Pan-cancer whole-genome comparison of primary and metastatic solid tumours.

Metastatic cancer remains an almost inevitably lethal disease1-3. A better understanding of disease progression and response to therapies therefore remains of utmost importance. Here we characterize the genomic differences between early-stage untreated primary tumours and late-stage treated metastatic tumours using a harmonized pan-cancer analysis (or reanalysis) of two unpaired primary4 and metastatic5 cohorts of 7,108 whole-genome-sequenced tumours. Metastatic tumours in general have a lower intratumour heterogeneity and a conserved karyotype, displaying only a modest increase in mutations, although frequencies of structural variants are elevated overall. Furthermore, highly variable tumour-specific contributions of mutational footprints of endogenous (for example, SBS1 and APOBEC) and exogenous mutational processes (for example, platinum treatment) are present. The majority of cancer types had either moderate genomic differences (for example, lung adenocarcinoma) or highly consistent genomic portraits (for example, ovarian serous carcinoma) when comparing early-stage and late-stage disease. Breast, prostate, thyroid and kidney renal clear cell carcinomas and pancreatic neuroendocrine tumours are clear exceptions to the rule, displaying an extensive transformation of their genomic landscape in advanced stages. Exposure to treatment further scars the tumour genome and introduces an evolutionary bottleneck that selects for known therapy-resistant drivers in approximately half of treated patients. Our data showcase the potential of pan-cancer whole-genome analysis to identify distinctive features of late-stage tumours and provide a valuable resource to further investigate the biological basis of cancer and resistance to therapies.

In silico saturation mutagenesis of cancer genes.

Despite the existence of good catalogues of cancer genes1,2, identifying the specific mutations of those genes that drive tumorigenesis across tumour types is still a largely unsolved problem. As a result, most mutations identified in cancer genes across tumours are of unknown significance to tumorigenesis3. We propose that the mutations observed in thousands of tumours-natural experiments testing their oncogenic potential replicated across individuals and tissues-can be exploited to solve this problem. From these mutations, features that describe the mechanism of tumorigenesis of each cancer gene and tissue may be computed and used to build machine learning models that encapsulate these mechanisms. Here we demonstrate the feasibility of this solution by building and validating 185 gene-tissue-specific machine learning models that outperform experimental saturation mutagenesis in the identification of  driver and passenger mutations. The models and their assessment of each mutation are designed to be interpretable, thus avoiding a black-box prediction device. Using these models, we outline the blueprints of potential driver mutations in cancer genes, and demonstrate the role of mutation probability in shaping the landscape of observed driver mutations. These blueprints will support the interpretation of newly sequenced tumours in patients and the study of the mechanisms of tumorigenesis of cancer genes across tissues.

Extracellular Kir2.1C122Y Mutant Upsets Kir2.1-PIP2 Bonds and Is Arrhythmogenic in Andersen-Tawil Syndrome.

