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Since the start of the pandemic, scientists have directed their research towards identifying COVID-19 risk factors and predictive elements. Numerous clinical studies have established a strong connection between hypoalbuminemia and an unfavorable prognosis for COVID-19. Here, we aim to explore the impact of human serum albumin (HSA) on SARS-CoV-2 infection. Our findings indicate that HSA plays a role in reducing the replication rate of SARS-CoV-2 in Vero E6 cells. This protective effect is due to HSA ability to bind to the S1 domain of the spike protein, effectively competing with ACE2. Moreover, we show that the protective role of HSA is dependent also on its ability to activate the protective axis within the RAS system pathway, which is responsible for inducing vasodilation and promoting anti-inflammatory, anti-fibrotic, and anti-apoptotic responses. In summary, the data presented in this study support the idea that reduced levels of circulating HSA in hypoalbuminemic patients may heighten their susceptibility to SARS-CoV-2 infection, as the spike protein is unhindered in its ability to bind to ACE2 and penetrate human cells. Besides, hypoalbuminemia exacerbates the imbalance of the RAS pathway towards the classical “detrimental” axis. This could potentially contribute to the increased severity and elevated mortality rate observed in individuals with low levels of circulating albumin.

The rivastigmine patch is the only existing transdermal delivery system used for the treatment of Alzheimer disease. Among the most common adverse events derived from its use are gastrointestinal events, particularly diarrhea. We report a clinical case of an 81-year-old patient admitted to our hospital under long-standing treatment with rivastigmine transdermal patch who presented with atypical watery diarrhea. Anamnesis showed that the patient presented with a likely infectious gastroenteric event, the diarrheal symptoms of which persisted upon resolution of the event and resolved only upon temporary discontinuation of acetylcholinesterase inhibitors. Failure to rapidly identify the causes of profuse diarrhea in older adults can have lethal consequences. When these symptoms occur, quickly recognizing the causes and providing proper management can be lifesaving.

The avian palaeognath phylogeny has been recently revised significantly due to the advancement of genome-wide comparative analyses and provides the opportunity to trace the evolution of the microstructure and crystallography of modern dinosaur eggshells. Here, eggshells of all major clades of Palaeognathae (including extinct taxa) and selected eggshells of Neognathae and non-avian dinosaurs are analysed with electron backscatter diffraction. Our results show the detailed microstructures and crystallographies of (previously) loosely categorized ostrich-, rhea-, and tinamou-style morphotypes of palaeognath eggshells. All rhea-style eggshell appears homologous, while respective ostrich-style and tinamou-style morphotypes are best interpreted as homoplastic morphologies (independently acquired). Ancestral state reconstruction and parsimony analysis additionally show that rhea-style eggshell represents the ancestral state of palaeognath eggshells both in microstructure and crystallography. The ornithological and palaeontological implications of the current study are not only helpful for the understanding of evolution of modern and extinct dinosaur eggshells, but also aid other disciplines where palaeognath eggshells provide useful archive for comparative contrasts (e.g. palaeoenvironmental reconstructions, geochronology, and zooarchaeology).

Abstract A new Cretaceous ootaxon (eggshell type) from the Kaiparowits Formation of Grand Staircase-Escalante National Monument is among a growing number of very small eggs described from the Mesozoic. Analyses of two partial eggs (~ 17.7 mm in diameter) and 29 eggshell fragments reveal that this new ootaxon exhibits nodose ornamentation with distinctive branching pore canals that open atop the nodes. Its two-layered microstructure consists of a mammillary layer and a continuous layer with rugged grain boundaries between calcite grains. Although the exact identity of the egg producer is unknown, the eggshell microstructure and small size is consistent with a small-bodied avian or non-avian theropod. The specific combination of small egg size, branching pores, two-layered microstructure, and dispersituberculate ornamentation preserved in this new ootaxon is unique among theropod eggs. This underscores that both eggshell and skeletal fossils of Cretaceous theropods can display a mosaic of transitional morphological and behavioural features characteristic of both avian and non-avian taxa. As such, this new ootaxon increases the diversity of Cretaceous eggs and informs our understanding of the evolution of theropod eggshell microstructure and morphology.

