160 results on '"Guy CA"'
Search Results
2. Synthesis and Anti-Trypanosoma cruzi Activity of 3‑Cyanopyridine Derivatives
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Brian W. Slafer, Marco A. Dessoy, Ramon G. de Oliveira, Maria C. Mollo, Eun Lee, An Matheeussen, Louis Maes, Guy Caljon, Leonardo L. G. Ferreira, Renata Krogh, Adriano D. Andricopulo, Luiza R. Cruz, Charles E. Mowbray, Jadel M. Kratz, and Luiz C. Dias
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Chemistry ,QD1-999 - Published
- 2024
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3. N6-methyltubercidin gives sterile cure in a cutaneous Leishmania amazonensis mouse model
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Cassandra Present, Roberson Donola Girão, Cai Lin, Guy Caljon, Serge Van Calenbergh, Otacilio Moreira, Leonardo Alexandre de Souza Ruivo, Marcos Meuser Batista, Raquel Azevedo, Denise da Gama Jaen Batista, and Maria de Nazaré Correia Soeiro
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combination treatment ,in vitro ,in vivo ,Leishmania amazonensis ,nucleoside analogues ,Biochemistry ,QD415-436 ,Infectious and parasitic diseases ,RC109-216 ,Microbiology ,QR1-502 - Abstract
Leishmania is a trypanosomatid parasite that causes skin lesions in its cutaneous form. Current therapies rely on old and expensive drugs, against which the parasites have acquired considerable resistance. Trypanosomatids are unable to synthesize purines relying on salvaging from the host, and nucleoside analogues have emerged as attractive antiparasitic drug candidates. 4-Methyl-7-β-D-ribofuranosyl-7H-pyrrolo[2,3-d]pyrimidine (CL5564), an analogue of tubercidin in which the amine has been replaced by a methyl group, demonstrates activity against Trypanosoma cruzi and Leishmania infantum. Herein, we investigated its in vitro and in vivo activity against L. amazonensis. CL5564 was 6.5-fold (P = 0.0002) more potent than milteforan™ (ML) against intracellular forms in peritoneal mouse macrophages, and highly selective, while combination with ML gave an additive effect. These results stimulated us to study the activity of CL5564 in mouse model of cutaneous Leishmania infection. BALB/c female and male mice infected by L. amazonensis treated with CL5564 (10 mg kg−1, intralesional route for five days) presented a >93% reduction of paw lesion size likely ML given orally at 40 mg kg−1, while the combination (10 + 40 mg kg−1 of CL5564 and ML, respectively) caused >96% reduction. The qPCR confirmed the suppression of parasite load, but only the combination approach reached 66% of parasitological cure. These results support additional studies with nucleoside derivatives.
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- 2024
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4. Q586B2 is a crucial virulence factor during the early stages of Trypanosoma brucei infection that is conserved amongst trypanosomatids
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Benoit Stijlemans, Patrick De Baetselier, Inge Van Molle, Laurence Lecordier, Erika Hendrickx, Ema Romão, Cécile Vincke, Wendy Baetens, Steve Schoonooghe, Gholamreza Hassanzadeh-Ghassabeh, Hannelie Korf, Marie Wallays, Joar E. Pinto Torres, David Perez-Morga, Lea Brys, Oscar Campetella, María S. Leguizamón, Mathieu Claes, Sarah Hendrickx, Dorien Mabille, Guy Caljon, Han Remaut, Kim Roelants, Stefan Magez, Jo A. Van Ginderachter, and Carl De Trez
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Science - Abstract
Abstract Human African trypanosomiasis or sleeping sickness, caused by the protozoan parasite Trypanosoma brucei, is characterized by the manipulation of the host’s immune response to ensure parasite invasion and persistence. Uncovering key molecules that support parasite establishment is a prerequisite to interfere with this process. We identified Q586B2 as a T. brucei protein that induces IL-10 in myeloid cells, which promotes parasite infection invasiveness. Q586B2 is expressed during all T. brucei life stages and is conserved in all Trypanosomatidae. Deleting the Q586B2-encoding Tb927.6.4140 gene in T. brucei results in a decreased peak parasitemia and prolonged survival, without affecting parasite fitness in vitro, yet promoting short stumpy differentiation in vivo. Accordingly, neutralization of Q586B2 with newly generated nanobodies could hamper myeloid-derived IL-10 production and reduce parasitemia. In addition, immunization with Q586B2 delays mortality upon a challenge with various trypanosomes, including Trypanosoma cruzi. Collectively, we uncovered a conserved protein playing an important regulatory role in Trypanosomatid infection establishment.
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- 2024
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5. Rescue of ApoE4-related lysosomal autophagic failure in Alzheimer’s disease by targeted small molecules
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Meenakshisundaram Balasubramaniam, Jagadeesh Narasimhappagari, Ling Liu, Akshatha Ganne, Srinivas Ayyadevara, Ramani Atluri, Haarika Ayyadevara, Guy Caldwell, Robert J. Shmookler Reis, Steven W. Barger, and W. Sue T. Griffin
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Biology (General) ,QH301-705.5 - Abstract
Abstract Homozygosity for the ε4 allele of APOE increases the odds of developing Alzheimer’s by 12 to 15 times relative to the most common ε3;ε3 genotype, and its association with higher plaque loads comports with evidence that APOEε4 compromises autophagy. The ApoE4 protein specifically binds a cis element (“CLEAR”) in the promoters of several autophagy genes to block their transcription. We used a multifaceted approach to identify a druggable site in ApoE4, and virtual screening of lead-like compounds identified small molecules that specifically bind to this site to impede ApoE4::DNA binding. We validated these molecules both in vitro and in vivo with models expressing ApoE4, including ApoE4 targeted-replacement mice. One compound was able to significantly restore transcription of several autophagy genes and protected against amyloid-like aggregation in a C. elegans AD model. Together, these findings provide proof-of-principle evidence for pharmacological remediation of lysosomal autophagy by ApoE4 via ApoE4-targeted lead molecules that represent a novel tack on neurodegenerative disorders.
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- 2024
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6. Long-term hematopoietic stem cells trigger quiescence in Leishmania parasites.
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Laura Dirkx, Sara I Van Acker, Yasmine Nicolaes, João Luís Reis Cunha, Rokaya Ahmad, Rik Hendrickx, Ben Caljon, Hideo Imamura, Didier G Ebo, Daniel C Jeffares, Yann G-J Sterckx, Louis Maes, Sarah Hendrickx, and Guy Caljon
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Immunologic diseases. Allergy ,RC581-607 ,Biology (General) ,QH301-705.5 - Abstract
Addressing the challenges of quiescence and post-treatment relapse is of utmost importance in the microbiology field. This study shows that Leishmania infantum and L. donovani parasites rapidly enter into quiescence after an estimated 2-3 divisions in both human and mouse bone marrow stem cells. Interestingly, this behavior is not observed in macrophages, which are the primary host cells of the Leishmania parasite. Transcriptional comparison of the quiescent and non-quiescent metabolic states confirmed the overall decrease of gene expression as a hallmark of quiescence. Quiescent amastigotes display a reduced size and signs of a rapid evolutionary adaptation response with genetic alterations. Our study provides further evidence that this quiescent state significantly enhances resistance to treatment. Moreover, transitioning through quiescence is highly compatible with sand fly transmission and increases the potential of parasites to infect cells. Collectively, this work identified stem cells in the bone marrow as a niche where Leishmania quiescence occurs, with important implications for antiparasitic treatment and acquisition of virulence traits.
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- 2024
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7. The ongoing risk of Leishmania donovani transmission in eastern Nepal: an entomological investigation during the elimination era
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Lalita Roy, Kristien Cloots, Surendra Uranw, Keshav Rai, Narayan R. Bhattarai, Tom Smekens, Rik Hendrickx, Guy Caljon, Epco Hasker, Murari L. Das, and Wim Van Bortel
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Visceral leishmaniasis ,Vector ,Phlebotomus argentipes ,Seasonality ,Leishmania donovani transmission ,Infection rate ,Infectious and parasitic diseases ,RC109-216 - Abstract
Abstract Background Visceral leishmaniasis (VL), a life-threatening neglected tropical disease, is targeted for elimination from Nepal by the year 2026. The national VL elimination program is still confronted with many challenges including the increasingly widespread distribution of the disease over the country, local resurgence and the questionable efficacy of the key vector control activities. In this study, we assessed the status and risk of Leishmania donovani transmission based on entomological indicators including seasonality, natural Leishmania infection rate and feeding behavior of vector sand flies, Phlebotomus argentipes, in three districts that had received disease control interventions in the past several years in the context of the disease elimination effort. Methods We selected two epidemiologically contrasting settings in each survey district, one village with and one without reported VL cases in recent years. Adult sand flies were collected using CDC light traps and mouth aspirators in each village for 12 consecutive months from July 2017 to June 2018. Leishmania infection was assessed in gravid sand flies targeting the small-subunit ribosomal RNA gene of the parasite (SSU-rRNA) and further sequenced for species identification. A segment (~ 350 bp) of the vertebrate cytochrome b (cytb) gene was amplified from blood-fed P. argentipes from dwellings shared by both humans and cattle and sequenced to identify the preferred host. Results Vector abundance varied among districts and village types and peaks were observed in June, July and September to November. The estimated Leishmania infection rate in vector sand flies was 2.2% (1.1%–3.7% at 95% credible interval) and 0.6% (0.2%–1.3% at 95% credible interval) in VL and non-VL villages respectively. The common source of blood meal was humans in both VL (52.7%) and non-VL (74.2%) villages followed by cattle. Conclusions Our findings highlight the risk of ongoing L. donovani transmission not only in villages with VL cases but also in villages not reporting the presence of the disease over the past several years within the districts having disease elimination efforts, emphasize the remaining threats of VL re-emergence and inform the national program for critical evaluation of disease elimination strategies in Nepal. Graphical Abstract
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- 2023
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8. Synthesis and pharmacological evaluation of fluoro/chloro-substituted acetyl and benzoyl esters of quinine as antimalarial agents
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Jean-Gonfi Mvondo Mbala, Dani Thierry Mawete, Alain Nanikafuako Makiese, Prosper Lwanzo Kwiraviwe, Bibiche Kuyubuka Pangu, Eric Buini Nguimi, Richard Cimanga Kanyanga, Luc Pieters, Gilles Degotte, Michel Frederich, Aristote Matondo, Natascha Van Pelt, Guy Caljon, Bernard Pirotte, Blaise Mbala Mavinga, and Sylvie-Mireille Bambi-Nyanguile
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Quinine ,Antiplasmodial activity ,Plasmodium falciparum ,Acetyl derivatives ,Benzoyl derivatives ,Chemistry ,QD1-999 - Abstract
After establishment of the pharmacokinetic and toxicological profile of quinine derivatives using in silico approaches, this study reports the synthesis of new acetyl and benzoyl esters of quinine bearing one or more fluorine or chlorine atoms on the acetyl/benzoyl moiety. The antimalarial activity of these compounds on Plasmodium falciparum 3D7 and K1 strains as well as the antiprotozoal activity on Trypanosoma brucei brucei and Trypanosoma cruzi were evaluated. Lastly, the cytotoxicity on MRC-5SV2 cells was established. The fluoroacetyl ester compounds were found to be more active in vitro against Plasmodium falciparum 3D7 strain than the reference compound quinine. All synthesized quinine derivatives were non-cytotoxic for MRC-5SV2 cells (CC50 > 64 µM). These results confirm that the introduction of one or more fluorine atoms into acetyl and benzoyl esters of quinine can sometimes improve the biological activity.
