ALS-linked protein disulfide isomerase variants cause motor dysfunction.

Disturbance of endoplasmic reticulum (ER) proteostasis is a common feature of amyotrophic lateral sclerosis (ALS). Protein disulfide isomerases (PDIs) areERfoldases identified as possibleALSbiomarkers, as well as neuroprotective factors. However, no functional studies have addressed their impact on the disease process. Here, we functionally characterized fourALS-linked mutations recently identified in two majorPDIgenes,PDIA1 andPDIA3/ERp57. Phenotypic screening in zebrafish revealed that the expression of thesePDIvariants induce motor defects associated with a disruption of motoneuron connectivity. Similarly, the expression of mutantPDIs impaired dendritic outgrowth in motoneuron cell culture models. Cellular and biochemical studies identified distinct molecular defects underlying the pathogenicity of thesePDImutants. Finally, targetingERp57 in the nervous system led to severe motor dysfunction in mice associated with a loss of neuromuscular synapses. This study identifiesERproteostasis imbalance as a risk factor forALS, driving initial stages of the disease.

Partial acquisition of stemness properties in tumorspheres obtained from interleukin-8-treated MCF-7 cells.

The interleukin-8 is an important regulator of the tumor microenvironment, promoting the epithelial-mesenchymal transition and the acquisition of stem-like cell properties in cancer cells. The tumorsphere-formation assay has been used for the identification of cancer stem cell. Interleukin-8 induces the formation of larger tumorspheres in Michigan Cancer Foundation-7 (MCF-7) cells, suggesting cancer stem cell enrichment. In this work, we aimed to study the phenotypic and functional characteristics of the cells present within the tumorspheres of MCF-7 cells previously treated with interleukin-8. MCF-7 cells treated for 5 days or not with this cytokine were further cultivated in ultralow attachment plates for another 5 days to allow tumorspheres formation. We showed that the enhanced sphere formation by MCF-7 cells was not a consequence of higher cell proliferation by interleukin-8 stimulation. Despite maintaining an epithelial-mesenchymal transition phenotype with the presence of epithelial and mesenchymal markers, basic stemness properties were impaired in tumorspheres and in those treated with interleukin-8, while others were increased. Self-renewal capacity was increased in interleukin-8-treated cells only in the first generation of tumorspheres but was not sustained in consecutive assays. Accordingly, self-renewal and reprogramming gene expression, differentiation capacity to adipocytes, and clonogenicity were also impaired. We showed also that tumorspheres were enriched in differentiated luminal cells (EpCAM+/CD49f-). Nevertheless, cells were more quiescent and maintain a partial epithelial-mesenchymal transition, consistent with their increased resistance to Paclitaxel and Doxorubicin. They also presented higher migration and interleukin-8-directed invasion. Therefore, the breast cancer cell line MCF-7, having a low stemness index, might partially acquire some stem-like cell attributes after interleukin-8 stimulation, increasing its aggressiveness.

Randomized Trial of Dexamethasone Versus Prednisone for Children with Acute Asthma Exacerbations.

OBJECTIVE: To determine whether 2 doses of dexamethasone is as effective as 5 days of prednisolone/prednisone therapy in improving symptoms and quality of life of children with asthma exacerbations admitted to the emergency department (ED). STUDY DESIGN: We conducted a randomized, noninferiority trial including patients aged 1-14 years who presented to the ED with acute asthma to compare the efficacy of 2 doses of dexamethasone (0.6 mg/kg/dose, experimental treatment) vs a 5-day course of prednisolone/prednisone (1.5 mg/kg/d, followed by 1 mg/kg/d on days 2-5, conventional treatment). Two follow-up telephone interviews were completed at 7 and 15 days. The primary outcome measures were the percentage of patients with asthma symptoms and quality of life at day 7. Secondary outcomes were unscheduled returns, admissions, adherence, and vomiting. RESULTS: During the study period, 710 children who met the inclusion criteria were invited to participate and 590 agreed. Primary outcome data were available in 557 patients. At day 7, experimental and conventional groups did not show differences related to persistence of symptoms (56.6%, 95% CI 50.6-62.6 vs 58.3%, 95% CI 52.3-64.2, respectively), quality of life score (80.0 vs 77.7, not significant [ns]), admission rate (23.9% vs 21.7%, ns), unscheduled ED return visits (4.6% vs 3.3%, ns), and vomiting (2.1% vs 4.4%, ns). Adherence was greater in the dexamethasone group (99.3% vs 96.0%, P < .05). CONCLUSION: Two doses of dexamethasone may be an effective alternative to a 5-day course of prednisone/prednisolone for asthma exacerbations, as measured by persistence of symptoms and quality of life at day 7. CLINICAL TRIAL REGISTRATION: clinicaltrialsregister.eu: 2013-003145-42.

