Biology subjects

Gonzalez, J.

Publications and source records attributed to Gonzalez, J..

At least 73 records · Page 4Linked to original sources

bioRxiv2021

Chemotherapy induces a YAP1-dependent fetal conversion to human Colorectal Cancer cells that is predictive of poor patient outcome

Current therapy against colorectal cancer is based on DNA-damaging agents that eradicate highly proliferative malignant cells. Whether sublethal chemotherapy affects tumor cell behavior and impacts on patient outcome is primarily unstudied. We now show that sublethal chemotherapy imposes a quiescent-like state to p53 wildtype human colorectal cancer (CRC) cells that is linked to the acquisition of a fetal phenotype downstream of YAP1, similar to that observed after intestinal damage. CRC cells displaying this fetal phenotype exhibit tumor- initiating activity comparable to untreated cells but superior metastatic capacity. Notably, nuclear YAP1 accumulation, or detection of the fetal signature in tumors predict poor prognosis in CRC patients carrying p53 wildtype tumors. Collectively, our results uncover a potential adverse response of tumor cells to suboptimal chemotherapy, and identify nuclear YAP1 and fetal conversion of colorectal tumors as biomarkers for prognosis and therapy prescription. Statement of significanceChemotherapy induces a quiescent-like phenotype to colorectal cancer cells that is linked to the acquisition of a YAP1-dependent fetal signature. Notably, this signature is predictive of patient outcome in different cohorts of human colorectal cancer.

cancer biology↗

bioRxiv2021

Note: Updating the metadata of four misidentified samples in the DrosRTEC dataset

This note details the consortiums rationale behind its decision to modify the metadata for putatively misidentified European samples in the DrosRTEC dataset. In brief, we use PCA on published datasets from North America and Europe to generate phylogeographic clusters reflective of worldwide D. melanogaster demography. We used this PCA to train a DAPC model in order the predict the group membership. Our results indicate that 4 out of 73 samples were misclassified and the metadata was updated accordingly. These samples are a spring-fall pair from Spain and Austria.

genomics↗

bioRxiv2020

Impact of transposable elements on the genome of the urban malaria vector Anopheles coluzzii

AO_SCPLOWBSTRACTC_SCPLOWO_ST_ABSBackgroundC_ST_ABSAnopheles coluzzii is one of the primary vectors of human malaria in sub-Saharan Africa. Recently, it has colonized the main cities of Central Africa threatening vector control programs. The adaptation of An. coluzzii to urban environments is partly due to an increased tolerance to organic pollution and insecticides. While some of the molecular mechanisms for ecological adaptation, including chromosome rearrangements and introgressions, are known, the role of transposable elements (TEs) in the adaptive processes of this species has not been studied yet. To assess the role of TEs in rapid urban adaptation, the first step is to accurately annotate TE insertions in the genomes of natural populations collected in urban settings. ResultsWe sequenced using long-reads six An. coluzzii genomes from natural breeding sites in two major Central Africa cities. We de novo annotated the complete set of TEs in these genomes and in an additional high-quality An. coluzzii genome available and identified 64 previously undescribed TE families. TEs were non-randomly distributed throughout the genome with significant differences in the number of insertions of several superfamilies across the studied genomes. We identified seven putatively active families with insertions near genes with functions related to vectorial capacity. Moreover, we identified several TE insertions providing promoter and transcription factor binding sites to insecticide resistance and immune-related genes. ConclusionsThe analysis of multiple genomes sequenced using long-read technologies allowed us to generate the most comprehensive TE annotations in this species to date. We identified several TE insertions that could potentially impact both genome architecture and the regulation of functionally relevant genes in An. coluzzii. These results provide a basis for future studies of the impact of TEs on the biology of An. coluzzii.

genomics↗

bioRxiv2020

Could TDX-1 explain the changes observed in endocrine pancreas due to chronic cola drink consumption in rats? A global point of view

