Salt-Induced Shape-Memory Effect in Gelatin-Based Hydrogels.
Hydrophilic biopolymers display a strong tendency for self-organization into stable secondary, tertiary, and quaternary structures in aqueous environments. These structures are sensitive to changes in external conditions, such as temperature, pH or ions/salts, which may lead to molecular and/or macroscopic transitions. Here, we report on biopolymer-based stimuli-sensitive switchable matrices showing a shape-memory function as an output being alternatively switched by two different input signals, such as environmental changes in salt concentration or temperature. This was realized by implementing a shape-memory function in hydrogels based on the coil-to-helix transition of protein chains in gelatin-based networks. The hydrogels exhibited mechanical properties similar to that of soft tissue (storage modulus G' = 1-100 kPa) and high swelling capabilities (Q = 1000-3000 vol %). In these gelatin-based networks, the covalent netpoints defined the permanent shape while after deformation helicalization of the gelatin acted as reversible stimuli-sensitive switches providing additional crosslinks capable of fixing the deformed temporary shape. By using either chaotropic salts to suppress gelatin helicalization or kosmotropic salts to support conformational changes of gelatin toward a helical orientation, these additional crosslinks could be cleaved or formed. In bending experiments, the strain fixity (Rf) and strain recovery ratios (Rr) were determined. While Rf ranged from 65 to 95% and was depending on the network composition, Rr were independent of the hydrogel composition with values about 100%. In addition, Rf and Rr were independent of the type of chaotropic salt that was used in this study, showing equal Rf and Rr values for MgCl2, NaSCN, and Mg(SCN)2.


The anharmonic vibrational potential and relaxation pathways of the amide I and II modes of N-methylacetamide.
We investigate the influence of isotopic substitution and solvation of N-methylacetamide (NMA) on anharmonic vibrational coupling and vibrational relaxation of the amide I and amide II modes. Differences in the anharmonic potential of isotopic derivatives of NMA in D2O and DMSO-d6 are quantified by extraction of the anharmonic parameters and the transition dipole moment angles from cross-peaks in the two-dimensional infrared (2D-IR) spectra. To interpret the effects of isotopic substitution and solvent interaction on the anharmonic potential, density functional theory and potential energy distribution calculations are performed. It is shown that the origin of anharmonic variation arises from differing local mode contributions to the normal modes of the NMA isotopologues, particularly in amide II. The time domain manifestation of the coupling is the coherent exchange of excitation between amide modes seen as the quantum beats in femtosecond pump-probes. The biphasic behavior of population relaxation of the pump-probe and 2D-IR experiments can be understood by the rapid exchange of strongly coupled modes within the peptide backbone, followed by picosecond dissipation into weakly coupled modes of the bath.


CEBP-β and PLK1 as Potential Mediators of the Breast Cancer/Obesity Crosstalk: In Vitro and In Silico Analyses.
Over the last two decades, obesity has reached pandemic proportions in several countries, and expanding evidence is showing its contribution to several types of malignancies, including breast cancer (BC). The conditioned medium (CM) from mature adipocytes contains a complex of secretes that may mimic the obesity condition in studies on BC cell lines conducted in vitro. Here, we report a transcriptomic analysis on MCF-7 BC cells exposed to adipocyte-derived CM and focus on the predictive functional relevance that CM-affected pathways/processes and related biomarkers (BMs) may have in BC response to obesity. CM was demonstrated to increase cell proliferation, motility and invasion as well as broadly alter the transcript profiles of MCF-7 cells by significantly modulating 364 genes. Bioinformatic functional analyses unraveled the presence of five highly relevant central hubs in the direct interaction networks (DIN), and Kaplan-Meier analysis sorted the CCAAT/enhancer binding protein beta (CEBP-β) and serine/threonine-protein kinase PLK1 (PLK1) as clinically significant biomarkers in BC. Indeed, CEBP-β and PLK1 negatively correlated with BC overall survival and were up-regulated by adipocyte-derived CM. In addition to their known involvement in cell proliferation and tumor progression, our work suggests them as a possible "deus ex machina" in BC response to fat tissue humoral products in obese women.


