El algoritmo HyRPNI y una aplicación en bioinformática

Proponemos un algoritmo de inferencia gramatical para lenguajes regulares que permite ahorrar cómputo al usar dos criterios diferentes para elegir los estados a ser procesados, un criterio se usa en la primera fase del proceso de inferencia (al principio) y el otro en el resto del proceso. Realizamos experimentos para observar el desempeño del algoritmo, para aprender sobre el tamaño ideal de su primera fase y para mostrar su aplicación en la solución de un problema específico en bioinformática: la predicción de sitios de corte en poliproteínas codificadas por virus de la familia Potyviridae./ We propose a grammar inference algorithm for regular languages which saves computational cost by using two different criteria to choose states to be processed: one in the first phase of the inference process (the beginning) and another for the rest of the process. We applied experiments to observe performance of the algorithm, to learn about the best size of its first phase and to show results of its application to solve a specific problem in Bioinformatics: the cleavage site prediction problem in polyproteins encoded by viruses of the Potyviridae family

The structure of radiatively induced Lorentz and CPT violation in QED at finite temperature

We obtain the induced Lorentz- and CPT-violating term in QED at finite temperature using imaginary-time formalism and dimensional regularization. Its form resembles a Chern-Simons-like structure, but, unexpectedly, it does not depend on the temporal component of the fixed $b_\mu$ constant vector that is coupled to the axial current. Nevertheless Ward identities are respected and its coefficient vanishes at T=0, consistently with previous computations with the same regularization procedure, and it is a non-trivial function of temperature. We argue that at finite $T$ a Chern-Simons-like Lorentz- and CPT-violating term is generically present, the value of its coefficient being unambiguously determined up to a $T-$independent constant, related to the zero-temperature renormalization conditions.Comment: 15 pages, Latex, 1 figure in eps-format (included

The procoagulant activity of tissue factor expressed on fibroblasts is increased by tissue factor-negative extracellular vesicles

Tissue factor (TF) is critical for the activation of blood coagulation. TF function is regulated by the amount of externalised phosphatidylserine (PS) and phosphatidylethanolamine (PE) on the surface of the cell in which it is expressed. We investigated the role PS and PE in fibroblast TF function. Fibroblasts expressed 6–9 x 104 TF molecules/cell but had low specific activity for FXa generation. We confirmed that this was associated with minimal externalized PS and PE and characterised for the first time the molecular species of PS/PE demonstrating that these differed from those found in platelets. Mechanical damage of fibroblasts, used to simulate vascular injury, increased externalized PS/PE and led to a 7-fold increase in FXa generation that was inhibited by annexin V and an anti-TF antibody. Platelet-derived extracellular vesicles (EVs), that did not express TF, supported minimal FVIIa-dependent FXa generation but substantially increased fibroblast TF activity. This enhancement in fibroblast TF activity could also be achieved using synthetic liposomes comprising 10% PS without TF. In conclusion, despite high levels of surface TF expression, healthy fibroblasts express low levels of external-facing PS and PE limiting their ability to generate FXa. Addition of platelet-derived TF-negative EVs or artificial liposomes enhanced fibroblast TF activity in a PS dependent manner. These findings contribute information about the mechanisms that control TF function in the fibroblast membrane

Spin and a Running Radius in RS1

We develop a renormalization group formalism for the compactified Randall-Sundrum scenario wherein the extra-dimensional radius serves as the scaling parameter. Couplings on the hidden brane scale as we move within local effective field theories with varying size of the warped extra dimension. We consider this RG approach applied to U(1) gauge theories and gravity. We use this method to derive a low energy effective theory.Comment: 18 pages, minor changes, references adde

Incorporating new approach methodologies into regulatory nonclinical pharmaceutical safety assessment

© 2023 The Author(s). ALTEX. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY), https://creativecommons.org/licenses/by/4.0/New approach methodologies (NAMs) based on human biology enable the assessment of adverse biological effects of pharmaceuticals and other chemicals. Currently, however, it is unclear how NAMs should be used during drug development to improve human safety evaluation. A series of 5 workshops with 13 international experts (regulators, preclinical scientists, and NAMs developers) was conducted to identify feasible NAMs and to discuss how to exploit them in specific safety assessment contexts. Participants generated four “maps” of how NAMs can be exploited in the safety assessment of the liver, respiratory, cardiovascular, and central nervous systems. Each map shows relevant endpoints measured and tools used (e.g., cells, assays, platforms), and highlights gaps where further development and validation of NAMs remains necessary. Each map addresses the fundamental scientific requirements for the safety assessment of that organ system, providing users with guidance on the selection of appropriate NAMs. In addition to generating the maps, participants offered suggestions for encouraging greater NAM adoption within drug development and their inclusion in regulatory guidelines. A specific recommendation was that pharmaceutical companies should be more transparent about how they use NAMs in-house. As well as giving guidance for the four organ systems, the maps provide a template that could be used for additional organ safety testing contexts. Moreover, their conversion to an interactive format would enable users to drill down to the detail necessary to answer specific scientific and regulatory questions.Peer reviewe

