Transcription of toll-like receptors 2, 3, 4 and 9, FoxP3 and Th17 cytokines in a susceptible experimental model of canine Leishmania infantum infection

Canine leishmaniosis (CanL) due to Leishmania infantum is a chronic zoonotic systemic disease resulting from complex interactions between protozoa and the canine immune system. Toll-like receptors (TLRs) are essential components of the innate immune system and facilitate the early detection of many infections. However, the role of TLRs in CanL remains unknown and information describing TLR transcription during infection is extremely scarce. The aim of this research project was to investigate the impact of L. infantum infection on canine TLR transcription using a susceptible model. The objectives of this study were to evaluate transcription of TLRs 2, 3, 4 and 9 by means of quantitative reverse transcription polymerase chain reaction (qRT-PCR) in skin, spleen, lymph node and liver in the presence or absence of experimental L. infantum infection in Beagle dogs. These findings were compared with clinical and serological data, parasite densities in infected tissues and transcription of IL-17, IL-22 and FoxP3 in different tissues in non-infected dogs (n = 10), and at six months (n = 24) and 15 months (n = 7) post infection. Results revealed significant down regulation of transcription with disease progression in lymph node samples for TLR3, TLR4, TLR9, IL-17, IL-22 and FoxP3. In spleen samples, significant down regulation of transcription was seen in TLR4 and IL-22 when both infected groups were compared with controls. In liver samples, down regulation of transcription was evident with disease progression for IL-22. In the skin, upregulation was seen only for TLR9 and FoxP3 in the early stages of infection. Subtle changes or down regulation in TLR transcription, Th17 cytokines and FoxP3 are indicative of the silent establishment of infection that Leishmania is renowned for. These observations provide new insights about TLR transcription, Th17 cytokines and Foxp3 in the liver, spleen, lymph node and skin in CanL and highlight possible markers of disease susceptibility in this model

Inhibiting the Plasmodium eIF2α Kinase PK4 Prevents Artemisinin-Induced Latency

Artemisinin and its derivatives (ARTs) are frontline antimalarial drugs. However, ART monotherapy is associated with a high frequency of recrudescent infection, resulting in treatment failure. A subset of parasites is thought to undergo ART-induced latency, but the mechanisms remain unknown. Here, we report that ART treatment results in phosphorylation of the parasite eukaryotic initiation factor-2α (eIF2α), leading to repression of general translation and latency induction. Enhanced phosphorylated eIF2α correlates with high rates of recrudescence following ART, and inhibiting eIF2α dephosphorylation renders parasites less sensitive to ART treatment. ART-induced eIF2α phosphorylation is mediated by the Plasmodium eIF2α kinase, PK4. Overexpression of a PK4 dominant-negative or pharmacological inhibition of PK4 blocks parasites from entering latency and abolishes recrudescence after ART treatment of infected mice. These results show that translational control underlies ART-induced latency and that interference with this stress response may resolve the clinical problem of recrudescent infection

Radiation induced apoptosis and initial DNA damage are inversely related in locally advanced breast cancer patients

<p>Abstract</p> <p>Background</p> <p>DNA-damage assays, quantifying the initial number of DNA double-strand breaks induced by radiation, have been proposed as a predictive test for radiation-induced toxicity. Determination of radiation-induced apoptosis in peripheral blood lymphocytes by flow cytometry analysis has also been proposed as an approach for predicting normal tissue responses following radiotherapy. The aim of the present study was to explore the association between initial DNA damage, estimated by the number of double-strand breaks induced by a given radiation dose, and the radio-induced apoptosis rates observed.</p> <p>Methods</p> <p>Peripheral blood lymphocytes were taken from 26 consecutive patients with locally advanced breast carcinoma. Radiosensitivity of lymphocytes was quantified as the initial number of DNA double-strand breaks induced per Gy and per DNA unit (200 Mbp). Radio-induced apoptosis at 1, 2 and 8 Gy was measured by flow cytometry using annexin V/propidium iodide.</p> <p>Results</p> <p>Radiation-induced apoptosis increased in order to radiation dose and data fitted to a semi logarithmic mathematical model. A positive correlation was found among radio-induced apoptosis values at different radiation doses: 1, 2 and 8 Gy (p < 0.0001 in all cases). Mean DSB/Gy/DNA unit obtained was 1.70 ± 0.83 (range 0.63-4.08; median, 1.46). A statistically significant inverse correlation was found between initial damage to DNA and radio-induced apoptosis at 1 Gy (p = 0.034). A trend toward 2 Gy (p = 0.057) and 8 Gy (p = 0.067) was observed after 24 hours of incubation.</p> <p>Conclusions</p> <p>An inverse association was observed for the first time between these variables, both considered as predictive factors to radiation toxicity.</p