BACKGROUND: Andersen-Tawil syndrome type 1 is a rare heritable disease caused by mutations in the gene coding the strong inwardly rectifying K+ channel Kir2.1. The extracellular Cys (cysteine)122-to-Cys154 disulfide bond in the channel structure is crucial for proper folding but has not been associated with correct channel function at the membrane. We evaluated whether a human mutation at the Cys122-to-Cys154 disulfide bridge leads to Kir2.1 channel dysfunction and arrhythmias by reorganizing the overall Kir2.1 channel structure and destabilizing its open state. METHODS: We identified a Kir2.1 loss-of-function mutation (c.366 A>T; p.Cys122Tyr) in an ATS1 family. To investigate its pathophysiological implications, we generated an AAV9-mediated cardiac-specific mouse model expressing the Kir2.1C122Y variant. We employed a multidisciplinary approach, integrating patch clamping and intracardiac stimulation, molecular biology techniques, molecular dynamics, and bioluminescence resonance energy transfer experiments. RESULTS: Kir2.1C122Y mice recapitulated the ECG features of ATS1 independently of sex, including corrected QT prolongation, conduction defects, and increased arrhythmia susceptibility. Isolated Kir2.1C122Y cardiomyocytes showed significantly reduced inwardly rectifier K+ (IK1) and inward Na+ (INa) current densities independently of normal trafficking. Molecular dynamics predicted that the C122Y mutation provoked a conformational change over the 2000-ns simulation, characterized by a greater loss of hydrogen bonds between Kir2.1 and phosphatidylinositol 4,5-bisphosphate than wild type (WT). Therefore, the phosphatidylinositol 4,5-bisphosphate-binding pocket was destabilized, resulting in a lower conductance state compared with WT. Accordingly, on inside-out patch clamping, the C122Y mutation significantly blunted Kir2.1 sensitivity to increasing phosphatidylinositol 4,5-bisphosphate concentrations. In addition, the Kir2.1C122Y mutation resulted in channelosome degradation, demonstrating temporal instability of both Kir2.1 and NaV1.5 proteins. CONCLUSIONS: The extracellular Cys122-to-Cys154 disulfide bond in the tridimensional Kir2.1 channel structure is essential for the channel function. We demonstrate that breaking disulfide bonds in the extracellular domain disrupts phosphatidylinositol 4,5-bisphosphate-dependent regulation, leading to channel dysfunction and defects in Kir2.1 energetic stability. The mutation also alters functional expression of the NaV1.5 channel and ultimately leads to conduction disturbances and life-threatening arrhythmia characteristic of Andersen-Tawil syndrome type 1.

Male androphilia, fraternal birth order, and female fecundity in Samoa: A 10-y retrospective.

Two separate but related literatures have examined familial correlates of male androphilia (i.e., sexual attraction and arousal to masculine adult males). The fraternal birth order effect (FBOE) is a widely established finding that each biological older brother a male has increased the probability of androphilia 20-35% above baseline rates. Other family demographic variables, such as reproduction by mothers, maternal aunts, and grandmothers, have been used to test evolutionary hypotheses that sexually antagonistic genes lead to androphilia among males, lowering or eliminating reproduction, which is offset by greater reproductive output among their female relatives. These proposed female fecundity effects (FFEs), and the FBOE, have historically been treated as separate yet complementary ways to understand the development and evolution of male androphilia. However, this approach ignores a vital confound within the data. The high overall reproductive output indicative of an FFE results in similar statistical patterns as the FBOE, wherein women with high reproductive output subsequently produce later-born androphilic sons. Thus, examination of the FBOE requires analytic approaches capable of controlling for the FFE, and vice-versa. Here, we present data simultaneously examining the FBOE and FFE for male androphilia in a large dataset collected in Samoa across 10 y of fieldwork, which only shows evidence of the FBOE.

A gain-of-function HCN4 mutant in the HCN domain is responsible for inappropriate sinus tachycardia in a Spanish family.

In a family with inappropriate sinus tachycardia (IST), we identified a mutation (p.V240M) of the hyperpolarization-activated cyclic nucleotide-gated type 4 (HCN4) channel, which contributes to the pacemaker current (If) in human sinoatrial node cells. Here, we clinically study fifteen family members and functionally analyze the p.V240M variant. Macroscopic (IHCN4) and single-channel currents were recorded using patch-clamp in cells expressing human native (WT) and/or p.V240M HCN4 channels. All p.V240M mutation carriers exhibited IST that was accompanied by cardiomyopathy in adults. IHCN4 generated by p.V240M channels either alone or in combination with WT was significantly greater than that generated by WT channels alone. The variant, which lies in the N-terminal HCN domain, increased the single-channel conductance and opening frequency and probability of HCN4 channels. Conversely, it did not modify the channel sensitivity for cAMP and ivabradine or the level of expression at the membrane. Treatment with ivabradine based on functional data reversed the IST and the cardiomyopathy of the carriers. In computer simulations, the p.V240M gain-of-function variant increases If and beating rate and thus explains the IST of the carriers. The results demonstrate the importance of the unique HCN domain in HCN4, which stabilizes the channels in the closed state.