Myelofibrosis (MF) is a progressive chronic myeloproliferative neoplasm characterized by hyperactivation of JAK/STAT signaling and dysregulation of the transcription factor GATA1 in megakaryocytes (MKs). TGF-β plays a pivotal role in the pathobiology of MF by promoting BM fibrosis and collagen deposition and by enhancing the dormancy of normal hematopoietic stem cells (HSCs). In this study, we show that MF-MKs elaborated significantly greater levels of TGF-β1 than TGF-β2 and TGF-β3 to a varying degree, and we evaluated the ability of AVID200, a potent TGF-β1/TGF-β3 protein trap, to block the excessive TGF-β signaling. Treatment of human mesenchymal stromal cells with AVID200 significantly reduced their proliferation, decreased phosphorylation of SMAD2, and interfered with the ability of TGF-β1 to induce collagen expression. Moreover, treatment of MF mononuclear cells with AVID200 led to increased numbers of progenitor cells (PCs) with WT JAK2 rather than mutated JAK2V617F. This effect of AVID200 on MF PCs was attributed to its ability to block TGF-β1–induced p57Kip2 expression and SMAD2 activation, thereby allowing normal rather than MF PCs to preferentially proliferate and form hematopoietic colonies. To assess the in vivo effects of AVID200, Gata1lo mice, a murine model of MF, were treated with AVID200, resulting in the reduction in BM fibrosis and an increase in BM cellularity. AVID200 treatment also increased the frequency and numbers of murine progenitor cells as well as short-term and long-term HSCs. Collectively, these data provide the rationale for TGF-β1 blockade, with AVID200 as a therapeutic strategy for patients with MF.

The coronavirus disease 2019 (COVID-19) mRNA vaccine developed by Pfizer/BioNTech has been shown to be capable of developing an excellent antibody response against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein, with good production of neutralizing antibodies. Herein, we analyzed differences in the antibody response elicited by inoculation of the Pfizer/BioNTech vaccine through a peptide-based enzyme-linked immunosorbent assay (ELISA) that utilizes synthetic peptides derived from the spike protein in the immuno-adsorbent phase. Immunoreactivity against synthetic peptides was measured at different time points from vaccination and was also correlated with the SARS-CoV-2 neutralizing capacity. Our results indicate that all vaccinated subjects except one show reactive antibodies to at least one peptide at both 30 and 60 days after injection of the first dose. Only one of the 19 analyzed subjects showed no antibody response toward any of the selected peptides, consistently with a lower neutralizing capacity. More importantly, our data showed that the antibody response elicited by inoculation of the two doses of the Pfizer vaccine appears to be qualitatively individual, both in the type of recognized peptides and in the temporal persistence of the antibody response. Together with previous published data, our findings suggest that for effective pandemic control, it is important to constantly monitor the antibody protection in the population, and the assay described here could be a valid tool for this purpose.

Analysis of ontogenetic changes in long bone microstructure aid in vertebrate life history reconstructions. Specifically, osteohistological examination of common fauna can be used to infer growth strategies of biologically uncommon, threatened, or extinct vertebrates. Although nine-banded armadillo biology has been studied extensively, work on growth history is limited. Here we describe long bone microstructure in tibiae and femora of a limited ontogenetic series of nine- banded armadillos (Dasypus novemcinctus) to elucidate patterns of bone growth. The cortex of the smallest individual is composed of compacted coarse cancellous bone (CCCB) and woven tissue. Extensive cortical drift is driven by periosteal erosion and further compaction of trabeculae resulting in an increase in the amount of CCCB. The cortex of the largest specimens is primarily CCCB with thickened endosteal bone and thin outer cortices of lamellar and parallel-fibered tissue. The outer cortices of the largest individuals are interpreted as an external fundamental system (EFS) indicating a cessation of appositional bone growth corresponding to skeletal maturity (i.e. asymptotic or adult size). The EFS forms in femora prior to tibiae, indicating femoral growth rates begin decreasing earlier than tibial in D. novemcinctus. Growth trends in common fauna like the nine-banded armadillo can be used as a foundation for understanding life histories of related, but uncommon or extinct, species of cingulates.

