conditions.We evaluated the chronopharmacology of the antihypertensive efficacy of the AhR blocker CH-223191 in CIH conditions (21% to 5% of O2, 5.6 cycles/h, 10.5 h/day, in inactive period of Wistar rats). BP was measured by radiotelemetry, at 8 am (active phase) and at 6 pm (inactive phase) of the animals. The circadian variation of AhR activation in the kidney in normoxia was also assessed, measuring the CYP1A1 (hallmark of AhR activation) protein levels.Despite drug administration before starting the inactive period of the animals, CH-223191 was not able to decrease BP during the inactive phase, in CIH conditions, therefore not reverting the non-dipping profile. These results suggest that a higher dose or different time of administration of CH-223191 might be needed for an antihypertensive effect throughout the 24-h cycle.

PyMEGABASE: Predicting Cell-Type-Specific Structural Annotations of Chromosomes Using the Epigenome.

The folding patterns of interphase genomes in higher eukaryotes, as obtained from DNA-proximity-ligation or Hi-C experiments, are used to classify loci into structural classes called compartments and subcompartments. These structurally annotated (sub) compartments are known to exhibit specific epigenomic characteristics and cell-type-specific variations. To explore the relationship between genome structure and the epigenome, we present PyMEGABASE (PYMB), a maximum-entropy-based neural network model that predicts (sub) compartment annotations of a locus based solely on the local epigenome, such as ChIP-Seq of histone post-translational modifications. PYMB builds upon our previous model while improving robustness, capability to handle diverse inputs and user-friendly implementation. We employed PYMB to predict subcompartments for over a hundred human cell types available in ENCODE, shedding light on the links between subcompartments, cell identity, and epigenomic signals. The fact that PYMB, trained on data for human cells, can accurately predict compartments in mice suggests that the model is learning underlying physicochemical principles transferable across cell types and species. Reliable at higher resolutions (up to 5 kbp), PYMB is used to investigate compartment-specific gene expression. Not only can PYMB generate (sub) compartment information without Hi-C experiments, but its predictions are also interpretable. Analyzing PYMB's trained parameters, we explore the importance of various epigenomic marks in each subcompartment prediction. Furthermore, the predictions of the model can be used as input for OpenMiChroM software, which has been calibrated to generate three-dimensional structures of the genome. Detailed documentation of PYMB is available at https://pymegabase.readthedocs.io, including an installation guide using pip or conda, and Jupyter/Colab notebook tutorials.

Lung Cancer Screening in Asia: An Expert Consensus Report.

INTRODUCTION: The incidence and mortality of lung cancer are highest in Asia compared with Europe and USA, with the incidence and mortality rates being 34.4 and 28.1 per 100,000 respectively in East Asia. Diagnosing lung cancer at early stages makes the disease amenable to curative treatment and reduces mortality. In some areas in Asia, limited availability of robust diagnostic tools and treatment modalities, along with variations in specific health care investment and policies, make it necessary to have a more specific approach for screening, early detection, diagnosis, and treatment of patients with lung cancer in Asia compared with the West. METHOD: A group of 19 advisors across different specialties from 11 Asian countries, met on a virtual Steering Committee meeting, to discuss and recommend the most affordable and accessible lung cancer screening modalities and their implementation, for the Asian population. RESULTS: Significant risk factors identified for lung cancer in smokers in Asia include age 50 to 75 years and smoking history of more than or equal to 20 pack-years. Family history is the most common risk factor for nonsmokers. Low-dose computed tomography screening is recommended once a year for patients with screening-detected abnormality and persistent exposure to risk factors. However, for high-risk heavy smokers and nonsmokers with risk factors, reassessment scans are recommended at an initial interval of 6 to 12 months with subsequent lengthening of reassessment intervals, and it should be stopped in patients more than 80 years of age or are unable or unwilling to undergo curative treatment. CONCLUSIONS: Asian countries face several challenges in implementing low-dose computed tomography screening, such as economic limitations, lack of efforts for early detection, and lack of specific government programs. Various strategies are suggested to overcome these challenges in Asia.