Multiple Genomic Landscapes of Recombination and Genomic Divergence in Wild Populations of House Mice-The Role of Chromosomal Fusions and Prdm9.

Chromosomal fusions represent one of the most common types of chromosomal rearrangements found in nature. Yet, their role in shaping the genomic landscape of recombination and hence genome evolution remains largely unexplored. Here, we take advantage of wild mice populations with chromosomal fusions to evaluate the effect of this type of structural variant on genomic landscapes of recombination and divergence. To this aim, we combined cytological analysis of meiotic crossovers in primary spermatocytes with inferred analysis of recombination rates based on linkage disequilibrium using single nucleotide polymorphisms. Our results suggest the presence of a combined effect of Robertsonian fusions and Prdm9 allelic background, a gene involved in the formation of meiotic double strand breaks and postzygotic reproductive isolation, in reshaping genomic landscapes of recombination. We detected a chromosomal redistribution of meiotic recombination toward telomeric regions in metacentric chromosomes in mice with Robertsonian fusions when compared to nonfused mice. This repatterning was accompanied by increased levels of crossover interference and reduced levels of estimated recombination rates between populations, together with high levels of genomic divergence. Interestingly, we detected that Prdm9 allelic background was a major determinant of recombination rates at the population level, whereas Robertsonian fusions showed limited effects, restricted to centromeric regions of fused chromosomes. Altogether, our results provide new insights into the effect of Robertsonian fusions and Prdm9 background on meiotic recombination.

Developmental and environmental plasticity in opsin gene expression in Lake Victoria cichlid fish.

In many organisms, sensory abilities develop and evolve according to the changing demands of navigating, foraging, and communication across different environments and life stages. Teleost fish inhabit heterogeneous light environments and exhibit a large diversity in visual system properties among species. Cichlids are a classic example of this diversity; visual system variation is generated by different tuning mechanisms that involve both genetic factors and phenotypic plasticity. Here, we document the developmental progression of visual pigment gene expression in Lake Victoria cichlids and test if these patterns are influenced by variation in light conditions. We reared two sister species of Pundamilia to adulthood in two distinct visual conditions that resemble the light environments that they naturally inhabit in Lake Victoria. We also included interspecific first-generation hybrids. We focused on the four opsins that are expressed in Pundamilia adults (using real-time quantitative polymerase chain reaction (RT-qPCR)) (SWS2B, SWS2A, RH2A, and LWS) at 17 time points. We find that opsin expression profiles progress from shorter-wavelength sensitive opsins to longer-wavelength sensitive opsins with increasing age, in both species and their hybrids. The developmental trajectories of opsin expression also responded plastically to the visual conditions. Developmental and environmental plasticity in opsin expression may provide an important stepping stone in the evolution of cichlid visual system diversity.

An improved method to study Phytophthora cinnamomi Rands zoospores interactions with host.

Phytophthora cinnamomi Rands is a highly prevalent phytopathogen worldwide, ranking among the top ten in terms of distribution. It inflicts crown rot, canker, and root rot on numerous plant species, significantly impacting the biodiversity of both flora and fauna within affected environments. With a host range spanning over 5,000 species, including important plants like Quercus suber, Quercus ilex, Castanea sativa, and commercially significant crops such as avocado (Persea americana), maize (Zea mays), and tomato (Solanum lycopersicum), Phytophthora cinnamomi poses a substantial threat to agriculture and ecosystems. The efficient dissemination of the oomycete relies on its short-lived asexually motile zoospores, which depend on water currents to infect host roots. However, managing these zoospores in the laboratory has long been challenging due to the complexity of the life cycle. Current protocols involve intricate procedures, including alternating cycles of growth, drought, and flooding. Unfortunately, these artificial conditions often result in a rapid decline in virulence, necessitating additional steps to maintain infectivity during cultivation. In our research, we sought to address this challenge by investigating zoospore survival under various conditions. Our goal was to develop a stable stock of zoospores that is both easily deployable and highly infective. Through direct freezing in liquid nitrogen, we have successfully preserved their virulence. This breakthrough eliminates the need for repeated culture transfers, simplifying the process of plant inoculation. Moreover, it enables more comprehensive studies of Phytophthora cinnamomi and its interactions with host plants.