Diapsids show an extremely wide range of reproductive strategies. Offspring may receive no parental care, care from only one sex, care from both parents, or care under more complex regimes. Young may vary from independent, super-precocial hatchlings to altricial neonates needing much care before leaving the nest. Parents can invest heavily in a few young, or less so in a larger number. Here we examine the evolution of these traits across a composite phylogeny spanning the extant diapsids and including the limited number of extinct taxa for which reproductive strategies can be well constrained. Generalized estimating equation(GEE)-based phylogenetic comparative methods demonstrate the influences of body mass, parental care strategy and hatchling maturity on clutch volume across the diapsids. The influence of polygamous reproduction is not important despite a large sample size. Applying the results of these models to the dinosaurs supports the hypothesis of paternal care (male only) in derived non-avian theropods, previously suggested based on simpler analyses. These data also suggest that sauropodomorphs did not care for their young. The evolution of parental-care occurs in an almost linear series of transitions. Paternal care rarely gives rise to other care strategies. Where hatchling condition changes, diapsids show an almost unidirectional tendency of evolution towards increased altriciality. Transitions to social monogamy from the ancestral state in diapsids, where both sexes are polygamous, are common. In contrast, once evolved, polygyny and polyandry are very evolutionarily stable. Polygyny and maternal care correlate, as do polyandry and paternal care. Ancestral-character estimation (ACE) of these care strategies with the character transition likelihoods estimated from the original data gives good confidence at most important nodes. These analyses suggest that the basalmost diapsids had no parental care. Crocodilians independently evolved maternal care, paternal care evolved in the saurischian line, prior to derived theropod dinosaurs, and the most basal neognaths likely exhibited biparental care. Overall, the evolution of parental care among diapsids shows a persistent trend towards increased care of offspring, and more complex care strategies and behaviors with time. Reversions to reduced care are infrequent.

Embryonic remains within a small (4.75 by 2.23 cm) egg from the Late Cretaceous, Mongolia are here re-described. High-resolution X-ray computed tomography (HRCT) was used to digitally prepare and describe the enclosed embryonic bones. The egg, IGM (Mongolian Institute for Geology, Ulaanbaatar) 100/2010, with a three-part shell microstructure, was originally assigned to Neoceratopsia implying extensive homoplasy among eggshell characters across Dinosauria. Re-examination finds the forelimb significantly longer than the hindlimbs, proportions suggesting an avian identification. Additional, postcranial apomorphies (strut-like coracoid, cranially located humeral condyles, olecranon fossa, slender radius relative to the ulna, trochanteric crest on the femur, and ulna longer than the humerus) identify the embryo as avian. Presence of a dorsal coracoid fossa and a craniocaudally compressed distal humerus with a strongly angled distal margin support a diagnosis of IGM 100/2010 as an enantiornithine. Re-identification eliminates the implied homoplasy of this tri-laminate eggshell structure, and instead associates enantiornithine birds with eggshell microstructure composed of a mammillary, squamatic, and external zones. Posture of the embryo follows that of other theropods with fore- and hindlimbs folded parallel to the vertebral column and the elbow pointing caudally just dorsal to the knees. The size of the egg and embryo of IGM 100/2010 is similar to the two other Mongolian enantiornithine eggs. Well-ossified skeletons, as in this specimen, characterize all known enantiornithine embryos suggesting precocial hatchlings, comparing closely to late stage embryos of modern precocial birds that are both flight- and run-capable upon hatching. Extensive ossification in enantiornithine embryos may contribute to their relatively abundant representation in the fossil record. Neoceratopsian eggs remain unrecognized in the fossil record.