The Protein-disulfide Isomerase ERp57 Regulates the Steady-state Levels of the Prion Protein.

Although the accumulation of a misfolded and protease-resistant form of the prion protein (PrP) is a key event in prion pathogenesis, the cellular factors involved in its folding and quality control are poorly understood. PrP is a glycosylated and disulfide-bonded protein synthesized at the endoplasmic reticulum (ER). The ER foldase ERp57 (also known as Grp58) is highly expressed in the brain of sporadic and infectious forms of prion-related disorders. ERp57 is a disulfide isomerase involved in the folding of a subset of glycoproteins in the ER as part of the calnexin/calreticulin cycle. Here, we show that levels of ERp57 increase mainly in neurons of Creutzfeldt-Jacob patients. Using gain- and loss-of-function approaches in cell culture, we demonstrate that ERp57 expression controls the maturation and total levels of wild-type PrP and mutant forms associated with human disease. In addition, we found that PrP physically interacts with ERp57, and also with the closest family member PDIA1, but not ERp72. Furthermore, we generated a conditional knock-out mouse for ERp57 in the nervous system and detected a reduction in the steady-state levels of the mono- and nonglycosylated forms of PrP in the brain. In contrast, ERp57 transgenic mice showed increased levels of endogenous PrP. Unexpectedly, ERp57 expression did not affect the susceptibility of cells to ER stress in vitro and in vivo. This study identifies ERp57 as a new modulator of PrP levels and may help with understanding the consequences of ERp57 up-regulation observed in human disease.

Salmonella enterica serovar Typhimurium immunotherapy for B-cell lymphoma induces broad anti-tumour immunity with therapeutic effect.

Despite the efficacy of current immune-chemotherapy for treatment of B-cell non-Hodgkin lymphoma, a substantial proportion of patients relapse, highlighting the need for new therapeutic modalities. The use of live microorganisms to develop anti-tumoural therapies has evolved since Coley's toxin and is now receiving renewed attention. Salmonella Typhimurium has been shown to be highly effective as an anti-tumour agent in many solid cancer models, but it has not been used in haemato-oncology. Here, we report that intra-tumoural administration of LVR01 (attenuated S. Typhimurium strain with safety profile) elicits local and systemic anti-tumour immunity, resulting in extended survival in a lymphoma model. LVR01 induces intra-tumoural recruitment of neutrophils and activated CD8(+) T cells, as well as increasing the natural killer cell activation status. Furthermore, a systemic specific anti-tumour response with a clear T helper type 1 profile was observed. This approach is an alternative therapeutic strategy for lymphoma patients that could be easily moved into clinical trials.

The MADS-box genes SOC1 and AGL24 antagonize XAL2 functions in Arabidopsis thaliana root development.

MADS-domain transcription factors play pivotal roles in numerous developmental processes in Arabidopsis thaliana. While their involvement in flowering transition and floral development has been extensively examined, their functions in root development remain relatively unexplored. Here, we explored the function and genetic interaction of three MADS-box genes (XAL2, SOC1 and AGL24) in primary root development. By analyzing loss-of-function and overexpression lines, we found that SOC1 and AGL24, both critical components in flowering transition, redundantly act as repressors of primary root growth as the loss of function of either SOC1 or AGL24 partially recovers the primary root growth, meristem cell number, cell production rate, and the length of fully elongated cells of the short-root mutant xal2-2. Furthermore, we observed that the simultaneous overexpression of AGL24 and SOC1 leads to short-root phenotypes, affecting meristem cell number and fully elongated cell size, whereas SOC1 overexpression is sufficient to affect columella stem cell differentiation. Additionally, qPCR analyses revealed that these genes exhibit distinct modes of transcriptional regulation in roots compared to what has been previously reported for aerial tissues. We identified 100 differentially expressed genes in xal2-2 roots by RNA-seq. Moreover, our findings revealed that the expression of certain genes involved in cell differentiation, as well as stress responses, which are either upregulated or downregulated in the xal2-2 mutant, reverted to WT levels in the absence of SOC1 or AGL24.

