Epithelial cells lining the intestinal mucosa constitute a selective-semipermeable barrier acting as first line of defense in the organism. The number of those cells remains constant during ...physiological conditions, but disruption of epithelial cell homeostasis has been observed in several pathologies. During colitis, epithelial cell proliferation decreases and cell death augments. The mechanism responsible for these changes remains unknown. Here, we show that the pro-inflammatory cytokine IFNγ contributes to the inhibition of epithelial cell proliferation in intestinal epithelial cells (IECs) by inducing the activation of mTORC1. Activation of mTORC1 in response to IFNγ was detected in IECs present along the crypt axis and in colonic macrophages. mTORC1 inhibition enhances cell proliferation, increases DNA damage in IEC. In macrophages, mTORC1 inhibition strongly reduces the expression of pro-inflammatory markers. As a consequence, mTORC1 inhibition exacerbated disease activity, increased mucosal damage, enhanced ulceration, augmented cell infiltration, decreased survival and stimulated tumor formation in a model of colorectal cancer CRC associated to colitis. Thus, our findings suggest that mTORC1 signaling downstream of IFNγ prevents epithelial DNA damage and cancer development during colitis.
•A. seminis phosphoglycerate mutase and elongation factor-Tu function as adhesins.•These proteins interact with sheep fibrinogen and fibronectin.•Immune sera against them inhibit the A. seminis ...adherence to epithelial cells.
Actinobacillus seminis is an autochthon of ovine reproductive organs. However, it is also considered to be a pathogen of these animals and is responsible for causing epididymitis and low fertility, among other pathological diseases. In this study, we describe the identification of two proteins functioning as adhesins in A. seminis. After obtaining surface proteins of this bacterium, two proteins of approximately 25 and 40 kDa were partially purified by ion interchange chromatography. Both proteins interacted with bovine fibronectin and fibrinogen, and they cross-reacted with a polyclonal serum from a sheep infected with A. seminis. Both proteins were identified by mass spectrometry analysis as phosphoglycerate mutase and elongation factor-Tu, respectively. A. seminis was able to adhere to cultured human bladder cells, and pre-incubation of A. seminis with the polyclonal sera against these proteins significantly inhibited their ability to adhere to cells but adherence was not affected by pre-immune serum, indicating their activity as adhesins. The identification of proteins involved in the adhesion of A. seminis to tissues and that serve as virulence factors will help furtherour understanding of the pathogenic mechanisms of this bacterium.
Background Multiple Sclerosis (MS) is a common neurological disease among white populations of European origin. Frequencies among Latin Americans continue to be studied, however, epidemiologic, and ...clinical characterization studies lack from Central American and Caribbean countries. Ethnicity in these countries is uniformly similar with a prevalent Mestizo population. Methods and results Data from January 2014 to December 2019 from Guatemala, El Salvador, Honduras, Nicaragua, Costa Rica, Panama, Dominican Republic, and Aruba on demographic, clinical, MRI and phenotypic traits were determined in coordinated studies: ENHANCE, a population-based, retrospective, observational study on incidence and clinical characteristics, and from the subgroup with MS national registries (Aruba, Dominican Republic, Honduras, and Panama), data on prevalence, phenotypes and demographics. Expanded Disability Status Scale (EDSS), and therapeutic schemes were included. ENHANCE data from 758 patients disclosed 79.8% of Mestizo ethnicity; 72.4% female; median age at onset 31.0 years and 33.2 at diagnosis. The highest incidence rate was from Aruba, 2.3–3.5 × 100,000 inhabitants, and the lowest, 0.07–0.15 × 100,000, from Honduras. Crude prevalence rates per 100,000 inhabitants fluctuated from 27.3 (Aruba) to 1.0 (Honduras). Relapsing MS accounted for 87.4% of cases; EDSS <3.0 determined in 66.6% (mean disease duration: 9.1 years, SD ± 5.0); CSF oligoclonal bands 85.7%, and 87% of subjects hydroxyvitamin D deficient. Common initial therapies were interferon and fingolimod. Switching from interferon to fingolimod was the most common escalation step. The COVID-19 pandemic affected follow-up aspects of these studies. Conclusion This is the first study providing data on frequencies and clinical characteristics from 8 countries from the Central American and Caribbean region, addressing MS as an emergent epidemiologic disorder. More studies from these areas are encouraged.