In previous studies, we reported evidence showing that chronic cola consumption in rats impairs pancreatic metabolism of insulin and glucagon and produces some alterations typically observed in the metabolic syndrome (i.e, hyperglycemia, and hypertriglyceridemia) with an increase in oxidative stress. Of note, no apoptosis nor proliferation of islet cells could be demonstrated. In the present study, 36 male Wistar rats were divided in three groups to freely drink regular cola, light cola, or water (controls). We assessed the impact of the three different beverages in glucose tolerance, lipid levels, creatinine levels and immunohistochemical changes addressed for the expression of insulin, glucagon, PDX-1 and NGN3 in islet cells, to evaluate the possible participation of PDX-1 in the changes observed in and {beta} cells after 6 months of treatment. On the other hand, we assessed by stereological methods, the mean volume of islets (Vi) and three important variables, the fractional {beta}-cell area, the cross-sectional area of alpha (A -cell) and beta cells (A {beta}-cell), and the number of {beta} and cell per body weight. Cola drinking caused impaired glucose tolerance as well as fasting hyperglycemia and increase of insulin immunolabeling. Immunohistochemical expression for PDX-1 was significantly high in regular cola consumption group compared to control. In this case, we observed cytoplasmatic and nuclear localization. Likewise, a mild but significant decrease of Vi was detected after 6 months of cola drink consumption compared with control group. Also, we observed a significant decrease of fractional {beta} cell area compared with control rats. Accordingly, a reduced mean value of islet and {beta} cell number per body weight compared to control was detected. Interestingly, consumption of light cola increased the Vi compared to control. In line with this, a decreased cross-sectional area of {beta}-cells was observed after chronic consumption of both, regular and light cola, compared to controls. On the other hand, NGN3 was negative in all three groups. Our results support for the first time, the idea that TDX-1 plays a key role in the dynamics of the pancreatic islets after chronic consumption of sweetened beverages. The loss of islets cells might be attributed to autophagy, favored by the local metabolic conditions.

systems biology↗

bioRxiv2020

Glutamatergic neurons in the preoptic hypothalamus promote wakefulness, destabilize NREM sleep, suppress REM sleep, and regulate cortical dynamics

Clinical and experimental data from the last nine decades indicate that the preoptic area of the hypothalamus is a critical node in a brain network that controls sleep onset and homeostasis. By contrast, we recently reported that a group of glutamatergic neurons in the lateral and medial preoptic area increases wakefulness, challenging the long-standing notion in sleep neurobiology that the preoptic area is exclusively somnogenic. However, the precise role of these subcortical neurons in the control of behavioral state transitions and cortical dynamics remains unknown. Therefore, in this study we used conditional expression of excitatory hM3Dq receptors in these preoptic glutamatergic (Vglut2+) neurons and show that their activation initiates wakefulness, decreases non-rapid eye movement (NREM) sleep, and causes a persistent suppression of rapid eye movement (REM) sleep. Activation of preoptic glutamatergic neurons also causes a high degree of NREM sleep fragmentation, promotes state instability with frequent arousals from sleep, and shifts cortical dynamics (including oscillations, connectivity, and complexity) to a more wake-like state. We conclude that a subset of preoptic glutamatergic neurons may initiate -but not maintain- arousals from sleep, and their inactivation may be required for NREM stability and REM sleep generation. Further, these data provide novel empirical evidence supporting the conclusion that the preoptic area causally contributes to the regulation of both sleep and wakefulness.

neuroscience↗

bioRxiv2020

The discovery, distribution and diversity of DNA viruses associated with Drosophila melanogaster in Europe

Drosophila melanogaster is an important model for antiviral immunity in arthropods, but very few DNA viruses have been described from the family Drosophilidae. This deficiency limits our opportunity to use natural host-pathogen combinations in experimental studies, and may bias our understanding of the Drosophila virome. Here we report fourteen DNA viruses detected in a metagenomic analysis of approximately 6500 pool-sequenced Drosophila, sampled from 47 European locations between 2014 and 2016. These include three new Nudiviruses, a new and divergent Entomopox virus, a virus related to Leptopilina boulardi filamentous virus, and a virus related to Musca domestica salivary gland hypertrophy virus. We also find an endogenous genomic copy of Galbut virus, a dsRNA Partitivirus, segregating at very low frequency. Remarkably, we find that Drosophila Vesanto virus, a small DNA virus previously described as a Bidnavirus, may be composed of up to 12 segments and represent a new lineage of segmented DNA viruses. Two of the DNA viruses, Drosophila Kallithea nudivirus and Drosophila Vesanto virus are relatively common, found in 2% or more of wild flies. The others are rare, with many likely to be represented by a single infected fly. We find that virus prevalence in Europe reflects the prevalence seen in publicly-available datasets, with Drosophila Kallithea nudivirus and Drosophila Vesanto virus the only ones commonly detectable in public data from wild-caught flies and large population cages, and the other viruses being rare or absent. These analyses suggest that DNA viruses are at lower prevalence than RNA viruses in D. melanogaster, and may be less likely to persist in laboratory cultures. Our findings go some way to redressing an earlier bias toward RNA virus studies in Drosophila, and lay the foundation needed to harness the power of Drosophila as a model system for the study of DNA viruses.

