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Alzheimer’s disease (AD) and dementia in general are age-related diseases with multiple contributing factors, including brain inflammation. Microglia, and specifically those expressing the AD risk gene TREM2, are considered important players in AD, but their exact contribution to pathology remains unclear. In this study, using high-throughput mass cytometry in the 5×FAD mouse model of amyloidosis, we identified senescent microglia that express high levels of TREM2 but also exhibit a distinct signature from TREM2-dependent disease-associated microglia (DAM). This senescent microglial protein signature was found in various mouse models that show cognitive decline, including aging, amyloidosis and tauopathy. TREM2-null mice had fewer microglia with a senescent signature. Treating 5×FAD mice with the senolytic BCL2 family inhibitor ABT-737 reduced senescent microglia, but not the DAM population, and this was accompanied by improved cognition and reduced brain inflammation. Our results suggest a dual and opposite involvement of TREM2 in microglial states, which must be considered when contemplating TREM2 as a therapeutic target in AD.

JAVIER RAMOS PERIODISTA Y ESCRITOR CRIMINALES A SUELDO. Además de actuar por su cuenta, los miembros de la Garduña llevaban a cabo trabajos para nobles o incluso para el Santo [...]

Graphical Abstract:

Recreating complex structures and functions of natural organisms in a synthetic form is a long-standing goal for humanity1. The aim is to create actuated systems with high spatial resolutions and complex material arrangements that range from elastic to rigid. Traditional manufacturing processes struggle to fabricate such complex systems2. It remains an open challenge to fabricate functional systems automatically and quickly with a wide range of elastic properties, resolutions, and integrated actuation and sensing channels2,3. We propose an inkjet deposition process called vision-controlled jetting that can create complex systems and robots. Hereby, a scanning system captures the three-dimensional print geometry and enables a digital feedback loop, which eliminates the need for mechanical planarizers. This contactless process allows us to use continuously curing chemistries and, therefore, print a broader range of material families and elastic moduli. The advances in material properties are characterized by standardized tests comparing our printed materials to the state-of-the-art. We directly fabricated a wide range of complex high-resolution composite systems and robots: tendon-driven hands, pneumatically actuated walking manipulators, pumps that mimic a heart and metamaterial structures. Our approach provides an automated, scalable, high-throughput process to manufacture high-resolution, functional multimaterial systems.

Author's Note: Findings and conclusions reported in this article are those of the authors and do not necessarily represent the official position or policies of the U.S. Department of Justice. [...]

The AS-48 bacteriocin is a potent antimicrobial polypeptide with enhanced stability due to its circular sequence of peptidic bonds. The mechanism of biological action is still not well understood in spite of both the elucidation of the molecular structure some years ago and several experiments performed that yielded valuable information about the AS-48 bacterial membrane poration activity. In this work, we present a computational study at an atomistic scale to analyze the membrane disruption mechanism. The process is based on the two-stage model: (1) peptide binding to the bilayer surface and (2) membrane poration due to the surface tension exerted by the peptide. Indeed, the induced membrane tension mechanism is able to explain stable formation of pores leading to membrane disruption. The atomistic detail obtained from the simulations allows one to envisage the contribution of the different amino acids during the poration process. Clustering of cationic residues and hydrophobic interactions between peptide and lipids seem to be essential ingredients in the process. GLU amino acids have shown to enhance the membrane disrupting ability of the bacteriocin. TRP24–TRP24 interactions make also an important contribution in the initial stages of the poration mechanism. The detailed atomistic information obtained from the simulations can serve to better understand bacteriocin structural characteristics to design more potent antimicrobial therapies.