Healthy immune function depends on precise regulation of lymphocyte activation. During the National Aeronautics and Space Administration (NASA) Apollo and Shuttle eras, multiple spaceflight studies ...showed depressed lymphocyte activity under microgravity (μg) conditions. Scientists on the ground use two models of simulated μg (sμg): 1) the rotating wall vessel (RWV) and 2) the random positioning machine (RPM), to study the effects of altered gravity on cell function before advancing research to the true μg when spaceflight opportunities become available on the International Space Station (ISS). The objective of this study is to compare the effects of true μg and sμg on the expression of key early T-cell activation genes in mouse splenocytes from spaceflight and ground animals. For the first time, we compared all three conditions of microgravity spaceflight, RPM, and RWV during immune gene activation of Il2, Il2rα, Ifnγ, and Tagap; moreover, we confirm two new early T-cell activation genes, Iigp1 and Slamf1. Gene expression for all samples was analyzed using quantitative real-time PCR (qRT-PCR). Our results demonstrate significantly increased gene expression in activated ground samples with suppression of mouse immune function in spaceflight, RPM, and RWV samples. These findings indicate that sμg models provide an excellent test bed for scientists to develop baseline studies and augment true μg in spaceflight experiments. Ultimately, sμg and spaceflight studies in lymphocytes may provide insight into novel regulatory pathways, benefiting both future astronauts and those here on earth suffering from immune disorders.
The activities of both the lateral and frontal cilia of Mercenaria mercenaria were unaffected, either by the two endogenous SCP-related peptides AMSFYFPRMamide and YFAFPRQamide, or by FMRFamide (all ...at 10-6 M). Dopamine (DA) inhibited the lateral cilia; the mean EC50 was 2× 10-6 M. The peptide YFAFPRQamide-but neither AMSFYFPRMamide nor FMRFamide-antagonized the inhibition induced by DA; this effect was dependent on both time and dose. At a DA concentration of 5× 10-7 M, the effect of YFAFPRQamide appeared within 20 min and became maximal within 40-60 min; the mean EC50 at these times was 4.7× 10-11 M. If the concentration of DA was increased to 10-6 M, the maximal effect of the peptide was delayed to 50 min, and the mean EC50 increased to 1.1× 10-7 M. Particle transport by the frontal cilia was inhibited by 5-hydroxytryptamine (5HT); the mean EC50 was 5.7× 10-7 M. Again, only YFAFPRQamide had an antagonistic effect on the 5HT-induced inhibition. At a 5HT concentration of 10-6 M, the effects of YFAFPRQamide did not appear until 45 min; the mean EC50 was 10-6 M. When radioimmunoassayed with an SCP antiserum, the elution profile of a gill extract overlapped those of the SCP-related peptides that had previously been identified in extracts of whole animals. These data suggest that all three SCP analogs occur in the gill. Immunohisto-chemistry of the gill, carried out with a monoclonal antibody raised to SCP B, stained many varicose neuronal fibers. Most of these were associated with the gill musculature, but a sparse innervation of the filaments underlying the cilia was also observed. Some fluorescent nerve cell bodies were also seen in the gill tissue. Our results are consistent with the hypothesis that YFAFPRQamide modulates branchial activities-muscular as well as ciliary-that are associated with feeding.
Subthalamic nucleus (STN) deep brain stimulation (DBS) represents a well-established treatment for patients with advanced Parkinson's disease (PD) insufficiently controlled with medical therapies. ...This study presents the long-term outcomes of patients with PD treated with STN-DBS using an MRI-guided/MRI-verified approach without microelectrode recording.