Efficacy and safety of chemotherapy in young patients with advanced gastroesophageal adenocarcinoma: data from the Spanish AGAMENON-SEOM registry.

BACKGROUND: Gastroesophageal adenocarcinoma in young adults (GCYA) counts for 10-15% of diagnoses. Previous studies have mainly focused on surgical outcomes in patients with resectable tumors; however, systemic therapy for advanced GCYA remains under-evaluated. This study aims to assess the efficacy-related outcomes and safety of first-line chemotherapy (CT) in younger versus older patients with advanced gastroesophageal adenocarcinoma. METHODS: Patients with advanced gastroesophageal adenocarcinoma from the AGAMENON-SEOM registry treated with first-line polychemotherapy between January 2008 and October 2022 were included. We compared clinicopathological features, therapies received, efficacy-related outcomes, and toxicity between individuals aged < and ≥ 45 years. RESULTS: Out of 3386 patients, 263 (7.8%) were < 45 years. Young patients exhibited a higher proportion of females affected, lower ECOG-PS ≥ 2, fewer comorbidities, and more aggressive disease-related features, such as higher proportion of diffuse subtype, signet-ring cells, plastic linitis, grade 3, peritoneal metastases and metastatic disease at diagnosis. They received more triple-agent combinations and underwent more surgeries in metastatic setting. No significant differences were observed between groups in overall response rate (53.1% vs. 52.3% in < and ≥ 45 years, respectively, p = 0.579), progression-free survival (6.1 vs. 6.83 months, p = 0.158) and overall survival (11.07 vs. 10.81 months, p = 0.82), even after adjusting for potential confounding factors. Grade 3-4 adverse events were comparable in both groups, although toxicity leading to treatment discontinuation was more frequent in older patients. CONCLUSIONS: In the AGAMENON-SEOM registry, younger patients with GCYA exhibited more aggressive clinicopathological features, and despite receiving more aggressive treatments, similar efficacy outcomes and toxicity profiles were achieved compared to their older counterparts. In the AGAMENON-SEOM registry, GEAC in < 45 years showed more aggressive clinicopathological features and, although treated with more intense first-line CT regimens, similar efficacy outcomes and toxicity were achieved compared to older patients.

Effects of omega-3 supplementation on anxiety-like behaviors and neuroinflammation in Wistar rats following cafeteria diet-induced obesity.

ABSTRACTObjetives: Omega-3 (n3) fatty acids have been studied as an option to alleviate the harmful effects of obesity. However, its role in obesity-related behavioral changes is still controversial. This study aimed to evaluate the effects of n3 on behavior and neuroinflammation in obese animals. Methods: Male Wistar rats were divided into four groups: control diet (CT), CT+n3, cafeteria diet (CAF), and CAF+n3. Diet was administered for 13 weeks, and n3 was supplemented during the last 5 weeks. Metabolic and biochemical parameters were evaluated, as well as anxiety-like behaviors. Immunoblots were conducted in the animals' cerebral cortex and hippocampus to assess changes in neuroinflammatory markers.Results: CAF-fed animals showed higher weight gain, visceral adiposity, fasting glucose, total cholesterol, triglycerides, and insulin levels, and n3 improved the lipid profile and restored insulin sensitivity. CAF-fed rats showed anxiety-like behaviors in the open field and light-dark box tasks but not in the contextual aversive conditioning. Omega-3 did not exert any effect on these behaviors. Regarding neuroinflammation, diet and supplementation acted in a region-specific manner. In the hippocampus, CAF reduced claudin-5 expression with no effect of n3, indicating a brain-blood barrier disruption following CAF. Furthermore, in the hippocampus, the glial fibrillary acidic protein (GFAP) and toll-like receptor 4 (TLR-4) were reduced in treated obese animals. However, n3 could not reverse the TLR-4 expression increase in the cerebral cortex.Discussion: Although n3 may protect against some neuroinflammatory manifestations in the hippocampus, it does not seem sufficient to reverse the increase in anxiolytic manifestations caused by CAF.