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- 2024
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9. Dengue Virus Serotype 1 Effects on Mosquito Survival Differ among Geographically Distinct Aedes aegypti Populations
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Milan S. G. Keirsebelik, Mariana R. David, Márcio Galvão Pavan, Dinair Couto-Lima, Miriam Palomino, Rafi Ur Rahman, Ary A. Hoffmann, Ana C. Bahia, Guy Caljon, and Rafael Maciel-de-Freitas
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Aedes aegypti ,vectorial capacity ,dengue ,mosquito-virus interaction ,survival ,fecundity ,Science - Abstract
The mosquito Aedes aegypti is distributed worldwide and is recognized as the primary vector for dengue in numerous countries. To investigate whether the fitness cost of a single DENV-1 isolate varies among populations, we selected four Ae. aegypti populations from distinct localities: Australia (AUS), Brazil (BRA), Pakistan (PAK), and Peru (PER). Utilizing simple methodologies, we concurrently assessed survival rates and fecundity. Overall, DENV-1 infection led to a significant decrease in mosquito survival rates, with the exception of the PER population. Furthermore, infected Ae. aegypti from PAK, the population with the lowest infection rate among those tested, exhibited a noteworthy reduction in egg laying. These findings collectively suggest that local mosquito-virus adaptations may influence dengue transmission in endemic settings.
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- 2024
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10. Design and Synthesis of 1,3-Diarylpyrazoles and Investigation of Their Cytotoxicity and Antiparasitic Profile
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Murat Bozdag, Freke Mertens, An Matheeussen, Natascha Van Pelt, Kenn Foubert, Nina Hermans, Guido R. Y. De Meyer, Koen Augustyns, Wim Martinet, Guy Caljon, and Pieter Van der Veken
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1,3-diarylpyrazole ,pyrazole ,antiparasitic activity ,cytotoxicity ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Herein, we report a series of 1,3-diarylpyrazoles that are analogues of compound 26/HIT 8. We previously identified this molecule as a ‘hit’ during a high-throughput screening campaign for autophagy inducers. A variety of synthetic strategies were utilized to modify the 1,3-diarylpyrazole core at its 1-, 3-, and 4-position. Compounds were assessed in vitro to identify their cytotoxicity properties. Of note, several compounds in the series displayed relevant cytotoxicity, which warrants scrutiny while interpreting biological activities that have been reported for structurally related molecules. In addition, antiparasitic activities were recorded against a range of human-infective protozoa, including Trypanosoma cruzi, T. brucei rhodesiense, and Leishmania infantum. The most interesting compounds displayed low micromolar whole-cell potencies against individual or several parasitic species, while lacking cytotoxicity against human cells.
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- 2024
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11. Recent Developments in Engineering Non-Paralytic Botulinum Molecules for Therapeutic Applications
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Aisha Zhantleuova, Charlotte Leese, Anna P. Andreou, Altynay Karimova, Guy Carpenter, and Bazbek Davletov
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botulinum neurotoxin ,treatment ,non-paralytic molecules ,efficacy ,safety ,Medicine - Abstract
This review discusses the expanding application of botulinum neurotoxin in treating neurological conditions. The article specifically explores novel approaches to using non-paralytic botulinum molecules. These new molecules, such as BiTox or el-iBoNT, offer an alternative for patients who face limitations in using paralytic forms of botulinum neurotoxin due to concerns about muscle function loss. We highlight the research findings that confirm not only the effectiveness of these molecules but also their reduced paralytic effect. We also discuss a potential cause for the diminished paralytic action of these molecules, specifically changes in the spatial parameters of the new botulinum molecules. In summary, this article reviews the current research that enhances our understanding of the application of new botulinum neurotoxins in the context of common conditions and suggests new avenues for developing more efficient molecules.
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- 2024
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12. Management of Oligometastatic Breast Cancer: An Expert Committee’s Opinion
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Dominique Leblanc, Guy Cantin, Alexandra Desnoyers, Jean Dufresne, Giuseppina Laura Masucci, Valérie Panet-Raymond, Éric Poirier, Sara Soldera, and Isabelle Gingras
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breast cancer ,metastasis ,management ,expert opinion ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Patients with oligometastatic breast cancer (BC) are candidates of choice for metastasis-directed therapy (MDT). This paper summarizes the opinions of an expert committee about the management of oligometastatic BC. The experts could complete the questionnaire from 13 September 2021, to 10 October 2021, followed by a discussion. The experts were physicians working in the Province of Quebec (Canada) and specialized in BC care, including surgical oncologists, medical oncologists, and radiation oncologists. The experts provided their opinions about the context of the disease and therapeutic approach, local and systemic therapies, and the prognosis of oligometastatic BC. In addition to the expert panel’s opinions about the management of oligometastatic disease per se, the experts stated that a prospective data registry should be implemented to collect data about oligometastatic BC to improve knowledge about oligometastatic BC and implement data-driven MDT. These data could also allow for the design of treatment algorithms. In conclusion, this paper presents the expert panel’s opinions about the management of oligometastatic BC and highlights the needs to be met to improve the care of this condition.
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- 2023
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13. Abstracts of the Cell Therapy Transplant Canada 2022 Annual Conference
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Stephanie A. Maier, Tobias Berg, Susan Berrigan, Jonathan Bramson, Chris Bredeson, Guy Cantin, Andrew Daly, Gwynivere A. Davies, Mahmoud Elsawy, Alejandro Garcia-Horton, Wilson Lam, Alix Lapworth, Kylie Lepic, Luciana Melo Garcia, Kirk R. Schultz, Ram Vasudevan Nampoothiri, Darrell White, and Jean-Sébastien Delisle
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hematopoietic stem cell transplantation ,cell therapy ,GVHD ,lymphoma ,acute myeloid leukemia ,myelodysplastic syndrome ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
On behalf of Cell Therapy Transplant Canada (CTTC), we are pleased to present the Abstracts of the CTTC 2022 Annual Conference. The conference was held in-person 15–18 June 2022, in Niagara Falls, Ontario. Poster authors presented their work during a lively and engaging welcome reception on Thursday, 16 June, and oral abstract authors were featured during the oral abstract session in the afternoon on Friday, 17 June 2022. Thirty-three (33) abstracts were selected for presentation as posters and six (6) as oral presentations. The top abstracts in each of four (4) categories, (1) Basic/Translational sciences, (2) Clinical Trials/Observations, (3) Laboratory/Quality, and (4) Pharmacy/Nursing/Other Transplant Support, received awards for both the oral and poster presentations. All of these were marked as “Award Recipient” with the relevant category. We congratulate all the presenters on their research and contribution to the field.
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- 2022
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14. Impact of pulmonary African trypanosomes on the immunology and function of the lung
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Dorien Mabille, Laura Dirkx, Sofie Thys, Marjorie Vermeersch, Daniel Montenye, Matthias Govaerts, Sarah Hendrickx, Peter Takac, Johan Van Weyenbergh, Isabel Pintelon, Peter Delputte, Louis Maes, David Pérez-Morga, Jean-Pierre Timmermans, and Guy Caljon
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Science - Abstract
A number of human African trypanosomiasis, or sleeping sickness, patients suffer from respiratory symptoms commonly attributed to cardiac insufficiency. Here, the authors characterise the role of pulmonary Trypanosoma brucei in respiratory infection.
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- 2022
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15. 3-nitroimidazo[1,2-b]pyridazine as a novel scaffold for antiparasitics with sub-nanomolar anti-Giardia lamblia activity
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Yang Zheng, Joachim Müller, Stefan Kunz, Marco Siderius, Louis Maes, Guy Caljon, Norbert Müller, Andrew Hemphill, Geert Jan Sterk, and Rob Leurs
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3-nitroimidazo[1,2-b]pyridazine ,Synthesis ,Giardia lamblia ,3′,5′-cyclic nucleotide phosphodiesterase ,In vitro ,Infectious and parasitic diseases ,RC109-216 - Abstract
As there is a continuous need for novel anti-infectives, the present study aimed to fuse two modes of action into a novel 3-nitroimidazo[1,2-b]pyridazine scaffold to improve antiparasitic efficacy. For this purpose, we combined known structural elements of phosphodiesterase inhibitors, a target recently proposed for Trypanosoma brucei and Giardia lamblia, with a nitroimidazole scaffold to generate nitrosative stress. The compounds were evaluated in vitro against a panel of protozoal parasites, namely Giardia lamblia, Trypanosoma brucei, T. cruzi, Leishmania infantum and Plasmodium falciparum and for cytotoxicity on MRC-5 cells. Interestingly, selective sub-nanomolar activity was obtained against G. lamblia, and by testing several analogues with and without the nitro group, it was shown that the presence of a nitro group, but not PDE inhibition, is responsible for the low IC50 values of these novel compounds. Adding the favourable drug-like properties (low molecular weight, cLogP (1.2–4.1) and low polar surface area), the key compounds from the 3-nitroimidazo[1,2-b]pyridazine series can be considered as valuable hits for further anti-giardiasis drug exploration and development.
