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Life expectancy has increased globally in recent decades, driving interest in maintaining a healthy life that includes preservation of physical and mental abilities, particularly in elderly people. The gut microbiome becomes increasingly perturbed with aging so the use of probiotics can be a strategy for maintaining a balanced gut microbiome. A previous report showed that Bifidobacterium animalis subsp. lactis BPL1™ induces through its lipoteichoic acid (LTA) fat reduction activities via the insulin/IGF-1 signaling pathway. Here, we have delved into the mechanism of action, eliminating alternative pathways as putative mechanisms. Furthermore, we have identified that BPL1™, its heat treated form (BPL1™ HT) and its LTA prolong longevity in Caenorhabditis elegans (C. elegans) in an insulin/IGF-1-dependent mechanism, and its consumption improves the oxidative stress response, gut permeability and protection against pathogenic infections. Furthermore, positive effects on C. elegans stress-related behaviors and in the Alzheimer's Disease model were found, highlighting the potential of the strain in improving the cognitive functions and proteotoxicity in the nematode. These results indicate the pivotal role of the IGF-1 pathway in the activity of the strain and pave the way for potential applications of BPL1™, BPL1™ HT and its LTA in the field of longevity and age-related markers.

To systematically investigate the complexity of neuron specification regulatory networks, we performed an RNA interference (RNAi) screen against all 875 transcription factors (TFs) encoded in Caenorhabditis elegans genome and searched for defects in nine different neuron types of the monoaminergic (MA) superclass and two cholinergic motoneurons. We identified 91 TF candidates to be required for correct generation of these neuron types, of which 28 were confirmed by mutant analysis. We found that correct reporter expression in each individual neuron type requires at least nine different TFs. Individual neuron types do not usually share TFs involved in their specification but share a common pattern of TFs belonging to the five most common TF families: homeodomain (HD), basic helix loop helix (bHLH), zinc finger (ZF), basic leucine zipper domain (bZIP), and nuclear hormone receptors (NHR). HD TF members are overrepresented, supporting a key role for this family in the establishment of neuronal identities. These five TF families are also prevalent when considering mutant alleles with previously reported neuronal phenotypes in C. elegans , Drosophila , and mouse. In addition, we studied terminal differentiation complexity focusing on the dopaminergic terminal regulatory program. We found two HD TFs (UNC-62 and VAB-3) that work together with known dopaminergic terminal selectors (AST-1, CEH-43, CEH-20). Combined TF binding sites for these five TFs constitute a cis -regulatory signature enriched in the regulatory regions of dopaminergic effector genes. Our results provide new insights on neuron-type regulatory programs in C. elegans that could help better understand neuron specification and evolution of neuron types., (© 2022 Jimeno-Martín et al.; Published by Cold Spring Harbor Laboratory Press.)

The potential use of electrodeposition to synthesize a hybrid magnetostrictive/magnetoelectric layered system is shown in this paper. By appropriately adjusting pH, growth potential, and electrolyte composition, it is possible to achieve thin films in which magnetoelectric oxide GaFeO 3 (GFO) is formed in close contact with magnetostrictive metallic FeGa alloy. X-ray diffractometry shows the formation of FeGa as well as GFO and Fe oxides. Electron microscopy observations reveal that GFO mainly segregates in grain boundaries. Samples are ferromagnetic with an isotropic magnetic behavior in the sample plane. Magnetic stripes are observed by magnetic force microscopy and are correlated to Fe 3 O 4 . When its segregation is minimal, the absence of stripes can be used to monitor Fe oxide segregation.

During development, signal-regulated transcription factors (TFs) act as basal repressors and upon signalling through morphogens or cell-to-cell signalling shift to activators, mediating precise and transient responses. Conversely, at the final steps of neuron specification, terminal selector TFs directly initiate and maintain neuron-type specific gene expression through enduring functions as activators. C. elegans contains 3 types of serotonin synthesising neurons that share the expression of the serotonin biosynthesis pathway genes but not of other effector genes. Here, we find an unconventional role for LAG-1, the signal-regulated TF mediator of the Notch pathway, as terminal selector for the ADF serotonergic chemosensory neuron, but not for other serotonergic neuron types. Regulatory regions of ADF effector genes contain functional LAG-1 binding sites that mediate activation but not basal repression. lag-1 mutants show broad defects in ADF effector genes activation, and LAG-1 is required to maintain ADF cell fate and functions throughout life. Unexpectedly, contrary to reported basal repression state for LAG-1 prior to Notch receptor activation, gene expression activation in the ADF neuron by LAG-1 does not require Notch signalling, demonstrating a default activator state for LAG-1 independent of Notch. We hypothesise that the enduring activity of terminal selectors on target genes required uncoupling LAG-1 activating role from receiving the transient Notch signalling., Competing Interests: The authors have declared that no competing interests exist.