Crystallography of honeycomb formation under geometric frustration.

As honeybees build their nests in preexisting tree cavities, they must deal with the presence of geometric constraints, resulting in nonregular hexagons and topological defects in the comb. In this work, we study how bees adapt to their environment in order to regulate the comb structure. Specifically, we identify the irregularities in honeycomb structure in the presence of various geometric frustrations. We 3D-print experimental frames with a variety of constraints imposed on the imprinted foundations. The combs constructed by the bees show clear evidence of recurring patterns in response to specific geometric frustrations on these starter frames. Furthermore, using an experimental-modeling framework, we demonstrate that these patterns can be successfully modeled and replicated through a simulated annealing process, in which the minimized potential is a variation of the Lennard-Jones potential that considers only first-neighbor interactions according to a Delaunay triangulation. Our simulation results not only confirm the connection between honeycomb structures and other crystal systems such as graphene, but also show that irregularities in the honeycomb structure can be explained as the result of analogous interactions between cells and their immediate surroundings, leading to emergent global order. Additionally, our computational model can be used as a first step to describe specific strategies that bees use to effectively solve geometric mismatches while minimizing cost of comb building.

The caloric value of food intake structurally adjusts a neuronal mushroom body circuit mediating olfactory learning in Drosophila.

Associative learning enables the adaptive adjustment of behavioral decisions based on acquired, predicted outcomes. The valence of what is learned is influenced not only by the learned stimuli and their temporal relations, but also by prior experiences and internal states. In this study, we used the fruit fly Drosophila melanogaster to demonstrate that neuronal circuits involved in associative olfactory learning undergo restructuring during extended periods of low-caloric food intake. Specifically, we observed a decrease in the connections between specific dopaminergic neurons (DANs) and Kenyon cells at distinct compartments of the mushroom body. This structural synaptic plasticity was contingent upon the presence of allatostatin A receptors in specific DANs and could be mimicked optogenetically by expressing a light-activated adenylate cyclase in exactly these DANs. Importantly, we found that this rearrangement in synaptic connections influenced aversive, punishment-induced olfactory learning but did not impact appetitive, reward-based learning. Whether induced by prolonged low-caloric conditions or optogenetic manipulation of cAMP levels, this synaptic rearrangement resulted in a reduction of aversive associative learning. Consequently, the balance between positive and negative reinforcing signals shifted, diminishing the ability to learn to avoid odor cues signaling negative outcomes. These results exemplify how a neuronal circuit required for learning and memory undergoes structural plasticity dependent on prior experiences of the nutritional value of food.

Digital Technologies in Cardiac Rehabilitation: A Science Advisory From the American Heart Association.

Cardiac rehabilitation has strong evidence of benefit across many cardiovascular conditions but is underused. Even for those patients who participate in cardiac rehabilitation, there is the potential to better support them in improving behaviors known to promote optimal cardiovascular health and in sustaining those behaviors over time. Digital technology has the potential to address many of the challenges of traditional center-based cardiac rehabilitation and to augment care delivery. This American Heart Association science advisory was assembled to guide the development and implementation of digital cardiac rehabilitation interventions that can be translated effectively into clinical care, improve health outcomes, and promote health equity. This advisory thus describes the individual digital components that can be delivered in isolation or as part of a larger cardiac rehabilitation telehealth program and highlights challenges and future directions for digital technology generally and when used in cardiac rehabilitation specifically. It is also intended to provide guidance to researchers reporting digital interventions and clinicians implementing these interventions in practice and to advance a framework for equity-centered digital health in cardiac rehabilitation.

Increasing Equity of Physical Activity Promotion for Optimal Cardiovascular Health in Adults: A Scientific Statement From the American Heart Association.