HIV drug resistance and implications for the introduction of antiretroviral therapy in resource-poor countries.
The development and transmission of HIV drug-resistant viruses is of serious concern and has been shown to significantly diminish the effectiveness of antiretroviral therapy. In addition, cross-resistance between drugs of the same class can seriously limit therapeutic options and may potentially be most problematic in resource-poor settings where new drugs are not widely available. Strategies based on avoidance of virological failure are therefore essential for the long-term success of therapy. In this regard, regionally adapted programs to facilitate proper adherence with therapy need to be urgently implemented, concomitant with expanded access to new antiretroviral drugs. The value of genotypic resistance testing as a prognostic tool to help guide therapeutic decisions has been established. However, the relatively high cost of this novel technology does not warrant its routine utilization at this time in resource-poor countries. Lastly, the genetic barrier of the antiretroviral agents that are prescribed is also an important consideration that needs to be integrated with knowledge of HIV-1 subtypes, drug pharmacology, and medical management of concurrent illnesses. The selection of appropriate first-line antiretroviral combination regimens may be an even more important consideration in developing than developed countries, given that options in the aftermath of treatment failure may be more limited in such settings.


The global bacterial regulator H-NS promotes transpososome formation and transposition in the Tn5 system.
The histone-like nucleoid structuring protein (H-NS) is an important regulator of stress response and virulence genes in gram-negative bacteria. In addition to binding regulatory regions of genes in a structure-specific manner, H-NS also binds in a structure-specific manner to sites in the Tn10 transpososome, allowing it to act as a positive regulator of Tn10 transposition. This is the only example to date of H-NS regulating a transposition system by interacting directly with the transposition machinery. In general, transposition complexes tend to include segments of deformed DNA and given the capacity of H-NS to bind such structures, and the results from the Tn10 system, we asked if H-NS might regulate another transposition system (Tn5) by directly binding the transposition machinery. We show in the current work that H-NS does bind Tn5 transposition complexes and use hydroxyl radical footprinting to characterize the H-NS interaction with the Tn5 transpososome. We also show that H-NS can promote Tn5 transpososome formation in vitro, which correlates with the Tn5 system showing a dependence on H-NS for transposition in vivo. Taken together the results suggest that H-NS might play an important role in the regulation of many different bacterial transposition systems and thereby contribute directly to lateral gene transfer.


Rapid preparation of auto-healing gels with actuating behaviour.
Gels with multiple stimuli-responsive actuating behaviour have shown great potential in many applications. Nevertheless, facile approaches to rapidly preparing gel actuators are still highly needed, and obtaining gels possessing both actuating and auto-healing capabilities remains a challenge. Herein, we report the rapid preparation of gel actuators with a self-healing ability. Dual-component gels, composed of poly(BA-co-VI-co-AM) (G-1) and poly(BA-co-AA-co-AM/β-CD) (G-2) (BA = butyl acrylate, VI = N-vinyl imidazole, AM = acrylamide, AA = acrylic acid, β-CD = β-cyclodextrin), are prepared within 10 minutes (min) via biphase frontal polymerization (FP). Both G-1 and G-2 gels show excellent intrinsic self-healing properties based on hydrogen bonds, with healing efficiencies of 91% and 97%, respectively; self-healing between G-1 and G-2 also occurs due to hydrogen bonding and host-guest interactions. Moreover, dual-component gels, in terms of G-1 and G-2 bilayer gel flowers and strips, heterogeneous healed bilayer gel strips, and microfluidic-directed bilayer gel microsphere ensembles, all show actuating behaviour in acidic, alkaline and organic solutions, with actuation degrees up to 96% in 5 min. The actuation mechanism is also proposed. This work might provide new insights into fast synthesis of self-healing dual-component gels towards application in the actuator field.