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- 2022
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16. Nucleoside analogues for the treatment of animal trypanosomiasis
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Dorien Mabille, Kayhan Ilbeigi, Sarah Hendrickx, Marzuq A. Ungogo, Fabian Hulpia, Cai Lin, Louis Maes, Harry P. de Koning, Serge Van Calenbergh, and Guy Caljon
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Animal trypanosomiasis ,Nucleoside analogues ,Infectious and parasitic diseases ,RC109-216 - Abstract
Animal trypanosomiasis (AT) is a parasitic disease with high socio-economic impact. Given the limited therapeutic options and problems of toxicity and drug resistance, this study assessed redirecting our previously identified antitrypanosomal nucleosides for the treatment of AT. Promising hits were identified with excellent in vitro activity across all important animal trypanosome species. Compound 7, an inosine analogue, and our previously described lead compound, 3′-deoxytubercidin (8), showed broad spectrum anti-AT activity, metabolic stability in the target host species and absence of toxicity, but with variable efficacy ranging from limited activity to full cure in mouse models of Trypanosoma congolense and T. vivax infection. Several compounds show promise against T. evansi (surra) and T. equiperdum (dourine). Given the preferred target product profile for a broad-spectrum compound against AT, this study emphasizes the need to include T. vivax in the screening cascade given its divergent susceptibility profile and provides a basis for lead optimization towards such broad spectrum anti-AT compound.
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- 2022
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17. Exploring the nexus link of environmental technology innovation, urbanization, financial development, and energy consumption on environmental pollution: Evidence from 27 emerging economies
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Fredrick Oteng Agyeman, Emmanuel Adu Gyamfi Kedjanyi, Agyemang Akwasi Sampene, Malcom Frimpong Dapaah, Abdul Razak Monto, Paul Buabeng, and Guy Carlos Guimatsie Samekong
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Environmental technology innovation ,Financial development ,Environmental pollution ,Trade openness ,Energy consumption ,Economic growth ,Science (General) ,Q1-390 ,Social sciences (General) ,H1-99 - Abstract
The core intent of the present study seeks to probe the connection linking environmental technology innovation (ENVTI), economic growth (ECG), financial development (FID), trade openness (TROP), urbanization (URB) and energy consumption (ENC) on environmental pollution (ENVP) by employing 27 chosen African economies panel data. These variables merit critical attention when implementing decarbonization policies and significantly safeguarding a country's well-being in pursuit of massive industrialization and economic expansion. The fully modified ordinary least squares (FMOLS), the dynamic ordinary least square (DOLS), and the pooled mean group (PMG) estimation techniques were utilized to analyze the series from 2000 through 2020. This research used the FMOLS for long-run connections interaction of the variables, while the DOLS and PMG were used for robustness checks. Further, the Pedroni, Kao, and Westerlund cointegration approaches were employed to determine cointegration in the series. Also, the cross-sectional Im, Pesaran, and Shin (CIPS) and the cross-sectional augmented Dickey-Fuller (CADF) unit root testing approaches were utilized to check the stationarity of the series. Again, the stochastic impact on regression, population, affluence, and technology (STIRPAT) model, and the environmental Kuznets curve (EKC) was used as the theoretical framework supporting this research. The findings of the long-run analysis give credence to the EKC assumption demonstrating that a significant long-term ECG will support the decrease in ENVP when nations experience increases in the level of income. Further, this study found that ENVTI and URB are conducive to reducing ENVP in the long run. The current research finding is sensitive to the respective nations' income levels. This empirical research furnishes prudent policies tailored for the respective countries' pursuit of ECG and reducing ENVP.
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- 2023
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18. Feedback in Medical Education: An Evidence-based Guide to Best Practices from the Council of Residency Directors in Emergency Medicine
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Sreeja Natesan, Jaime Jordan, Alexander Sheng, Guy Carmelli, Brian Barbas, Andrew King, Kataryza Gore, Molly Estes, and Michael Gottlieb
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Medicine ,Medical emergencies. Critical care. Intensive care. First aid ,RC86-88.9 - Abstract
Within medical education, feedback is an invaluable tool to facilitate learning and growth throughout a physician’s training and beyond. Despite the importance of feedback, variations in practice indicate the need for evidence-based guidelines to inform best practices. Additionally, time constraints, variable acuity, and workflow in the emergency department (ED) pose unique challenges to providing effective feedback. This paper outlines expert guidelines for feedback in the ED setting from members of the Council of Residency Directors in Emergency Medicine Best Practices Subcommittee, based on the best evidence available through a critical review of the literature. We provide guidance on the use of feedback in medical education, with a focus on instructor strategies for giving feedback and learner strategies for receiving feedback, and we offer suggestions for fostering a culture of feedback.
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- 2023
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19. Detection of novel transcripts and evaluation of expression levels of Igf2 in mouse placenta
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Giang Tran Van and Guy Cathala
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Veterinary medicine ,SF600-1100 - Abstract
The imprinted Igf2 gene (Insulin-like growth factor 2) encodes a growth factor that plays an important role in the formation of the placenta and embryonic development. This study results showed that several new transcripts of the Igf2 gene were detected in the placenta of mice, and the new promoter in the placenta P0L and PU2 were found. Expression levels of these promoters as well as of the Igf2 gene were evaluated in the placentas of mice. The expression levels of these two promoters were investigated in different tissues; P0L is very well expressed in the brain and is clearly expressed in the placenta, tongue, and kidney; P0 is well expressed in the placenta, but also in the kidney and heart; PU2 is expressed in addition to the placenta, tongue, and muscles.
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- 2022
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20. Long-term hematopoietic stem cells as a parasite niche during treatment failure in visceral leishmaniasis
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Laura Dirkx, Sarah Hendrickx, Margot Merlot, Dimitri Bulté, Marick Starick, Jessy Elst, André Bafica, Didier G. Ebo, Louis Maes, Johan Van Weyenbergh, and Guy Caljon
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Biology (General) ,QH301-705.5 - Abstract
Long-term hematopoietic stem cells may act as protective niches for the Leishmania parasite, potentially contributing to treatment failure in cases of visceral leishmaniasis.
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- 2022
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21. 6-Methyl-7-deazapurine nucleoside analogues as broad-spectrum antikinetoplastid agents
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Cai Lin, Fabian Hulpia, Izet Karalic, Laurens De Schepper, Louis Maes, Guy Caljon, and Serge Van Calenbergh
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Nucleosides ,Antikinetoplastid agents ,Trypanosoma cruzi ,Leishmania infantum ,Trypanosoma brucei ,Infectious and parasitic diseases ,RC109-216 - Abstract
Kinetoplastid parasites are the causative agents of Chagas disease (CD), leishmaniasis and human African trypanosomiasis (HAT). Despite a sustained decrease in the number of HAT cases, more efforts are needed to discover safe and effective therapies against CD and leishmaniasis. Kinetoplastid parasites lack the capability to biosynthesize purines de novo and thus critically depend on uptake and processing of purines from host cells. As such, modified purine nucleoside analogues may act as broad-spectrum antikinetoplastid agents. This study assessed the in vitro activity profile of 7-modified 6-methyl tubercidin derivatives against Trypanosoma cruzi, Leishmania infantum, Trypanosoma brucei brucei and T. b. rhodesiense, and led to the identification of analogues that display activity against all these species, such as 7-ethyl (13) and 7-chloro (7) analogues. These selected analogues also proved sufficiently stable in liver microsomes to warrant in vivo follow-up evaluation.
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- 2021
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22. Detecting change in the routine of the elderly
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Soumaya Msaad, Yannick Wend Kuni Zoetgnandé, Jean-Louis Dillenseger, and Guy Carrault
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Elderly ,Routine ,Fraitly ,Depth sensor ,Deep learning ,Machine learning ,Electric apparatus and materials. Electric circuits. Electric networks ,TK452-454.4 - Abstract
Recent studies shown that elderly persons have a well-defined, regular life routine, organized around their postures, habits, environment, and social relations. Monitoring the daily routine will allow to detect person behavior changes. In this paper, we propose two solutions for detecting changes in the elderly person behavior based on the daily living activities monitoring. For both proposed methods, the person’s activity is recorded with a depth sensor to preserve his anonymity. In a first step, the recorded images are classified according to the posture of the person (sitting, standing, lying down, absent and fall) by a modified ResNet-18 model. The first method is a binary decision problem and consists in classifying routine and non routine day according to the postures. Then a behavior index is built using the output of the classifier. The second method consists in describing the routine day by the temporal succession in postures. A similarity between the recorded day and the routine day postures is computed using the minimum edit distance which acts as a behavior index. The number of transformations reflects the change in the person’s behavior. Both methods have been tested on a database of depth images recorded in a nursing home over a 85 days period. Inferring the whole dataset gives an accuracy of 89.09% and a F1-score of 85.84% for posture estimation. Using Random Forest, an accuracy of 92% was retrieved for routine/non routine day classification. The two proposed indexes proved their reliability in monitoring behavior changes. The first approach proposes a behavioral index with a median magnitude error less that 0.01 compared to the ground truth. The second one provides a significant difference in the number of transformations between the postures in routine days (Interquartile range 25th-75th=[28, 48]) and non routine days (Interquartile range 25th-75th=[55, 62]).
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- 2022
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23. The deficiency in Th2-like Tfh cells affects the maturation and quality of HIV-specific B cell response in viremic infection
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Alessandra Noto, Madeleine Suffiotti, Victor Joo, Antonio Mancarella, Francesco A. Procopio, Guy Cavet, Yvonne Leung, Jean-Marc Corpataux, Matthias Cavassini, Agostino Riva, Leonidas Stamatatos, Raphael Gottardo, Adrian B. McDermott, Richard A. Koup, Craig Fenwick, Matthieu Perreau, and Giuseppe Pantaleo
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lymph nodes ,follicular T helper cells ,germinal center B cells (GC B cells) ,HIV-1 infection ,T helper cell ,Immunologic diseases. Allergy ,RC581-607 - Abstract
Optimal T follicular helper (Tfh) cells function is important to promote the development of germinal centers and maturation of high affinity antigen-specific B cells. We have found that the expression of CXCR3 defines distinct Tfh subsets: CXCR3+ Th1-like Tfh cells mainly producing single IFN-γ and dual IL-21/IFN-γ and CXCR3- Th2-like Tfh cells mainly producing single IL-4 and dual IL-21/IL-4 cytokines. CXCR3- Th2-like Tfhs are significantly reduced during ongoing HIV replication. While the percentage of Th2-like Tfh cells correlates with that of total and cycling HIV-specific B cells, the percentage of CXCR3+ Th1-like Tfhs correlates with HIV-specific B cells expressing T-bet and CXCR3. Of note, only IL-4 and IL-21 cytokines boosted efficient maturation of HIV-specific B cells while IFN-γ induced expression of T-bet and CXCR3 in B cells. Interestingly, total and HIV-specific CXCR3+ B cells showed lower rate of somatic hypermutation, as compared to CXCR3- B cells. Therefore, the imbalance in Th2/Th1-like Tfhs affects B cell responses in viremic HIV infection.