Surface Acoustic Waves (SAW) are one of the possible solutions to target the challenges faced by modern spintronic devices. The stress carried by the SAW can decrease the current required to achieve magnetic switching or domain wall movement by spin transfer torque. Although the last decade has produced very relevant results in this field, it is still important to study the effects of a SAW on the basic unit of many spintronic devices, a ferromagnetic nanostrip. In this work, we perform a complete set of measurements and simulations to characterize the magnetization process of a Ni nanostrip under the influence of a SAW. We find that the SAW increases the mobility and the depinning ability of the magnetic domain walls and consequently, promotes a sharper approach to saturation and substantially decreases coercivity. We have also found other two interesting effects. When the SAW has sufficient energy, is able to trigger irreversible transitions even before switching the direction of the external magnetic field. Additionally, we have found that the magnetization process depends on the direction of the travelling SAW.

Neuronal specification is a protracted process that begins with the commitment of progenitor cells and culminates with the generation of mature neurons. Many transcription factors are continuously expressed during this process but it is presently unclear how these factors modify their targets as cells transition through different stages of specification. In olfactory bulb adult neurogenesis, the transcription factor PBX1 controls neurogenesis in progenitor cells and the survival of migrating neuroblasts. Here, we show that, at later differentiation stages, PBX1 also acts as a terminal selector for the dopaminergic neuron fate. PBX1 is also required for the morphological maturation of dopaminergic neurons and to repress alternative interneuron fates, findings that expand the known repertoire of terminal-selector actions. Finally, we reveal that the temporal diversification of PBX1 functions in neuronal specification is achieved, at least in part, through the dynamic regulation of alternative splicing. In Caenorhabditis elegans , PBX/CEH-20 also acts as a dopaminergic neuron terminal selector, which suggests an ancient role for PBX factors in the regulation of terminal differentiation of dopaminergic neurons., Competing Interests: Competing interestsThe authors declare no competing or financial interests., (© 2020. Published by The Company of Biologists Ltd.)

Cell differentiation is controlled by individual transcription factors (TFs) that together activate a selection of enhancers in specific cell types. How these combinations of TFs identify and activate their target sequences remains poorly understood. Here, we identify the cis -regulatory transcriptional code that controls the differentiation of serotonergic HSN neurons in Caenorhabditis elegans . Activation of the HSN transcriptome is directly orchestrated by a collective of six TFs. Binding site clusters for this TF collective form a regulatory signature that is sufficient for de novo identification of HSN neuron functional enhancers. Among C. elegans neurons, the HSN transcriptome most closely resembles that of mouse serotonergic neurons. Mouse orthologs of the HSN TF collective also regulate serotonergic differentiation and can functionally substitute for their worm counterparts which suggests deep homology. Our results identify rules governing the regulatory landscape of a critically important neuronal type in two species separated by over 700 million years., Competing Interests: CL, MM, CM, AA, ÁJ, LC, PW, NF No competing interests declared, (© 2018, Lloret-Fernández et al.)