Rapid recovery of lung histology correlates with clearance of influenza virus by specific CD8+ cytotoxic T cells.
Previous studies have shown that influenza nucleoprotein (NP)-specific cytotoxic T-cell clones do not prevent influenza infection of mice but lead to a more rapid viral clearance and recovery of the host. Here we examine the histology of the lung to see if viral clearance by cytotoxic T cells (Tc) correlates with recovery of pulmonary pathology or if it is in any way deleterious. Intransasal (i.n.) A/X31 virus infection of BALB/c mice produces lung tissue changes lasting 8-10 days in BALB/c mice, with the most severe abnormalities appearing between Days 4 and 6 (e.g. loss of epithelium, airway obliteration, peribronchiolar and perivascular cell accumulation). The transfer of Tc clone T9/13 into i.n.-infected BALB/c mice induces a transient enhanced loss of epithelium on Day 4, while by Day 6 epithelial abnormalities are much reduced in the lung compared to control infected mice. This correlates with a significant reduction in lung virus titres by Day 6; by Day 8 virus is cleared in Tc recipients and lung histology is normal. Another Tc clone (T5/5) with greater cytolytic activity resulted in significant recovery of the lung tissues by Day 4. Tc clones also resulted in enhanced perivascular infiltration of cells and variation in the infiltrating cell type. Quantification in our system required careful attention to the level of the airway assessed. These histological findings showing an enhanced tissue recovery support the previous assessment of reduced lung viral levels following the transfer of Tc cells, and show that a transient increase in lung pathology can occur.


[Ecosystem carbon exchange in Artemisia ordosica shrubland of Ordos Plateau in two different precipitation years].
Characteristics of ecosystem carbon exchange and its impact factors in Artemisia ordosica shrubland in 2011 (low precipitation) and 2012 (high precipitation), Ordos Plateau, were studied using eddy covariance methods. The results showed that the diurnal dynamics of ecosystem carbon exchange could be expressed as single-peak and double-peak curves in the two different precipitation years. In 2011, three carbon absorption peaks and three carbon release peaks of ecosystem carbon exchange presented in the growing season. In 2012, four carbon absorption peaks and one carbon release peak appeared in the growing season. The A. ordosica shrubland was a net carbon sink from June to September and a carbon source in October in 2011. In 2012, A. ordosica shrubland was a net carbon sink in the whole growing season. The amount of carbon fixed by A. ordosica shrubland in the growing season in 2012 was 268.90 mg CO2 x m(-2) x s(-1) higher than that in 2011. The ecosystem carbon exchange of A. ordosica shrubland was controlled by PAR (photosynthetically active radiation) on the day scale, and affected by both abiotic (precipitation and soil water content) and biotic (aboveground net primary, productivity) factors on the growing season scale.


Perceived Dangerousness as Related to Psychiatric Symptoms and Psychiatric Service Use - a Vignette Based Representative Population Survey.
Perceptions of dangerousness are an influential component of mental health stigma and can be driven by the display of psychiatric symptoms and the use of psychiatric service institutions. Yet, no previous study compared symptoms and service use associated perceptions of dangerousness. Therefore, we conducted a representative survey (N = 2,207) in the canton of Basel-Stadt, Switzerland. Participants were asked to answer the perceived dangerousness scale with respect to a vignette that either depicted psychiatric symptoms of a fictitious character or a psychiatric service institution the fictitious character had been admitted to. Between the vignettes, type of symptoms, type of psychiatric service, dangerousness, and gender were systematically varied. Perceived dangerousness was significantly lower as related to psychiatric service use than related to psychiatric symptoms. Overall, symptoms of alcohol dependency, behavior endangering others, and male gender of the fictitious character tend to increase perceived dangerousness. Furthermore, being hospitalized in a psychiatric unit at a general hospital or the rater being familiar with psychiatric services tends to decrease perceived dangerousness. Effective anti-stigma initiatives should integrate education about dangerousness as well as methods to increase familiarity with psychiatry. Additionally, an integration of modern psychiatry in somato-medical care institutions might decrease stigmatization.