Fewer than 1 in 4 adults achieves the recommended amount of physical activity, with lower activity levels reported among some groups. Addressing low levels of physical activity among underresourced groups provides a modifiable target with the potential to improve equity in cardiovascular health. This article (1) examines physical activity levels across strata of cardiovascular disease risk factors, individual level characteristics, and environmental factors; (2) reviews strategies for increasing physical activity in groups who are underresourced or at risk for poor cardiovascular health; and (3) provides practical suggestions for physical activity promotion to increase equity of risk reduction and to improve cardiovascular health. Physical activity levels are lower among those with elevated cardiovascular disease risk factors, among certain groups (eg, older age, female, Black race, lower socioeconomic status), and in some environments (eg, rural). There are strategies for physical activity promotion that can specifically support underresourced groups such as engaging the target community in designing and implementing interventions, developing culturally appropriate study materials, identifying culturally tailored physical activity options and leaders, building social support, and developing materials for those with low literacy. Although addressing low physical activity levels will not address the underlying structural inequities that deserve attention, promoting physical activity among adults, especially those with both low physical activity levels and poor cardiovascular health, is a promising and underused strategy to reduce cardiovascular health inequalities.

Upregulation of the secretory pathway Ca2+/Mn2+-ATPase isoform 1 in LPS-stimulated microglia and its involvement in Mn2+-induced Golgi fragmentation.

Microglia play an important protective role in the healthy nervous tissue, being able to react to a variety of stimuli that induce different intracellular cascades for specific tasks. Ca2+ signaling can modulate these pathways, and we recently reported that microglial functions depend on the endoplasmic reticulum as a Ca2+ store, which involves the Ca2+ transporter SERCA2b. Here, we investigated whether microglial functions may also rely on the Golgi, another intracellular Ca2+ store that depends on the secretory pathway Ca2+/Mn2+-transport ATPase isoform 1 (SPCA1). We found upregulation of SPCA1 upon lipopolysaccharide stimulation of microglia BV2 cells and primary microglia, where alterations of the Golgi ribbon were also observed. Silencing and overexpression experiments revealed that SPCA1 affects cell morphology, Golgi apparatus integrity, and phagocytic functions. Since SPCA1 is also an efficient Mn2+ transporter and considering that Mn2+ excess causes manganism in the brain, we addressed the role of microglial SPCA1 in Mn2+ toxicity. Our results revealed a clear effect of Mn2+ excess on the viability and morphology of microglia. Subcellular analysis showed Golgi fragmentation and subsequent alteration of SPCA1 distribution from early stages of toxicity. Removal of Mn2+ by washing improved the culture viability, although it did not effectively reverse Golgi fragmentation. Interestingly, pretreatment with curcumin maintained microglia cultures viable, prevented Mn2+-induced Golgi fragmentation, and preserved SPCA Ca2+-dependent activity, suggesting curcumin as a potential protective agent against Mn2+-induced Golgi alterations in microglia.

Metabolic changes contribute to maladaptive right ventricular hypertrophy in pulmonary hypertension beyond pressure overload: an integrative imaging and omics investigation.

Right ventricular (RV) failure remains the strongest determinant of survival in pulmonary hypertension (PH). We aimed to identify relevant mechanisms, beyond pressure overload, associated with maladaptive RV hypertrophy in PH. To separate the effect of pressure overload from other potential mechanisms, we developed in pigs two experimental models of PH (M1, by pulmonary vein banding and M2, by aorto-pulmonary shunting) and compared them with a model of pure pressure overload (M3, pulmonary artery banding) and a sham-operated group. Animals were assessed at 1 and 8 months by right heart catheterization, cardiac magnetic resonance and blood sampling, and myocardial tissue was analyzed. Plasma unbiased proteomic and metabolomic data were compared among groups and integrated by an interaction network analysis. A total of 33 pigs completed follow-up (M1, n = 8; M2, n = 6; M3, n = 10; and M0, n = 9). M1 and M2 animals developed PH and reduced RV systolic function, whereas animals in M3 showed increased RV systolic pressure but maintained normal function. Significant plasma arginine and histidine deficiency and complement system activation were observed in both PH models (M1&M2), with additional alterations to taurine and purine pathways in M2. Changes in lipid metabolism were very remarkable, particularly the elevation of free fatty acids in M2. In the integrative analysis, arginine-histidine-purines deficiency, complement activation, and fatty acid accumulation were significantly associated with maladaptive RV hypertrophy. Our study integrating imaging and omics in large-animal experimental models demonstrates that, beyond pressure overload, metabolic alterations play a relevant role in RV dysfunction in PH.

