Time-series transcriptomics and proteomics reveal alternative modes to decode p53 oscillations.

The cell stress-responsive transcription factor p53 influences the expression of its target genes and subsequent cellular responses based in part on its dynamics (changes in level over time). The mechanisms decoding p53 dynamics into subsequent target mRNA and protein dynamics remain unclear. We systematically quantified p53 target mRNA and protein expression over time under two p53 dynamical regimes, oscillatory and rising, using RNA-sequencing and TMT mass spectrometry. Oscillatory dynamics allowed for a greater variety of dynamical patterns for both mRNAs and proteins. Mathematical modeling of empirical data revealed three distinct mechanisms that decode p53 dynamics. Specific combinations of these mechanisms at the transcriptional and post-transcriptional levels enabled exclusive induction of proteins under particular dynamics. In addition, rising induction of p53 led to higher induction of proteins regardless of their functional class, including proteins promoting arrest of proliferation, the primary cellular outcome under rising p53. Our results highlight the diverse mechanisms cells employ to distinguish complex transcription factor dynamics to regulate gene expression.

Severity of gastrointestinal bleeding is similar between patients receiving direct oral anticoagulants or vitamin K antagonists.

BACKGROUND: Gastrointestinal bleeding (GIB) is a common adverse event related to anticoagulation therapy. However, evidence comparing the severity, etiology and outcome of GIB in patients taking direct oral anticoagulants (DOAC) vs. vitamin K antagonists (VKA) is scarce. AIMS: To evaluate the severity, etiology and outcomes of GIB in patients under DOACs compared to VKA. METHODS: Patients under oral anticoagulant therapy admitted to the emergency department with acute GIB were prospectively recruited from July 2016 to January 2018 at a tertiary referral hospital. Demographic and clinical outcome were obtained from medical records. Severity of the GIB event was classified as mild, major or severe according to clinical presentation and the type of support needed. Etiology and location of bleeding, number of packed red blood cells transfused (PRBC) and length of hospital stay were recorded until discharge or in-hospital death. RESULTS: A total of 208 patients with acute GIB under oral anticoagulant treatment were recruited: 119 patients were on VKA and 89 patients on DOAC with similar characteristics. Thirty-one patients had severe GIB; 134 major and 43 mild, with no differences in severity, number of PRBC and length of hospital stay between the groups. Peptic disease was the most frequent etiology of GIB in patients on VKA (20.2 % vs. 13.6%, p=0.20). Diverticular bleeding was the most frequent adverse event in patients on DOAC (14.3% vs. 24.8%, p= 0.056). CONCLUSIONS: Severity and clinical outcomes of GIB are similar between patients on DOAC and patients on VKA, regardless of etiology of GIB.

Delayed introduction of sirolimus in paediatric intestinal transplant recipients: indications and long-term benefits.

To review our experience using sirolimus in a single centre paediatric intestinal transplantation cohort. Intestinal transplant patients with more than 3 months follow-up were divided into two groups according to their immunosuppression regimen: tacrolimus, (TAC group, n = 45 grafts) or sirolimus (SRL group, n = 38 grafts), which included those partially or completely converted from tacrolimus to sirolimus. The indications to switch were tacrolimus side effects and immunological complications. Survival and complications were retrospectively analysed comparing both groups. SRL was introduced 9 months (0 months-16.9 years) after transplant. The main cause for conversion was worsening renal function (45%), followed by haemolytic anaemia (21%) and graft-versus-host-disease (16%). Both groups showed a similar overall patient/graft survival (P = 0.76/0.08) and occurrence of rejection (24%/17%, P = 0.36). Immunological complications did not recur after conversion. Renal function significantly improved in most SRL patients. After a median follow-up of 65.17 months, 28/46 survivors were on SRL, 26 with monotherapy, with good graft function. Over one-third of our patients eventually required SRL conversion that allowed to improve their kidney function and immunological events, without entailing additional complications or survival impairment. Further trials are warranted to clarify the potential improvement of the standard tacrolimus maintenance by sirolimus conversion or addition.