Protocol for the systematic review of the reporting of transoral robotic surgery.
Transoral robotic surgery (TORS) has been adopted in some parts of the world as an innovative approach to the resection of oropharyngeal tumours. The development, details and outcomes of early-to-later phase evaluation of this technique and the quality of evidence to support its adoption into practice have hitherto not been summarised. The aim of this review is to identify and summarise the early and later phase studies of, and evidence for, TORS and to understand how early phase studies report intervention development, governance procedures and selection and reporting of outcomes to optimise methods for using the Idea, Development, Exploration, Assessment, Long-term follow-up (IDEAL) framework for surgical innovation that informs evidence-based practice. The protocol has been written in line with the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols checklist. Electronic searches in OVID SP versions of Medline and EMBASE, the Cochrane Central Register of Controlled Trials and the Cochrane Database of Systematic Reviews from the start of indexing to 30 April 2017 will identify studies reporting TORS. At least two independent researchers will identify studies for inclusion. Two researchers will extract data from each paper. Studies will be categorised into IDEAL stages of study design from 'pre-IDEAL' to randomised controlled trials (stage 3). Data will be collected about the (1) novel intervention and criteria for modification, (2) governance arrangements and patient information provision, (3) outcome domains selected and reported and (4) quality of study design, conduct and reporting. Descriptive statistics and a narrative synthesis will be presented. The results of this systematic review will be presented at relevant conferences. The methods will be used to inform future reviews exploring other novel surgical innovations. The findings will be published in a peer-reviewed journal. This study does not require ethical approval.


Interactions between Fusobacterium necrophorum hemolysin, erythrocytes and erythrocyte membranes.
The interactions between the hemolysin of Fusobacterium necrophorum subsp. necrophorum, erythrocytes and erythrocyte membranes were studied as an attempt to determine the initial characteristics leading to hemolysis. The spectrum of erythrocyte sensitivity indicated that horse, dog and mouse erythrocytes were highly sensitive whereas those of cattle, sheep, goat and chicken were insensitive to the hemolysin. Binding of hemolysin to horse and dog erythrocytes or their ghosts was more pronounced than to those of cattle and sheep as detected by a decrease of hemolytic activity from hemolysin preparations. The kinetics of hemolysis revealed that lysis is preceded by a prelytic phase characterized by binding of hemolysin to erythrocytes. Treatment of horse erythrocytes with hemolysin at various temperatures prior to incubation at 37 degrees C also revealed that this binding prelytic phase is temperature independent. This was followed by a temperature dependent lytic stage since erythrocytes pretreated with hemolysin and incubated at 4 degrees C showed no hemolysis. An inverse relation was found between erythrocyte concentration and hemolytic activity suggesting a multiple-hit mechanism of hemolysis.


Ethyl acetate fraction of Huogu formula inhibits adipogenic differentiation of bone marrow stromal cells via the BMP and Wnt signaling pathways.
Elevated adipogenesis of bone marrow stromal cells (BMSCs) is closely associated with non-traumatic osteonecrosis of femoral head (ONFH). Our previous studies have shown that Huogu (HG) formula was effective both in clinic experience and experimental ONFH. How HG impacts the differentiation of BMSCs and what is the underlying molecular mechanism remain largely unknown. Our results showed that ethyl acetate extract of HG (HGE) significantly decreased the adipocyte differentiation as determined by oil red staining, while slightly increased the ALP activity. Investigation of the molecular mechanism revealed that HGE could inhibit the mRNA and protein expression of peroxisome proliferators-activated receptor (PPAR)γ, lipoprotein lipase (LPL) and adipocyteprotein2 (AP2). Interestingly, the inhibition of adipogenic differentiation in BMSCs by HGE could be restored by DKK-1, an inhibitor of Wnts. However, Noggin (an inhibitor of BMPs) displayed an additive role with HGE in suppressing the expression of PPARγ, LPL, and AP2. Furthermore, the bone marrow fat formation, as well as the expression of Wnt3a and PPARγ, was effectively regulated by HGE in the steroid-induced ONFH rats. Our results demonstrated that HGE treatment significantly inhibited adipogenesis and slightly promoted osteogenesis of BMSCs through regulating the BMP and Wnt pathways. The findings shed lights on the molecular mechanism of HGE in the inhibition of adipogenesis and provide scientific rationale for its clinical application of HGE in the treatment of ONFH.