Artificial intelligence of arterial Doppler waveforms to predict major adverse outcomes among patients with diabetes mellitus.

OBJECTIVE: Patients with diabetes mellitus (DM) are at increased risk for peripheral artery disease (PAD) and its complications. Arterial calcification and non-compressibility may limit test interpretation in this population. Developing tools capable of identifying PAD and predicting major adverse cardiac event (MACE) and limb event (MALE) outcomes among patients with DM would be clinically useful. Deep neural network analysis of resting Doppler arterial waveforms was used to detect PAD among patients with DM and to identify those at greatest risk for major adverse outcome events. METHODS: Consecutive patients with DM undergoing lower limb arterial testing (April 1, 2015-December 30, 2020) were randomly allocated to training, validation, and testing subsets (60%, 20%, and 20%). Deep neural networks were trained on resting posterior tibial arterial Doppler waveforms to predict all-cause mortality, MACE, and MALE at 5 years using quartiles based on the distribution of the prediction score. RESULTS: Among 11,384 total patients, 4211 patients with DM met study criteria (mean age, 68.6 ± 11.9 years; 32.0% female). After allocating the training and validation subsets, the final test subset included 856 patients. During follow-up, there were 262 deaths, 319 MACE, and 99 MALE. Patients in the upper quartile of prediction based on deep neural network analysis of the posterior tibial artery waveform provided independent prediction of death (hazard ratio [HR], 3.58; 95% confidence interval [CI], 2.31-5.56), MACE (HR, 2.06; 95% CI, 1.49-2.91), and MALE (HR, 13.50; 95% CI, 5.83-31.27). CONCLUSIONS: An artificial intelligence enabled analysis of a resting Doppler arterial waveform permits identification of major adverse outcomes including all-cause mortality, MACE, and MALE among patients with DM.

The Proportion of Catagen and Telogen Hair Follicles in Occipital Scalp of Male Androgenetic Alopecia Patients: Challenging the Established Dogma.

The hair follicle can cycle throughout a lifetime, undergoing periods of growth (anagen), regression (catagen) and relative quiescence (telogen). The time that a hair follicle spends in each of these stages is crucial to determine the length of hair fibre that it produces. Perturbations in this regard can manifest in various hair diseases such as anagen effluvium, or acute and chronic telogen effluvium. The established 'dogma' when considering how many hair follicles there are in each stage has long been that the majority are in anagen (85%-90%), followed by telogen (10%-15%) and catagen (1%-2%). These values are based on various studies using different methodologies such as hair plucking, phototrichograms and histology. However, these methods have flaws when it comes to differentiating between catagen and telogen follicles. We sought to determine the catagen: telogen ratio through the ex vivo stereomicroscopic examination of hundreds of hair follicles removed from the occipital scalp of 14 Caucasian males during routine hair transplantation procedures. Using this methodology, and in agreement with a similar observation by another research group, we found that the percentage of catagen hair follicles was higher (7.5%) than telogen (3.5%) in all patients assessed. Consequently, we believe that the percentage of catagen follicles is clearly underestimated and therefore challenge the current established dogma.

Epidermal growth factor receptor/mitogen-activated kinase inhibitor treatment induces a distinct inflammatory hair follicle response that includes collapse of immune privilege.