Association between co-sleeping in the first year of life and preschoolers´ sleep patterns.

This study aimed to investigate the association between co-sleeping practiced during the first year of life and preschoolers' sleep patterns. A cross-sectional study including toddlers was designed to analyze their sleep patterns. The Brief Infant Sleep Questionnaire, validated in Spanish, was used to measure sleep quality. A latent class analysis was performed to identify qualitative subgroups in the sample and explore the effects of co-sleeping. The sleep patterns of 276 children were analyzed. A total of 181 (65%) parents reported having practiced co-sleeping with their children. The latent class analysis identified a two-class solution with two different sleep patterns. One of them showed a worse quality sleep pattern, which had a significant association with having practiced co-sleeping during the first year of life, and with the fact that they were still sleeping in the parents' room, among other characteristics related to co-sleeping and parental concerns. Breastfeeding also showed association with a worse quality sleep pattern.  Conclusion: Based on the present findings, co-sleeping during the first year of life appears to be associated with poor sleep patterns in young preschoolers. What is Known: • Co-sleeping shows benefits for infants and parents, mainly facilitating successful breastfeeding. • Literature on the effect of co-sleeping in lately sleep quality in children and their parents is very limited. What is New: • Co-sleeping practiced during the first year of life could be associated with a worse sleep pattern measured with BISQ-E tool. • A balance between the correct practice of co-sleeping and the achievement of a healthy sleep routine in preschool should probably be part of parents' health education.

Treatment of Behçet disease with oral roflumilast, an observational study.

INTRODUCTION: Mucocutaneous Behcet's disease is often a therapeutic challenge. Roflumilast has shown promise in other inflammatory dermatological conditions. The objective of this study is to evaluate the characteristics, effectiveness and safety of roflumilast in the treatment of Behçet's Disease-associated aphthosis in routine clinical practice. METHODS: Single cohort ambispective observational study. 11 patients with Behçet disease treated with roflumilast participated. Data collection included demographic, clinical and outcome variables. Statistical analysis compared 12 weeks of treatment with roflumilast with a previous period without treatment and with a period with the previous treatment. RESULTS: During treatment with roflumilast, a reduction in flare-ups and oral ulcers was observed compared to the untreated period and the previous treatment period. A reduction in genital ulcers, pain and ulcer duration was observed between the Whitout treatment period and the Roflumilast treatment period.Adverse effects occurred in 54% of patients, most of which were self-limiting or manageable with dose adjustment. No patient withdrew treatment. DISCUSSION: Roflumilast appears a promising option in the treatment of Behçet's disease with favourable effectiveness, safety and tolerability profiles. Although further research is needed, roflumilast offers a promising treatment option for Behçet's Disease-associated aphthosis, which could improve patients' quality of life and address unmet therapeutic needs.

Mohs micrographic surgery in immunosuppressed vs immunocompetent patients: Results of a prospective nationwide cohort study (REGESMOHS, Spanish registry of Mohs surgery).