Layered topological semimetal GaGeTe: New polytype with non-centrosymmetric structure

[EN] GaGeTe is a layered van der Waals material composed of germanene and GaTe sublayers that has been recently predicted to be a basic Z2 topological semimetal. To date, only one polytype of GaGeTe is known with trigonal centrosymmetric structure (a phase, space group R-3m, No. 166). Here we show that asgrown samples of GaGeTe show traces of at least another polytype with hexagonal noncentrosymmetric structure (f3 phase, space group P63mc, No. 186). Moreover, we suggest that another bulk hexagonal polytype (g phase, space group P-3m1, No. 164) could also be found near room conditions. Both a and f3 polytypes have been identified and characterized by means of X-ray diffraction and Raman scattering measurements with the support of ab initio calculations. We provide the vibrational properties of both polytypes and show that the Raman spectrum reported for GaGeTe almost forty years ago and attributed to the a phase, was, in fact, that of the secondary f3 phase. Additionally, we show that a Fermi resonance occurs in a-GaGeTe under non-resonant excitation conditions, but not under resonant excitation conditions. Theoretical calculations show that bulk f3-GaGeTe is a non-centrosymmetric weak topological semimetal with even smaller lattice thermal conductivity than centrosymmetric bulk aGaGeTe. In perspective, our work paves the way for the control and engineering of GaGeTe polytypes to design and implement complex van der Waals heterostructures formed by a combination of centrosymmetric and non-centrosymmetric layers of up to three different polytypes in a single material, suitable for a number of fundamental studies and technological applications.This publication is part of the project MALTA Consolider Team network (RED2018-102612-T) , financed by MINECO/AEI/10.13039/501100003329; by I ? D ? i projects PID2019-106383 GB -41/42/43 financed by MCIN/AEI/10.13039/501100011033; and by project PROMETEO/2018/123 (EFIMAT) financed by Generalitat Valenciana. E.B. would like to thank the Universitat Politecnica de Valencia for his postdoctoral contract (Ref. PAID -10-21) . AHR was supported by the U.S. Department of Energy (DOE) , Office of Science, Basic Energy Sciences under award DE-SC0021375. We also acknowledge the computational resources awarded by XSEDE, a project supported by National Science Foundation grant number ACI-1053575. The authors also acknowledge the support from the Texas Advances Computer Center (with the Stampede2 and Bridges supercom- puters) . E.L.d.S would like to acknowledge the Network of Extreme Conditions Laboratories (NECL) , financed by FCT and co -financed by NORTE 2020, through the program Portugal 2020 and FEDER; the High Performance Computing Chair-a R & D infrastructure (based at the University of ? Evora; PI: M. Avillez) ; and for the computational support provided by the HPC center OBLIVION -U. ? Evora to perform the lattice thermal conductivity calculations. A.L. and D.E. would like to thank the Generalitat Valenciana for the Ph.D. Fellowship no. GRISOLIAP/2019/025.Gallego-Parra, S.; Bandiello, E.; Liang, A.; Da Silva, EL.; Rodriguez-Hernandez, P.; Muñoz, A.; Radescu, S.... (2022). Layered topological semimetal GaGeTe: New polytype with non-centrosymmetric structure. Materials Today Advances. 16:1-16. https://doi.org/10.1016/j.mtadv.2022.1003091161