RECAPACITA PROJECT: Impact of the New York Convention on capacity modification judgments in persons with severe mental disorders: A comparative study using mixed methodology.

In 2013, Spain aligned its capacity modification processes (CM) legislation with the UN Convention on the rights of persons with disabilities, specifically for individuals with severe mental disorders (SMD). The reforms replaced incapacity verdicts with support provision and introduced the term "CM". However, the social impact of these changes remains uncertain. The RECAPACITA project was initiated to generate knowledge on SMD and CM, and this study aims to investigate modifications in CM sentences and associated terminology. Using a qualitative-quantitative methodology, content analysis was conducted on 56 sentences from individuals with SMD. Terminology analysis utilized 19 sentences to achieve information saturation. A comparison was made between sentences prior to 2013 and those spanning 2014 to 2023, analyzing the data through ANOVA and Bonferroni tests (significance level: 0.05). The analysis revealed that psychiatric illness, its evolution, lack of self-governance, and economic management were frequently mentioned aspects in the sentences. However, no significant correlations were found. Qualitatively, mentions of self-governance were more prevalent in sentences before 2013. Conversely, after 2013, there was an increased focus on substances use, lack of insight and medical adherence, and the need for support in daily life. The term "incapable person" appeared in 100% of the sentences, indicating no differences in terminology. The study suggests that current CM sentences provide increasingly individualized information, addressing the specific support needs of individuals. To enhance future legal proceedings, incorporating neuroscience in studying SMD individuals and reconsidering terminology based on Convention guidelines is recommended.

Inkjet-printed morphogenesis of tumor-stroma interface using bi-cellular bioinks of collagen-poly(N-isopropyl acrylamide-co-methyl methacrylate) mixture.

Recent advances in biomaterials and 3D printing/culture methods enable various tissue-engineered tumor models. However, it is still challenging to achieve native tumor-like characteristics due to lower cell density than native tissues and prolonged culture duration for maturation. Here, we report a new method to create tumoroids with a mechanically active tumor-stroma interface at extremely high cell density. This method, named "inkjet-printed morphogenesis" (iPM) of the tumor-stroma interface, is based on a hypothesis that cellular contractile force can significantly remodel the cell-laden polymer matrix to form densely-packed tissue-like constructs. Thus, differential cell-derived compaction of tumor cells and cancer-associated fibroblasts (CAFs) can be used to build a mechanically active tumor-stroma interface. In this methods, two kinds of bioinks are prepared, in which tumor cells and CAFs are suspended respectively in the mixture of collagen and poly (N-isopropyl acrylamide-co-methyl methacrylate) solution. These two cellular inks are inkjet-printed in multi-line or multi-layer patterns. As a result of cell-derived compaction, the resulting structure forms tumoroids with mechanically active tumor-stroma interface at extremely high cell density. We further test our working hypothesis that the morphogenesis can be controlled by manipulating the force balance between cellular contractile force and matrix stiffness. Furthermore, this new concept of "morphogenetic printing" is demonstrated to create more complex structures beyond current 3D bioprinting techniques.

Phagocyte-specific S100 proteins in the local response to the Echinococcus granulosus larva.

Infection by larval Echinococcus granulosus is usually characterized by tight inflammatory control. However, various degrees of chronic granulomatous inflammation are also observed, reaching a high point in infection of cattle by the most prevalent parasite strain worldwide, which is not well adapted to this host species. In this context, epithelioid and multinucleated giant macrophages surround the parasite, and the secreted products of these cells often associate with the larval wall. The phagocyte-specific S100 proteins, S100A8, S100A9 and S100A12, are important non-conventionally secreted amplifiers of inflammatory responses. We have analysed by proteomics and immunohistochemistry the presence of these proteins at the E. granulosus larva-host interface. We found that, in the context of inflammatory control as observed in human infections, the S100 proteins are not abundant, but S100A9 and S100A8 can be expressed by eosinophils distal to the parasite. In the granulomatous inflammation context as observed in cattle infections, we found that S100A12 is one of the most abundant host-derived, parasite-associated proteins, while S100A9 and S100A8 are not present at similarly high levels. As expected, S100A12 derives mostly from the epithelioid and multinucleated giant cells. S100A12, as well as cathepsin K and matrix metalloproteinase-9, also expressed by E. granulosus-elicited epithelioid cells, are connected to the Th17 arm of immunity, which may therefore be involved in this granulomatous response.

