Molecular and Metabolic Subtypes Correspondence for Pancreatic Ductal Adenocarcinoma Classification

Pancreatic ductal adenocarcinoma (PDAC), the most common form of pancreatic cancer, is an extremely lethal disease due to late diagnosis, aggressiveness and lack of effective therapies. Considering its intrinsic heterogeneity, patient stratification models based on transcriptomic and genomic signatures, with partially overlapping subgroups, have been established. Besides molecular alterations, PDAC tumours show a strong desmoplastic response, resulting in profound metabolic reprogramming involving increased glucose and amino acid consumption, as well as lipid scavenging and biosynthesis. Interestingly, recent works have also revealed the existence of metabolic subtypes with differential prognosis within PDAC, which correlated to defined molecular subclasses in patients: lipogenic subtype correlated with a classical/progenitor signature, while glycolytic tumours associated with the highly aggressive basal/squamous profile. Bioinformatic analyses have demonstrated that the representative genes of each metabolic subtype are up-regulated in PDAC samples and predict patient survival. This suggests a relationship between the genetic signature, metabolic profile, and aggressiveness of the tumour. Considering all this, defining metabolic subtypes represents a clear opportunity for patient stratification considering tumour functional behaviour independently of their mutational background

Sucesión de Polygnátidos (Conodontos) del Emsiense (Devónico Inferior) en los Pirineos Centrales Españoles

A comprehensive conodont study of five sections of Emsian age, carried out in the Spanish Central Pyrenees, has revealed an important succession of polygnathids that can be used for identifying basal boundaries of globally recognized biozones. This succession consists of Polygnathus excavatus excavatus, Po. gronbergi, Po. nothoperbonus, Po. mashkovae, Po. laticostatus, and the new species Polygnathus luciae that allows the identification of the excavatus, nothoperbonus and laticostatus Zones. The nothoperbonus Zone is further subdivided into Lower and Upper nothoperbonus subzones, relying upon the lowest occurrence of Po. mashkovae. These biostratigraphic data from the Spanish Central Pyrenees corroborate the succession of conodont indexes in other regions of Europe (north-western France and southern Italy), North Africa (Morocco), Central Asia, Australia, and North America (Alaska, Nevada and Canada).El estudio exhaustivo de cinco secciones de edad Emsiense en el Pirineo Central Español ha proporcionado una importante sucesión de especies de conodontos del género Polygnathus que puede usarse para reconocer los límites de diferentes biozonas de aplicación global. Esta sucesión consiste en Polygnathus excavatus excavatus, Po. gronbergi, Po. nothoperbonus, Po. mashkovae, Po. laticostatus y la nueva especie Polygnathus luciae, lo que permite identificar las biozonas excavatus, nothoperbonus y laticostatus. Además, el primer registro de Po. mashkovae se usa para subdividir la Zona nothoperbonus en las Subzonas nothoperbonus Inferior y Superior. Estos datos corroboran la sucesión de los índices de conodontos registrada en otras regiones de Europa (noroeste de Francia y sur de Italia), norte de África (Marruecos), Asia central, Australia y Norte América (Alaska, Nevada y Canadá)

A molecular tool to detect genetic introgression from Spermatheca content

The genetic integrity of Apis mellifera mellifera is threatened by introgression in many places of its native distribution, after recurrent importations of commercial queens typically belonging to the divergent C-lineage. A growing interest in keeping and protecting A. m. mellifera has motivated the development of conservation programs in many places of Europe. As part of the conservation efforts, isolated mating stations are set to avoid unwanted crosses, but these are not always effective as matings with unwanted drones are frequently reported. An interesting method to monitor the degree of isolation of mating stations could be through genetic analysis of the queen spermatheca contents. While this method implies that queens selected for monitoring are sacrificed, it can be a powerful way of assessing the effectiveness of mating stations because it would allow easy detection of unwanted alleles. Here, we developed an SNP-based tool suited to the analysis of DNA extracted from spermatheca or from pooled DNA of varying sources. To that end, we first designed an SNP panel from whole-genome sequence data generated from 228 drones, of which 148 belonged to the M-lineage (117 A. m. iberiensis and 31 A. m. mellifera) and 80 to the C-lineage (46 A. m. carnica and 34 A. m. ligustica). A total of 5,007 highly differentiated SNPs was found. Based on different criteria, 130 SNPs were selected to be included in the genotyping tool. This tool is based on the NEBNext Direct Genotyping Solution that allows high-throughput, sequence-based target genotyping of single-individual or pooled DNA. To assess the tool’s sensitivity and accuracy, 142 samples (DNA extracted from spermatheca and tissue, as well as known DNA mixtures) were genotyped. After removing the problematic SNPs, 81 were retained and these were able to provide an estimate of the pool introgression level with great accuracy. This tool represents a significant advance in the genetic analysis of honey bee colonies with a variety of applications, including breeding and conservation of A. m. mellifera.info:eu-repo/semantics/publishedVersio