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- 2022
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24. Structural Optimization of BIPPO Analogs as Potent Antimalarials
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Yang Zheng, An Matheeussen, Louis Maes, Guy Caljon, Geert Jan Sterk, and Rob Leurs
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antimalarial ,BIPPO analogs ,structural optimization ,Organic chemistry ,QD241-441 - Abstract
Malaria continues to pose a significant health threat, causing thousands of deaths each year. The limited availability of vaccines and medications, combined with the emergence of drug resistance, further complicates the fight against this disease. In this study, we aimed to enhance the antimalarial potency of the previously reported hit compound BIPPO (pIC50 5.9). Through systematic modification of pyrazolopyrimidinone analogs, we discovered the promising analog 30 (NPD-3547), which exhibited approximately one log unit higher in vitro potency (pIC50 6.8) against Plasmodium falciparum. Furthermore, we identified several other BIPPO analogs (23, 28, 29 and 47a) with potent antimalarial activity (pIC50 > 6.0) and favorable metabolic stability in mouse liver microsomes. These compounds can serve as new tools for further optimization towards the development of potential candidates for antimalarial studies.
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- 2023
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25. To Target or Not to Target Schistosoma mansoni Cyclic Nucleotide Phosphodiesterase 4A?
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Yang Zheng, Susanne Schroeder, Georgi K. Kanev, Sanaa S. Botros, Samia William, Abdel-Nasser A. Sabra, Louis Maes, Guy Caljon, Carmen Gil, Ana Martinez, Irene G. Salado, Koen Augustyns, Ewald Edink, Maarten Sijm, Erik de Heuvel, Iwan J. P. de Esch, Tiffany van der Meer, Marco Siderius, Geert Jan Sterk, David Brown, and Rob Leurs
- Subjects
Schistosoma mansoni ,phosphodiesterase ,drug target ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Schistosomiasis is a neglected tropical disease with high morbidity. Recently, the Schistosoma mansoni phosphodiesterase SmPDE4A was suggested as a putative new drug target. To support SmPDE4A targeted drug discovery, we cloned, isolated, and biochemically characterized the full-length and catalytic domains of SmPDE4A. The enzymatically active catalytic domain was crystallized in the apo-form (PDB code: 6FG5) and in the cAMP- and AMP-bound states (PDB code: 6EZU). The SmPDE4A catalytic domain resembles human PDE4 more than parasite PDEs because it lacks the parasite PDE-specific P-pocket. Purified SmPDE4A proteins (full-length and catalytic domain) were used to profile an in-house library of PDE inhibitors (PDE4NPD toolbox). This screening identified tetrahydrophthalazinones and benzamides as potential hits. The PDE inhibitor NPD-0001 was the most active tetrahydrophthalazinone, whereas the approved human PDE4 inhibitors roflumilast and piclamilast were the most potent benzamides. As a follow-up, 83 benzamide analogs were prepared, but the inhibitory potency of the initial hits was not improved. Finally, NPD-0001 and roflumilast were evaluated in an in vitro anti-S. mansoni assay. Unfortunately, both SmPDE4A inhibitors were not effective in worm killing and only weakly affected the egg-laying at high micromolar concentrations. Consequently, the results with these SmPDE4A inhibitors strongly suggest that SmPDE4A is not a suitable target for anti-schistosomiasis therapy.
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- 2023
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26. Early bradycardia detection and therapeutic interventions in preterm infant monitoring
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Matthieu Doyen, Alfredo I. Hernández, Cyril Flamant, Antoine Defontaine, Géraldine Favrais, Miguel Altuve, Bruno Laviolle, Alain Beuchée, Guy Carrault, and Patrick Pladys
- Subjects
Medicine ,Science - Abstract
Abstract In very preterm infants, cardio-respiratory events and associated hypoxemia occurring during early postnatal life have been associated with risks of retinopathy, growth alteration and neurodevelopment impairment. These events are commonly detected by continuous cardio-respiratory monitoring in neonatal intensive care units (NICU), through the associated bradycardia. NICU nurse interventions are mainly triggered by these alarms. In this work, we acquired data from 52 preterm infants during NICU monitoring, in order to propose an early bradycardia detector which is based on a decentralized fusion of three detectors. The main objective is to improve automatic detection under real-life conditions without altering performance with respect to that of a monitor commonly used in NICU. We used heart rate lower than 80 bpm during at least 10 sec to define bradycardia. With this definition we observed a high rate of false alarms (64%) in real-life and that 29% of the relevant alarms were not followed by manual interventions. Concerning the proposed detection method, when compared to current monitors, it provided a significant decrease of the detection delay of 2.9 seconds, without alteration of the sensitivity (97.6% vs 95.2%) and false alarm rate (63.7% vs 64.1%). We expect that such an early detection will improve the response of the newborn to the intervention and allow for the development of new automatic therapeutic strategies which could complement manual intervention and decrease the sepsis risk.
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- 2021
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27. The effect of the sugar metabolism on Leishmania infantum promastigotes inside the gut of Lutzomyia longipalpis: A sweet relationship?
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Sarah Hendrickx and Guy Caljon
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Arctic medicine. Tropical medicine ,RC955-962 ,Public aspects of medicine ,RA1-1270 - Abstract
It is well-known that Leishmania parasites can alter the behavior of the sand fly vector in order to increase their transmission potential. However, little is known about the contribution of the infecting host's blood composition on subsequent sand fly infection and survival. This study focused on the host's glucose metabolism and the insulin/insulin-like growth factor 1 (IGF-1) pathway as both metabolic processes are known to impact vector-parasite interactions of other protozoa and insect species. The focus of this study was inspired by the observation that the glycemic levels in the blood of infected Syrian golden hamsters inversely correlated to splenic and hepatic parasite burdens. To evaluate the biological impact of these findings on further transmission, Lutzomyia longipalpis sand flies were infected with blood that was artificially supplemented with different physiological concentrations of several monosaccharides, insulin or IGF-1. Normoglycemic levels resulted in transiently higher parasite loads and faster appearance of metacyclics, whereas higher carbohydrate and insulin/IGF-1 levels favored sand fly survival. Although the recorded effects were modest or transient of nature, these observations support the concept that the host blood biochemistry may affect Leishmania transmission and sand fly longevity.
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- 2022
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28. Aspects of the reproductive ecology of Trachycephalus cunauaru (Anura: Hylidae) in the southern Amazon
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Janaina da Costa de NORONHA, Cynthia P. A. PRADO, Jean-Marc HERO, Guy CASTLEY, and Domingos de Jesus RODRIGUES
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phytotelmata ,artificial reproductive sites ,canopy sampling ,oophagy ,amphibians ,Science (General) ,Q1-390 - Abstract
ABSTRACT Trachycephalus cunauaru is an Amazonian hylid that uses phytotelmata to reproduce. There is relatively little information about the species, mainly due to the difficulty of accessing their reproductive sites. In this study, we gathered data on the ecology and natural history of T. cunauaru in the southern Amazon, in the state of Mato Grosso, Brazil. In addition to natural phytotelmata, we used buckets installed at a height of 10 m as artificial phytotelmata. We compared physical and chemical characteristics, as well as the presence of tadpoles between natural and artificial phytotelmata. We also collected data on the reproductive behavior of the species through the use of camera traps. We recorded a density of 14.1 reproductive sites per km². Environmental parameters differed significantly between artificial and natural phytotelmata. In artificial sites, the presence of tadpoles was directly related to trees with a larger diameter. We registered oophagy for the first time for the species and observed that males can use more than one phytotelm. We also recorded the presence of snakes within the reproductive sites. We determined that artificial sites and digital camera traps are a satisfactory alternative for behavioral observations of T. cunauaru and possibly for other species with a similar habit.
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- 2021
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29. Cloning and Characterization of Trypanosoma congolense and T. vivax Nucleoside Transporters Reveal the Potential of P1-Type Carriers for the Discovery of Broad-Spectrum Nucleoside-Based Therapeutics against Animal African Trypanosomiasis
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Marzuq A. Ungogo, Mustafa M. Aldfer, Manal J. Natto, Hainan Zhuang, Robyn Chisholm, Katy Walsh, MarieClaire McGee, Kayhan Ilbeigi, Jamal Ibrahim Asseri, Richard J. S. Burchmore, Guy Caljon, Serge Van Calenbergh, and Harry P. De Koning
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Trypanosoma vivax ,Trypanosoma congolense ,nucleoside antimetabolite ,adenosine transporter ,nucleoside transporter ,animal trypanosomiasis ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
African Animal Trypanosomiasis (AAT), caused predominantly by Trypanosoma brucei brucei, T. vivax and T. congolense, is a fatal livestock disease throughout Sub-Saharan Africa. Treatment options are very limited and threatened by resistance. Tubercidin (7-deazaadenosine) analogs have shown activity against individual parasites but viable chemotherapy must be active against all three species. Divergence in sensitivity to nucleoside antimetabolites could be caused by differences in nucleoside transporters. Having previously characterized the T. brucei nucleoside carriers, we here report the functional expression and characterization of the main adenosine transporters of T. vivax (TvxNT3) and T. congolense (TcoAT1/NT10), in a Leishmania mexicana cell line (‘SUPKO’) lacking adenosine uptake. Both carriers were similar to the T. brucei P1-type transporters and bind adenosine mostly through interactions with N3, N7 and 3′-OH. Expression of TvxNT3 and TcoAT1 sensitized SUPKO cells to various 7-substituted tubercidins and other nucleoside analogs although tubercidin itself is a poor substrate for P1-type transporters. Individual nucleoside EC50s were similar for T. b. brucei, T. congolense, T. evansi and T. equiperdum but correlated less well with T. vivax. However, multiple nucleosides including 7-halogentubercidines displayed pEC50>7 for all species and, based on transporter and anti-parasite SAR analyses, we conclude that nucleoside chemotherapy for AAT is viable.