The complexes formed by BCL10, MALT1 and specific members of the family of CARMA proteins (CBM complex), have recently focused much attention because they represent a central hub regulating activation of the transcription factor NF-κB following various cellular stimulations. In this manuscript, we report the functional characterization of a Danio rerio 241 amino acids polypeptide ortholog of the Caspase recruiting domain (CARD)-containing protein BCL10. Biochemical studies show that zebrafish Bcl10 (zBcl10) dimerizes and binds to components of the CBM complex. Fluorescence microscopy observations demonstrate that zBcl10 forms cytoplasmic filaments similar to that formed by human BCL10 (hBCL10). Functionally, in human cells zBcl10 is more effective in activating NF-κB compared to hBCL10, possibly due to the lack of carboxy-terminal inhibitory serine residues present in the human protein. Also, depletion experiments carried out through expression of short hairpin RNAs targeting hBCL10 indicate that zBcl10 can functionally replace the human protein. Finally, we show that the zebrafish cell line PAC2 is suitable to carry out reporter assays for monitoring the activation state of NF- kB transcription factor. In conclusion, this work shows that zebrafish may excellently serve as a model organism to study complex and intricate signal transduction pathways, such as those that control NF-κB activation.

A second nearly complete, articulated specimen of the basal troodontid Mei long (DNHM D2154) is reported from the Early Cretaceous (Hauterivian-Valanginian) lower Yixian Formation, Liaoning Province, China. New diagnostic features of Mei long are identified, including: a uniquely shaped maxilla, low with small, low maxillary fenestra; sacrum with an extremely wide caudal portion and elongate 4(th) and 5(th) sacral processes; and a large distal articular surface on the tibiotarsus which continues caudally on the tibia. A phylogenetic analysis including new data from the second specimen recovered Mei as a basal troodontid, in keeping with previous analyses. Although the skeleton exhibits several juvenile-like features including free cervical ribs, unfused frontals and nasals, and a short snouted skull, other attributes, full fusion of all neurocentral synostoses and the sacrum, and dense exteriors to cortical bone, suggest a small, mature individual. Microscopic examination of tibia and fibula histology confirms maturity and suggests an individual greater than two years old with slowed growth. Despite being one of the smallest dinosaurs, Mei long exhibits multi-year growth and cortical bone consisting largely of fibro-lamellar tissue marked by lines of arrested growth as in much larger and more basal theropods. This Mei long specimen lies in a similar but mirrored sleeping position to that of the holotype, strengthening the hypothesis that both specimens were preserved in a stereotypical life position. Like many Liaoning specimens, the new specimen also lacks extensive taphonomic and stratigraphic data, making further behavioral inference problematic.

BackgroundTyrannosaurus rex and other tyrannosaurid fossils often display multiple, smooth-edged full-thickness erosive lesions on the mandible, either unilaterally or bilaterally. The cause of these lesions in the Tyrannosaurus rex specimen FMNH PR2081 (known informally by the name 'Sue') has previously been attributed to actinomycosis, a bacterial bone infection, or bite wounds from other tyrannosaurids.Methodology/principal findingsWe conducted an extensive survey of tyrannosaurid specimens and identified ten individuals with full-thickness erosive lesions. These lesions were described, measured and photographed for comparison with one another. We also conducted an extensive survey of related archosaurs for similar lesions. We show here that these lesions are consistent with those caused by an avian parasitic infection called trichomonosis, which causes similar abnormalities on the mandible of modern birds, in particular raptors.Conclusions/significanceThis finding represents the first evidence for the ancient evolutionary origin of an avian transmissible disease in non-avian theropod dinosaurs. It also provides a valuable insight into the palaeobiology of these now extinct animals. Based on the frequency with which these lesions occur, we hypothesize that tyrannosaurids were commonly infected by a Trichomonas gallinae-like protozoan. For tyrannosaurid populations, the only non-avian dinosaur group that show trichomonosis-type lesions, it is likely that the disease became endemic and spread as a result of antagonistic intraspecific behavior, consumption of prey infected by a Trichomonas gallinae-like protozoan and possibly even cannibalism. The severity of trichomonosis-related lesions in specimens such as Tyrannosaurus rex FMNH PR2081 and Tyrannosaurus rex MOR 980, strongly suggests that these animals died as a direct result of this disease, mostly likely through starvation.