Comparison of human amniotic membrane and collagen nerve wraps around sciatic nerve reverse autografts in a rat model.

Human amniotic membrane (hAM) and collagen nerve wraps are biomaterials that have been investigated as therapies for improving outcomes of peripheral nerve regeneration; however, their efficacy has not been compared. The purpose of this study is to compare the efficacy of collagen and human amniotic membrane nerve wraps in a rodent sciatic nerve reverse autograft model. Lewis rats (n = 29) underwent sciatic nerve injury and repair in which a 10-mm gap was bridged with reverse autograft combined with either no nerve wrap (control), collagen nerve wrap or hAM nerve wrap. Behavioral analyses were performed at baseline and 4, 8 and 12 weeks. Electrophysiological studies were conducted at 8, 10 and 12 weeks. Additional outcomes assessed included gastrocnemius muscle weights, nerve adhesions, axonal regeneration and scarring at 12 weeks. Application of both collagen and hAM nerve wraps resulted in improvement of functional and histologic outcomes when compared with controls, with a greater magnitude of improvement for the experimental group treated with hAM nerve wraps. hAM-treated animals had significantly higher numbers of axons compared to control animals (p < 0.05) and significantly less perineural fibrosis than both control and collagen treated nerves (p < 0.05). The ratio of experimental to control gastrocnemius weights was significantly greater in hAM compared to control samples (p < 0.05). We conclude that hAM nerve wraps are a promising biomaterial that is effective for improving outcomes of peripheral nerve regeneration, resulting in superior nerve regeneration and functional recovery compared to collagen nerve wraps and controls.

Histochemical staining for intestinal dysganglionosis: over 30 years experience with more than 1,500 biopsies.

PURPOSE: Intestinal dysganglionosis are a group of anomalies of the enteric nervous system that constitute infrequent but severe forms of constipation. Histochemical stainings are the gold standard diagnostic procedure for intestinal dysganglionosis. This study describes our experience with histochemistry in a large series of patients. METHODS: Between 1977 and 2010, 1,589 biopsies from children with persistent chronic constipation were studied. The specimens were snap frozen, sectioned and stained with acetylcholinesterase (AChE), acetylcholinesterase counterstained with hematoxilin and succinic dehydrogenase (SDH) histochemical stainings. RESULTS: Among the 1,589 biopsies, 946 (59.5%) were rectal biopsies, 242 (15.2%) were internal sphincter biopsies, 346 (21.8%) were intestinal mapping studies and 42 (2.7%) of them were colon specimens from surgical resections. From the rectal biopsy group, 544 (57.5%) patients were reported as normal. Hirschsprung disease was found in 163 (17.2%) patients with a median age at diagnosis of 8 months and a male to female ratio of 3:1. Intestinal neuronal dysplasia was found in 162 (17.2%) patients, hypoganglionosis in 3 (0.3%) of them and ganglioneuromatosis in 1 (0.1%). In 73 (7.7%) patients, the biopsy was not conclusive for different reasons. 34 out of the 42 resected colon specimens were Hirschsprung disease. Intestinal neuronal dysplasia was found in the proximal segment of the aganglionic bowel in 15 out of 34 (44%) patients. All the aganglionic resected colon specimens had a previous aganglionic rectal biopsy. There were no false positive results in this group. CONCLUSIONS: Histochemical stainings continue to be the gold standard in the diagnosis of intestinal dysganglionosis. The combination of two histochemical staining techniques provides a high level of accuracy in the diagnosis of intestinal dysganglionosis.

Smartphones addiction associated with academic achievement among dental students: A cross-sectional study.