The reaction of the complexes [Ti(η5-C5H3R′SiMe2Cl)Cl3] (R′ = H, SiMe3) with the terpenoid preligand C7H6Me3(OH)(NCH2CH2NH2) affords the stereospecific synthesis of the constrained-geometry chiral titanium complexes [Ti{(η5-C5H3R′SiMe2N(CH2)2NC7H6Me3O)-κ3N,N′,O}Cl] (R′ = H, 1; R′ = SiMe32), bearing a new cyclopentadienyl-terpenoid ligand derived from α-pinene. The corresponding alkyl derivatives [Ti{(η5-C5H4SiMe2N(CH2)2NC7H6Me3O)-κ3N,N′,O}R] (R = Me, 4; R = nBu, 5) have been prepared by treatment with suitable alkylating reagents. The reactivity of the methyl complex 4with different protonic reagents such as alcohols and thiols proceeds via protonation of the amido nitrogen to stereospecifically give the corresponding strain-free alkoxide- and thiolate-methyl compounds [Ti{(η5-C5H4SiMe2NH(CH2)2NC7H6Me3O)-κO}Me(XR)] (X = O, R = iPr, 6; X = S, R = Et, 7; R = p-MeC6H4, 8). The reversibility of this protonation reaction is observed in the case of the thiolate compounds, which are thermically converted, via methane release, into the corresponding constrained-geometry thiolate derivatives [Ti{(η5-C5H4SiMe2N(CH2)2NC7H6Me3O)-κ3N,N′,O}(SR)] (R = Et, 9; R = C6H4-p-Me, 10). However, the analogous alkoxide-methyl compound 6does not undergo a similar transformation. To gain further insights into the results reached in the reactions of 4with alcohols and thiols and to understand the different behavior of the strain-free alkoxide- and thiolate-methyl complexes with regard to the thermal decomposition, calculations using DFT methods have been performed.

The dose of thiopurine drugs in combined treatments with anti-TNF in inflammatory bowel disease (IBD) has not been clearly established. The purpose of this study is to assess whether the dose of azathioprine influences clinical and biochemical response/remission rates, and anti-TNF drug levels/antibody formation.

This paper argues that current voting advice applications (VAAs) do not sufficiently fulfil their stated aim of increasing voters' political competence. First, we define four criteria to evaluate whether their methods are likely to increase political competence: informativeness, respect for users' way of comparing and aggregating policy issues, reliability, and transparency. Second, we argue that current VAAs compare and aggregate users' and parties' policy preferences following a weak method that fails in two of them. To prove it, we analyse the methodology of most currents VAAs and use the outcomes from the EU-Vox 2014 in several countries. Third, we discuss two possibilities by which VAAs could improve: (1) by using ex-ante survey data to fill their gaps, or (2) by creating a learning algorithm to adapt the VAA to users' preferences. We found that some changes need to be made if VAAs aim to have an impact on users' political competence.

Andean lupin (Lupinus mutabilisSweet) has health benefits with promising possibilities for food industry. The aim of this research was to determine the effect of processing (water debittering, extrusion, and spray‐drying) on chemical composition, heat damage and in vitro protein digestibility in Andean lupin. The processing treatment modified all the parameters while the genotype showed limited effect. The untreated lupins had high protein and lipid content (47.4 and 16.2 g/100 g dry matter). The extruded products showed higher protein content (55.7 g/100 g) and digestibility (68.1%) than the untreated lupins, along with limited heat damage (8.7 mg furosine/100 g protein). Spray‐drying led to the lowest protein content (31.8 g/100 g) and, when maltodextrin was used, the highest heat damage (54.1 ± 20.7 mg furosine/100 g protein; 0.60 mg hydroxymethylfurfural/kg; 0.58 mg glycosylisomaltol/kg), but also to the maximum protein digestibility (72.8%–74.0%). The chemical composition of Andean lupin was improved by the technological treatments (debittering, extrusion, and spray‐drying) applied. Processing enhanced nutritional value and digestibility, without inducing relevant heat damage. Extrusion and spray‐drying improve the in vitro protein digestibility of Andean lupin flour causing limited heat damage.

Blood-borne pathogens can cause systemic inflammatory response syndrome (SIRS) followed by protracted, potentially lethal immunosuppression. The mechanisms responsible for impaired immunity post-SIRS remain unclear. We show that SIRS triggered by pathogen mimics or malaria infection leads to functional paralysis of conventional dendritic cells (cDCs). Paralysis affects several generations of cDCs and impairs immunity for 3–4 weeks. Paralyzed cDCs display distinct transcriptomic and phenotypic signatures and show impaired capacity to capture and present antigens in vivo. They also display altered cytokine production patterns upon stimulation. The paralysis program is not initiated in the bone marrow but during final cDC differentiation in peripheral tissues under the influence of local secondary signals that persist after resolution of SIRS. Vaccination with monoclonal antibodies that target cDC receptors or blockade of transforming growth factor β partially overcomes paralysis and immunosuppression. This work provides insights into the mechanisms of paralysis and describes strategies to restore immunocompetence post-SIRS.