BACKGROUND: Immunosuppressed (IS) patients, particularly solid organ transplant recipients and those on immunosuppressive therapy, face a higher incidence and recurrence of nonmelanoma skin cancers (NMSC), including basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). Mohs micrographic surgery (MMS) is the preferred treatment for high-risk NMSC due to its high cure rate and margin examination capabilities. However, IS patients may experience more complications, such as surgical site infections, and a greater risk of recurrence, making their outcomes a subject of interest. OBJECTIVES: This study aimed to compare IS and immunocompetent (IC) patients undergoing MMS for NMSC in terms of baseline characteristics, intra- and post-surgical complications, and postoperative recurrence rates. METHODS: The study utilized data from the REGESMOHS registry, a 7-year prospective cohort study in Spain. It included 5226 patients, categorizing them into IC (5069) and IS (157) groups. IS patients included solid organ transplant recipients, those on immunosuppressive treatments, individuals with haematological tumours and HIV-positive patients. Patient data, tumour characteristics, surgical details and outcomes were collected and analysed. RESULTS: IS patients demonstrated a higher proportion of SCC, multiple synchronous tumours and tumours invading deeper structures. Complex closures, unfinished MMS and more surgical sections were observed in the IS group. Although intra-operative morbidity was higher among IS patients, this difference became non-significant when adjusted for other variables such as year of surgery, antiplatelet/anticoagulant treatment or type of closure. Importantly, IS patients had a substantially higher recurrence rate (IRR 2.79) compared to IC patients. CONCLUSIONS: This study suggests that IS patients may be at a higher risk of development of AE such as bleeding or tumour necrosis and are at a higher risk of tumour recurrence. Close follow-up and consideration of the specific characteristics of NMSC in IS patients are crucial. Further research with extended follow-up is needed to better understand the long-term outcomes for this patient group.

Microchromosomes are building blocks of bird, reptile, and mammal chromosomes.

Microchromosomes, once considered unimportant shreds of the chicken genome, are gene-rich elements with a high GC content and few transposable elements. Their origin has been debated for decades. We used cytological and whole-genome sequence comparisons, and chromosome conformation capture, to trace their origin and fate in genomes of reptiles, birds, and mammals. We find that microchromosomes as well as macrochromosomes are highly conserved across birds and share synteny with single small chromosomes of the chordate amphioxus, attesting to their origin as elements of an ancient animal genome. Turtles and squamates (snakes and lizards) share different subsets of ancestral microchromosomes, having independently lost microchromosomes by fusion with other microchromosomes or macrochromosomes. Patterns of fusions were quite different in different lineages. Cytological observations show that microchromosomes in all lineages are spatially separated into a central compartment at interphase and during mitosis and meiosis. This reflects higher interaction between microchromosomes than with macrochromosomes, as observed by chromosome conformation capture, and suggests some functional coherence. In highly rearranged genomes fused microchromosomes retain most ancestral characteristics, but these may erode over evolutionary time; surprisingly, de novo microchromosomes have rapidly adopted high interaction. Some chromosomes of early-branching monotreme mammals align to several bird microchromosomes, suggesting multiple microchromosome fusions in a mammalian ancestor. Subsequently, multiple rearrangements fueled the extraordinary karyotypic diversity of therian mammals. Thus, microchromosomes, far from being aberrant genetic elements, represent fundamental building blocks of amniote chromosomes, and it is mammals, rather than reptiles and birds, that are atypical.

Structure-Based Optimization of Carbendazim-Derived Tubulin Polymerization Inhibitors through Alchemical Free Energy Calculations.

Carbendazim derivatives, commonly used as antiparasitic drugs, have shown potential as anticancer agents due to their ability to induce cell cycle arrest and apoptosis in human cancer cells by inhibiting tubulin polymerization. Crystallographic structures of α/ß-tubulin multimers complexed with nocodazole and mebendazole, two carbendazim derivatives with potent anticancer activity, highlighted the possibility of designing compounds that occupy both benzimidazole- and colchicine-binding sites. In addition, previous studies have demonstrated that the incorporation of a phenoxy group at position 5/6 of carbendazim increases the antiproliferative activity in cancer cell lines. Despite the significant progress made in identifying new tubulin-targeting anticancer compounds, further modifications are needed to enhance their potency and safety. In this study, we explored the impact of modifying the phenoxy substitution pattern on antiproliferative activity. Alchemical free energy calculations were used to predict the binding free energy difference upon ligand modification and define the most viable path for structure optimization. Based on these calculations, seven compounds were synthesized and evaluated against lung and colon cancer cell lines. Our results showed that compound 5a, which incorporates an α-naphthyloxy substitution, exhibits the highest antiproliferative activity against both cancer lines (SK-LU-1 and SW620, IC50 < 100 nM) and induces morphological changes in the cells associated with mitotic arrest and mitotic catastrophe. Nevertheless, the tubulin polymerization assay showed that 5a has a lower inhibitory potency than nocodazole. Molecular dynamics simulations suggested that this low antitubulin activity could be associated with the loss of the key H-bond interaction with V236. This study provides insights into the design of novel carbendazim derivatives with anticancer activity.