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- 2023
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30. The Role of mTOR and Injury in Developing Salispheres
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Rimah Saleem and Guy Carpenter
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salivary glands ,salispheres ,mTOR ,LiCl ,ligation ,Biology (General) ,QH301-705.5 - Abstract
Salispheres are the representative primitive cells of salivary glands grown in vitro in a nonadherent system. In this study, we used the ligation model for salisphere isolation after seven days of obstruction of the main excretory duct of the submandibular gland. The mammalian target of rapamycin (mTOR) is a critical signalling pathway involved in many cellular functions and is suggested to play a role in atrophy. We determined the role of mTOR and injury in the formation and development of salispheres. Morphological assessments and Western blot analysis illustrated how mTOR inhibition by rapamycin impaired the assembly of salispheres and how indirect stimulation of mTOR by lithium chloride (LiCl) assisted in the expansion of the salispheres. The use of rapamycin highlighted the necessity of mTOR for the development of salispheres as it affected the morphology and inhibited the phosphorylation of the eukaryotic translation initiation factor 4E-binding protein (4e-bp1). mTOR activity also appeared to be a crucial regulator for growing salispheres, even from the ligated gland. However, atrophy induced by ductal ligation resulted in a morphological alteration. The phosphorylation of 4e-bp1 and S6 ribosomal protein in cultured salispheres from ligated glands suggests that mTOR was not responsible for the morphological modification, but other unexplored factors were involved. This exploratory study indicates that active mTOR is essential for growing healthy salispheres. In addition, mTOR stimulation by LiCl could effectively play a role in the expansion of salispheres. The impact of atrophy on salispheres suggests a complex mechanism behind the morphological alteration, which requires further investigation.
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- 2023
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31. Targeting the tsetse-trypanosome interplay using genetically engineered Sodalis glossinidius.
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Linda De Vooght, Karin De Ridder, Shahid Hussain, Benoît Stijlemans, Patrick De Baetselier, Guy Caljon, and Jan Van Den Abbeele
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Immunologic diseases. Allergy ,RC581-607 ,Biology (General) ,QH301-705.5 - Abstract
Sodalis glossinidius, a secondary bacterial symbiont of the tsetse fly, is currently considered as a potential delivery system for anti-trypanosomal components interfering with African trypanosome transmission (i.e. paratransgenesis). Nanobodies (Nbs) have been proposed as potential candidates to target the parasite during development in the tsetse fly. In this study, we have generated an immune Nb-library and developed a panning strategy to select Nbs against the Trypanosoma brucei brucei procyclic developmental stage present in the tsetse fly midgut. Selected Nbs were expressed, purified, assessed for binding and tested for their impact on the survival and growth of in vitro cultured procyclic T. b. brucei parasites. Next, we engineered S. glossinidius to express the selected Nbs and validated their ability to block T. brucei development in the tsetse fly midgut. Genetically engineered S. glossinidius expressing Nb_88 significantly compromised parasite development in the tsetse fly midgut both at the level of infection rate and parasite load. Interestingly, expression of Nb_19 by S. glossinidius resulted in a significantly enhanced midgut establishment. These data are the first to show in situ delivery by S. glossinidius of effector molecules that can target the trypanosome-tsetse fly crosstalk, interfering with parasite development in the fly. These proof-of-principle data represent a major step forward in the development of a control strategy based on paratransgenic tsetse flies. Finally, S. glossinidius-based Nb delivery can also be applied as a powerful laboratory tool to unravel the molecular determinants of the parasite-vector association.
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- 2022
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32. Impact of long-lasting moderate-intensity stage cycling event on cardiac function in young female athletes: A case study.
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Solène Le Douairon Lahaye, Gaëlle Kervio, Vincent Menard, Anna Barrero, Thibault Lachard, Guy Carrault, David Matelot, François Carré, and Frédéric Schnell
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Medicine ,Science - Abstract
PurposeEffects of intense and/or prolonged exercise have been studied extensively in male athletes. Nevertheless, data are scare on the effect of long duration events on cardiac function in female athletes. Our aim was to investigate the effect of a long-lasting moderate-intensity stage cycling event on cardiac function of young female athletes.MethodsSeven well-trained female cyclists were included. They completed a cycling event of 3529 km on 23 days. All underwent an echocardiography on 6 time-points (baseline and at the arrival of day (D) 3, 7, 12, 13 and 23). Cardiac function was assessed by conventional echocardiography, tissue Doppler imaging and speckle tracking techniques. Daily exercise load was determined by heart rate (HR), power output and rate of perceived exertion data (RPE, Borg scale).ResultsAll stages were mainly done at moderate intensity (average HR: 65% of maximal, average aerobic power output: 36% of maximal, average RPE: 4). Resting HR measured at the time of echocardiography did not vary during the event. Resting cardiac dimensions did not significantly change during the 23 days of cycling. No significant modification of cardiac function, whatever the studied cavity, were observed all along the event.ConclusionThe results suggest that, in the context of our case study, the long-lasting moderate-intensity stage cycling event was not associated with cardiac function alteration. Nevertheless, we must be careful in interpreting them due to the limits of an underpowered study.
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- 2022
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33. Impact of clinically acquired miltefosine resistance by Leishmania infantum on mouse and sand fly infection
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Lieselotte Van Bockstal, Dimitri Bulté, Sarah Hendrickx, Jovana Sadlova, Petr Volf, Louis Maes, and Guy Caljon
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Visceral leishmaniasis ,Leishmania infantum ,Miltefosine-resistance ,Bioluminescent imaging ,Lutzomyia longipalpis ,Phlebotomus perniciosus ,Infectious and parasitic diseases ,RC109-216 - Abstract
Objectives: This study evaluated the implications of clinically acquired miltefosine resistance (MIL-R) by assessing virulence in mice and sand flies to reveal the potential of MIL-R strains to circulate. Methods: Experimental infections with the MIL-R clinical Leishmania infantum isolate MHOM/FR/2005/LEM5159, having a defect in the LiROS3 subunit of the MIL-transporter, and its syngeneic experimentally reconstituted MIL-S counterpart (LEM5159LiROS3) were performed in BALB/c mice and Lutzomyia longipalpis and Phlebotomus perniciosus sand flies. In mice, the amastigote burdens in liver and spleen were compared microscopically using Giemsa smears and by bioluminescent imaging. During the sand fly infections, the percentage of infected flies, parasite load, colonization of the stomodeal valve and metacyclogenesis were evaluated. The stability of the MIL-R phenotype after sand fly and mouse passage was determined as well. Results: The fitness of the MIL-R strain differed between the mouse and sand fly infection model. In mice, a clear fitness loss was observed compared to the LiROS3-reconstituted susceptible strain. This defect could be rescued by episomal reconstitution with a wildtype LiROS3 copy. However, this fitness loss was not apparent in the sand fly vector, resulting in metacyclogenesis and efficient colonization of the stomodeal valve. Resistance was stable after passage in both sand fly and mouse. Conclusion: The natural MIL-R strain is significantly hampered in its ability to multiply and cause a typical visceral infection pattern in BALB/c mice. However, this LiROS3-deficient strain efficiently produced mature infections and metacyclic promastigotes in the sand fly vector highlighting the transmission potential of this particular MIL-R clinical Leishmania strain.
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- 2020
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34. Evaluation of a pan-Leishmania SL RNA qPCR assay for parasite detection in laboratory-reared and field-collected sand flies and reservoir hosts
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Myrthe Pareyn, Rik Hendrickx, Nigatu Girma, Sarah Hendrickx, Lieselotte Van Bockstal, Natalie Van Houtte, Simon Shibru, Louis Maes, Herwig Leirs, and Guy Caljon
- Subjects
Spliced leader RNA ,Kinetoplast DNA ,Nucleic acid extraction ,Sand fly ,Reservoir ,Real-time PCR ,Infectious and parasitic diseases ,RC109-216 - Abstract
Abstract Background In eco-epidemiological studies, Leishmania detection in vectors and reservoirs is frequently accomplished by high-throughput and sensitive molecular methods that target minicircle kinetoplast DNA (kDNA). A pan-Leishmania SYBR green quantitative PCR (qPCR) assay which detects the conserved spliced-leader RNA (SL RNA) sequence was developed recently. This study assessed the SL RNA assay performance combined with a crude extraction method for the detection of Leishmania in field-collected and laboratory-reared sand flies and in tissue samples from hyraxes as reservoir hosts. Methods Field-collected and laboratory-infected sand fly and hyrax extracts were subjected to three different qPCR approaches to assess the suitability of the SL RNA target for Leishmania detection. Nucleic acids of experimentally infected sand flies were isolated with a crude extraction buffer with ethanol precipitation and a commercial kit and tested for downstream DNA and RNA detection. Promastigotes were isolated from culture and sand fly midguts to assess whether there was difference in SL RNA and kDNA copy numbers. Naive sand flies were spiked with a serial dilution of promastigotes to make a standard curve. Results The qPCR targeting SL RNA performed well on infected sand fly samples, despite preservation and extraction under presumed unfavorable conditions for downstream RNA detection. Nucleic acid extraction by a crude extraction buffer combined with a precipitation step was highly compatible with downstream SL RNA and kDNA detection. Copy numbers of kDNA were found to be identical in culture-derived parasites and promastigotes isolated from sand fly midguts. SL RNA levels were slightly lower in sand fly promastigotes (ΔCq 1.7). The theoretical limit of detection and quantification of the SL RNA qPCR respectively reached down to 10−3 and 10 parasite equivalents. SL RNA detection in stored hyrax samples was less efficient with some false-negative assay results, most likely due to the long-term tissue storage in absence of RNA stabilizing reagents. Conclusions This study shows that a crude extraction method in combination with the SL RNA qPCR assay is suitable for the detection and quantification of Leishmania in sand flies. The assay is inexpensive, sensitive and pan-Leishmania specific, and accordingly an excellent assay for high-throughput screening in entomological research.