Conservative Management (CM) has become a therapeutic option in Advanced Chronic Kidney Disease in the elderly. However, there is a lack of evidence about prognosis of these patients in terms of survival and health related quality of life (HRQoL).

El tratamiento renal conservador (TRC) se ha convertido en una opción terapéutica en la enfermedad renal crónica avanzada en ancianos. Se sabe poco sobre la evolución pronóstica de estos pacientes en términos de supervivencia y calidad de vida relacionada con la salud (CVRS).

The article focuses on the issue of the freedom the press in Mexico. Topics discussed include violence against journalists covering crime, drug cartels, and their nexus with local politics, shrinking budgets for resources for investigative reporting that promote accountability and corruption by public officials.

The article focuses on the partnership of Florida Department of Juvenile Justice with the Georgetown University in Washington and Vanderbilt University in Tennessee in an effort to increase the use of research in criminal justice and correctional practices. Topics discussed include implementation of Standardized Program Evaluation Protocol in partnership, positive outcomes from the partnership, and unique knowledge and resources in the partnership.

Suicide attempts are an important predictor of completed suicide and may differ in terms of severity of medical consequences or medical lethality. There is little evidence on serious suicide attempt (SSA) and very few studies have compared SSA with non-SSA.

Introducción: Las principales guías de práctica clínica recomiendan la realización de endoscopia dentro de las 24 horas posteriores a la admisión en Urgencias en pacientes con hemorragia digestiva alta no variceal. Sin embargo, es un margen de tiempo muy amplio y el papel de la endoscopia urgente (<6 horas) es controvertido.

Craniopharyngioma is a histologically benign brain malformation with a fundamental role in satiety modulation, causing obesity in up to 52% of patients.

CD69 targeting induces bystander T cell proliferation but does not affect antigen‐specific proliferation. In spite of an initially proposed role as a costimulatory molecule for CD69, in vivo studies showed it as a regulator of immune responses and lymphocyte egress. We found constitutive CD69 expression by T cell subsets and pDC. We examined a possible effect of CD69 on T cell proliferation using transfer models and in vitro assays. In mice locally expressing or receiving antigen, anti‐CD692.2 treatment did not affect the proliferation of antigen‐specific transgenic T cells in ADLN, although we observed the presence of proliferated T cells in non‐ADLN and spleen. This was not affected by FTY720 treatment and thus, not contributed by increased egress of proliferated lymphocytes from ADLN. In the absence of antigen, anti‐CD69 2.2 treatment induced bystander proliferation of transferred memory phenotype T cells. This proliferation was mediated by IL‐2, as it was inhibited by anti‐IL‐2 or anti‐CD25 antibodies in vitro and by anti‐CD25 antibodies in vivo. It was also dependent on CD69 expression by donor T cells and recipient cells. CD69 targeting on T cells enhanced IL‐2‐mediated proliferation and CD25 expression. However, it did not lead to increased early IL‐2 production by T cells. No T cell subset was found to be specifically required in the recipient. Instead, CD69 targeting on pDC induced their expression of IL‐2 and CD25, and pDC depletion showed that this subset was involved in the proliferation induction. These results indicate that CD69 targeting induces bystander T cell proliferation through pDC IL‐2 production and T cell sensitization to IL‐2 without affecting antigen‐driven T cell proliferation.

Alloreactivity after transplantation is associated with profound immune suppression, and consequent opportunistic infection results in high morbidity and mortality. This immune suppression is most profound during GVHD after bone marrow transplantation where an inflammatory cytokine storm dominates. Contrary to current dogma, which avers that this is a T-cell defect, we demonstrate that the impairment lies within conventional dendritic cells (cDCs). Significantly, exogenous antigens can only be presented by the CD8−cDC subset after bone marrow transplantation, and inflammation during GVHD specifically renders the MHC class II presentation pathway in this population incompetent. In contrast, both classic and cross-presentation within MHC class I remain largely intact. Importantly, this defect in antigen processing can be partially reversed by TNF inhibition or the adoptive transfer of donor cDCs generated in the absence of inflammation.