Differential effects of social and novelty enrichment on individual differences in impulsivity and behavioral flexibility.
Early life experience profoundly impacts behavior and cognitive functions in rats. The present study investigated how the presence of conspecifics and/or novel objects, could independently influence individual differences in impulsivity and behavioral flexibility. Twenty-four rats were reared in an isolated condition, an isolated condition with a novel object, a pair-housed social condition, or a pair-housed social condition with a novel object. The rats were then tested on an impulsive choice task, a behavioral flexibility task, and an impulsive action task. Novelty enrichment produced an overall increase in impulsive choice, while social enrichment decreased impulsive choice in the absence of novelty enrichment and also produced an overall increase in impulsive action. In the behavioral flexibility task, social enrichment increased regressive errors, whereas both social and novelty enrichment reduced never-reinforced errors. Individual differences analyses indicated a significant relationship between performance in the behavioral flexibility and impulsive action tasks, which may reflect a common psychological correlate of action inhibition. Moreover, there was a relationship between delay sensitivity in the impulsive choice task and performance on the DRL and behavioral flexibility tasks, suggesting a dual role for timing and inhibitory processes in driving the interrelationship between these tasks. Overall, these results indicate that social and novelty enrichment produce distinct effects on impulsivity and adaptability, suggesting the need to parse out the different elements of enrichment in future studies. Further research is warranted to better understand how individual differences in sensitivity to enrichment affect individuals' interactions with and the resulting consequences of the rearing environment.


Dietary gluten triggers concomitant activation of CD4+ and CD8+ αβ T cells and γδ T cells in celiac disease.
Celiac disease is an intestinal autoimmune disease driven by dietary gluten and gluten-specific CD4(+) T-cell responses. In celiac patients on a gluten-free diet, exposure to gluten induces the appearance of gluten-specific CD4(+) T cells with gut-homing potential in the peripheral blood. Here we show that gluten exposure also induces the appearance of activated, gut-homing CD8(+) αβ and γδ T cells in the peripheral blood. Single-cell T-cell receptor sequence analysis indicates that both of these cell populations have highly focused T-cell receptor repertoires, indicating that their induction is antigen-driven. These results reveal a previously unappreciated role of antigen in the induction of CD8(+) αβ and γδ T cells in celiac disease and demonstrate a coordinated response by all three of the major types of T cells. More broadly, these responses may parallel adaptive immune responses to viral pathogens and other systemic autoimmune diseases.


The State-of-the-Art Solution-Processed Single Component Organic Photodetectors Achieved by Strong Quenching of Intermolecular Emissive State and High Quadrupole Moment in Non-Fullerene Acceptors.
A bulk-heterojunction (BHJ) blend is commonly used as the photoactive layer in organic photodetectors (OPDs) to utilize the donor (D)/acceptor (A) interfacial energetic offset for exciton dissociation. However, this strategy often complicates optimization procedures, raising serious concerns over device processability, reproducibility, and stability. Herein, highly efficient OPDs fabricated with single-component organic semiconductors are demonstrated via solution-processing. The non-fullerene acceptors (NFAs) with strong intrinsic D/A character are used as the photoactive layer, where the emissive intermolecular charge transfer excitonic (CTE) states are formed within <1 ps, and efficient photocurrent generation is achieved via strong quenching of these CTE states by reverse bias. Y6 and IT-4F-based OPDs show excellent OPD performances, low dark current density (≈10-9 A cm-2 ), high responsivity (≥0.15 A W-1 ), high specific detectivity (>1012 Jones), and fast photo-response time (<10 µs), comparable to the state-of-the-art BHJ OPDs. Together with strong CTE state quenching by electric field, these excellent OPD performances are also attributed to the high quadrupole moments of NFA molecules, which can lead to large interfacial energetic offset for efficient CTE dissociation. This work opens a new way to realize efficient OPDs using single-component systems via solution-processing and provides important molecular design rules.


The utility of 'country of birth' for the classification of ethnic groups in health research: the Dutch experience.
The relationship between ethnicity and health is attracting increasing attention in international health research. Different measures are used to operationalise the concept of ethnicity. Presently, self-definition of ethnicity seems to gain favour. In contrast, in the Netherlands, the use of country of birth criteria have been widely accepted as a basis for the identification of ethnic groups. In this paper, we will discuss its advantages as well as its limitations and the solutions to these limitations from the Dutch perspective with a special focus on survey studies. The country of birth indicator has the advantage of being objective and stable, allowing for comparisons over time and between studies. Inclusion of parental country of birth provides an additional advantage for identifying the second-generation ethnic groups. The main criticisms of this indicator seem to refer to its validity. The basis for this criticism is, firstly, the argument that people who are born in the same country might have a different ethnic background. In the Dutch context, this limitation can be addressed by the employment of additional indicators such as geographical origin, language, and self-identified ethnic group. Secondly, the country of birth classification has been criticised for not covering all dimensions of ethnicity, such as culture and ethnic identity. We demonstrate in this paper how this criticism can be addressed by the use of additional indicators. In conclusion, in the Dutch context, country of birth can be considered a useful indicator for ethnicity if complemented with additional indicators to, first, compensate for the drawbacks in certain conditions, and second, shed light on the mechanisms underlying the association between ethnicity and health.