Long-term follow-up of olfactory and gustatory dysfunction in COVID-19: 6 months case-control study of health workers.

PURPOSE: The study aimed to determine the incidence and long-term evolution of COVID-related olfactory (OD) and gustatory (GD) dysfunction, the recovery timeline, and the association with other symptoms. The secondary objective was to identify the predictive clinical factors for the evolution of these symptoms. METHODS: A prospective case-control study was conducted from March 15 to October 15, 2020, in health workers with COVID-19 related symptoms in a tertiary care hospital. 320 patients were included after 6 months of follow-up: 195 in the case group and 125 in the control group. Olfactory dysfunction (OD), dysosmia, and gustatory dysfunction (GD) onset and recovery rate after 6 months follow-up are analyzed in both groups. RESULTS: There were 125 (64.1%) in case group patients with OD and 118 (60.5%) with GD. Total or partial recovery OD and GD was found in 89%, mainly in the first 2 months. In the control group, there were 14 (11.2%) patients with OD and 33 (26.4%) patients with GD, with 100% of total/partial recovery. CONCLUSION: In both groups, OD and GD showed high-resolution rates during the first two months after the onset of symptoms. Nevertheless, 11% of the case group patients did not show any recovery, and the partial resolution was present in 30% of our patients, at the 6 months follow-up. We found a high correlation between OD and GD, both in the appearance of symptoms and in their recovery. Nasal obstruction and dyspnea have been identified as risk factors for the persistence of symptoms.

Synthetic circuits reveal how mechanisms of gene regulatory networks constrain evolution.

Phenotypic variation is the raw material of adaptive Darwinian evolution. The phenotypic variation found in organismal development is biased towards certain phenotypes, but the molecular mechanisms behind such biases are still poorly understood. Gene regulatory networks have been proposed as one cause of constrained phenotypic variation. However, most pertinent evidence is theoretical rather than experimental. Here, we study evolutionary biases in two synthetic gene regulatory circuits expressed in Escherichia coli that produce a gene expression stripe-a pivotal pattern in embryonic development. The two parental circuits produce the same phenotype, but create it through different regulatory mechanisms. We show that mutations cause distinct novel phenotypes in the two networks and use a combination of experimental measurements, mathematical modelling and DNA sequencing to understand why mutations bring forth only some but not other novel gene expression phenotypes. Our results reveal that the regulatory mechanisms of networks restrict the possible phenotypic variation upon mutation. Consequently, seemingly equivalent networks can indeed be distinct in how they constrain the outcome of further evolution.

Mueller matrix study of the dichroism in nanorods dimers: rod separation effects.

We have studied the optical response of chiral metastructures composed of a disordered array of couples of plasmonic Au nanorods helically piled along the vertical direction. The fabrication is based on the use of multiaxial and multimaterial evaporation of the different metastructure building blocks through nanohole masks. From the analysis of the Mueller Matrix elements of the system, obtained both experimentally and from dedicated numerical simulations in forward and backward illumination conditions, we have been able to determine the linear and circular dichroic response of the system, as well as to sort out the optical anisotropy and intrinsic circular dichroism contributions to the circular differential extinction. We have also analyzed the dependence of the optical properties as a function of the angle between the rods and of the thickness of the dielectric separator. The study of quasi-planar as well as three-dimensional structures allows unraveling the role played by interactions between the constituting building blocks and, in particular, the distance between rods. We have experimentally and theoretically observed a decrease of the circular dichroic contribution and a change of the optical anisotropic contribution when the structures evolve from non-planar to planar.

A spectrum of modularity in multi-functional gene circuits.

A major challenge in systems biology is to understand the relationship between a circuit's structure and its function, but how is this relationship affected if the circuit must perform multiple distinct functions within the same organism? In particular, to what extent do multi-functional circuits contain modules which reflect the different functions? Here, we computationally survey a range of bi-functional circuits which show no simple structural modularity: They can switch between two qualitatively distinct functions, while both functions depend on all genes of the circuit. Our analysis reveals two distinct classes: hybrid circuits which overlay two simpler mono-functional sub-circuits within their circuitry, and emergent circuits, which do not. In this second class, the bi-functionality emerges from more complex designs which are not fully decomposable into distinct modules and are consequently less intuitive to predict or understand. These non-intuitive emergent circuits are just as robust as their hybrid counterparts, and we therefore suggest that the common bias toward studying modular systems may hinder our understanding of real biological circuits.