Glaucoma medical treatment as a predictor of XEN45 subconjunctival gel implant hypotensive efficacy.

PURPOSE: The aim of this study was to determine the preoperative characteristics influencing hypotensive efficacy of the XEN45 gel stent in patients with open-angle glaucoma at one-year follow-up. MATERIALS AND METHODS: This was a retrospective multicentre study. All patients who underwent XEN45 gel stent implantation between January 2017 and January 2021 were included. The main study outcome was the assessment of one-year postoperative intraocular pressure (IOP) and glaucoma medication differences according to the number and type of preoperative topical treatments or glaucoma surgery, glaucoma stage and time since diagnosis. Follow-up period was 1-year post-surgery in all cases. IOP reduction and surgery success (not requiring reoperation or pressure failures [IOP > 18 mmHg and < 20% reduction in IOP]), safety and cost savings in topical glaucoma therapy after surgery were secondarily assessed. Linear regression analysis to determine the preoperative parameters influence on 1-year postoperative results was performed. RESULTS: XEN45 gel stent was implanted in 85 patients. One-year postoperative mean IOP dropped from 20.6 ± 4.1 to 13.7 ± 2.8 mmHg (p < 0.0001). Likewise, mean number of topical treatments decreased from 2.05 ± 0.9 to 0.36 ± 0.65 (p < 0.001). Both were mainly influenced by the number of preoperative glaucoma treatments, such that for each one-glaucoma medication increase, postoperative intraocular pressure increased by 1.18 mmHg (95% CI 0.56-1.79, p < 0.0001) and number of glaucoma medications increased by 0.3 (95% CI 0.16-0.43, p < 0.001). Overall success rates (with and without supplemental glaucoma medication use) were 97.6% (95% CI 94.5-100%), 87.1% (95% CI 80.2-87.1%) and 61.2% (95% CI 51.6-72.5%) at 3, 6 months and 1 year after surgery. No sight-threatening adverse events were reported. Mean annual cost savings on medical treatment since surgery reached EUR 251.19 ± 169. 93 euros. CONCLUSIONS: One year after surgery, XEN45 gel implant significantly reduced IOP and number of topical medications with an adequate safety profile being both mainly influenced by the number of preoperative glaucoma treatments.

Efficacy and safety of the PreserFlo implant with mitomycin C in childhood glaucoma after previous failed glaucoma surgeries.

PURPOSE: This study aims to evaluate the efficacy and safety of the PreserFlo MicroShunt (Santen, Osaka, Japan) in lowering intraocular pressure (IOP) in childhood glaucoma patients with previous failed glaucoma surgeries. METHODS: This is a prospective case review of consecutive PreserFlo procedures performed in childhood glaucoma patients after failed surgeries. Age, sex, diagnosis, and previous glaucoma surgeries, as well as visual acuity, IOP, and treatment in the preoperative visit and all follow-up visits were collected. Outcome measures included IOP reduction from baseline, mean IOP change from baseline at month 6, medication use at 6 months, complications, adverse events, and need for further procedures. RESULTS: Fourteen patients were included, 8 (57%) males and 6 (43%) females; the mean age was 27.5 ± 13.5 years. Nine patients (64%) had at least two trabeculectomies, and 6 patients (43%) had at least one trabeculectomy and a glaucoma drainage implant. The mean IOP change from baseline was 11.3 ± 4.9 mmHg at 12 months. At 12 months, 12 patients (86%) presented ≥ 20% IOP lowering from baseline, and 11 patients (79%) presented ≥ 30%. The mean medication count decreased from 3.9 ± 0.7 (baseline) to 0.7 ± 1.3 (12 months). No intraoperative complications were reported. No adverse events were noted. No secondary filtration surgery was required, although bleb needling was required in one case, 1 month after the surgery. CONCLUSIONS: PreserFlo with MMC can be used successfully to treat uncontrolled IOP in childhood glaucoma cases with previous failed surgeries. Larger studies with longer follow-up are needed to further explore the role of the device in resistant childhood glaucoma cases.