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- 2020
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35. Phenotypic adaptations of Leishmania donovani to recurrent miltefosine exposure and impact on sand fly infection
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Sarah Hendrickx, Lieselotte Van Bockstal, Dimitri Bulté, Annelies Mondelaers, Hamide Aslan, Luis Rivas, Louis Maes, and Guy Caljon
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Miltefosine ,Leishmania ,Fitness ,Lutzomyia longipalpis ,Drug uptake ,Infectious and parasitic diseases ,RC109-216 - Abstract
Abstract Background Since the introduction of miltefosine (MIL) as first-line therapy in the kala-azar elimination programme in the Indian subcontinent, treatment failure rates have been increasing. Since parasite infectivity and virulence may become altered upon treatment relapse, this laboratory study assessed the phenotypic effects of repeated in vitro and in vivo MIL exposure. Methods Syngeneic Leishmania donovani lines either or not exposed to MIL were compared for drug susceptibility, rate of promastigote multiplication and metacyclogenesis, macrophage infectivity and behaviour in the sand fly vector, Lutzomyia longipalpis. Results Promastigotes of both in vitro and in vivo MIL-selected strains displayed a slightly reduced drug susceptibility that was associated with a reduced MIL-accumulation linked to a lower copy number (disomic state) of chromosome 13 harboring the miltefosine transporter (LdMT) gene. In vitro selected promastigotes showed a lower rate of metacyclogenesis whereas the in vivo derived promastigotes displayed a moderately increased growth rate. Repeated MIL exposure did neither influence the parasite load nor metacyclogenesis in the sand fly vector. Conclusions Recurrent in vitro and in vivo MIL exposure evokes a number of very subtle phenotypic and genotypic changes which could make promastigotes less susceptible to MIL without attaining full resistance. These changes did not significantly impact on infection in the sand fly vector.
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- 2020
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36. Combining tubercidin and cordycepin scaffolds results in highly active candidates to treat late-stage sleeping sickness
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Fabian Hulpia, Dorien Mabille, Gustavo D. Campagnaro, Gabriela Schumann, Louis Maes, Isabel Roditi, Anders Hofer, Harry P. de Koning, Guy Caljon, and Serge Van Calenbergh
- Subjects
Science - Abstract
Trypanosoma brucei relies on uptake and conversion of purines from the host, which constitutes a potential drug target. Here, Hulpia et al. combine structural elements from known trypanocidal nucleoside analogues and develop a potent trypanocide with curative activity in animal models of acute and late stage sleeping sickness.
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- 2019
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37. Impaired development of a miltefosine-resistant Leishmania infantum strain in the sand fly vectors Phlebotomus perniciosus and Lutzomyia longipalpis
- Author
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Lieselotte Van Bockstal, Jovana Sádlová, Hamide Aslan Suau, Sarah Hendrickx, Claudio Meneses, Shaden Kamhawi, Petr Volf, Louis Maes, and Guy Caljon
- Subjects
Infectious and parasitic diseases ,RC109-216 - Abstract
Objectives: To gain insight into the propagation of miltefosine (MIL) resistance in visceral leishmaniasis, this laboratory study explored development of resistant parasites with a defective miltefosine transporter (MT) in sand flies. Methods: Infectivity, colonization of stomodeal valve and metacyclogenesis of a MIL-resistant (MIL-R) Leishmania infantum LEM3323 line with a defective MT were assessed in the natural sand fly vectors Phlebotomus perniciosus and Lutzomyia longipalpis. Given our recent description of partial drug dependency of the MT-deficient line, the impact of MIL pre-exposure on sand fly infectivity was explored as well. Results: A significant reduction in sand fly infection, stomodeal valve colonization and differentiation into metacyclics (determined by a lower flagellum/cell body length ratio) was observed in both vectors for MIL-R as compared to the isogenic parent MIL-susceptible line. Re-introduction of the wildtype MT gene into MIL-R tended to partially rescue the capacity to infect sand flies. Pre-exposure to MIL did not alter infectivity of the MIL-R line. Conclusion: The MIL resistant L. infantum LEM3323 line is significantly hampered in its development and transmissibility potential in two sand fly vector species. Additional studies are warranted to evaluate whether this applies to other visceral Leishmania parasites with acquired MIL-resistance. Keywords: Leishmania infantum, Miltefosine-resistance, Phlebotomus perniciosus, Lutzomyia longipalpis, Metacyclogenesis, Fitness
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- 2019
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38. Comparison of Bioluminescent Substrates in Natural Infection Models of Neglected Parasitic Diseases
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Sarah Hendrickx, Dimitri Bulté, Dorien Mabille, Roxanne Mols, Mathieu Claes, Kayhan Ilbeigi, Rokaya Ahmad, Laura Dirkx, Sara I. Van Acker, and Guy Caljon
- Subjects
reporter gene technology ,bioluminescence ,D-luciferin ,CycLuc1 ,AkaLumine-HCl ,Trypanosoma ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
The application of in vivo bioluminescent imaging in infectious disease research has significantly increased over the past years. The detection of transgenic parasites expressing wildtype firefly luciferase is however hampered by a relatively low and heterogeneous tissue penetrating capacity of emitted light. Solutions are sought by using codon-optimized red-shifted luciferases that yield higher expression levels and produce relatively more red or near-infrared light, or by using modified bioluminescent substrates with enhanced cell permeability and improved luminogenic or pharmacokinetic properties. In this study, the in vitro and in vivo efficacy of two modified bioluminescent substrates, CycLuc1 and AkaLumine-HCl, were compared with that of D-luciferin as a gold standard. Comparisons were made in experimental and insect-transmitted animal models of leishmaniasis (caused by intracellular Leishmania species) and African trypanosomiasis (caused by extracellular Trypanosoma species), using parasite strains expressing the red-shifted firefly luciferase PpyRE9. Although the luminogenic properties of AkaLumine-HCl and D-luciferin for in vitro parasite detection were comparable at equal substrate concentrations, AkaLumine-HCl proved to be unsuitable for in vivo infection follow-up due to high background signals in the liver. CycLuc1 presented a higher in vitro luminescence compared to the other substrates and proved to be highly efficacious in vivo, even at a 20-fold lower dose than D-luciferin. This efficacy was consistent across infections with the herein included intracellular and extracellular parasitic organisms. It can be concluded that CycLuc1 is an excellent and broadly applicable alternative for D-luciferin, requiring significantly lower doses for in vivo bioluminescent imaging in rodent models of leishmaniasis and African trypanosomiasis.
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- 2022
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39. Validity of Ultra-Short-Term HRV Analysis Using PPG—A Preliminary Study
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Aline Taoum, Alexis Bisiaux, Florian Tilquin, Yann Le Guillou, and Guy Carrault
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heart rate variability (HRV) ,ultra-short-term HRV analysis ,wearable devices ,Chemical technology ,TP1-1185 - Abstract
Continuous measurement of heart rate variability (HRV) in the short and ultra-short-term using wearable devices allows monitoring of physiological status and prevention of diseases. This study aims to evaluate the agreement of HRV features between a commercial device (Bora Band, Biosency) measuring photoplethysmography (PPG) and reference electrocardiography (ECG) and to assess the validity of ultra-short-term HRV as a surrogate for short-term HRV features. PPG and ECG recordings were acquired from 5 healthy subjects over 18 nights in total. HRV features include time-domain, frequency-domain, nonlinear, and visibility graph features and are extracted from 5 min 30 s and 1 min 30 s duration PPG recordings. The extracted features are compared with reference features of 5 min 30 s duration ECG recordings using repeated-measures correlation, Bland–Altman plots with 95% limits of agreements, Cliff’s delta, and an equivalence test. Results showed agreement between PPG recordings and ECG reference recordings for 37 out of 48 HRV features in short-term durations. Sixteen of the forty-eight HRV features were valid and retained very strong correlations, negligible to small bias, with statistical equivalence in the ultra-short recordings (1 min 30 s). The current study concludes that the Bora Band provides valid and reliable measurement of HRV features in short and ultra-short duration recordings.
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- 2022
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40. Is the Severity of the Clinical Expression of Anorexia Nervosa Influenced by an Anxiety, Depressive, or Obsessive-Compulsive Comorbidity Over a Lifetime?
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Elise Riquin, Agathe Raynal, Lama Mattar, Christophe Lalanne, France Hirot, Caroline Huas, Jeanne Duclos, EVHAN group, Sylvie Berthoz, Nathalie Godart, Hélène Roux, Marie Raphaële Thiébaud, Sarah Vibert, Tamara Hubert, Annaig Courty, Damien Ringuenet, Jean-pierre Benoit, Corinne Blanchet, Marie Rose Moro, Laura Bignami, Clémentine Nordon, Frédéric Rouillon, Solange Cook, Catherine Doyen, Marie-Christine Mouren Siméoni, Priscille Gerardin, Sylvie Lebecq, Marc-Antoine Podlipski, Claire Gayet, Malaika Lasfar, Marc Delorme, Xavier Pommereau, Stéphanie Bioulac, Manuel Bouvard, Jennifer Carrere, Karine Doncieux, Sophie Faucher, Catherine Fayollet, Amélie Prexl, Stéphane Billard, François Lang, Virginie Mourier-Soleillant, Régine Greiner, Aurélia Gay, Guy Carrot, Sylvain Lambert, Morgane Rousselet, Ludovic Placé, Jean-luc Venisse, Marie Bronnec, Bruno Falissard, Christophe Genolini, Christine Hassler, Jean-Marc Tréluyer, Olivier Chacornac, Maryline Delattre, Nellie Moulopo, Christelle Turuban, and Auger Christelle
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anorexia nervosa ,anxiety ,depression ,nutritional status ,body mass index ,Psychiatry ,RC435-571 - Abstract
Purpose: The relationship between anxiety or depressive comorbidities, their chronology of onset, and the severity of anorexia nervosa (AN) is not well-studied. We hypothesize that the existence of a comorbidity, particularly before the onset of AN, is associated with greater severity of AN.Methods: One hundred seventy-seven subjects were assessed. The prevalence of major depressive disorder (MDD), obsessive-compulsive disorder (OCD), generalized anxiety disorder (GAD), and social phobia (SP) as well as their chronology of onset were studied. The assessment criteria of AN severity were the overall clinical condition, body mass index (BMI) on admission, lowest BMI, intensity of the eating symptoms, age at the onset of AN, illness duration, number of hospitalizations, and quality of life.Results: Patients with AN had the greatest clinical severity when they had a comorbid disorder over their lifetime, such as MDD, GAD, or SP. These comorbidities along with OCD were associated with a higher level of eating symptoms and a more altered quality of life. A profile of maximum severity was associated with a higher prevalence of MDD and GAD. Concerning the chronology of onset, the age at the start of AN was later in cases of MDD or GAD prior to AN.Conclusion: There seems to be an association between severity of AN and both MDD and GAD. The chronology of onset of the comorbidity did not seem to be associated with the severity.
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- 2021
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41. Miltefosine enhances infectivity of a miltefosine-resistant Leishmania infantum strain by attenuating its innate immune recognition.