PURPOSE: The study sought to examine the association between dental students' smartphone addiction and academic achievement. METHODS: Study participants were 374 dental students from the Universidad Cooperativa de Colombia school of dentistry. Smartphone addiction was assessed using the short version of the Smartphone Addiction Scale (SAS-SV), an instrument that was validated a priori using item response theory, information function test, and confirmatory factor analysis. Students' semester grade point average (GPA) served as a measure of academic performance. The association between SAS-SV scores and GPA was tested using generalized linear modeling adjusting for covariates. RESULTS: The prevalence of smartphone addiction was low (4.8%) in this sample of dental students. Smartphone use was significantly and positively associated with GPA (b = 0.012; 95% confidence interval = 0.005-0.020; P = 0.001) while accounting for students' age and year of study. CONCLUSIONS: Smartphone usage was positively associated with dental students' academic performance. Importantly, a small number of students were identified as suffering from smartphone addiction. Future research should help clarify the mechanisms underlying this association, identify students at risk for smartphone addiction, and further elucidate the relevance of these findings in dental education.

[Dermatological emergencies. Prospective and multicentric study in Argentina]. / Urgencias dermatológicas. Estudio prospectivo y multicéntrico en Argentina.

Dermatological emergencies are a frequent reason for emergency departments consultation. In order to determine the prevalence of dermatological emergencies, to describe the kind of dermatological diseases that present as emergencies, to analyze the coincidence between the diagnoses received by the patients in those cases with a previous consultations for the same cutaneous manifestation, and to analyze the behavior according to the health system segment in which they were attended: public segment and private segment; a prospective, observational, analytical, cross-sectional and multi-center study was carried out. Two thousand eight hundred one patients were included. The prevalence of consultations for dermatological emergencies in adults was 15% in the same time period (public segment: 10.6 and private segment: 22.5%, p < 0.05). The consultation was due to an infectious disease in 35.5%, allergic in 29.6% and neoplastic in 8.6%; 0.7% of patients were hospitalized. In 31.7% of patients who had a previous consultation, a coincidence was found between the diagnoses made in 80.7% of those attended by a dermatologist, and 52.6% evaluated by non-dermatologist physician. The high prevalence of dermatological consultations and the existing differences in the probability of receiving an appropriate diagnosis according to the specialization of the intervening professional, show the importance of the presence of dermatology-trained physicians in the emergency area.

Las urgencias dermatológicas constituyen un motivo de consulta frecuente en los departamentos de urgencias. Con el objetivo de determinar la prevalencia de las consultas por urgencias dermatológicas, describir las mismas, analizar la coincidencia entre los diagnósticos recibidos por los pacientes, en los casos que realizaron dos consultas por el mismo cuadro, y analizar el comportamiento de las variables de acuerdo al subsector del sistema de salud en el cual fueron atendidos: subsector público, y subsector privado, se realizó un estudio prospectivo, observacional, analítico, de corte transversal y multicéntrico. Se incluyeron 2801 pacientes. La prevalencia de las consultas por urgencias dermatológicas en adultos fue de 15% en el mismo período horario (subsector público: 10.6% y subsector privado: 22.5%, p < 0.05). Motivó la consulta una enfermedad infecciosa en el 35.5%, alérgica en el 29.6% y neoplásica en el 8.6%. Se hospitalizó el 0.7% de los pacientes. El 31.7% de los pacientes había realizado consultas previas. En estos casos se encontró coincidencia entre los diagnósticos realizados en el 80.7% de los atendidos de forma precedente por un médico dermatólogo, y el 52.6% de los evaluados por médicos no dermatólogos. La alta prevalencia de las consultas por urgencias dermatológicas y las diferencias existentes en la probabilidad de recibir un diagnóstico apropiado de acuerdo con la especialización del profesional interviniente, muestran la importancia de la presencia de un médico con formación en dermatología en el área de urgencias.

Acute Effects of Sitting Out of Bed and Exercise on Lung Aeration and Oxygenation in Critically Ill Subjects.