The Molecular Clockwork of the Fire Ant Solenopsis invicta

This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication

Differential Role of Human Choline Kinase α and β Enzymes in Lipid Metabolism: Implications in Cancer Onset and Treatment

11 pages, 6 figures, 1 table.Background The Kennedy pathway generates phosphocoline and phosphoethanolamine through its two branches. Choline Kinase (ChoK) is the first enzyme of the Kennedy branch of synthesis of 1phosphocholine, the major component of the plasma membrane. ChoK family of proteins is composed by ChoKα and ChoKβ isoforms, the first one with two different variants of splicing. Recently ChoKα has been implicated in the carcinogenic process, since it is over-expressed in a variety of human cancers. However, no evidence for a role of ChoKβ in carcinogenesis has been reported. Methodology/Principal Findings Here we compare the in vitro and in vivo properties of ChoKα1 and ChoKβ in lipid metabolism, and their potential role in carcinogenesis. Both ChoKα1 and ChoKβ showed choline and ethanolamine kinase activities when assayed in cell extracts, though with different affinity for their substrates. However, they behave differentially when overexpressed in whole cells. Whereas ChoKβ display an ethanolamine kinase role, ChoKα1 present a dual choline/ethanolamine kinase role, suggesting the involvement of each ChoK isoform in distinct biochemical pathways under in vivo conditions. In addition, while overexpression of ChoKα1 is oncogenic when overexpressed in HEK293T or MDCK cells, ChoKβ overexpression is not sufficient to induce in vitro cell transformation nor in vivo tumor growth. Furthermore, a significant upregulation of ChoKα1 mRNA levels in a panel of breast and lung cancer cell lines was found, but no changes in ChoKβ mRNA levels were observed. Finally, MN58b, a previously described potent inhibitor of ChoK with in vivo antitumoral activity, shows more than 20-fold higher efficiency towards ChoKα1 than ChoKβ. Conclusion/Significance This study represents the first evidence of the distinct metabolic role of ChoKα and ChoKβ isoforms, suggesting different physiological roles and implications in human carcinogenesis. These findings constitute a step forward in the design of an antitumoral strategy based on ChoK inhibition.This work has been supported by grants to JCL from Comunidad de Madrid (GR-SAL-0821-2004), Ministerio de Ciencia e Innovación (SAF2008-03750, RD06/0020/0016), Fundación Mutua Madrileña, and by a grant to ARM from Fundación Mutua Madrileña.Peer reviewe

Rol de sCD40L en la predicción de súper-respuesta a la terapia de resincronización cardiaca