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Dimitri Bulté, Lieselotte Van Bockstal, Laura Dirkx, Magali Van den Kerkhof, Carl De Trez, Jean-Pierre Timmermans, Sarah Hendrickx, Louis Maes, and Guy Caljon
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Arctic medicine. Tropical medicine ,RC955-962 ,Public aspects of medicine ,RA1-1270 - Abstract
BackgroundMiltefosine (MIL) is currently the only oral drug available to treat visceral leishmaniasis but its use as first-line monotherapy has been compromised by an increasing treatment failure. Despite the scarce number of resistant clinical isolates, MIL-resistance by mutations in a single aminophospholipid transporter gene can easily be selected in a laboratory environment. These mutations result in a reduced survival in the mammalian host, which can partially be restored by exposure to MIL, suggesting a kind of drug-dependency.Methodology/principal findingsTo enable a combined study of the infection dynamics and underlying immunological events for differential in vivo survival, firefly luciferase (PpyRE9) / red fluorescent protein (DsRed) double-reporter strains were generated of MIL-resistant (MIL-R) and syngeneic MIL-sensitive (MIL-S) Leishmania infantum. Results in C57Bl/6 and BALB/c mice show that MIL-R parasites induce an increased innate immune response that is characterized by enhanced influx and infection of neutrophils, monocytes and dendritic cells in the liver and elevated serum IFN-γ levels, finally resulting in a less efficient establishment in liver macrophages. The elevated IFN-γ levels were shown to originate from an increased response of hepatic NK and NKT cells to the MIL-R parasites. In addition, we demonstrated that MIL could increase the in vivo fitness of MIL-R parasites by lowering NK and NKT cell activation, leading to a reduced IFN-γ production.Conclusions/significanceDifferential induction of innate immune responses in the liver was found to underlie the attenuated phenotype of a MIL-R parasite and its peculiar feature of drug-dependency. The impact of MIL on hepatic NK and NKT activation and IFN-γ production following recognition of a MIL-R strain indicates that this mechanism may sustain infections with resistant parasites and contribute to treatment failure.
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- 2021
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42. Pharmacological Assessment of the Antiprotozoal Activity, Cytotoxicity and Genotoxicity of Medicinal Plants Used in the Treatment of Malaria in the Greater Mpigi Region in Uganda
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Fabien Schultz, Ogechi Favour Osuji, Anh Nguyen, Godwin Anywar, John R. Scheel, Guy Caljon, Luc Pieters, and Leif-Alexander Garbe
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malaria ,antiprotozoal ,cytotoxicity ,genotoxicity ,medicinal plants ,Uganda ,Therapeutics. Pharmacology ,RM1-950 - Abstract
We investigated the potential antimalarial and toxicological effects of 16 medicinal plants frequently used by traditional healers to treat malaria, fever, and related disorders in the Greater Mpigi region in Uganda. Species studied were Albizia coriaria, Cassine buchananii, Combretum molle, Erythrina abyssinica, Ficus saussureana, Harungana madagascariensis, Leucas calostachys, Microgramma lycopodioides, Morella kandtiana, Plectranthus hadiensis, Securidaca longipedunculata, Sesamum calycinum subsp. angustifolium, Solanum aculeastrum, Toddalia asiatica, Warburgia ugandensis, and Zanthoxylum chalybeum. In addition, the traditional healers indicated that P. hadiensis is used as a ritual plant to boost fertility and prepare young women and teenagers for motherhood in some Ugandan communities where a high incidence of rapidly growing large breast masses in young female patients was observed (not necessarily breast cancer). We present results from various in vitro experiments performed with 56 different plant extracts, namely, 1) an initial assessment of the 16 species regarding their traditional use in the treatment of malaria by identifying promising plant extract candidates using a heme biocrystallization inhibition library screen; 2) follow-up investigations of antiprotozoal effects of the most bioactive crude extracts against chloroquine-resistant P. falciparum K1; 3) a cytotoxicity counterscreen against human MRC-5SV2 lung fibroblasts; 4) a genotoxicity evaluation of the extract library without and with metabolic bioactivation with human S9 liver fraction; and 5) an assessment of the mutagenicity of the ritual plant P. hadiensis. A total of seven extracts from five plant species were selected for antiplasmodial follow-up investigations based on their hemozoin formation inhibition activity in the heme biocrystallization assay. Among other extracts, an ethyl acetate extract of L. calostachys leaves exhibited antiplasmodial activity against P. falciparum K1 (IC50 value: 5.7 µg/ml), which was further characterized with a selectivity index of 2.6 (CC50 value: 14.7 µg/ml). The experiments for assessment of potential procarcinogenic properties of plant extracts via evaluation of in vitro mutagenicity and genotoxicity indicated that few extracts cause mutations. The species T. asiatica showed the most significant genotoxic effects on both bacterial test strains (without metabolic bioactivation at a concentration of 500 µg/plate). However, none of the mutagenic extracts from the experiments without metabolic bioactivation retained their genotoxic activity after metabolic bioactivation of the plant extract library through pre-incubation with human S9 liver fraction. While this study did not show that P. hadiensis has genotoxic properties, it did provide early stage support for the therapeutic use of the medicinal plants from the Greater Mpigi region.
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- 2021
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43. Structure Activity Relationship of N-Substituted Phenyldihydropyrazolones Against Trypanosoma cruzi Amastigotes
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Maarten Sijm, Louis Maes, Iwan J. P. de Esch, Guy Caljon, Geert Jan Sterk, and Rob Leurs
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structure activity relationship ,chagas disease ,phenotypic optmization ,trypanosama cruzi ,phenylpyrazolones ,Chemistry ,QD1-999 - Abstract
Current drugs for Chagas disease have long treatment regimens with occurrence of adverse drug effects leading to poor treatment compliance. Novel and efficacious medications are therefore highly needed. We previously reported on the discovery of NPD-0227 (2-isopropyl-5-(4-methoxy-3-(pyridin-3-yl)phenyl)-4,4-dimethyl-2,4-dihydro-3H-pyrazol-3-one) as a potent in vitro inhibitor of Trypanosoma cruzi (pIC50 = 6.4) with 100-fold selectivity over human MRC-5 cells. The present work describes a SAR study on the exploration of substituents on the phenylpyrazolone nitrogen. Modifications were either done directly onto this pyrazolone nitrogen or alternatively by introducing a piperidine linker. Attention was pointed toward the selection of substituents with a cLogP preferably below NPD-0227s cLogP of 3.5. Generally the more apolar compounds showed better activities then molecules with cLogPs
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- 2021
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44. Distinct clonal evolution of B-cells in HIV controllers with neutralizing antibody breadth
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Deniz Cizmeci, Giuseppe Lofano, Evan Rossignol, Anne-Sophie Dugast, Dongkyoon Kim, Guy Cavet, Ngan Nguyen, Yann Chong Tan, Michael S Seaman, Galit Alter, and Boris Julg
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neutralizing antibodies ,b-cell evolution ,BCR repertoire ,HIV infection ,Medicine ,Science ,Biology (General) ,QH301-705.5 - Abstract
A minor subset of individuals infected with HIV-1 develop antibody neutralization breadth during the natural course of the infection, often linked to chronic, high-level viremia. Despite significant efforts, vaccination strategies have been unable to induce similar neutralization breadth and the mechanisms underlying neutralizing antibody induction remain largely elusive. Broadly neutralizing antibody responses can also be found in individuals who control HIV to low and even undetectable plasma levels in the absence of antiretroviral therapy, suggesting that high antigen exposure is not a strict requirement for neutralization breadth. We therefore performed an analysis of paired heavy and light chain B-cell receptor (BCR) repertoires in 12,591 HIV-1 envelope-specific single memory B-cells to determine alterations in the BCR immunoglobulin gene repertoire and B-cell clonal expansions that associate with neutralizing antibody breadth in 22 HIV controllers. We found that the frequency of genomic mutations in IGHV and IGLV was directly correlated with serum neutralization breadth. The repertoire of the most mutated antibodies was dominated by a small number of large clones with evolutionary signatures suggesting that these clones had reached peak affinity maturation. These data demonstrate that even in the setting of low plasma HIV antigenemia, similar to what a vaccine can potentially achieve, BCR selection for extended somatic hypermutation and clonal evolution can occur in some individuals suggesting that host-specific factors might be involved that could be targeted with future vaccine strategies.
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- 2021
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45. Comparative genomic analysis of six Glossina genomes, vectors of African trypanosomes
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Geoffrey M. Attardo, Adly M. M. Abd-Alla, Alvaro Acosta-Serrano, James E. Allen, Rosemary Bateta, Joshua B. Benoit, Kostas Bourtzis, Jelle Caers, Guy Caljon, Mikkel B. Christensen, David W. Farrow, Markus Friedrich, Aurélie Hua-Van, Emily C. Jennings, Denis M. Larkin, Daniel Lawson, Michael J. Lehane, Vasileios P. Lenis, Ernesto Lowy-Gallego, Rosaline W. Macharia, Anna R. Malacrida, Heather G. Marco, Daniel Masiga, Gareth L. Maslen, Irina Matetovici, Richard P. Meisel, Irene Meki, Veronika Michalkova, Wolfgang J. Miller, Patrick Minx, Paul O. Mireji, Lino Ometto, Andrew G. Parker, Rita Rio, Clair Rose, Andrew J. Rosendale, Omar Rota-Stabelli, Grazia Savini, Liliane Schoofs, Francesca Scolari, Martin T. Swain, Peter Takáč, Chad Tomlinson, George Tsiamis, Jan Van Den Abbeele, Aurelien Vigneron, Jingwen Wang, Wesley C. Warren, Robert M. Waterhouse, Matthew T. Weirauch, Brian L. Weiss, Richard K. Wilson, Xin Zhao, and Serap Aksoy
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Tsetse ,Trypanosomiasis ,Hematophagy ,Lactation ,Disease ,Neglected ,Biology (General) ,QH301-705.5 ,Genetics ,QH426-470 - Abstract
Abstract Background Tsetse flies (Glossina sp.) are the vectors of human and animal trypanosomiasis throughout sub-Saharan Africa. Tsetse flies are distinguished from other Diptera by unique adaptations, including lactation and the birthing of live young (obligate viviparity), a vertebrate blood-specific diet by both sexes, and obligate bacterial symbiosis. This work describes the comparative analysis of six Glossina genomes representing three sub-genera: Morsitans (G. morsitans morsitans, G. pallidipes, G. austeni), Palpalis (G. palpalis, G. fuscipes), and Fusca (G. brevipalpis) which represent different habitats, host preferences, and vectorial capacity. Results Genomic analyses validate established evolutionary relationships and sub-genera. Syntenic analysis of Glossina relative to Drosophila melanogaster shows reduced structural conservation across the sex-linked X chromosome. Sex-linked scaffolds show increased rates of female-specific gene expression and lower evolutionary rates relative to autosome associated genes. Tsetse-specific genes are enriched in protease, odorant-binding, and helicase activities. Lactation-associated genes are conserved across all Glossina species while male seminal proteins are rapidly evolving. Olfactory and gustatory genes are reduced across the genus relative to other insects. Vision-associated Rhodopsin genes show conservation of motion detection/tracking functions and variance in the Rhodopsin detecting colors in the blue wavelength ranges. Conclusions Expanded genomic discoveries reveal the genetics underlying Glossina biology and provide a rich body of knowledge for basic science and disease control. They also provide insight into the evolutionary biology underlying novel adaptations and are relevant to applied aspects of vector control such as trap design and discovery of novel pest and disease control strategies.