Incorporating new approach methodologies into regulatory nonclinical pharmaceutical safety assessment

New approach methodologies (NAMs) based on human biology enabletheassessment of adverse biological effects of pharmaceuticals and other chemicals. Currently,however, it is unclear how NAMsshould be usedduring drug development to improve human safety evaluation. A series of 5 workshops with 13 international experts (regulators, preclinical scientists and NAMs developers) were conducted to identify feasible NAMsand to discuss how to exploit them in specific safety assessmentcontexts. Participants generated four‘maps’of how NAMs can be exploited in the safety assessment ofthe liver, respiratory, cardiovascular,and central nervous systems. Each map showsrelevant end points measured, tools used (e.g.,cells, assays, platforms), and highlights gaps where furtherdevelopment and validation of NAMs remainsnecessary. Each map addresses the fundamental scientific requirements for the safety assessment of that organ system, providing users with guidance on the selection of appropriate NAMs. In addition to generating the maps, participants offered suggestions for encouraging greater NAM adoption within drug development and their inclusion in regulatory guidelines. A specific recommendation was that pharmaceutical companies should be more transparent about how they use NAMs in-house. As well as giving guidance for the fourorgan systems, the maps providea template that could be used for additional organ safety testing contexts.Moreover, their conversion to an interactive format would enable users to drill down to the detail necessary to answer specific scientific and regulatory questions. 1IntroductionExtensive nonclinical safety studies are undertaken on new pharmaceuticals prior to and alongside clinical trials. Their purpose is to identify and understand the toxic effects of thecompoundin order to determine whether its anticipated benefit versusrisk profile justifies clinical evaluation and, if so, to inform the design and monitoring of clinical studies. The nonclinical safety studies are mandated by regulatory guidelines and include a variety of safety pharmacologyand toxicology investigations.Safety pharmacology studies aimto determinewhether pharmaceuticalscause on-or off-target effects on biological processes which can affect the function of critical organ systems (e.g.,cardiovascular, respiratory, gastrointestinal,and central nervous systems)and to assess potency, which is needed to assess safety margins versushuman clinical drug exposure. Safety pharmacology studiesalso help informthe selectionof follow-on investigations that can aid human risk assessmentand may provide insight into mechanismswhich underlie any effectsthat arise in humans.Multiple leading pharmaceutical companies (e.g.,AstraZeneca, GlaxoSmithKline, Novartis,and Pfizer) have outlined the advantages provided by in vitrosafety pharmacological profiling, including early identification of off-target interactionsandthe prediction ofclinical side effects that may be missed in animalstudies, and have highlighted that these studies enable much more cost-effective and rapid profiling of large numbers of compounds than animal procedures (Bowes et al., 2012).Toxicology studies evaluate systemic organ toxicities, behavioraleffects, reproductive and developmental toxicology, genetic toxicology,eye irritancy and dermal sensitization. They include single and repeat dose studies in rodent and non-rodentanimal species, which identify target organs, assessseverity andreversibility,and define dose-response and no observed adverse effect levels. These are critical parameters which are essential for regulatory decision-makingon whether the compound can be progressed into clinical trials and if so, estimation ofa suitable starting dose,maximum dose, dose escalation regime,andany non-standard clinical safety monitoringthat may be needed.Toxicity observedinnonclinical animal safety studies is an important cause of the high attrition rate of candidate drugs prior to clinicaltrials that occurs inmultiple pharmaceutical companies(Cook et al., 2014).However, many drugs cause clinically serious adverseeffects in humans which are not detectedin animals(Bailey et al., 2015). For example, human drug induced liver injury(DILI),which is not detected in animal safety studies,is animportant cause of attrition late in clinical development, failed licensing and/or of restrictive drug labelling(Watkins, 2011). Attrition due to toxicity observed in animals and/or in humans isanimportant cause of the high failure rate of clinical drug development(Cook et al., 2014; Watkins, 2011; Thomas et al., 2021).New approach methodologies (NAMs)includemethods which predict and evaluate biological processes by which pharmaceuticals may elicit desirable pharmacological effects and/or may cause undesirable toxicity. Many different types of NAMs have been described. Theseinclude simple in vitrocell-based tests, more complex organotypic or microphysiologicalsystems (MPS)/organ-on-a-chipdevices,and whole human tissuesmaintained ex vivo. Interpretation ofthe invivorelevance of the data providedby these methods is complementedbycomputational toolswhichsimulate and predict in vivodrug disposition and kinetics, in particular physiologically based pharmacokinetic (PBPK) models. Accurate in vitroto in vivoextrapolation isfurther aided by human low-dose testing and microdosing studies (phase 0 testing), which provide precise data on systemic human drug exposure and kineticsin vivo