[Metformin associated with lactic acidosis in treatment of type 2 diabetes].
Metformin (MET) is the first-line agent in treatment of type 2 diabetes. However, MET has been associated with lactic acidosis (MALA), a potential but rare complication which has influenced treatment strategies in decades. Recently, guidelines have been changed in regards of age and heart failure and the contradiction of chronic renal impairment has been debated. This article identifies potential risk groups and situations that would benefit from a temporary interruption in the MET treatment.


[Comparing BFA with BuCyA as a myeloablative conditioning regimen for allogeneic stem cell transplantation in acute leukemias].
To compare BFA (busulfan, fludarabine plus cytarabine) with BuCyA (busulfan, cyclophoshpamide plus cytarabine) as the conditioning regimens in allogeneic stem cell transplantation for acute leukemias. 83 patients with acute leukemia were allocated to BFA group (busulfan 3.2 mg/(kg x d), -9 d-6 d; fludarabine 30 mg/(m2 x d), -5 d(-) -1 d; cytarabine, 1 g/(m2 x d), -5 d(-) - 1 d) or BuCyA group (busulfan, 3.2 mg/(kg x d), -8 d(-) - 5 d; cyclophoshpamide 60 mg/(kg x d),-2 d(-) - 1 d; cytarabine, 3 g/(m2 x d), -4 d(-) - 3 d). Their three-year disease-free survival (DFS) rate, complete remission (CR) rate and incidences of acute graft versus host disease (aGVHD) and hemorrhagic cystitis were monitored. BuCyA group had lower DFS (40.0% vs 61.9%, P = 0.039 9) and lower CR (44.0% vs 71.6%, P = 0.031 0) than BFA group. About 20% of patients treated with BuCyA were not in remission, compared with 51.6% of those treated with BFA. aGVHD occurred in 46.7% patients in the BuCyA group and 50.9% patients in the BFA group, which were 23.3% and 9.4%, respectively, for those graded III - IV. Severe infection occurred in 23.3% patients in the BuCyA group and 22.9% patients in the BFA group. Severe bleeding occurred in 26.7% patients in the BuCyA group and 11.4% patients in the BFA group. The incidence of hemorrhagic cystitis in the BuCyA group and BFA group was 16.7% and 5.7%, respectively. BFA is a safer and more effective conditioning regimen compared with BuCyA.


[Classification of pulmonary alveolar proteinosis in newborns, infants, and children].
Pulmonary alveolar proteinoses are rare pulmonary diseases characterised by an intraalveolar accumulation of surfactant protein A. Subtyping of alveolar proteinoses: Type I alveolar proteinoses: severe respiratory insufficiency in newborns, which will take a lethal course without lung transplant; hereditary SP-B deficiency and an intraalveolar accumulation of N-terminal incompletely processed SP-C. Type II alveolar proteinoses: occur in newborns and infants; often take a lethal course; show intraalveolar accumulation of precursors of SP-B and mature SP-B as well as an accompanying interstitial lung disease of variable severity. Type III alveolar proteinoses: in infants and children; do not generally take a lethal course; they are characterised by an intraalveolar accumulation of precursors of SP-B and mature SP-B without accompanying interstitial lung disease. "Cryptogenic" congenital, acquired (idiopathic), and secondary type III alveolar proteinoses can be distinguished. In newborns, infants, and children with pulmonary alveolar proteinosis, a detailed pathological-anatomical examination including immunohistochemical and molecular genetic analyses, should be performed in order to optimise the therapeutical management.