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- 2019
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46. An international comparison of THA patients, implants, techniques, and survivorship in Sweden, Australia, and the United States
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Elizabeth W Paxton, Guy Cafri, Szilard Nemes, Michelle Lorimer, Johan Kärrholm, Henrik Malchau, Stephen E Graves, Robert S Namba, and Ola Rolfson
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Orthopedic surgery ,RD701-811 - Abstract
Background and purpose — International comparisons of total hip arthroplasty (THA) practices and outcomes provide an opportunity to enhance the quality of care worldwide. We compared THA patients, implants, techniques, and survivorship in Sweden, Australia, and the United States. Patients and methods — Primary THAs due to osteoarthritis were identified using Swedish (n = 159,695), Australian (n = 279,693), and US registries (n = 69,641) (2003–2015). We compared patients, practices, and implant usage across the countries using descriptive statistics. We evaluated time to all-cause revision using Kaplan–Meier survival curves. We assessed differences in countries’ THA survival using chi-square tests of survival probabilities. Results — Sweden had fewer comorbidities than the United States and Australia. Cement fixation was used predominantly in Sweden and cementless in the United States and Australia. The direct anterior approach was used more frequently in the United States and Australia. Smaller head sizes (≤ 32 mm vs. ≥ 36 mm) were used more often in Sweden than the United States and Australia. Metal-on-highly cross-linked polyethylene was used more frequently in the United States and Australia than in Sweden. Sweden’s 5- (97.8%) and 10-year THA survival (95.8%) was higher than the United States’ (5-year: 97.0%; 10-year: 95.2%) and Australia (5-year: 96.3%; 10-year: 93.5%). Interpretation — Patient characteristics, surgical techniques, and implants differed across the 3 countries, emphasizing the need to adjust for demographics, surgical techniques, and implants and the need for global standardized definitions to compare THA survivorship internationally.
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- 2019
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47. 2-aminobenzimidazoles for leishmaniasis: From initial hit discovery to in vivo profiling.
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Rafael Augusto Alves Ferreira, Celso de Oliveira Rezende Junior, Pablo David Grigol Martinez, Paul John Koovits, Bruna Miranda Soares, Leonardo L G Ferreira, Simone Michelan-Duarte, Rafael Consolin Chelucci, Adriano D Andricopulo, Mariana K Galuppo, Silvia R B Uliana, An Matheeussen, Guy Caljon, Louis Maes, Simon Campbell, Jadel M Kratz, Charles E Mowbray, and Luiz Carlos Dias
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Arctic medicine. Tropical medicine ,RC955-962 ,Public aspects of medicine ,RA1-1270 - Abstract
Leishmaniasis is a major infectious disease with hundreds of thousands of new cases and over 20,000 deaths each year. The current drugs to treat this life-threatening infection have several drawbacks such as toxicity and long treatment regimens. A library of 1.8 million compounds, from which the hits reported here are publicly available, was screened against Leishmania infantum as part of an optimization program; a compound was found with a 2-aminobenzimidazole functionality presenting moderate potency, low metabolic stability and high lipophilicity. Several rounds of synthesis were performed to incorporate chemical groups capable of reducing lipophilicity and clearance, leading to the identification of compounds that are active against different parasite strains and have improved in vitro properties. As a result of this optimization program, a group of compounds was further tested in anticipation of in vivo evaluation. In vivo tests were carried out with compounds 29 (L. infantum IC50: 4.1 μM) and 39 (L. infantum IC50: 0.5 μM) in an acute L. infantum VL mouse model, which showed problems of poor exposure and lack of efficacy, despite the good in vitro potency.
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- 2021
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48. Tsetse salivary glycoproteins are modified with paucimannosidic N-glycans, are recognised by C-type lectins and bind to trypanosomes.
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Radoslaw P Kozak, Karina Mondragon-Shem, Christopher Williams, Clair Rose, Samirah Perally, Guy Caljon, Jan Van Den Abbeele, Katherine Wongtrakul-Kish, Richard A Gardner, Daniel Spencer, Michael J Lehane, and Álvaro Acosta-Serrano
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Arctic medicine. Tropical medicine ,RC955-962 ,Public aspects of medicine ,RA1-1270 - Abstract
African sleeping sickness is caused by Trypanosoma brucei, a parasite transmitted by the bite of a tsetse fly. Trypanosome infection induces a severe transcriptional downregulation of tsetse genes encoding for salivary proteins, which reduces its anti-hemostatic and anti-clotting properties. To better understand trypanosome transmission and the possible role of glycans in insect bloodfeeding, we characterized the N-glycome of tsetse saliva glycoproteins. Tsetse salivary N-glycans were enzymatically released, tagged with either 2-aminobenzamide (2-AB) or procainamide, and analyzed by HILIC-UHPLC-FLR coupled online with positive-ion ESI-LC-MS/MS. We found that the N-glycan profiles of T. brucei-infected and naïve tsetse salivary glycoproteins are almost identical, consisting mainly (>50%) of highly processed Man3GlcNAc2 in addition to several other paucimannose, high mannose, and few hybrid-type N-glycans. In overlay assays, these sugars were differentially recognized by the mannose receptor and DC-SIGN C-type lectins. We also show that salivary glycoproteins bind strongly to the surface of transmissible metacyclic trypanosomes. We suggest that although the repertoire of tsetse salivary N-glycans does not change during a trypanosome infection, the interactions with mannosylated glycoproteins may influence parasite transmission into the vertebrate host.
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- 2021
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49. Discovery of Diaryl Ether Substituted Tetrahydrophthalazinones as TbrPDEB1 Inhibitors Following Structure-Based Virtual Screening
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Erik de Heuvel, Albert J. Kooistra, Ewald Edink, Sjors van Klaveren, Jeffrey Stuijt, Tiffany van der Meer, Payman Sadek, Dorien Mabille, Guy Caljon, Louis Maes, Marco Siderius, Iwan J. P. de Esch, Geert Jan Sterk, and Rob Leurs
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virtual screening ,phosphodiesterase TbrPDEB1 ,trypanosomiasis ,cAMP ,tetrahydrophthalazinones ,medicinal chemistry ,Chemistry ,QD1-999 - Abstract
Several members of the 3′,5′-cyclic nucleotide phosphodiesterase (PDE) family play an essential role in cellular processes, which has labeled them as interesting targets for various diseases. The parasitic protozoan Trypanosoma brucei, causative agent of human African trypanosomiasis, contains several cyclic AMP specific PDEs from which TbrPDEB1 is validated as a drug target. The recent discovery of selective TbrPDEB1 inhibitors has increased their potential for a novel treatment for this disease. Compounds characterized by a rigid biphenyl tetrahydrophthalazinone core structure were used as starting point for the exploration of novel TbrPDEB1 inhibitors. Using a virtual screening campaign and structure-guided design, diaryl ether substituted phthalazinones were identified as novel TbrPDEB1 inhibitors with IC50 values around 1 μM against T. brucei. This study provides important structure-activity relationship (SAR) information for the future design of effective parasite-specific PDE inhibitors.
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- 2021
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50. Diminished cytokine-induced Jak/STAT signaling is associated with rheumatoid arthritis and disease activity.
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Jason Ptacek, Rachael E Hawtin, Dongmei Sun, Brent Louie, Erik Evensen, Barbara B Mittleman, Alessandra Cesano, Guy Cavet, Clifton O Bingham, Stacey S Cofield, Jeffrey R Curtis, Maria I Danila, Chander Raman, Richard A Furie, Mark C Genovese, William H Robinson, Marc C Levesque, Larry W Moreland, Peter A Nigrovic, Nancy A Shadick, James R O'Dell, Geoffrey M Thiele, E William St Clair, Christopher C Striebich, Matthew B Hale, Houman Khalili, Franak Batliwalla, Cynthia Aranow, Meggan Mackay, Betty Diamond, Garry P Nolan, Peter K Gregersen, and S Louis Bridges
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Medicine ,Science - Abstract
Rheumatoid arthritis (RA) is a systemic and incurable autoimmune disease characterized by chronic inflammation in synovial lining of joints. To identify the signaling pathways involved in RA, its disease activity, and treatment response, we adapted a systems immunology approach to simultaneously quantify 42 signaling nodes in 21 immune cell subsets (e.g., IFNα→p-STAT5 in B cells) in peripheral blood mononuclear cells (PBMC) from 194 patients with longstanding RA (including 98 patients before and after treatment), and 41 healthy controls (HC). We found multiple differences between patients with RA compared to HC, predominantly in cytokine-induced Jak/STAT signaling in many immune cell subsets, suggesting pathways that may be associated with susceptibility to RA. We also found that high RA disease activity, compared to low disease activity, was associated with decreased (e.g., IFNα→p-STAT5, IL-10→p-STAT1) or increased (e.g., IL-6→STAT3) response to stimuli in multiple cell subsets. Finally, we compared signaling in patients with established, refractory RA before and six months after initiation of methotrexate (MTX) or TNF inhibitors (TNFi). We noted significant changes from pre-treatment to post-treatment in IFNα→p-STAT5 signaling and IL-10→p-STAT1 signaling in multiple cell subsets; these changes brought the aberrant RA signaling profiles toward those of HC. This large, comprehensive functional signaling pathway study provides novel insights into the pathogenesis of RA and shows the potential of quantification of cytokine-induced signaling as a biomarker of disease activity or treatment response.
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- 2021
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