BackgroundLiving birds possess a unique heterogeneous pulmonary system composed of a rigid, dorsally-anchored lung and several compliant air sacs that operate as bellows, driving inspired air through the lung. Evidence from the fossil record for the origin and evolution of this system is extremely limited, because lungs do not fossilize and because the bellow-like air sacs in living birds only rarely penetrate (pneumatize) skeletal bone and thus leave a record of their presence.Methodology/principal findingsWe describe a new predatory dinosaur from Upper Cretaceous rocks in Argentina, Aerosteon riocoloradensis gen. et sp. nov., that exhibits extreme pneumatization of skeletal bone, including pneumatic hollowing of the furcula and ilium. In living birds, these two bones are pneumatized by diverticulae of air sacs (clavicular, abdominal) that are involved in pulmonary ventilation. We also describe several pneumatized gastralia ("stomach ribs"), which suggest that diverticulae of the air sac system were present in surface tissues of the thorax.Conclusions/significanceWe present a four-phase model for the evolution of avian air sacs and costosternal-driven lung ventilation based on the known fossil record of theropod dinosaurs and osteological correlates in extant birds: (1) Phase I-Elaboration of paraxial cervical air sacs in basal theropods no later than the earliest Late Triassic. (2) Phase II-Differentiation of avian ventilatory air sacs, including both cranial (clavicular air sac) and caudal (abdominal air sac) divisions, in basal tetanurans during the Jurassic. A heterogeneous respiratory tract with compliant air sacs, in turn, suggests the presence of rigid, dorsally attached lungs with flow-through ventilation. (3) Phase III-Evolution of a primitive costosternal pump in maniraptoriform theropods before the close of the Jurassic. (4) Phase IV-Evolution of an advanced costosternal pump in maniraptoran theropods before the close of the Jurassic. In addition, we conclude: (5) The advent of avian unidirectional lung ventilation is not possible to pinpoint, as osteological correlates have yet to be identified for uni- or bidirectional lung ventilation. (6) The origin and evolution of avian air sacs may have been driven by one or more of the following three factors: flow-through lung ventilation, locomotory balance, and/or thermal regulation.

The biological control of insect pests is based on the use of natural enemies. However, the growing information on the molecular mechanisms underpinning the interactions between insects and their natural antagonists can be exploited to develop "bio-inspired" pest control strategies, mimicking suppression mechanisms shaped by long co-evolutionary processes. Here we focus on a virulence factor encoded by the polydnavirus associated with the braconid wasp Toxoneuron nigriceps (TnBV), an endophagous parasitoid of noctuid moth larvae. This virulence factor (TnBVANK1) is a member of the viral ankyrin (ANK) protein family, and appears to be involved both in immunosuppression and endocrine alterations of the host. Transgenic tobacco plants expressing TnBVANK1 showed insecticide activity and caused developmental delay in Spodoptera littoralis larvae feeding on them. This effect was more evident in a transgenic line showing a higher number of transcripts of the viral gene. However, this effect was not associated with evidence of translocation into the haemocoel of the entire protein, where the receptors of TnBVANK1 are putatively located. Indeed, immunolocalization experiments evidenced the accumulation of this viral protein in the midgut, where it formed a thick layer coating the brush border of epithelial cells. In vitro transport experiments demonstrated that the presence of recombinant TnBVANK1 exerted a dose-dependent negative impact on amino acid transport. These results open new perspectives for insect control and stimulate additional research efforts to pursue the development of novel bioinsecticides, encoded by parasitoid-derived genes. However, future work will have to carefully evaluate any effect that these molecules may have on beneficial insects and on non-target organisms.