Development and validation of a model to predict complex Mohs micrographic surgery in clinical practice: REGESMOSH scale.

INTRODUCTION: There is still a need to develop a simple algorithm to identify patients likely to need complex Mohs micrographic surgery (MMS) and optimize MMS schedule. The main objectives of this study are to identify factors associated with a complex MMS and develop a predictor model of the number of stages needed in surgery and the need for a complex closure. MATERIALS AND METHODS: A nationwide prospective cohort study (REGESMOHS, the Spanish Mohs surgery registry) was conducted including all patients with a histological diagnosis of basal cell carcinoma (BCC). Factors related to three or more stages and a complex closure (that needing a flap and/or a graft) were explored and predictive models were constructed and validated to construct the REGESMOSH scale. RESULTS: A total of 5226 patients that underwent MMS were included in the REGESMOHS registry, with 4402 (84%) having a histological diagnosis of BCC. A total of 3689 (88.9%) surgeries only needed one or two stages and 460 (11.1%) required three or more stages. A model to predict the need for three or more stages included tumour dimension, immunosuppression, recurrence, location in risk areas, histological aggressiveness and previous surgery. Regarding the closure type, 1616 (38.8%) surgeries were closed using a non-complex closure technique and 2552 (61.2%) needed a complex closure. A model to predict the need for a complex closure included histological aggressiveness, evolution time, patient age, maximum tumour dimension and location. CONCLUSION: We present a model to predict MMS needing ≥3 stages and a complex closure based on epidemiological and clinical data validated in a large population (with real practice variability) including different centres that could be easily implemented in clinical practice. This model could be used to optimize surgery schedule and properly inform patients about the surgery duration.

Ureteral Stenosis and Fistula after Kidney Transplantation.

INTRODUCTION: Ureteral complications after kidney transplantation are frequent and may have a negative impact on morbidity and graft function. Treatment modalities include conservative, endourological, and surgical techniques, with variable outcomes. The purpose of this study was to report the incidence, characteristics, treatment, and outcomes of ureteral complications at our center. METHODS: Retrospective study of kidney transplants performed at our unit between 2015 and 2020, analyzing incidence, characteristics, treatment, and outcomes of ureteral stenoses and fistulas. RESULTS: Of 648 kidney transplants, we present 3.24% stenosis and 2.16% ureteral fistulas, with a mean time from transplantation of 101.4 and 24.4 days, respectively. Primary treatment was open surgical repair in 52.4% stenosis and 100% fistulas, with a success rate of 90.9% and 71.4%, respectively. Anterograde balloon dilatations were performed in 33.3% of stenosis with 40% success. Three patients required surgery as a secondary approach with 100% success. Major complications (Clavien-Dindo III) were observed in 18.5% following surgical repair. After a mean follow-up of 31.1 ± 20.9 months, we observe 88.6% of functioning grafts. We found no significant differences in graft survival between patients with or without ureteral complications (p 0.948). CONCLUSION: Surgical repair of ureteral complications offers satisfactory results with low associated morbidity. Endourological techniques are less effective and should be reserved for selected cases. With adequate management, there is no impact on graft survival.

Differential response of RTGUTGC and RTGILL-W1 rainbow trout epithelial cell lines to viral stimulation.