BACKGROUND: Inhibitors of epidermal growth factor receptor (EGFRi) or mitogen-activated kinase (MEKi) induce a folliculitis in 75-90% of patients, the pathobiology of which remains insufficiently understood. OBJECTIVES: To characterize changes in the skin immune status and global transcriptional profile of patients treated with EGFRi; to investigate whether EGFRi affects the hair follicle's (HF) immune privilege (IP); and to identify early proinflammatory signals induced by EGFRi/MEKi in human scalp HFs ex vivo. METHODS: Scalp biopsies were taken from patients exhibiting folliculitis treated long term with EGFRi ('chronic EGFRi' group, n = 9) vs. healthy scalp skin (n = 9) and patients prior to commencing EGFRi treatment and after 2 weeks of EGFRi therapy ('acute EGFRi' group, n = 5). Healthy organ-cultured scalp HFs were exposed to an EGFRi (erlotinib, n = 5) or a MEKi (cobimetinib, n = 5). Samples were assessed by quantitative immunohistomorphometry, RNA sequencing (RNAseq) and in situ hybridization. RESULTS: The 'chronic EGFRi' group showed CD8+ T-cell infiltration of the bulge alongside a partial collapse of the HF's IP, evidenced by upregulated major histocompatibility complex (MHC) class I, ß2-microglobulin (B2 M) and MHC class II, and decreased transforming growth factor-ß1 protein expression. Healthy HFs treated with EGFRi/MEKi ex vivo also showed partial HF IP collapse and increased transcription of human leucocyte antigen (HLA)-A, HLA-DR and B2 M transcripts. RNAseq analysis showed increased transcription of chemokines (CXCL1, CXCL13, CCL18, CCL3, CCL7) and interleukin (IL)-26 in biopsies from the 'chronic EGFRi' cohort, as well as increased IL-33 and decreased IL-37 expression in HF biopsies from the 'acute EGFRi' group and in organ-cultured HFs. CONCLUSIONS: The data show that EGFRi/MEKi compromise the physiological IP of human scalp HFs and suggest that future clinical management of EGFRi/MEKi-induced folliculitis requires HF IP protection and inhibition of IL-33.

About 75­90% of people with cancer who are treated with drugs called EGFR inhibitors (EGFRi) and MEK inhibitors (MEKi) will get a skin condition called folliculitis. This is where the hair follicles become inflamed. Despite this, the reasons why some patients develop this are not well understood. In this study, we had three goals. We wanted to understand how these medications alter the skin's immune response and genetic processes. We also wished to determine the impact of the medications on the immune protection of hair follicles. Finally, we wanted to find early signs of inflammation in hair follicles caused by the medications. We studied scalp samples from people who got folliculitis after long-term EGFRi treatment and compared them to samples of healthy scalp skin. We also examined patients before and after they began EGFRi treatment. In the lab, we exposed healthy hair follicles to an EGFRi called 'erlotinib' or a MEKi called 'cobimetinib'. We then carried out detailed imaging and genetic analyses. We found that long-term treatment with EGFRi increased certain immune cells (called CD8+ T cells) in the hair follicle area. This led to a breakdown in the immune protection around hair follicles. A similar breakdown was found in lab-treated healthy follicles. Genetic changes linked to inflammation were also found. Our findings suggest that EGFRi and MEKi treatments could affect the natural immune defence of hair follicles in the scalp and cause folliculitis. Protecting the immune system and controlling inflammation might be the key to treating people with these drug-related skin conditions.

A rare presentation of infective endocarditis: Phase 4 block of the left bundle branch as key for the diagnosis. A case report.

Definitive diagnosis of infective endocarditis (IE) is mainly based on microbiological and imaging criteria. In a minority of cases, particularly when perivalvular area is involved, cardiac conduction disorders (CCD) may appear, which implies worse prognosis. In this scenario, different degrees of auriculoventricular block can occur, but development of bundle branch block is rare. Herein, we present a case of IE with negative initial imaging tests, where the occurrence of phase 4 bundle branch block after a sequence of type I second degree AV block was crucial to establish a definitive diagnosis and an optimal therapeutic approach.