microbiology↗

bioRxiv2020

Humoral response to SARS-CoV-2 by healthy and sick dogs during COVID-19 pandemic in Spain.

COVID-19 is a zoonotic disease originated by SARS-CoV-2. Infection of animals with SARS-CoV-2 are being reported during last months, and also an increase of severe lung pathologies in domestic dogs has been detected by veterinarians in Spain. Therefore it is necessary to describe the pathological processes in those animals that show symptoms similar to those described in humans affected by COVID-19. The potential for companion animals contributing to the continued human-to-human disease, infectivity, and community spread is an urgent issue to be considered. Forty animals with pulmonary pathologies were studied by chest X-ray, ultrasound study, and computed tomography. Nasopharyngeal and rectal swab were analyzed to detect canine pathogens, including SARS-CoV-2. Twenty healthy dogs living in SARS-CoV-2 positive households were included. Immunoglobulin detection by different immunoassays was performed. Our findings show that sick dogs presented severe alveolar or interstitial pattern, with pulmonary opacity, parenchymal abnormalities, and bilateral lesions. Forty dogs were negative for SARS-CoV-2 but Mycoplasma spp. was detected in 26 of 33 dogs. Five healthy and one pathological dog presented IgG against SARS-CoV-2. Here we report that despite detecting dogs with IgG -SARS-CoV-2, we never obtained a positive RT-qPCR, not even in dogs with severe pulmonary disease; suggesting that even in the case of a canine infection transmission would be unlikely. Moreover, dogs living in COVID-19 positive households could have been more exposed to be infected during outbreaks.

microbiology↗

bioRxiv2020

Power and coherence in the EEG of the rat: impact of behavioral states, cortical area, lateralization and light/dark phases

The sleep-wake cycle is constituted by three behavioral states: wakefulness (W), non-REM (NREM) and REM sleep. These states are associated with drastic changes in cognitive capacities, mostly determined by the function of the thalamo-cortical system. Thalamo-cortical activity can be examined by means of the intra-cranial electroencephalogram (iEEG). With the purpose to study in depth the basal activity of the iEEG in adult rats, we analyzed the spectral power and coherence of the iEEG during W and sleep in the paleocortex (olfactory bulb), as well as in motor, somatosensory and visual neocortical areas. We also analyzed the laterality (right Vs. left hemispheres) of the signals, as well as the iEEG in function of the light and dark phases. We found that the iEEG power and coherence of the whole spectrum were largely affected by behavioral states and were highly dependent on the cortical areas recorded. We also determined that there are night/day differences in power and coherence during sleep, but not in W. Finally, while we did not find right/left differences in power either in W or sleep, we observed that during REM sleep intra-hemispheric coherence differs between both hemispheres. We conclude that the iEEG dynamics is highly dependent on the cortical area and behavioral states. We also determine that there are light/dark phases disparities in the iEEG that emerge during sleep, and that intra-hemispheric connectivity differs between both hemispheres only during REM sleep.

neuroscience↗

bioRxiv2020

Identification of a long non-coding RNA regulator of liver carcinoma cell survival

ABSTRACTGenomic studies have significantly improved our understanding of hepatocellular carcinoma (HCC) biology and have led to the discovery of multiple protein-coding genes driving hepatocarcinogenesis. In addition, these studies have identified thousands of new non-coding transcripts deregulated in HCC. We hypothesize that some of these transcripts may be involved in disease progression. Long non-coding RNAs are a large class of non-coding transcripts which participate in the regulation of virtually all cellular functions. However, a majority of lncRNAs remain dramatically understudied. Here, we applied a pooled shRNA-based screen to identify lncRNAs essential for HCC cell survival. We validated our screening results using RNAi, CRISPRi, and antisense oligonucleotides. We found a lncRNA, termed ASTILCS, that is critical for HCC cell growth and is overexpressed in tumors from HCC patients. We demonstrated that HCC cell death upon ASTILCS knockdown is associated with apoptosis induction and downregulation of a neighboring gene, Protein Tyrosine Kinase 2 (PTK2), a crucial protein for HCC cell survival. Taken together, our study describes a new, non-coding RNA regulator of HCC.Competing Interest StatementThe authors have declared no competing interest.View Full Text

cancer biology↗

bioRxiv2020

Gamma band alterations and REM-like traits underpin the acute effect of the atypical psychedelic ibogaine