This study provides a general approach to the presence and possible role of orexins and their receptors in the gut (three gastric chambers and intestine) of confined environment bottlenose dolphin. The expression of prepro-orexin, orexin A and B and orexin 1 and 2 receptors were investigated by single immunostaining and western blot analysis. The co-localization of vasoactive intestinal peptide and orexin 1 receptor in the enteric nervous system was examined by double immunostaining. Also, orexin A concentration were measured in plasma samples to assess the possible diurnal variation of the plasma level of peptide in this species. Our results showed that the orexin system is widely distributed in bottlenose dolphin enteric nervous system of the all gastrointestinal tract examined. They are very peculiar and partially differs from that of terrestrial mammals. Orexin peptides and prepro-orexin were expressed in the main stomach, pyloric stomach and proximal intestine; while orexin receptors were expressed in the all examined tracts, with the exception of main stomach where found no evidence of orexin 2 receptor. Co-localization of vasoactive intestinal peptide and orexin 1 receptor were more evident in the pyloric stomach and proximal intestine. These data could suggest a possible role of orexin system on the contractility of bottlenose dolphin gastrointestinal districts. Finally, in agreement with several reports, bottlenose dolphin orexin A plasma level was higher in the morning during fasting. Our results emphasize some common features between bottlenose dolphin and terrestrial mammals. Certainly, further functional investigations may help to better explain the role of the orexin system in the energy balance of bottlenose dolphin and the complex interaction between feeding and digestive physiology.

We describe an extensive ichnofossil assemblage from the likely Cenomanian-age 'lower' and 'upper' units of the 'Kem Kem beds' in southeastern Morocco. In the lower unit, trace fossils include narrow vertical burrows in cross-bedded sandstones and borings in dinosaur bone, with the latter identified as the insect ichnotaxon Cubiculum ornatus. In the upper unit, several horizons preserve abundant footprints from theropod dinosaurs. Sauropod and ornithischian footprints are much rarer, similar to the record for fossil bone and teeth in the Kem Kem assemblage. The upper unit also preserves a variety of invertebrate traces including Conichnus (the resting trace of a sea-anemone), Scolicia (a gastropod trace), Beaconites (a probable annelid burrow), and subvertical burrows likely created by crabs for residence and detrital feeding on a tidal flat. The ichnofossil assemblage from the Upper Cretaceous Kem Kem beds contributes evidence for a transition from predominantly terrestrial to marine deposition. Body fossil and ichnofossil records together provide a detailed view of faunal diversity and local conditions within a fluvial and deltaic depositional setting on the northwestern coast of Africa toward the end of the Cretaceous.

Adenoidal hypertrophy (AH) is a frequent problem in children. A preliminary study evidenced that intranasal hypertonic solutions may exert an anti-inflammatory activity. The aim of the study is to evaluate the effect of intranasal hypertonic or isotonic solutions in children affected with AH. For this purpose, 78 children with AH were evaluated in a randomised and controlled study. Inclusion criteria for the study required that each patient had to have a III or IV degree of AH on the initial endoscopic examination. Children were treated with intranasal hypertonic or isotonic saline solution for 8 weeks. After treatment, endoscopy was performed to evaluate AH degree. Hypertonic treatment was associated with significant (p

Troodontids are a predominantly small-bodied group of feathered theropod dinosaurs notable for their close evolutionary relationship with Avialae. Despite a diverse Asian representation with remarkable growth in recent years, the North American record of the clade remains poor, with only one controversial species--Troodon formosus--presently known from substantial skeletal remains.Here we report a gracile new troodontid theropod--Talos sampsoni gen. et sp. nov.--from the Upper Cretaceous Kaiparowits Formation, Utah, USA, representing one of the most complete troodontid skeletons described from North America to date. Histological assessment of the holotype specimen indicates that the adult body size of Talos was notably smaller than that of the contemporary genus Troodon. Phylogenetic analysis recovers Talos as a member of a derived, latest Cretaceous subclade, minimally containing Troodon, Saurornithoides, and Zanabazar. MicroCT scans reveal extreme pathological remodeling on pedal phalanx II-1 of the holotype specimen likely resulting from physical trauma and subsequent infectious processes.Talos sampsoni adds to the singularity of the Kaiparowits Formation dinosaur fauna, which is represented by at least 10 previously unrecognized species including the recently named ceratopsids Utahceratops and Kosmoceratops, the hadrosaurine Gryposaurus monumentensis, the tyrannosaurid Teratophoneus, and the oviraptorosaurian Hagryphus. The presence of a distinct troodontid taxon in the Kaiparowits Formation supports the hypothesis that late Campanian dinosaurs of the Western Interior Basin exhibited restricted geographic ranges and suggests that the taxonomic diversity of Late Cretaceous troodontids from North America is currently underestimated. An apparent traumatic injury to the foot of Talos with evidence of subsequent healing sheds new light on the paleobiology of deinonychosaurians by bolstering functional interpretations of prey grappling and/or intraspecific combat for the second pedal digit, and supporting trackway evidence indicating a minimal role in weight bearing.