Rare B decays and Tevatron top-pair asymmetry

The recent Tevatron result on the top quark forward-backward asymmetry, which deviates from its standard model prediction by 3.4$\sigma$, has prompted many authors to build new models to account for this anomaly. Among the various proposals, we find that those mechanisms which produce $t\bar t$ via $t$- or $u$-channel can have a strong correlation to the rare B decays. We demonstrate this link by studying a model with a new charged gauge boson, $W'$. In terms of the current measurements on $B\to \pi K$ decays, we conclude that the branching ratio for $B^-\to \pi^- \bar K^0$ is affected most by the new effects. Furthermore, using the world average branching ratio for the exclusive B decays at $2\sigma$ level, we discuss the allowed values for the new parameters. Finally, we point out that the influence of the new physics effects on the direct CP asymmetry in B decays is insignificant.Comment: 15 page, 6 figures, typos corrected and references added, final version to appear journa

International consensus on (ICON) anaphylaxis

ICON: Anaphylaxis provides a unique perspective on the principal evidence-based anaphylaxis guidelines developed and published independently from 2010 through 2014 by four allergy/immunology organizations. These guidelines concur with regard to the clinical features that indicate a likely diagnosis of anaphylaxis -- a life-threatening generalized or systemic allergic or hypersensitivity reaction. They also concur about prompt initial treatment with intramuscular injection of epinephrine (adrenaline) in the mid-outer thigh, positioning the patient supine (semi-reclining if dyspneic or vomiting), calling for help, and when indicated, providing supplemental oxygen, intravenous fluid resuscitation and cardiopulmonary resuscitation, along with concomitant monitoring of vital signs and oxygenation. Additionally, they concur that H1-antihistamines, H2-antihistamines, and glucocorticoids are not initial medications of choice. For self-management of patients at risk of anaphylaxis in community settings, they recommend carrying epinephrine auto-injectors and personalized emergency action plans, as well as follow-up with a physician (ideally an allergy/immunology specialist) to help prevent anaphylaxis recurrences. ICON: Anaphylaxis describes unmet needs in anaphylaxis, noting that although epinephrine in 1 mg/mL ampules is available worldwide, other essentials, including supplemental oxygen, intravenous fluid resuscitation, and epinephrine auto-injectors are not universally available. ICON: Anaphylaxis proposes a comprehensive international research agenda that calls for additional prospective studies of anaphylaxis epidemiology, patient risk factors and co-factors, triggers, clinical criteria for diagnosis, randomized controlled trials of therapeutic interventions, and measures to prevent anaphylaxis recurrences. It also calls for facilitation of global collaborations in anaphylaxis research. In addition to confirming the alignment of major anaphylaxis guidelines, ICON: Anaphylaxis adds value by including summary tables and citing 130 key references. It is published as an information resource about anaphylaxis for worldwide use by healthcare professionals, academics, policy-makers, patients, caregivers, and the public

Simple models for the top asymmetry: constraints and predictions

We perform a comprehensive study of the allowed range for the Tevatron t tbar forward-backward asymmetries in six representative new physics models: a flavour-changing Z' boson, a scalar isodoublet, a W' boson, a heavy axigluon, a colour-triplet and a colour-sextet scalar. We devote special attention to the constraints from the t tbar tail at LHC on the parameter space, which will be dramatic if the measurements agree with the SM prediction, specially for Z' and W' bosons. We also study the predictions for the charge asymmetries at LHC and compare several proposed definitions.Comment: LaTeX 27 pages. Version to appear in JHE

The Pediatric and Young Adult Choroidal and Ciliary Body Melanoma Genetic Study, A Survey by the European Ophthalmic Oncology Group

PURPOSE:To explore the genetic background of choroidal and ciliary body melanoma among children and young adults, with special focus on BAP1 germline variants in this age group. METHODS:Patients under the age of 25 and with confirmed choroidal or ciliary body melanoma were included in this retrospective, multicenter observational study. Nuclear BAP1 immunopositivity was used to evaluate the presence of functional BAP1 in the tumor. Next-generation sequencing using Ion Torrent platform was used to determine pathogenic variants of BAP1, EIF1AX, SF3B1, GNAQ and GNA11 and chromosome 3 status in the tumor or in DNA extracted from blood or saliva. Survival was analyzed using Kaplan-Meier estimates. RESULTS:The mean age at diagnosis was 17 years (range 5.0–24.8). A germline BAP1 pathogenic variant was identified in an 18-year-old patient, and a somatic variant, based mainly on immunohistochemistry, in 13 (42%) of 31 available specimens. One tumor had a somatic SF3B1 pathogenic variant. Disomy 3 and the absence of a BAP1 pathogenic variant in the tumor predicted the longest metastasis-free survival. Males showed longer metastasis-free survival than females (P = 0.018). CONCLUSIONS:We did not find a stronger-than-average BAP1 germline predisposition for choroidal and ciliary body melanoma among children and young adults compared to adults. Males had a more favorable survival and disomy 3, and the absence of a BAP1 mutation in the tumor tissue predicted the most favorable metastasis-free survival. A BAP1 germline pathogenic variant was identified in one patient (1%), and a somatic variant based mainly on immunohistochemistry in 13 (42%).</p