Mucosal surfaces constitute the main route of entry of pathogens into the host. In fish, these mucosal tissues include, among others, the gastrointestinal tract, the gills and the skin. However, knowledge about the mechanisms of regulation of immunity in these tissues is still scarce, being essential to generate a solid base that allows the development of prevention strategies against these infectious agents. In this work, we have used the RTgutGC and RTgill-W1 epithelial-like cell lines, derived from the gastrointestinal tract and the gill of rainbow trout (Oncorhynchus mykiss), respectively, to investigate the transcriptional response of mucosal epithelial cells to a viral mimic, the dsRNA poly I:C, as well as to two important viral rainbow trout pathogens, namely viral haemorrhagic septicaemia virus (VHSV) and infectious pancreatic necrosis virus (IPNV). Additionally, we have established how the exposure to poly I:C affected the susceptibility of RTgutGC and RTgill-W1 cells to both viruses. Our results reveal important differences in the way these two cell lines respond to viral stimuli, providing interesting information on these cell lines that have emerged in the past years as useful tools to study mucosal responses in fish.

Hypoxia classifier for transcriptome datasets.

Molecular gene signatures are useful tools to characterize the physiological state of cell populations, but most have developed under a narrow range of conditions and cell types and are often restricted to a set of gene identities. Focusing on the transcriptional response to hypoxia, we aimed to generate widely applicable classifiers sourced from the results of a meta-analysis of 69 differential expression datasets which included 425 individual RNA-seq experiments from 33 different human cell types exposed to different degrees of hypoxia (0.1-5%[Formula: see text]) for 2-48 h. The resulting decision trees include both gene identities and quantitative boundaries, allowing for easy classification of individual samples without control or normoxic reference. Each tree is composed of 3-5 genes mostly drawn from a small set of just 8 genes (EGLN1, MIR210HG, NDRG1, ANKRD37, TCAF2, PFKFB3, BHLHE40, and MAFF). In spite of their simplicity, these classifiers achieve over 95% accuracy in cross validation and over 80% accuracy when applied to additional challenging datasets. Our results indicate that the classifiers are able to identify hypoxic tumor samples from bulk RNAseq and hypoxic regions within tumor from spatially resolved transcriptomics datasets. Moreover, application of the classifiers to histological sections from normal tissues suggest the presence of a hypoxic gene expression pattern in the kidney cortex not observed in other normoxic organs. Finally, tree classifiers described herein outperform traditional hypoxic gene signatures when compared against a wide range of datasets. This work describes a set of hypoxic gene signatures, structured as simple decision tress, that identify hypoxic samples and regions with high accuracy and can be applied to a broad variety of gene expression datasets and formats.

Seeking the Optimal Descriptor for SN2 Reactions through Statistical Analysis of Density Functional Theory Results.

Bimolecular nucleophilic substitution is one of the fundamental reactions in organic chemistry, yet there is still knowledge to be gained on the role of the nucleophile and the substrate. A statistical treatment of over 600 density functional theory (DFT)-computed barriers for bimolecular nucleophilic substitution at methyl derivatives (SN2@C) leads to the identification of numerical descriptors that best represent the entering and leaving ability of 26 different nucleophiles. The treatment is based on singular value decomposition (SVD) of a matrix of computed energy barriers. The current work represents the extension to a problem of reactivity of the hidden descriptor methodology that we had previously developed for the thermodynamic problem of bond dissociation energies in transition-metal complexes. The analysis of the results shows that a single descriptor is sufficient. This hidden descriptor has different values for nucleophilic and leaving abilities and, contrary to expectation, does not correlate especially well with either frontier molecular orbital descriptors or solvation descriptors. In contrast, it correlates with other thermodynamic and geometric parameters. This statistical procedure can be in principle extended to additional chemical fragments and other reactions.

Complications Associated with Mohs Micrographic Surgery: Data from the Nationwide Prospective Cohort REGESMOHS.