Transcriptional activation of the EVI1 oncogene (3q26) leads to aggressive forms of human acute myeloid leukemia (AML). However, the mechanism of EVI1-mediated leukemogenesis has not been fully elucidated. Previously, by characterizing the EVI1 promoter, we have shown that RUNX1 and ELK1 directly regulate EVI1 transcription. Intriguingly, bioinformatic analysis of the EVI1 promoter region identified the presence of several EVI1 potential binding sites. Thus, we hypothesized that EVI1 could bind to these sites regulating its own transcription. In this study, we show that there is a functional interaction between EVI1 and its promoter, and that the different EVI1 isoforms (EVI1-145kDa, EVI1-Δ324 and MDS1-EVI1) regulate the transcription of EVI1 transcripts through distinct promoter regions. Moreover, we determine that the EVI1-145kDa isoform activates EVI1 transcription, whereas EVI1-Δ324 and MDS1-EVI1 act as repressors. Finally, we demonstrate that these EVI1 isoforms are involved in cell transformation; functional experiments show that EVI1-145kDa prolongs the maintenance of hematopoietic stem and progenitor cells; conversely, MDS1-EVI1 repressed hematopoietic stem and progenitor colony replating capacity. We demonstrate for the first time that EVI1 acts as a regulator of its own expression, highlighting the complex regulation of EVI1, and open new directions to better understand the mechanisms of EVI1 overexpressing leukemias., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Magnetic nanoparticles were generated by ultrashort pulsed laser ablation of an iron target in water, methanol, ethanol, acetone and toluene. The relationship between ablation rate, liquid properties and the physical and chemical properties of the nanoparticles was studied. Composition, morphology and magnetic properties were investigated by TEM, XPS and vibrating-sample (VSM) and SQUID magnetometry. The properties of the generated nanoparticle ensembles reflected the influence of the liquid environment on the particle formation process. For example, the composition was strongly dependent on the carbon to oxygen ratio within the molecules of the liquid. In contrast to short pulsed laser ablation in liquids, the nanoparticles generated by ultrashort pulses had a higher level of polycrystallinity., (© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Objectives: PSA is a frequently used marker in the daily clinical practice for the diagnosis and management of prostate cancer. We analysed the use of PSA in our health department in patients with and without prostate cancer diagnosis., Methods: The registry of all PSA petitions in our health department during 2011 and 2012 was used. Demographic data were used to establish each year's population and the data corresponding to the prevalence of prostate cancer patients, performing a descriptive study. Thus, the use of PSA in patients with or without prostate cancer was studied., Results: 25.700 PSA petitions are issued annually in our department over a total of 67.000 males older than 45. This entails a cost of 332.815 Euros annually. Within the group of patients with no prostate cancer diagnosis, it was noticed that the percentage of individuals with at least one annual PSA petition per decade of age is of 23% in males in their fifties, 40% in their sixties, 46% in their seventies, and 36% in their eighties or successive decades. Furthermore, in these cancer-free patients, around 3.800 annual petitions fall on individuals over 75 and with PSA under 4 ng/ml, from which 20% are repeated petitions over the same individual in the same year. Over 1100 males under 45 have an annual PSA. Regarding the average PSA value for decade of age in cancer-free patients, it is of 0.89 +/- 0.4 ng/ml in the forties decade, 1.26 +/- 1.07 ng/ml in the fifties, 1.67 +/- 1.38 ng/ml in the sixties, 1.96 +/- 1.78 ng/ml in the seventies, and 2.24 +/- 2.16 ng/ml in the eighties. We ascertained, also, that for every 144 PSA petitions one prostate cancer case is diagnosed. Regarding the use of this marker in cancer patients, 1.800 petitions are destined to patients follow up annually, and over 200 fall on the newly diagnosed cases., Conclusions: Even though annually less than 50% of males get PSA petitions in any decade of age, its use is sometimes incorrect, including repeated petitions in a short period of time or in individuals of extreme age.

The CD69 type II C-type lectin is one of the earliest indicators of leukocyte activation acting in lymphocyte migration and cytokine secretion. CD69 expression in hematopoietic lineage undergoes rapid changes depending on the cell-lineage, the activation state or the localization of the cell where it is expressed, suggesting a complex and tightly controlled regulation. Here we provide new insights on the transcriptional regulation of CD69 gene in mammal species. Through in silico studies, we analyzed several regulatory features of the 4 upstream conserved non-coding sequences (CNS 1-4) previously described, confirming a major function of CNS2 in the transcriptional regulation of CD69. In addition, multiple transcription binding sites are identified in the CNS2 region by DNA cross-species conservation analysis. By functional approaches we defined a core region of 226bp located within CNS2 as the main enhancer element of CD69 transcription in the hematopoietic cells analyzed. By chromatin immunoprecipitation, binding of RUNX1 to the core-CNS2 was shown in a T cell line. In addition, we found an activating but not essential role of RUNX1 in CD69 gene transcription by site-directed mutagenesis and RNA silencing, probably through the interaction with this potent enhancer specifically in the hematopoietic lineage. In summary, in this study we contribute with new evidences to the landscape of the transcriptional regulation of the CD69 gene., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Germline GATA2 mutations have been identified as the cause of familial syndromes with immunodeficiency and predisposition to myeloid malignancies. GATA2 mutations appear to cause loss of function of the mutated allele leading to haploinsufficiency; however, this postulate has not been experimentally validated as the basis of these syndromes. We hypothesized that mutations that are translated into abnormal proteins could affect the transcription of GATA2, triggering GATA2 deficiency. Chromatin immunoprecipitation and luciferase assays showed that the human GATA2 protein activates its own transcription through a specific region located at -2.4 kb, whereas the p.Thr354Met, p.Thr355del, and p.Arg396Gln germline mutations impair GATA2 promoter activation. Accordingly, GATA2 expression was decreased to ∼58% in a patient with p.Arg396Gln, compared with controls. p.Arg396Gln is the second most common mutation in these syndromes, and no previous functional analyses have been performed. We therefore analyzed p.Arg396Gln. Our data show that p.Arg396Gln is a loss-of-function mutation affecting DNA-binding ability and, as a consequence, it fails to maintain the immature characteristics of hematopoietic stem and progenitor cells, which could result in defects in this cell compartment. In conclusion, we show that human GATA2 binds to its own promoter, activating its transcription, and that the aforementioned mutations impair the transcription of GATA2. Our results indicate that they can affect other GATA2 target genes, which could partially explain the variability of symptoms in these diseases. Moreover, we show that p.Arg396Gln is a loss-of-function mutation, which is unable to retain the progenitor phenotype in cells where it is expressed., (Copyright © 2015 by The American Association of Immunologists, Inc.)