Ibogaine is a psychedelic alkaloid that has attracted scientific interest because of its important antiaddictive properties evidenced in observational studies in humans, and in models for substance-use-disorders in rodents. Its subjective effect has been described as intense vivid dream-like experiences occurring while awake; hence, ibogaine is often referred to as an oneirogenic psychedelic. While this unique dream-like profile has been hypothesized to aid the antiaddictive effects in the past, the electrophysiological signatures of the ibogaine psychedelic state remain unknown. In our previous work, we showed in rats that ibogaine administration promotes a waking state with abnormal motor behavior, accompanied by a decrease in NREM and REM sleep. Here, we performed an in-depth analysis of the intracranial electroencephalogram during "ibogaine wakefulness". Ibogaine induced gamma oscillations with larger power than control levels but less coherent and less complex; i.e., this state shows clear REM sleep traits within the gamma frequency band. Thus, our results provide novel biological evidence for the association between the psychedelic state and REM sleep, and an empirical basis for the oneirogenic conjecture of ibogaine.

neuroscience↗

bioRxiv2020

The loss of the pyoverdine secondary receptor in Pseudomonas aeruginosa results in a fitter strain suitable for population invasion

The rapid emergence of antibiotic resistant bacterial pathogens constitutes a critical problem in healthcare and requires the development of novel treatments. Potential strategies include the exploitation of microbial social interactions based on public goods, which are produced at a fitness cost by cooperative microorganisms, but can be exploited by cheaters that do not produce these goods. Cheater invasion has been proposed as a Trojan horse approach to infiltrate pathogen populations with strains deploying built-in weaknesses (e.g. sensitiveness to antibiotics). However, previous attempts have been often unsuccessful because population invasion by cheaters was prevented by various mechanisms including the presence of spatial structure (e.g. growth in biofilms), which limits the diffusion and exploitation of public goods. Here we followed an alternative approach and examined whether the manipulation of public good uptake and not its production could result in potential Trojan horses suitable for population invasion. We focused on the siderophore pyoverdine produced by the human pathogen Pseudomonas aeruginosa MPAO1 and manipulated its uptake by deleting and/or overexpressing the pyoverdine primary (FpvA) and secondary (FpvB) receptors. We found that receptor synthesis feeds back on pyoverdine production and uptake rates, which led to strains with altered pyoverdine-associated costs and benefits. Moreover, we found that the receptor FpvB was advantageous under iron-limited conditions but revealed hidden costs in the presence of an antibiotic stressor (gentamicin). As a consequence, FpvB mutants became the fittest strain under gentamicin exposure, displacing the wildtype in liquid cultures, and in biofilms and during infections of the wax moth larvae Galleria mellonella, which both represent structured environments. Our findings reveal that an evolutionary trade-off associated with the costs and benefits of a versatile pyoverdine uptake strategy can be harnessed for devising a Trojan horse candidate for medical interventions.

microbiology↗

bioRxiv2020

Communication through coherence by means of cross-frequency coupling

The theory of communication through coherence (CTC) posits the synchronization of brain oscillations as a key mechanism for information sharing and perceptual binding. In a parallel literature, hippocampal theta activity (4 - 10 Hz) has been shown to modulate the appearance of neocortical fast gamma oscillations (100 - 150 Hz), a phenomenon known as cross-frequency coupling (CFC). Even though CFC has also been previously associated with information routing, it remains to be determined whether it directly relates to CTC. In particular, for the theta-fast gamma example at hand, a critical question is to know if the phase of the theta cycle influences gamma synchronization across the neocortex. To answer this question, we designed a new screening method for detecting the modulation of the cross-regional high-frequency synchronization by the phase of slower oscillations. Upon applying the method, we found that the long-distance synchronization of neocortical fast gamma during REM sleep depends on the instantaneous phase of the theta rhythm. These results show that CFC is likely to aid long-range information transfer by facilitating the cross-regional synchronization of faster rhythms, thus consistent with classical CTC views.