Background. The aim of this paper is to analyze the role of the biomarkers Interleukin 6, Tumoral Necrosis Factor α, sCD40L, high sensitive Troponin T, high sensitive C-Reactive Protein and Galectin-3 in predicting super response (SR) to Cardiac Resynchronization Therapy (CRT), as they have not been studied in this field before. Methods. Clinical, electrocardiographic and echocardiographic data was obtained preimplant and after one year. SR was defined as reduction in LVESV ≥ 30% at one year follow-up. Blood samples were extracted preimplant. Multivariate logistic regression and ROC curves were performed. Results. 50 patients were included, 23 (46%) were SR. Characteristics related to SR were: female (35 vs. 11%, p=0.04), suffering from less ischemic cardiomyopathy (13 vs. 63%, p<0.0001) and lateral (0 vs. 18%, p=0.03), inferior (4 vs. 33%, p=0.01) and posterior infarction (0 vs. 22%, p=0.01); absence of mitral regurgitation (47% vs. 22%, p=0.04), wider QRS width (157.7±22.9 vs. 140.8±19.2ms, p=0.01), higher concentrations of sCD40L (6.9±5.1 vs. 4.4±3.3 ng/mL, p=0.02), and left ventricular lead more frequent in lateral medial position (69 vs. 26%, p=0.002). QRS width, lateral medial position of the lead and absence of mitral regurgitation were independent predictors of SR. sCD40L showed a moderate direct correlation with SR (r=0.39, p=0.02) and with the reduction of LVESV (r=0.44, p=0.02). Conclusion. sCD40L correlates significantly with SR to CRT. QRS width, absence of mitral regurgitation and lateral medial position of the lead are independent predictors of SR in this cohort.Fundamento. Analizar los biomarcadores Interleuquina 6, factor de necrosis tumoral α, sCD40L, troponina T hipersensible, proteína C-reactiva hipersensible y galectina-3 en la predicción de súper-respuesta (SR) a la terapia de resincronización cardiaca (TRC), ya que no han sido valorados con anterioridad. Material y métodos. Se recopilaron datos clínicos, electrocardiográficos y ecocardiográficos preimplante y al año. Se definió SR como disminución del VTSVI ≥ 30% al año de seguimiento. Las muestras sanguíneas fueron extraídas preimplante. Se realizó regresión logística multivariante y curvas ROC. Resultados. Se incluyeron 50 pacientes, 23 (46%) fueron SR.Las características relacionadas con la SR fueron: ser mujer (35 vs. 11%, p=0,04), sufrir menos cardiopatía isquémica (13 vs. 63%, p<0,0001) e infarto lateral (0 vs. 18%, p=0,03), inferior (4 vs. 33%, p=0,01) y posterior (0 vs. 22%, p=0,01); ausencia de insuficiencia mitral (47% vs. 22%, p=0,04), mayor anchura del QRS (157,7±22,9 vs. 140,8±19,2 ms, p=0,01), mayor concentración de sCD40L (6,9±5,1 vs. 4,4±3,3 ng/mL, p=0,02), y electrodo ventricular izquierdo más frecuentemente en posición lateral media (69 vs. 26%, p=0,002). El QRS, la posición lateral media del electrodo y la ausencia de insuficiencia mitral fueron predictores independientes de SR. sCD40L mostró una correlación moderada directa con SR (r=0,39, p=0,02) y con la disminución del VTSVI (r=0,44, p=0,02). Conclusiones. sCD40L se correlaciona significativamente con SR a la TRC. El QRS, la ausencia de insuficiencia mitral y la posición lateral media del electrodo son predictores independientes de SR en esta cohorte

HTLV-1 infection in solid organ transplant donors and recipients in Spain

Background: HTLV-1 infection is a neglected disease, despite infecting 10–15 million people worldwide and severe illnesses develop in 10% of carriers lifelong. Acknowledging a greater risk for developing HTLV-1 associated illnesses due to immunosuppression, screening is being widely considered in the transplantation setting. Herein, we report the experience with universal HTLV testing of donors and recipients of solid organ transplants in a survey conducted in Spain. Methods: All hospitals belonging to the Spanish HTLV network were invited to participate in the study. Briefly, HTLV antibody screening was performed retrospectively in all specimens collected from solid organ donors and recipients attended since the year 2008. Results: A total of 5751 individuals were tested for HTLV antibodies at 8 sites. Donors represented 2312 (42.2%), of whom 17 (0.3%) were living kidney donors. The remaining 3439 (59.8%) were recipients. Spaniards represented nearly 80%. Overall, 9 individuals (0.16%) were initially reactive for HTLV antibodies. Six were donors and 3 were recipients. Using confirmatory tests, HTLV-1 could be confirmed in only two donors, one Spaniard and another from Colombia. Both kidneys of the Spaniard were inadvertently transplanted. Subacute myelopathy developed within 1 year in one recipient. The second recipient seroconverted for HTLV-1 but the kidney had to be removed soon due to rejection. Immunosuppression was stopped and 3 years later the patient remains in dialysis but otherwise asymptomatic. Conclusion: The rate of HTLV-1 is low but not negligible in donors/recipients of solid organ transplants in Spain. Universal HTLV screening should be recommended in all donor and recipients of solid organ transplantation in Spain. Evidence is overwhelming for very high virus transmission and increased risk along with the rapid development of subacute myelopath