Holographic Phonons.

We present a class of holographic massive gravity models that realize a spontaneous breaking of translational symmetry-they exhibit transverse phonon modes whose speed relates to the elastic shear modulus according to elasticity theory. Massive gravity theories thus emerge as versatile and convenient theories to model generic types of translational symmetry breaking: explicit, spontaneous, and a mixture of both. The nature of the breaking is encoded in the radial dependence of the graviton mass. As an application of the model, we compute the temperature dependence of the shear modulus and find that it features a glasslike melting transition.

Dynamics of gene circuits shapes evolvability.

To what extent does the dynamical mechanism producing a specific biological phenotype bias the ability to evolve into novel phenotypes? We use the interpretation of a morphogen gradient into a single stripe of gene expression as a model phenotype. Although there are thousands of three-gene circuit topologies that can robustly develop a stripe of gene expression, the vast majority of these circuits use one of just six fundamentally different dynamical mechanisms. Here we explore the potential for gene circuits that use each of these six mechanisms to evolve novel phenotypes such as multiple stripes, inverted stripes, and gradients of gene expression. Through a comprehensive and systematic analysis, we find that circuits that use alternative mechanisms differ in the likelihood of reaching novel phenotypes through mutation. We characterize the phenotypic transitions and identify key ingredients of the evolutionary potential, such as sensitive interactions and phenotypic hubs. Finally, we provide an intuitive understanding on how the modular design of a particular mechanism favors the access to novel phenotypes. Our work illustrates how the dynamical mechanism by which an organism develops constrains how it can evolve. It is striking that these dynamical mechanisms and their impact on evolvability can be observed even for such an apparently simple patterning task, performed by just three-node circuits.

Surface States in Holographic Weyl Semimetals.

We study the surface states of a strongly coupled Weyl semimetal within holography. By explicit numerical computation of an inhomogeneous holographic Weyl semimetal, we observe the appearance of an electric current restricted to the surface in the presence of an electric chemical potential. The integrated current is universal in the sense that it only depends on the topology of the phases showing that the bulk-boundary correspondence holds even at strong coupling. The implications of this result are subtle and may shed some light on anomalous transport at weak coupling.

Phylogenetic relationships of Mesoamerican spider monkeys (Ateles geoffroyi): Molecular evidence suggests the need for a revised taxonomy.

Mesoamerican spider monkeys (Ateles geoffroyi sensu lato) are widely distributed from Mexico to northern Colombia. This group of primates includes many allopatric forms with morphologically distinct pelage color and patterning, but its taxonomy and phylogenetic history are poorly understood. We explored the genetic relationships among the different forms of Mesoamerican spider monkeys using mtDNA sequence data, and we offer a new hypothesis for the evolutionary history of the group. We collected up to ∼800 bp of DNA sequence data from hypervariable region 1 (HV1) of the control region, or D-loop, of the mitochondrion for multiple putative subspecies of Ateles geoffroyi sensu lato. Both maximum likelihood and Bayesian reconstructions, using Ateles paniscus as an outgroup, showed that (1) A. fusciceps and A. geoffroyi form two different monophyletic groups and (2) currently recognized subspecies of A. geoffroyi are not monophyletic. Within A. geoffroyi, our phylogenetic analysis revealed little concordance between any of the classifications proposed for this taxon and their phylogenetic relationships, therefore a new classification is needed for this group. Several possible clades with recent divergence times (1.7-0.8 Ma) were identified within Ateles geoffroyi sensu lato. Some previously recognized taxa were not separated by our data (e.g., A. g. vellerosus and A. g. yucatanensis), while one distinct clade had never been described as a different evolutionary unit based on pelage or geography (Ateles geoffroyi ssp. indet. from El Salvador). Based on well-supported phylogenetic relationships, our results challenge previous taxonomic arrangements for Mesoamerican spider monkeys. We suggest a revised arrangement based on our data and call for a thorough taxonomic revision of this group.