Summary:Langevin molecular dynamics (LMD) simulations have been performed in order to understand the role of the short chain branches (SCB) on the formation of ordered domains by cooling ethylene/α‐olefins single chain models. Different long single‐chain models (C2000) with 0, 5 and 10 branches each 1000 carbons were selected. The branches were randomly distributed along the backbone chain. Furthermore, C1(methyl) and C4(butyl) branches were taken into account. These models mimic the molecular architecture of ethylene/1‐butene and ethylene/1‐hexene random copolymers. The simulations are performed according to the following protocol: 20 random chain conformations for each model were equilibrated at high temperature (T* = 13.3) and then they were cooled in steps of 0.45 until the final temperature (T* = 6.2) by running a total of 35 × 106LMD steps. The distribution peaks of crystallization for each model were calculated by differentiating the global order parameter with respect to the temperature. The Tc* (crystallization temperature) decrease as the number of branches increases as it is experimentally observed. The formation of order in the copolymers is affected by the type and amount of the SCB in the backbone of the polymer chain. The stem lenght and crystallization fraction (α) were defined using the local‐bond order parameter. Both parameters decrease as the number of branches increase. In all cases here shown, the C4branches are excluded from the ordered domains. However, we have observed that the methyl branch can be incorporated into the ordered regions. These facts satisfactorily agree with experimental data available in the literature.

The management of globally distributed software teams is complex because of problems of linguistic differences, geographical dispersion, different time zones, and the cultural diversity of the team members; what is particularly common in software development environments. These problems are amplified when a single software development team is composed of highly skilled individuals working in dispersed geographical locations, and they have to work as a team across distances. This paper describes several of the most important factors that contribute to the correct and effective management of global virtual teams for software development and underlying solutions are addressed to reduce cultural and time barriers. These factors are obtained from an industrial case study, which lasted 36 months, corresponding to a huge software development project that involved several global virtual teams. These success factors consider different perspectives as technology, human factors and process.

Background Pancreatic adenosquamous carcinoma (PASC) is a rare subtype of pancreatic cancer characterized by a dual histological component and aggressive behavior. This form is not well known, its histogenesis is uncertain, and there are different opinions on the diagnostic histopathological criteria. The differential diagnosis with more common ductal adenocarcinoma, squamous cell carcinoma, squamous or adenosquamous metastases is complex. The available therapies do not improve the poor prognosis and it is difficult to find long-term survivors (more than 1 year), even after demolitive surgery with complementary therapies.Case report We report a case of advanced PASC with excellent progression-free survival and overall survival, 20 months and 29 months, respectively. Furthermore, an almost complete response was obtained to first-line chemotherapy with gemcitabine/oxaliplatin (GEMOX) followed by maintenance gemcitabine.Conclusion GEMOX followed by gemcitabine as maintenance could be an effective treatment for this pancreatic entity. Further reports are needed to confirm this outcome.

Global and local descriptors of chemical reactivity and selectivity are used in order to characterize the nature of the active species of bis(imino)pyridyl iron, a catalyst for olefin polymerization. It is shown that chemical potential, hardness, electrophilicity, as well as the dual and multiphilic descriptors for chemical reactivity and selectivity, are adequate for characterizing the global and local reactivity trends of this organo-metallic complex. Most theoretical evidence presented in this paper indicates that the catalyst of Fe3seems to be more active for olefin polymerization than that of Fe2. However, when the cocatalyst is considered, catalysts of Fe2and Fe3present similar electrophilic activity to orientate the nucleophilic attack. It is observed that this activity is well localized at the metallic center in the ferric species whereas it appears to be more delocalized on the ligands of the ferrous species.

A density functional theory (B3LYP) computational study of the ethylene–styrene copolymerization process using meso‐Et(H4Ind)2Zr(CH3)2 as the catalyst is presented. The monomer insertion barriers in meso species are evaluated and compared with previously obtained barriers in rac diastereoisomers. Differences related to ethylene homopolymerization and ethylene–styrene copolymerization activities as well as styrene incorporation into the copolymer are found between the meso and rac diastereoisomers. Nevertheless, a migratory insertion mechanism seems to hold for both diastereoisomeric species. © 2006 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 44: 4752–4761, 2006

The leukocyte activation marker CD69 is a novel regulator of the immune response, modulating the production of cytokines including transforming growth factor-β (TGF-β). We have generated an antimurine CD69 monoclonal antibody (mAb), CD69.2.2, which down-regulates CD69 expression in vivo but does not deplete CD69-expressing cells. Therapeutic administration of CD69.2.2 to wild-type mice induces significant natural killer (NK) cell–dependent antitumor responses to major histocompatibility complex (MHC) class I low RMA-S lymphomas and to RM-1 prostatic carcinoma lung metastases. These in vivo antitumor responses are comparable to those seen in CD69-/- mice. Enhanced host NK cytotoxic activity correlates with a reduction in NK-cell TGF-β production and is independent of tumor priming. In vitro studies demonstrate the novel ability of anti-CD69 mAbs to activate resting NK cells in an Fc receptor–independent manner, resulting in a substantial increase in both NK-cell cytolytic activity and interferon γ (IFNγ) production. Modulation of the innate immune system with monoclonal antibodies to host CD69 thus provides a novel means to antagonize tumor growth and metastasis.