A cohort of 41 patients who underwent STN-DBS were followed for a minimum period of 5 years, with a subgroup of 12 patients being followed for 8-11 years. Motor status was evaluated using part III of the Unified Parkinson's Disease Rating Scale (UPDRS-III), in on- and off-medication/on-stimulation conditions. Preoperative and postoperative assessments further included activities of daily living (UPDRS-II), motor complications (UPDRS-IV), neuropsychological and speech assessments, as well as evaluation of quality of life. Active contacts localisation was calculated and compared with clinical outcomes.
STN-DBS significantly improved the off-medication UPDRS-III scores, compared with baseline. However, UPDRS scores increased over time after DBS. Dyskinesias, motor fluctuations and demands in dopaminergic medication remained significantly reduced in the long term. Conversely, UPDRS-III on-medication scores deteriorated at 5 and 8 years, mostly driven by axial and bradykinesia subscores. Quality of life, as well as depression and anxiety scores, did not significantly change at long-term follow-up compared with baseline. In our series, severe cognitive decline was observed in 17.1% and 16.7% of the patients at 5 and 8 years respectively.
Our data confirm that STN-DBS, using an MRI-guided/MRI-verified technique, remains an effective treatment for motor 'off' symptoms of PD in the long term with low morbidity.
En su libro Casas del Vedado (1983), la autora cubana María Elena Llana explora temas y estrategias compositivas de las tradiciones literarias no realistas que han mantenido vigencia en ...Hispanoamérica hasta nuestros días. En este trabajo se analiza uno de sus cuentos, «Claudina», con el objetivo de obtener una comprensión de su poética específica en el marco general de la ficción sobrenatural de nuestro continente, así como del sentido simbólico de lo sobrenatural textual empleado por la autora en este relato.
Resumen En su libro Casas del Vedado (1983), la autora cubana María Elena Llana explora temas y estrategias compositivas de las tradiciones literarias no realistas que han mantenido vigencia en ...Hispanoamérica hasta nuestros días. En este trabajo se analiza uno de sus cuentos, «Claudina», con el objetivo de obtener una comprensión de su poética específica en el marco general de la ficción sobrenatural de nuestro continente, así como del sentido simbólico de lo sobrenatural textual empleado por la autora en este relato.
Duchenne muscular dystrophy (DMD) is caused by deficient expression of the cytoskeletal protein, dystrophin. One third of DMD patients also have mental retardation (MR), likely due to mutations ...preventing expression of dystrophin and other brain products of the DMD gene expressed from distinct internal promoters. Loss of Dp71, the major DMD-gene product in brain, is thought to contribute to the severity of MR; however, the specific function of Dp71 is poorly understood.
Complementary approaches were used to explore the role of Dp71 in neuronal function and identify mechanisms by which Dp71 loss may impair neuronal and cognitive functions. Besides the normal expression of Dp71 in a subpopulation of astrocytes, we found that a pool of Dp71 colocalizes with synaptic proteins in cultured neurons and is expressed in synaptic subcellular fractions in adult brains. We report that Dp71-associated protein complexes interact with specialized modular scaffolds of proteins that cluster glutamate receptors and organize signaling in postsynaptic densities. We then undertook the first functional examination of the brain and cognitive alterations in the Dp71-null mice. We found that these mice display abnormal synapse organization and maturation in vitro, altered synapse density in the adult brain, enhanced glutamatergic transmission and reduced synaptic plasticity in CA1 hippocampus. Dp71-null mice show selective behavioral disturbances characterized by reduced exploratory and novelty-seeking behavior, mild retention deficits in inhibitory avoidance, and impairments in spatial learning and memory.
Results suggest that Dp71 expression in neurons play a regulatory role in glutamatergic synapse organization and function, which provides a new mechanism by which inactivation of Dp71 in association with that of other DMD-gene products may lead to increased severity of MR.
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