BACKGROUND: Large prospective studies on the safety of Mohs micrographic (MMS) surgery are scarce, and most focus on a single type of surgical adverse event. Mid-term scar alterations and functional loss have not been described. OBJECTIVES: To describe the risk of MMS complications and the risk factors for them. METHODS: A nationwide prospective cohort collected all adverse events on consecutive patients in 22 specialised centres. We used multilevel mixed-effects logistic regression to find out factors associated with adverse events. RESULTS: 5,017 patients were included, with 14,421 patient-years of follow-up. 7.0% had some perioperative morbidity and 6.5% had mid-term and scar-related complications. The overall risk of complications was mainly associated with use of antiaggregant/anticoagulant and larger tumours, affecting deeper structures, not reaching a tumour-free border, and requiring complex repair. Age and outpatient setting were not linked to the incidence of adverse events. Risk factors for haemorrhage (0.9%) were therapy with antiaggregant/anticoagulants, tumour size, duration of surgery, and unfinished surgery. Wound necrosis (1.9%) and dehiscence (1.0%) were associated with larger defects and complex closures. Immunosuppression was only associated with an increased risk of necrosis. Surgeries reaching deeper structures, larger tumours and previous surgical treatments were associated with wound infection (0.9%). Aesthetic scar alterations (5.4%) were more common in younger patients, with larger tumours, in H-area, and in flap and complex closures. Risk factors for functional scar alterations (1.7%) were the need for general anaesthesia, larger tumours that had received previous surgery, and flaps or complex closures. CONCLUSIONS: MMS shows a low risk of complications. Most of the risk factors for complications were related to tumour size and depth, and the resulting need for complex surgery. Antiaggregant/anticoagulant intake was associated with a small increase in the risk of haemorrhage, that probably does not justify withdrawal. Age and outpatient setting were not linked to the risk of adverse events.

Is hysterosalpingo-foam sonography (HyFoSy) more tolerable in terms of pain and anxiety than hysterosalpingography (HSG)? A prospective real-world setting multicentre study.

BACKGROUND: In 60% of sterile couples a female factor is present, with these being tubal factors in 30-50% of cases. A tubal patency test is also required in women without a male partner undergoing fertility treatment. Thus, an accurate, safe and tolerable technique should be available. The aim of this study is to determine and to compare hysterosalpingo-foam sonography (HyFoSy) and hysterosalpingography (HSG) tolerability in terms of pain and anxiety. METHODS: This is a prospective real-world setting multicentre study conducted in two tertiary hospitals in Madrid. 210 infertile women/women without a male partner looking to get pregnant were recruited; 111 for the HyFoSy group and 99 for the HSG group. Tolerability was measured in terms of anxiety by the State Trait Anxiety Inventory (STAI) and pain by the Visual Analogue Scale (VAS). RESULTS: Median VAS score in HyFoSy group was 2 (P25; P75: 1; 3) versus 5 (4; 8) in HSG group, p < 0.001. The median State-STAI score in the HSG group was 18 points (10; 26) versus 10 (7; 16) in the HyFoSy group (p < 0.001); the median Trait-STAI score in the HSG group was 15 (11; 21) versus 13 (9; 17) in the HyFoSy group (p = 0.044). CONCLUSIONS: HyFoSy shows higher tolerability to both: pain and anxiety. It is related to less pain and less post-test anxiety than HSG.

Genetics and Epigenetics of Bone Remodeling and Metabolic Bone Diseases.

Bone metabolism consists of a balance between bone formation and bone resorption, which is mediated by osteoblast and osteoclast activity, respectively. In order to ensure bone plasticity, the bone remodeling process needs to function properly. Mesenchymal stem cells differentiate into the osteoblast lineage by activating different signaling pathways, including transforming growth factor ß (TGF-ß)/bone morphogenic protein (BMP) and the Wingless/Int-1 (Wnt)/ß-catenin pathways. Recent data indicate that bone remodeling processes are also epigenetically regulated by DNA methylation, histone post-translational modifications, and non-coding RNA expressions, such as micro-RNAs, long non-coding RNAs, and circular RNAs. Mutations and dysfunctions in pathways regulating the osteoblast differentiation might influence the bone remodeling process, ultimately leading to a large variety of metabolic bone diseases. In this review, we aim to summarize and describe the genetics and epigenetics of the bone remodeling process. Moreover, the current findings behind the genetics of metabolic bone diseases are also reported.