Ex vivo-generated erythroblasts represent alternative transfusion products. However, inclusion of bovine components in media used for their growth precludes clinical use, highlighting the importance of developing culture media based on pharmaceutical grade reagents. In addition, because adult blood generates ex vivo lower numbers of erythroblasts than cord blood, cord blood has been proposed as the source of choice for ex vivo erythroblast production. To clarify the potential of adult blood to generate erythroblasts ex vivo, experiments were designed to identify growth factors [stem cell factor (SCF), interleukin-3 (IL-3), erythropoietin (EPO), and/or thrombopoietin (TPO)] and the optimal concentration and addition schedule of hormones (dexamethasone and estradiol) sustaining maximal erythroid amplification from adult blood mononuclear cells (MNC) using media with serum previously defined as human erythroid massive amplification culture (HEMA ser ). Adult MNC stimulated with SCF and IL-3 in combination with EPO generated a 6–12-fold increase in erythroid cells while TPO was ineffective. Dexamethasone and estradiol (both at 10 −6 M) exerted partially overlapping but nonredundant functions. Dexamethasone was indispensable in the first 10 days of culture while estradiol was required from day 10 on. The growth factor and hormone combinations identified in HEMA ser were then used to formulate a media composed of dialyzed pharmaceutical grade human albumin, human albumin-lipid liposomes, and iron-saturated recombinant human tranferrin (HEMA def ). HEMA def sustained erythroid amplification as efficiently as HEMA ser for cord blood MNC and 10-fold higher than HEMA ser for adult blood MNC. In fact, the numbers of erythroblasts generated in HEMA def by adult MNC were similar to those generated by cord blood MNC. In conclusion, this study identifies growth factors, hormone combinations, and human protein-based media that allow similar levels of ex vivo erythroid expansion from adult and cord blood MNC, paving the way to evaluate adult blood as a source of ex vivo-expanded erythroblasts for transfusion.

The most common allergic diseases, such as rhinitis, asthma and atopic dermatitis, are sustained by allergic inflammation, the treatment of which requires anti-inflammatory activity. Among the available treatments, allergen immunotherapy (IT) has a documented impact on allergic inflammation which persists after its discontinuation and modifies the natural course of allergy. The anti-inflammatory effects of IT, and particularly of sublingual IT (SLIT), are based on the ability to modify the phenotype of T cells which, in allergic subjects, are characterized by a prevalence of the Th2 type, with production of IL-4, IL-5, IL-13, IL-17, and IL-32 cytokines. IT-induced changes result in a Th1-type response (immune deviation) related to an increased IFN-gamma and IL-2 production or in a Th2 reduced activity, through a mechanism of anergy or tolerance. It is now known that T cell tolerance is characterized by the generation of allergen-specific Treg cells, which produce cytokines such as IL-10 and TGF-beta with immunosuppressant and/or immunoregulatory activity. Recent studies suggest that the anti-inflammatory mechanism of SLIT is similar to classical, subcutaneous IT, with a prominent role in SLIT for mucosal dendritic cells. The tolerance pattern induced by Treg accounts for the suppressed or reduced activity of inflammatory cells and for the isotypic switch of antibody synthesis from IgE to IgG, and especially to IgG4. Data obtained from biopsies clearly indicate that the pathophysiology of the oral mucosa plays a pivotal role in inducing tolerance to the sublingually administered allergen.