BACKGROUND: Early mobilization during critical illness is safe and has beneficial effects on functional outcomes. However, its impact on pulmonary function has not been thoroughly explored. We hypothesized that a sitting position out of bed coupled with exercise could result in an improvement in oxygenation and lung aeration. METHODS: The study was conducted on a cohort of adult subjects within a week of their admission to an ICU. Subjects were transferred to a chair and undertook a 15-min session of exercise, either active or passive. Subjects in the control group were only transferred to a chair. Electrical impedance tomography, a reliable bedside technique monitoring regional lung aeration and the distribution of ventilation, was continuously performed, and blood gases were assessed at baseline and 20 min post-exercise. RESULTS: The cohort included 40 subjects, 17 of whom were mechanically ventilated and 23 spontaneously breathing. The control group for each modality consisted of 5 mechanically ventilated or 5 spontaneously breathing subjects. Mild hypoxemia was present in 45% of the spontaneously breathing cohort, whereas the mechanically ventilated subjects demonstrated moderate (50%) or severe (12%) hypoxemia. Compared with the control group, early mobilization induced a significant increase in lung aeration. In mechanically ventilated subjects, lung aeration increased, especially in the anterior lung regions (mean impedance [95% CI]: T1 (baseline in bed) = 1,265 [691-1,839]; T2 (chair sitting) = 2,003 [1,042-2,963]; T3 (exercise) = 1,619 [810 2,427]; T4 (post exercise in chair) = 2,320 [1,186-3,455]). In spontaneously breathing subjects, lung aeration increased mainly in the posterior lung regions (mean impedance [95% CI]: T1 = 380 [124-637]; T2 = 655 [226-1,084]; T3 = 621 [335-906]; T4 = 600 [340-860]). [Formula: see text] increased, especially in subjects with lower [Formula: see text] at baseline (< 200) (133 ± 31 to 158 ± 48, P = .041). CONCLUSIONS: For critically ill subjects, a sitting position and exercise increased lung aeration and were associated with an improvement in [Formula: see text] in the more severely hypoxemic subjects.

Mucosal administration of flagellin protects mice from Streptococcus pneumoniae lung infection.

Streptococcus pneumoniae is a major cause of pneumonia in infants and the elderly. Innate defenses are essential to the control of pneumococcal infections, and deficient responses can trigger disease in susceptible individuals. Here we showed that flagellin can locally activate innate immunity and thereby increase the resistance to acute pneumonia. Flagellin mucosal treatment improved S. pneumoniae clearance in the lungs and promoted increased survival of infection. In addition, lung architecture was fully restored after the treatment of infected mice, indicating that flagellin allows the reestablishment of steady-state conditions. Using a flagellin mutant that is unable to signal through Toll-like receptor 5 (TLR5), we established that TLR5 signaling is essential for protection. In the respiratory tract, flagellin induced neutrophil infiltration into airways and upregulated the expression of genes coding for interleukin 6 (IL-6), tumor necrosis factor alpha (TNF-α), CXCL1, CXCL2, and CCL20. Using depleting antibodies, we demonstrated that neutrophils are major effectors of protection. Further, we found that B- and T-cell-deficient SCID mice clear S. pneumoniae challenge to the same extent as immunocompetent animals, suggesting that these cell populations are not required for flagellin-induced protection. In conclusion, this study emphasizes that mucosal stimulation of innate immunity by a TLR not naturally engaged by S. pneumoniae can increase the potential to cure pneumococcal pneumonia.

Subtype-specific characterization of breast cancer invasion using a microfluidic tumor platform.

Understanding progression of breast cancers to invasive ductal carcinoma (IDC) can significantly improve breast cancer treatments. However, it is still difficult to identify genetic signatures and the role of tumor microenvironment to distinguish pathological stages of pre-invasive lesion and IDC. Presence of multiple subtypes of breast cancers makes the assessment more challenging. In this study, an in-vitro microfluidic assay was developed to quantitatively assess the subtype-specific invasion potential of breast cancers. The developed assay is a microfluidic platform in which a ductal structure of epithelial cancer cells is surrounded with a three-dimensional (3D) collagen matrix. In the developed platform, two triple negative cancer subtypes (MDA-MB-231 and SUM-159PT) invaded into the surrounding matrix but the luminal A subtype, MCF-7, did not. Among invasive subtypes, SUM-159PT cells showed significantly higher invasion and degradation of the surrounding matrix than MDA-MB-231. Interestingly, the cells cultured on the platform expressed higher levels of CD24 than in their conventional 2D cultures. This microfluidic platform may be a useful tool to characterize and predict invasive potential of breast cancer subtypes or patient-derived cells.