Simplified Derivatives of Dibenzylbutyrolactone Lignans from Hydrocotyle bonariensis as Antitrypanosomal Candidates.
The search for the pharmacophore of a bioactive compound, crucial for drug discovery studies, involves the adequate arrangement of different atoms in the molecule. As part of a continuous work aiming discovery of new drug candidates against the protozoan parasite Trypanosoma cruzi, the hexane extract of Hydrocotyle bonariensis was subjected to a bioactivity-guided fractionation to afford two chemically related dibenzylbutyrolactone lignans - hinokinin (1) and hibalactone (2). Compounds 1 and 2 showed activity against trypomastigote with EC50 values of 17.0 and 69.4 μM, respectively. Compound 1 was also active against the clinically relevant form of the parasite, amastigotes, displaying an EC50 value of 34.4 μM. The structure-activity relationship (SAR) indicated that the absence of the double bond at C-7 is a crucial feature for the increment of the antiparasitic activity. The lethal action of the most potent compound 1 was investigated in the trypomastigotes. The fluorescent-based assay with SYTOX Green demonstrated a significant alteration of the plasma membrane permeability of the parasite. Additionally, compound 1 demonstrated no significant hemolytic activity in mice erythrocytes at 200 μM. To search the pharmacophore, three different simplified compounds - 3,4-methylenedioxydihydrocinnamic acid (3), 3,4-methylenedioxydihydrocinnamic alcohol (4) and 3,4-methylenedioxycinnamic acid (5) - were prepared and tested against T. cruzi. These derivatives displayed EC50 values of 37.2 (3), 25.8 (4) and 73.5 (5) μM against trypomastigotes, and 41.3 (3) and 48.2 (4) μM against amastigotes, whereas compound 5 was inactive. Except for compound 2, which resulted in a CC50 value of 114.5 μM, all compounds showed no mammalian cytotoxicity at 200 μM. An in silico ADMET study was performed and predicted values demonstrated an acceptable drug-likeness profile for compounds 1-5. Despite the minor reduction in the potency, the simplified derivatives retained the antitrypanosomal activity against the intracellular amastigotes, even with 95 % reduction of their molecular weight. Additionally, in silico studies suggested them as more soluble compounds, making these simplified structures promising scaffolds for optimization studies in Chagas disease.


[Scleroderma, dermatomyositis].
Systemic sclerosis (scleroderma, SSc) is a progressive and often fatal disorder characterized clinically by sclerotic changes in the skin, joints and internal organ systems such as the gastrointestinal tract, heart, lungs and kidneys, moreover pathologically by abnormalities of mucopolysaccharides, fibrous tissue deposition, atrophy of parenchymal structures in skin and various internal organs, and by vascular insufficiency. Little is known of its etiology and pathogenesis. Transforming growth factor-beta (TGF-beta), platelet derived growth factor-AA (PDGF-AA) and PDGF-alpha receptor interaction may play an important role in the pathogenesis of scleroderma. Furthermore, many of the proteoglycans act as modulators of growth factor activities. Dermatomyositis is also a complex connective tissue disease of unknown etiology, in which inflammatory change in the skin, muscle, and lung in association with vascular insufficiency and internal malignancy.


Allele-specific expression at the RET locus in blood and gut tissue of individuals carrying risk alleles for Hirschsprung disease.
RET common variants are associated with Hirschsprung disease (HSCR; colon aganglionosis), a congenital defect of the enteric nervous system. We analyzed a well-known HSCR-associated RET haplotype that encompasses linked alleles in coding and noncoding/regulatory sequences. This risk haplotype correlates with reduced level of RET expression when compared with the wild-type counterpart. As allele-specific expression (ASE) contributes to phenotypic variability in health and disease, we investigated whether RET ASE could contribute to the overall reduction of RET mRNA detected in carriers. We tested heterozygous neuroblastoma cell lines, ganglionic gut tissues (18 HSCR and 14 non-HSCR individuals) and peripheral blood mononuclear cells (PBMCs; 16 HSCR and 14 non-HSCR individuals). Analysis of the data generated by SNaPshot and Pyrosequencing revealed that the RET risk haplotype is significantly more expressed in gut than in PBMCs (P = 0.0045). No ASE difference was detected between patients and controls, irrespective of the sample type. Comparison of total RET expression levels between gut samples with and without ASE, correlated reduced RET expression with preferential transcription from the RET risk haplotype. Nonrandom RET ASE occurs in ganglionic gut regardless of the disease status. RET ASE should not be excluded as a disease mechanism acting during development.