Pharmacological targeting of the receptor ALK inhibits tumorigenicity and overcomes chemoresistance in pancreatic ductal adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) is an extremely aggressive disease characterized by its metastatic potential and chemoresistance. These traits are partially attributable to the highly tumorigenic pancreatic cancer stem cells (PaCSCs). Interestingly, these cells show unique features in order to sustain their identity and functionality, some of them amenable for therapeutic intervention. Screening of phospho-receptor tyrosine kinases revealed that PaCSCs harbored increased activation of anaplastic lymphoma kinase (ALK). We subsequently demonstrated that oncogenic ALK signaling contributes to tumorigenicity in PDAC patient-derived xenografts (PDXs) by promoting stemness through ligand-dependent activation. Indeed, the ALK ligands midkine (MDK) or pleiotrophin (PTN) increased self-renewal, clonogenicity and CSC frequency in several in vitro local and metastatic PDX models. Conversely, treatment with the clinically-approved ALK inhibitors Crizotinib and Ensartinib decreased PaCSC content and functionality in vitro and in vivo, by inducing cell death. Strikingly, ALK inhibitors sensitized chemoresistant PaCSCs to Gemcitabine, as the most used chemotherapeutic agent for PDAC treatment. Consequently, ALK inhibition delayed tumor relapse after chemotherapy in vivo by effectively decreasing the content of PaCSCs. In summary, our results demonstrate that targeting the MDK/PTN-ALK axis with clinically-approved inhibitors impairs in vivo tumorigenicity and chemoresistance in PDAC suggesting a new treatment approach to improve the long-term survival of PDAC patients

A novel SNP-based tool for estimating C-lineage introgression in the dark honey bee (Apis mellifera mellifera)

The natural distribution ofthe honeybee (Apis mellifera L.) hás been changed by humans in recent decades to such an extent that the formerly widest-spread European subspecies, Apís mellifera mellifera, is threatened by extinction through introgression from highly divergent commercial strains in large tracts of its range. Conservation efforts for A. m. mellifera are underway in multiple European countries requiring reliable and cost-efficient molecular tools to identify purebred colonies. Here, we developed four ancestry-informative SNP assays for high sample throughput genotyping using the iPLEX Mass Array system. Our customized assays were tested on DNA from individual and pooled, haploid and diploid honeybee samples extracted from different tissues using a diverse range of protocols. The assays had a high genotyping success rate and yielded accurate genotypes. Performance assessed against whole-genome data showed that individual assays behaved well, although the most accurate introgression estimates were obtained forthe fourassays combined (117 SNPs). The best compromise between accuracy ana genotyping costs was achieved when combining two assays (62 SNPs). We provide a ready-to-use cost-effective tool for accurate molecular identification and estimation of introgression leveis to more effectively monitor and manage A. m. mellífera conservatories.info:eu-repo/semantics/publishedVersio

VAV2 signaling promotes regenerative proliferation in both cutaneous and head and neck squamous cell carcinoma

Regenerative proliferation capacity and poor differentiation are histological features usually linked to poor prognosis in head and neck squamous cell carcinoma (hnSCC). However, the pathways that regulate them remain ill-characterized. Here, we show that those traits can be triggered by the RHO GTPase activator VAV2 in keratinocytes present in the skin and oral mucosa. VAV2 is also required to maintain those traits in hnSCC patient-derived cells. This function, which is both catalysis- and RHO GTPase-dependent, is mediated by c-Myc- and YAP/TAZ-dependent transcriptomal programs associated with regenerative proliferation and cell undifferentiation, respectively. High levels of VAV2 transcripts and VAV2-regulated gene signatures are both associated with poor hnSCC patient prognosis. These results unveil a druggable pathway linked to the malignancy of specific SCC subtypes. The Rho signalling pathway is frequently activated in squamous carcinomas. Here, the authors find that the Rho GEF VAV2 is over expressed in both cutaneous and head and neck squamous cell carcinomas and that at the molecular level VAV2 promotes a pro-tumorigenic stem cell-like signalling programme