Mortality, Functional Status, and Quality of Life after 5 Years of Patients Admitted to Critical Care for Spontaneous Intracerebral Hemorrhage.

BACKGROUND: The objective of this study was to assess long-term outcome in patients with spontaneous intracerebral hemorrhage admitted to the intensive care unit. METHODS: Mortality and Glasgow Outcome Scale, Barthel Index, and 5-level EQ-5D version (EQ-5D-5L) scores were analyzed in a multicenter cohort study of three Spanish hospitals (336 patients). Mortality was also analyzed in the Medical Information Mart for Intensive Care III (MIMIC-III) database. RESULTS: The median (25th percentile-75th percentile) age was 62 (50-70) years, the median Glasgow Coma Score was 7 (4-11) points, and the median Acute Physiology and Chronic Health disease Classification System II (APACHE-II) score was 21 (15-26) points. Hospital mortality was 54.17%, mortality at 90 days was 56%, mortality at 1 year was 59.2%, and mortality at 5 years was 66.4%. In the Glasgow Outcome Scale, a normal or disabled self-sufficient situation was recorded in 21.5% of patients at 6 months, in 25.5% of patients after 1 year, and in 22.1% of patients after 5 years of follow-up (4.5% missing). The Barthel Index score of survivors improved over time: 50 (25-80) points at 6 months, 70 (35-95) points at 1 year, and 90 (40-100) points at 5 years (p < 0.001). Quality of life evaluated with the EQ-5D-5L at 1 year and 5 years indicated that greater than 50% of patients had no problems or slight problems in all items (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression). In the MIMIC-III study (N = 1354), hospital mortality was 31.83% and was 40.5% at 90 days and 56.2% after 5 years. CONCLUSIONS: In patients admitted to the intensive care unit with a diagnosis of nontraumatic intracerebral hemorrhage, hospital mortality up to 90 days after admission is very high. Between 90 days and 5 years after admission, mortality is not high. A large percentage of survivors presented a significant deficit in quality of life and functional status, although with progressive improvement over time. Five years after the hemorrhagic stroke, a survival of 30% was observed, with a good functional status seen in 20% of patients who had been admitted to the hospital.

Emery-Dreifuss muscular dystrophy Type 1 is associated with a high risk of malignant ventricular arrhythmias and end-stage heart failure.

BACKGROUND AND AIMS: Emery-Dreifuss muscular dystrophy (EDMD) is caused by variants in EMD (EDMD1) and LMNA (EDMD2). Cardiac conduction defects and atrial arrhythmia are common to both, but LMNA variants also cause end-stage heart failure (ESHF) and malignant ventricular arrhythmia (MVA). This study aimed to better characterize the cardiac complications of EMD variants. METHODS: Consecutively referred EMD variant-carriers were retrospectively recruited from 12 international cardiomyopathy units. MVA and ESHF incidences in male and female variant-carriers were determined. Male EMD variant-carriers with a cardiac phenotype at baseline (EMDCARDIAC) were compared with consecutively recruited male LMNA variant-carriers with a cardiac phenotype at baseline (LMNACARDIAC). RESULTS: Longitudinal follow-up data were available for 38 male and 21 female EMD variant-carriers [mean (SD) ages 33.4 (13.3) and 43.3 (16.8) years, respectively]. Nine (23.7%) males developed MVA and five (13.2%) developed ESHF during a median (inter-quartile range) follow-up of 65.0 (24.3-109.5) months. No female EMD variant-carrier had MVA or ESHF, but nine (42.8%) developed a cardiac phenotype at a median (inter-quartile range) age of 58.6 (53.2-60.4) years. Incidence rates for MVA were similar for EMDCARDIAC and LMNACARDIAC (4.8 and 6.6 per 100 person-years, respectively; log-rank P = .49). Incidence rates for ESHF were 2.4 and 5.9 per 100 person-years for EMDCARDIAC and LMNACARDIAC, respectively (log-rank P = .09). CONCLUSIONS: Male EMD variant-carriers have a risk of progressive heart failure and ventricular arrhythmias similar to that of male LMNA variant-carriers. Early implantable cardioverter defibrillator implantation and heart failure drug therapy should be considered in male EMD variant-carriers with cardiac disease.