neuroscience↗

bioRxiv2020

Electrocortical temporal complexity during wakefulness and sleep: an updated account

The states of sleep and wakefulness are critical physiological processes associated with different brain patterns of activity. The intracranial electroencephalogram allows us to measure these changes, thus, it is a critical tool for its study. Recently, we showed that the electrocortical temporal complexity decreased from wakefulness to sleep. Nevertheless, the origin of this complex activity remains a controversial topic due to the existence of possible artifacts contaminating the brain signals. In this work, we showed that complexity decreases during sleep, independently of the electrode configuration employed. This fact strongly suggests that the basis for the behavioral-state differences in complexity does not have an extracranial origin; i.e., generated from the brain.

neuroscience↗

bioRxiv2019

Genomic adaptations to aquatic and aerial life in mayflies and the origin of wings in insects

The first winged insects underwent profound morphological and functional transformations leading to the most successful animal radiations in the history of earth. Despite this, we still have a very incomplete picture of the changes in their genomes that underlay this radiation. Mayflies (Ephemeroptera) are one of the extant sister groups of all other winged insects and therefore are at a key phylogenetic position to understand this radiation. Here, we describe the genome of the cosmopolitan mayfly Cloeon dipterum and study its expression along development and in specific organs. We discover an expansion of odorant-binding proteins, some expressed specifically in the breathing gills of aquatic nymphs, suggesting a novel sensory role for gills. In contrast, as flying adults, mayflies make use of an enlarged set of opsins and utilise these visual genes in a sexually dimorphic manner, with some opsins expressed only in males. Finally, to illuminate the origin of wings, we identify a core set of deeply conserved wing-specific genes at the root of the pterygote insects. Globally, this is the first comprehensive study of the structure and expression of the genome of a paleopteran insect and shows how its genome has kept a record of its functional adaptations.

evolutionary biology↗

bioRxiv2019

Applying Nanopore sequencing to a One-Health scenario for colistin resistance transmission among pigs, cows and the farmer

One-Health studies applying massive-parallel and single-molecule sequencing are a suitable approximation to try to understand how antibiotic resistances flow between the human-animal-environment scenario. Colistin has been withdrawn in human medicine due to its toxicity, limiting its usage as a last-resort treatment option for multidrug-resistant Gram-negative bacteria. However, it is still used orally to treat Enterobacteriaceae infections in veterinary medicine. Since 2015, colistin resistance appeared to be located in mobile genetic elements, raising the concern of the likelihood of transmission by horizontal gene transfer between animals and humans. In this study, 202 faecal samples were collected in a mixed farm from pigs, calves, and the farmer. PCR for the mcr-1 gene was positive for 18 of the isolates, and Nanopore sequencing allowed us to determine the location of the gene, either on the chromosome or in plasmids. Three types of replicons were found within the positive isolates harbouring the mcr-1: IncX4, IncI2, and IncHI2. Four different genetic contexts probably indicate different stages of gene stabilization, either in the chromosome or plasmid, with ISApl1 as the main insertion element flanking the gene. Moreover, 43 other resistance genes were found in our samples, related to more than six different antibiotic families (e.g. aminoglycosides, lincosamides, beta-lactams, macrolides, trimethoprim, phenicols, and sulphonamides). We found resistance genes against colistin and that six antibiotic families together in at least one of the isolates from human, swine, and bovine. Isolate 15B-22 harboured one plasmid with seven resistance genes related to four families of antibiotics other than polymyxins, meaning that there are more chances to maintain colistin resistance even with the withdrawn of colistin. Nanopore long reads allowed us to assemble the DNA elements within the isolates easily and determine the genetic context of the mcr-1 gene. Furthermore, they allowed us to describe and locate more antimicrobial resistance genes to other antibiotic families and antiseptic compounds.

microbiology↗

bioRxiv2019

First fossil skull of an anteater (Vermilingua, Myrmecophagidae) from northern South America, a taxonomic reassessment of Neotamandua and a discussion of the myrmecophagid diversification