MADS-Box Genes Are Key Components of Genetic Regulatory Networks Involved in Abiotic Stress and Plastic Developmental Responses in Plants.

Plants, as sessile organisms, adapt to different stressful conditions, such as drought, salinity, extreme temperatures, and nutrient deficiency, via plastic developmental and growth responses. Depending on the intensity and the developmental phase in which it is imposed, a stress condition may lead to a broad range of responses at the morphological, physiological, biochemical, and molecular levels. Transcription factors are key components of regulatory networks that integrate environmental cues and concert responses at the cellular level, including those that imply a stressful condition. Despite the fact that several studies have started to identify various members of the MADS-box gene family as important molecular components involved in different types of stress responses, we still lack an integrated view of their role in these processes. In this review, we analyze the function and regulation of MADS-box gene family members in response to drought, salt, cold, heat, and oxidative stress conditions in different developmental processes of several plants. In addition, we suggest that MADS-box genes are key components of gene regulatory networks involved in plant responses to stress and plant developmental plasticity in response to seasonal changes in environmental conditions.

Genomic Analysis of Colombian Leishmania panamensis strains with different level of virulence.

The establishment of Leishmania infection in mammalian hosts and the subsequent manifestation of clinical symptoms require internalization into macrophages, immune evasion and parasite survival and replication. Although many of the genes involved in these processes have been described, the genetic and genomic variability associated to differences in virulence is largely unknown. Here we present the genomic variation of four Leishmania (Viannia) panamensis strains exhibiting different levels of virulence in BALB/c mice and its application to predict novel genes related to virulence. De novo DNA sequencing and assembly of the most virulent strain allowed comparative genomics analysis with sequenced L. (Viannia) panamensis and L. (Viannia) braziliensis strains, and showed important variations at intra and interspecific levels. Moreover, the mutation detection and a CNV search revealed both base and structural genomic variation within the species. Interestingly, we found differences in the copy number and protein diversity of some genes previously related to virulence. Several machine-learning approaches were applied to combine previous knowledge with features derived from genomic variation and predict a curated set of 66 novel genes related to virulence. These genes can be prioritized for validation experiments and could potentially become promising drug and immune targets for the development of novel prophylactic and therapeutic interventions.

Electrocardiographic Changes After Suicidal Digoxin Intoxication in a Healthy Woman.

BACKGROUND: Suicidal digoxin intoxication is a rare clinical entity. Clinical suspicious remains of paramount importance as adequate interpretation of the electrocardiographic changes enable to readily initiate treatment. METHOD: We describe a case of suicidal attempt after massive digoxin intake that was satisfactory managed with conservative management strategy that involved a close clinical surveillance of the evolving electrocardiographic changes and digoxin serum levels.

Disulfide cross-linked multimers of TDP-43 and spinal motoneuron loss in a TDP-43A315T ALS/FTD mouse model.

Tar DNA binding protein 43 (TDP-43) is the principal component of ubiquitinated protein inclusions present in nervous tissue of most cases of both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Previous studies described a TDP-43A315T transgenic mouse model that develops progressive motor dysfunction in the absence of protein aggregation or significant motoneuron loss, questioning its validity to study ALS. Here we have further characterized the course of the disease in TDP-43A315T mice using a battery of tests and biochemical approaches. We confirmed that TDP-43 mutant mice develop impaired motor performance, accompanied by progressive body weight loss. Significant differences were observed in life span between genders, where females survived longer than males. Histopathological analysis of the spinal cord demonstrated a significant motoneurons loss, accompanied by axonal degeneration, astrogliosis and microglial activation. Importantly, histopathological alterations observed in TDP-43 mutant mice were similar to some characteristic changes observed in mutant SOD1 mice. Unexpectedly, we identified the presence of different species of disulfide-dependent TDP-43 aggregates in cortex and spinal cord tissue. Overall, this study indicates that TDP-43A315T transgenic mice develop key features resembling key aspects of ALS, highlighting its relevance to study disease pathogenesis.