We investigated the in vivo role of CD69 by analyzing the susceptibility of CD69−/− mice to tumors. CD69−/− mice challenged with MHC class I− tumors (RMA-S and RM-1) showed greatly reduced tumor growth and prolonged survival compared with wild-type (WT) mice. The enhanced anti–tumor response was NK cell and T lymphocyte–mediated, and was due, at least in part, to an increase in local lymphocytes. Resistance of CD69−/− mice to MHC class I− tumor growth was also associated with increased production of the chemokine MCP-1, diminished TGF-β production, and decreased lymphocyte apoptosis. Moreover, the in vivo blockade of TGF-β in WT mice resulted in enhanced anti–tumor response. In addition, CD69 engagement induced NK and T cell production of TGF-β, directly linking CD69 signaling to TGF-β regulation. Furthermore, anti-CD69 antibody treatment in WT mice induced a specific down-regulation in CD69 expression that resulted in augmented anti–tumor response. These data unmask a novel role for CD69 as a negative regulator of anti–tumor responses and show the possibility of a novel approach for the therapy of tumors.

La ecografía intestinal se considera una alternativa para la evaluación de la recurrencia posquirúrgica (RPQ) de la enfermedad de Crohn. El objetivo de este estudio es evaluar la correlación entre los hallazgos ecográficos y endoscópicos.

Craniosynostosis in Apert syndrome is routinely treated by wide frontal and bilateral supraorbital reshaping and posterior cranial decompression. Dynamic cranial vault expansion has proved to be useful in craniofacial surgery, and its use has extended to syndromic patients. Although a controversy remains between conventional osteotomy and application of the spring-mediated technique in surgical treatment of craniosynostosis, there have been several positive clinical reports on expansion techniques for nonsyndromic and syndromic craniosynostosis. Simultaneous fronto-orbital advancement and posterior cranial vault expansion have been applied successfully to 2 patients of Apert syndrome, without intraoperative complications or postoperative morbidity and improving final cranial shape.

Introduction The distortion of the anatomy in some spine pathologies such as severe scoliosis and tumors, make the surgery a complex event, and the planning plays an important role. The image study interpretation in this kind of cases is difficult.Methods Biomodelism provides a better understanding of the anatomy and the surgical plan. Two models performed before the surgery of a complex spine deformity, we obtain DICOM images with a CT scan with reconstruction of 64 slides, 1 mm of thickness, and an interval of 1 mm and a reconstruction was done, the data were transferred to a stereolithographic format to print the model. The model was used to plan the surgery, check the trajectory of the pedicular screw, the approach, and the education of the family. The model was sterilized before and used as a tactile guide in the surgery.Results Before the surgery, the family and the patients understand the surgical procedure, the surgical team could evaluate the anatomy to understand the pathology. During the surgery, the model serves as a guide to realize the approach and the screw placement in a simple and systematized manner according to the surgery plan, and helps to evaluate the event after the surgery.Discussion D'Urso et al got a huge experience with biomodelism, we believe that the result in they work like in our work bring satisfactory results before, in the surgery and after the surgery, in the planning and the development of the procedure, as well as the postoperative evaluation with the use on the plastic model.Conclusion The use of biomodeling should be a frequent tool in spine complex cases where the anatomy could be affected.

We have developed a highly efficient DNA-synthesizing system with isolated intact rat liver mitochondria. The ATP requirements for this in organello DNA synthesis are provided by endogenous synthesis in the presence of exogenous ADP and an oxidizable substrate. In this system, mitochondrial DNA synthesis strikingly proceeds at a constant rate for about 5 h at 37°C. Gel electrophoresis, hybridization and restriction enzyme analyses show that intact mitochondria synthesize nucleic acids with a size of 16.5 kb, that correspond to mitochondrial DNA, and that both DNA strands are replicated. This in organello DNA synthesis requires the supply of dNTPs and decreases at high ADP concentration in the incubation medium.