Why choose the rabbit to work in reproductive technology?

Rabbits have played a significant role in both livestock production and the advancement of reproductive scientific research. Their unique biological traits, including induced ovulation and a reproductive process that closely mirrors that of humans, have been pivotal in their use as a model. Moreover, their body size is perfectly aligned with the 3Rs principles: Replacement, Reduction, and Refinement. Consequently, techniques for gamete collection and embryo recovery, followed by their use in artificial insemination or embryo transfer, are characterized by being minimally invasive. However, refining in vitro fertilization and embryo culture techniques continues to present challenges. The incorporation of cutting-edge genomic editing tools, such as CRISPR/Cas9, has reestablished rabbits as essential models in genetic and biomedical research, driving scientific progress. This review aims to describe the most effective reproductive biotechnologies for both male and female rabbits and how these methodologies are in line with the 3Rs principles-Replacement, Reduction, and Refinement-highlighting their significance in conducting ethical research.

UHPLC-ESI-QTOF-MS metabolite profiles of different extracts from Pelargonium endlicherianum parts and their biological properties based on network pharmacological approaches.

In the present study, we aimed to investigate the chemical profiles and biological activities of different extracts (ethyl acetate, dichloromethane, ethanol, and water) of Pelargonium endlicherianum parts (aerial parts and roots). Free radical scavenging, reducing power, phosphomolybdenum, and metal chelating were assayed for antioxidant properties. To detect enzyme inhibitory properties, cholinesterase, amylase, glucosidase, and tyrosinase were chosen as target enzymes. The ethanol extract of the aerial parts contained higher amounts of total bioactive compounds (120.53 mg GAE/g-24.46 mg RE/g). The ethanol and water extracts of these parts were tentatively characterized by UHPLC-ESI-QTOF-MS and 95 compounds were annotated. In addition, the highest acetylcholiesterase (3.74 mg GALAE/g) and butyrylcholinesterase (3.92 mg GALAE/g) abilities were observed by the ethanol extract of roots. The water extract from aerial parts exhibited the most pronounced inhibitory effects on multiple cancer cell lines, especially A549 (IC50: 23.2 µg/mL) and HT-29 (IC50: 27.43 µg/mL) cells. Using network pharmacology, P. endlicherianum compounds were studied against cancer, revealing well-connected targets such as epidermal growth factor receptor (EGFR), phosphoinositide-3-kinase (PI3K), AKT, receptor tyrosine-protein kinase erbB-2, and growth factor receptor bound protein 2 (GRB2) with significant impact on cancer-related pathways. The results could open a new path from natural treasure to functional applications with P. endlicherianum and highlight a new study on other uninvestigated Pelargonium species.

Valorization applications of pineapple and papaya byproducts in food industry.

The recent increase in the harvesting and industrial processing of tropical fruits such as pineapple and papaya is leading to unavoidable amounts of byproducts rich in valuable compounds. Given the significance of the chemical composition of these byproducts, new research avenues are opening up to exploit them in the food industry. In this sense, the revalorization of pineapple and papaya byproducts is an emerging trend that is encouraging the full harnessing of these tropical fruits, offering the opportunity for developing innovative value-added products. Therefore, the main aim of this review is to provide an overview of the state of the art of the current valorization applications of pineapple and papaya byproducts in the field of food industry. For that proposal, comprehensive research of valorization applications developed in the last years has been conducted using scientific databases, databases, digital libraries, and scientific search engines. The latest valorization applications of pineapple and papaya byproducts in the food industry have been systematically revised and gathered with the objective of synthesizing and critically analyzing existing scientific literature in order to contribute to the advancement of knowledge in the field of tropical byproduct revalorization providing a solid foundation for further research and highlighting scientific gaps and new challenges that should be addressed in the future.