Transcription factors that drive neuron type-specific terminal differentiation programs in the developing nervous system are often expressed in several distinct neuronal cell types, but to what extent they have similar or distinct activities in individual neuronal cell types is generally not well explored. We investigate this problem using, as a starting point, the C. elegans LIM homeodomain transcription factor ttx-3, which acts as a terminal selector to drive the terminal differentiation program of the cholinergic AIY interneuron class. Using a panel of different terminal differentiation markers, including neurotransmitter synthesizing enzymes, neurotransmitter receptors and neuropeptides, we show that ttx-3 also controls the terminal differentiation program of two additional, distinct neuron types, namely the cholinergic AIA interneurons and the serotonergic NSM neurons. We show that the type of differentiation program that is controlled by ttx-3 in different neuron types is specified by a distinct set of collaborating transcription factors. One of the collaborating transcription factors is the POU homeobox gene unc-86, which collaborates with ttx-3 to determine the identity of the serotonergic NSM neurons. unc-86 in turn operates independently of ttx-3 in the anterior ganglion where it collaborates with the ARID-type transcription factor cfi-1 to determine the cholinergic identity of the IL2 sensory and URA motor neurons. In conclusion, transcription factors operate as terminal selectors in distinct combinations in different neuron types, defining neuron type-specific identity features.

Hereby we wish to present the clinical and pathological results of a rare paratesticular sarcome of the spermatic cord. This tumor was a fibrosarcoma in a 55 year old male that started in a most unusual way and developed very quickly. We practised a radical orquitectomy with inguinal ligation of the pedicule without post-operatory therapy. After a 5 year follow up, there is no trace of clinical or radiological recurrence in the region or metastasis. We consider radical surgery to be the only therapeutic alternative, even for cases of fast developing, being in our case a good pronostic.

Unlabelled: Differentiating a primary retroperitoneal seminoma from a metastatic testicular tumor with an occult testicular primary or a burned out testicular cancer remains difficult. We present a case of a burned out tumor. The patient had a retroperitoneal seminoma with ultrasonically and pathologically demonstrated abnormalities in both testes, but without evidence of tumor. The patient received chemotherapy and underwent surgery of the residual retroperitoneal mass and bilateral orchiectomy. All surgical specimens were negative for testis cancer., Conclusion: Primary extragonadal germ cell tumors in the retroperitoneum are a rare entity. The presence of a retroperitoneal tumor with ultrasonographical abnormalities in testicular evaluation should be considered as a metastases of a burned out testicular cancer, and biopsy is mandatory. Surgical evaluation and orchiectomy should be evaluated in a individual setting.

A case of granulocytic sarcoma (chloroma) of hepatic localization is presented. It is a extramedullary strange tumour, composed of immature precursors of myeloid cells. Clinically it can show, before, during or after a acute myeloid leukemia, chronic myeloproliferative disorders or myelodysplastic syndromes. Our patient, 81 year-old male, presented a process of important acute jaundice, with negative image technics, what indicated us the intrahepatic origin, negative tumorals markers, negative serology and hepatic biopsy (the piece of greenish coloration is described) what showed a hepatic sinusoides diffuse infiltration by indifferentiation cellularity, with study immuno-histochemical that was positive for the myeloperoxydase, giving a diagnose compatible with hepatic infiltration for acute myeloid leukemia. The patient doesn't present affectation of peripheral blood, and he died for acute hepatic and renal failure after 8 days of entrance.

A case of primary adrenal bilateral non-Hodgking lymphoma, with depressed adrenal reserve is presented. This rare neoplasm causes rapid evolution and fatal outcome in most cases. In our patient, lethal outcome was associated with severe hypercalcemia and refractary hypotension. Many other complications are due to tumoral lysis syndrome associated with high steroid doses in adrenal insufficiency. This rare entity must be included in the differencial diagnosis of adrenal masses, uni or bilateral, because early diagnostic is important for preventing complications, potentially lethals and for improving survival. Image thecnics and ultrasound-guided or computed-tomography-guided FNA, are best diagnostic methods, but in many cases, definitive diagnostic is obtained by necropsy.