Stereoscopic disambiguation of vector magnetograms: first applications to SO/PHI-HRT data

Spectropolarimetric reconstructions of the photospheric vector magnetic field are intrinsically limited by the 180$^\circ$-ambiguity in the orientation of the transverse component. So far, the removal of such an ambiguity has required assumptions about the properties of the photospheric field, which makes disambiguation methods model-dependent. The basic idea is that the unambiguous line-of-sight component of the field measured from one vantage point will generally have a non-zero projection on the ambiguous transverse component measured by the second telescope, thereby determining the ``true'' orientation of the transverse field. Such an idea was developed and implemented in the Stereoscopic Disambiguation Method (SDM), which was recently tested using numerical simulations. In this work we present a first application of the SDM to data obtained by the High Resolution Telescope (HRT) onboard Solar Orbiter during the March 2022 campaign, when the angle with Earth was 27 degrees. The method is successfully applied to remove the ambiguity in the transverse component of the vector magnetogram solely using observations (from HRT and from the Helioseismic and Magnetic Imager), for the first time. The SDM is proven to provide observation-only disambiguated vector magnetograms that are spatially homogeneous and consistent. A discussion about the sources of error that may limit the accuracy of the method, and of the strategies to remove them in future applications, is also presented.Comment: 32 pages, 12 figures, accepted in A&A on 09/07/202

Settling Decisions and Heterospecific Social Information Use in Shrikes

Animals often settle near competitors, a behavior known as social attraction, which belies standard habitat selection theory. Two hypotheses account for these observations: individuals obtain Allee benefits mediated by the physical presence of a competitor, or they use successfully settled individual as a source of information indicating the location of high quality habitat. We evaluated these hypotheses experimentally in two species of shrikes. These passerine birds with a raptor-like mode of life impale prey to create larders that serve as an indicator of male/habitat quality. Thus, two forms of indirect information are available in our system: a successfully settled shrike and its larder. Typically these two cues are associated with each other, however, our experimental treatment created an unnatural situation by disassociating them. We manipulated the presence of larders of great grey shrikes and examined the settling decisions of red-backed shrikes within and outside the great grey shrike territories. Male red-backed shrikes did not settle sooner on plots with great grey shrikes compared to plots that only contained artificial larders indicating that red-backed shrikes do not use the physical presence of a great grey shrike when making settling decisions which is inconsistent with the Allee effect hypothesis. In contrast, for all plots without great grey shrikes, red-backed shrikes settled, paired and laid clutches sooner on plots with larders compared to plots without larders. We conclude that red-backed shrikes use larders of great grey shrikes as a cue to rapidly assess habitat quality

Natural Cross Chlamydial Infection between Livestock and Free-Living Bird Species

The study of cross-species pathogen transmission is essential to understanding the epizootiology and epidemiology of infectious diseases. Avian chlamydiosis is a zoonotic disease whose effects have been mainly investigated in humans, poultry and pet birds. It has been suggested that wild bird species play an important role as reservoirs for this disease. During a comparative health status survey in common (Falco tinnunculus) and lesser (Falco naumanni) kestrel populations in Spain, acute gammapathies were detected. We investigated whether gammapathies were associated with Chlamydiaceae infections. We recorded the prevalence of different Chlamydiaceae species in nestlings of both kestrel species in three different study areas. Chlamydophila psittaci serovar I (or Chlamydophila abortus), an ovine pathogen causing late-term abortions, was isolated from all the nestlings of both kestrel species in one of the three studied areas, a location with extensive ovine livestock enzootic of this atypical bacteria and where gammapathies were recorded. Serovar and genetic cluster analysis of the kestrel isolates from this area showed serovars A and C and the genetic cluster 1 and were different than those isolated from the other two areas. The serovar I in this area was also isolated from sheep abortions, sheep faeces, sheep stable dust, nest dust of both kestrel species, carrion beetles (Silphidae) and Orthoptera. This fact was not observed in other areas. In addition, we found kestrels to be infected by Chlamydia suis and Chlamydia muridarum, the first time these have been detected in birds. Our study evidences a pathogen transmission from ruminants to birds, highlighting the importance of this potential and unexplored mechanism of infection in an ecological context. On the other hand, it is reported a pathogen transmission from livestock to wildlife, revealing new and scarcely investigated anthropogenic threats for wild and endangered species