Revisiting the phylogenetic relationships, biogeography, and taxonomy of spider monkeys (genus Ateles) in light of new molecular data.

Spider monkeys (Ateles) are one of the most endangered groups of primates in the Neotropics. The genus is widely distributed from Mexico to the north of Bolivia and includes many morphologically distinct forms in terms of pelage color and patterning. The taxonomy, phylogenetic relationships, and biogeographic history of the genus have been subject to much debate, making scientific communication difficult and creating challenges for conservation actions. We extracted DNA from samples of all currently recognized species of spider monkeys collected from across the geographic range of the genus, sequenced ∼3.5 kilobases of coding sequence from the mitochondrial genome, and used this large dataset to (a) infer the phylogenetic relationships among the different forms of spider monkeys, (b) evaluate whether currently recognized species of spider monkeys form reciprocally monophyletic groups that are concordant with contemporary classifications, and (c) estimate divergence dates among the different lineages of Ateles. We found that all proposed species of spider monkeys for which we have samples from multiple localities indeed appear to form monophyletic groups. However, in contrast to previous studies, several of our analyses robustly inferred Ateles marginatus from northeast Brazil as the sister taxon to all other spider monkeys. A Bayesian dating analysis suggests that the most recent common ancestor of extant Ateles dates to ∼6.7 Ma, in the late Miocene, and most species-level splits within the genus took place in the late Pliocene, suggesting that the modern diversity in spider monkeys cannot be explained principally by isolation and divergence of populations in forest refugia during the Pleistocene. Based on our new phylogenetic inference and dating analysis, we propose a revised biogeographic scenario for the evolution of this genus.

Principles, mechanisms and functions of entrainment in biological oscillators.

Entrainment is a phenomenon in which two oscillators interact with each other, typically through physical or chemical means, to synchronize their oscillations. This phenomenon occurs in biology to coordinate processes from the molecular to organismal scale. Biological oscillators can be entrained within a single cell, between cells or to an external input. Using six illustrative examples of entrainable biological oscillators, we discuss the distinctions between entrainment and synchrony and explore features that contribute to a system's propensity to entrain. Entrainment can either enhance or reduce the heterogeneity of oscillations within a cell population, and we provide examples and mechanisms of each case. Finally, we discuss the known functions of entrainment and discuss potential functions from an evolutionary perspective.

Upside-down kidney placement: An alternative in pediatric renal transplantation.

PURPOSE: "Upside-down" kidney placement has been reported as an acceptable alternative in cases of technical difficulty in kidney transplantation but there are few reports in the pediatric population. The aim of our study is to analyze whether the placement of the upside-down kidney could affect graft outcome or produce more complications. MATERIALS AND METHODS: A retrospective study was conducted of pediatric kidney transplants performed in our center between 2005 and 2017 with at least 6 months' follow-up. Epidemiological and anthropometric data, type of donor (deceased/living), graft position (normal/upside-down), reason for the upside-down placement, early, medium and long-term complications and renal function were analyzed and compared with patients transplanted in the same period with a normal graft placement. RESULTS: From 181 transplants, 167 grafts were placed in a normal position (mean age: 10 y and mean weight: 30 kg) and 14 were placed upside-down (10 y, 37 kg) mainly because of vessel shortness after laparoscopic nephrectomy. Male predominance was observed in both groups. 57% of grafts from the control group and 64% of those from study group came from a living donor. Four vascular and two ureteral re-anastomoses were recorded in the control group and two vascular and one ureteral re-anastomosis in the study group (p > 0.05). In the latter group, no grafts have been lost due to vascular or urological causes and no patients have required dialysis. CONCLUSIONS: When necessary, an upside-down placement for the renal graft is a safe alternative in the pediatric population. LEVEL OF EVIDENCE: Level III.