The evolutionary history of the South American anteaters, Vermilingua, is incompletely known as consequence of the fragmentary and geographically biased nature of the fossil record of this group. Neotamandua borealis is the only recorded extinct species from northern South America, specifically from the Middle Miocene of La Venta area, southwestern Colombia. A new genus and species of myrmecophagid for La Venta, Gen. et sp. nov., is here described based on a new partial skull. Additionally, given that the co-occurrent species of Gen. et sp. nov., N. borealis, was originally referred to as Neotamandua, the taxonomic status of this genus is revised. The morphological and taxonomic analyses of these taxa indicate that Gen. et sp. nov. may be related to Tamandua and that the justification of the generic assignments of the species referred to as Neotamandua is weak or insufficient. Two species previously referred to as Neotamandua (N. magna and N.? australis) were designated as species inquirendae and new diagnostic information for the redefined genus and its type species, N. conspicua, is provided. Together, these results suggest that the diversification of Myrmecophagidae was taxonomically and biogeographically more complex than what has been proposed so far. Considering the new evidence, it is proposed a synthetic model on the diversification of these xenartrans during the late Cenozoic based on the probable relationships between their intrinsic ecological constraints and some major abiotic changes in the Americas.

paleontology↗

bioRxiv2019

Historical recombination variability contributes to deciphering the genetic basis of phenotypic traits

Recombination is a main source of genetic variability. However, the potential role of the variation generated by recombination in phenotypic traits, including diseases, remains unexplored as there is currently no method to infer chromosomal subpopulations based on recombination patterns differences. We developed recombClust, a method that uses SNP-phased data to detect differences in historic recombination in a chromosome population. We validated our method by performing simulations and by using real data to accurately predict the alleles of well known recombination modifiers, including common inversions in Drosophila melanogaster and human, and the chromosomes under selective pressure at the lactase locus in humans. We then applied recombClust to the complex human 1q21.1 region, where nonallelic homologous recombination produces deleterious phenotypes. We discovered and validated the presence of two different recombination histories in these regions that significantly associated with the differential expression of ANKRD35 in whole blood and that were in high linkage with variants previously associated with hypertension. By detecting differences in historic recombination, our method opens a way to assess the influence of recombination variation in phenotypic traits.

bioinformatics↗

bioRxiv2019

Lipid metabolism links nutrient-exercise timing to insulin sensitivity in men classified as overweight or obese.

ContextPre-exercise nutrient availability alters acute metabolic responses to exercise, which could modulate training responsiveness. We hypothesised that in men with overweight/obesity, acute exercise before versus after nutrient ingestion would increase whole-body and intramuscular lipid utilization, translating into greater increases in oral glucose insulin sensitivity over 6-weeks of training.\n\nDesign and ParticipantsWe showed in men with overweight/obesity (mean{+/-}SD for BMI: 30.2{+/-}3.5 kgxm-2 for acute, crossover study, 30.9{+/-}4.5 kgxm-2 for randomized, controlled, training study) a single exercise bout before versus after nutrient provision increased lipid utilisation at the whole-body level, but also in both type I (p<0.01) and type II muscle fibres (p=0.02). We then used a 6-week training intervention to show sustained, 2-fold increases in lipid utilisation with exercise before versus after nutrient provision (p<0.01).\n\nMain Outcome MeasuresPostprandial glycemia was not differentially affected by exercise training before vs after nutrient provision (p>0.05), yet plasma was reduced with exercise training before, but not after nutrient provision (p=0.03), resulting in increased oral glucose insulin sensitivity when training was performed before versus after nutrient provision (25{+/-}38 vs -21{+/-}32 mLxmin-1xm-2; p=0.01) and this was associated with increased lipid utilisation during exercise (r=0.50, p=0.02). Regular exercise prior to nutrient provision augmented remodelling of skeletal muscle phospholipids and protein content of the glucose transport protein GLUT4 (p<0.05).\n\nConclusionsExperiments investigating exercise training and metabolic health should consider nutrient-exercise timing, and exercise performed before versus after nutrient intake (i.e., in the fasted state) may exert beneficial effects on lipid utilisation and reduce postprandial insulinemia.\n\nPrecisExercise in the fasted-versus fed-state increased intramuscular and whole-body lipid use, translating into increased muscle adaptation and insulin sensitivity when regularly performed over 6 weeks.

physiology↗