Rcor2 Is Required for Somatic Differentiation and Represses Germline Cell Fate.
Rcor2, the corepressor 2 of REST, a transcriptional repressor, is predominantly expressed in embryonic stem cells (ESCs) and plays a major role in regulating ESC pluripotency and neurogenesis. The function of Rcor2 in development of other germ layers is yet unclear. We utilized a Rcor2-/- mouse embryonic stem cell (mESC) line to investigate the role of Rcor2 in mESC differentiation. Rcor2-/- mESC shows reduced proliferation and severely compromised capacity to differentiate to all three germ layers. In contrast, Rcor2 knockout promotes primordial germ cells (PGCs) specific gene expression and possibly PGC formation. Mechanistically, we revealed that Rcor2 inhibits expression of genes required for PGC development, such as Dppa3 and Dazl, by associating to their promoters and enhancing local suppressive H3K9me3 modifications. Our results suggest that Rcor2 plays an important role in somatic cell fate determination by suppressing PGC differentiation through regulating epigenetic modifications of PGC specific genes.


Upregulated Fcrl5 disrupts B cell anergy causes autoimmune disease.
B cell anergy plays a critical role in maintaining self-tolerance by inhibiting autoreactive B cell activation to prevent autoimmune diseases. Here, we demonstrated that Fc receptor-like 5 (Fcrl5) upregulation contributes to autoimmune disease pathogenesis by disrupting B cell anergy. Fcrl5-a gene whose homologs are associated with human autoimmune diseases-is highly expressed in age/autoimmunity-associated B cells (ABCs), an autoreactive B cell subset. By generating B cell-specific Fcrl5 transgenic mice, we demonstrated that Fcrl5 overexpression in B cells caused systemic autoimmunity with age. Additionally, Fcrl5 upregulation in B cells exacerbated the systemic lupus erythematosus-like disease model. Furthermore, an increase in Fcrl5 expression broke B cell anergy and facilitated toll-like receptor signaling. Thus, Fcrl5 is a potential regulator of B cell-mediated autoimmunity by regulating B cell anergy. This study provides important insights into the role of Fcrl5 in breaking B cell anergy and its effect on the pathogenesis of autoimmune diseases.


Transcriptomic Insights into the Response of the Olfactory Bulb to Selenium Treatment in a Mouse Model of Alzheimer's Disease.
Alzheimer's disease (AD) is a devastating neurodegenerative disorder characterized by the presence of extracellular senile plaques primarily composed of Aβ peptides and intracellular neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau proteins. Olfactory dysfunction is an early clinical phenotype in AD and was reported to be attributable to the presence of NFTs, senile Aβ plaques in the olfactory bulb (OB). Our previous research found that selenomethionine (Se-Met), a major form of selenium (Se) in organisms, effectively increased oxidation resistance as well as reduced the generation and deposition of Aβ and tau hyperphosphorylation in the olfactory bulb of a triple transgenic mouse model of AD (3×Tg-AD), thereby suggesting a potential therapeutic option for AD. In this study, we further investigated changes in the transcriptome data of olfactory bulb tissues of 7-month-old triple transgenic AD (3×Tg-AD) mice treated with Se-Met (6 µg/mL) for three months. Comparison of the gene expression profile between Se-Met-treated and control mice revealed 143 differentially expressed genes (DEGs). Among these genes, 21 DEGs were upregulated and 122 downregulated. The DEGs were then annotated against the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases. The results show that upregulated genes can be roughly classified into three types. Some of them mainly regulate the regeneration of nerves, such as Fabp7, Evt5 and Gal; some are involved in improving cognition and memory, such as Areg; and some are involved in anti-oxidative stress and anti-apoptosis, such as Adcyap1 and Scg2. The downregulated genes are mainly associated with inflammation and apoptosis, such as Lrg1, Scgb3a1 and Pglyrp1. The reliability of the transcriptomic data was validated by quantitative real time polymerase chain reaction (qRT-PCR) for the selected genes. These results were in line with our previous study, which indicated therapeutic effects of Se-Met on AD mice, providing a theoretical basis for further study of the treatment of AD by Se-Met.