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Aromatic N -heterocycles, especially benzimidazoquinazolinones featuring alkyl chains, hold significant pharmaceutical relevance. Here, we introduce a streamlined one-pot, 2-fold Cu-catalyzed C-N bond formation protocol for the efficient synthesis of diverse N -alkyl benzimidazoquinazolinone derivatives. This method showcases a broad substrate scope, leveraging readily accessible alkyl halides and delivers the desired cyclized products in excellent yields. Additionally, the methodology enabled the synthesis of an antitumor agent with satisfactory yield, highlighting its utility in medicinal chemistry endeavors., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

FeRh alloys in the CsCl-type (B2) chemically ordered phase present an antiferromagnetic to ferromagnetic order transition around 370 K observed in bulk and continuous films but absent in nanoclusters. In this study, we investigate the thermal magnetic behavior of a thick film composed of assembled FeRh nanoclusters preformed in the gas phase. This work reveals a broad and asymmetric metamagnetic transition with a consequent residual magnetization at low temperature. Due to the coexistence of different grain sizes in the sample, we confront the results with a description that involves two populations of B2-FeRh particles, and the existence of a discriminating size below which the magnetic order transition does not take place.

Chronic Toxoplasma gondii infection induces brain-resident CD8+ T cells (bTr), but the protective functions and differentiation cues of these cells remain undefined. Here, we used a mouse model of latent infection by T. gondii leading to effective CD8+ T cell-mediated parasite control. Thanks to antibody depletion approaches, we found that peripheral circulating CD8+ T cells are dispensable for brain parasite control during chronic stage, indicating that CD8+ bTr are able to prevent brain parasite reactivation. We observed that the retention markers CD69, CD49a, and CD103 are sequentially acquired by brain parasite-specific CD8+ T cells throughout infection and that a majority of CD69/CD49a/CD103 triple-positive (TP) CD8+ T cells also express Hobit, a transcription factor associated with tissue residency. This TP subset develops in a CD4+ T cell-dependent manner and is associated with effective parasite control during chronic stage. Conditional invalidation of Transporter associated with Antigen Processing (TAP)-mediated major histocompatibility complex (MHC) class I presentation showed that presentation of parasite antigens by glutamatergic neurons and microglia regulates the differentiation of CD8+ bTr into TP cells. Single-cell transcriptomic analyses revealed that resistance to encephalitis is associated with the expansion of stem-like subsets of CD8+ bTr. In summary, parasite-specific brain-resident CD8+ T cells are a functionally heterogeneous compartment which autonomously ensure parasite control during T. gondii latent infection and which differentiation is shaped by neuronal and microglial MHC I presentation. A more detailed understanding of local T cell-mediated immune surveillance of this common parasite is needed for harnessing brain-resident CD8+ T cells in order to enhance control of chronic brain infections., Competing Interests: Competing interests statement:The authors declare no competing interest.

Objectives: The management of upper aerodigestive tract cancers is a complex specialty. It is essential to provide an update to establish optimal care. At the initiative of the INCa and under the auspices of the SFORL, the scientific committee, led by Professor Béatrix Barry, Dr. Gilles Dolivet, and Dr. Dominique De Raucourt, decided to develop a reference framework aimed at defining, in a scientific and consensus-based manner, the general principles of treatment for upper aerodigestive tract cancers applicable to all sub-locations., Methodology: To develop this framework, a multidisciplinary team of practitioners was formed. A systematic analysis of the literature was conducted to produce recommendations classified by grades, in accordance with the standards of the French National Authority for Health (HAS)., Results: The grading of recommendations according to HAS standards has allowed the establishment of a reference for patient care based on several criteria. In this framework, patients benefit from differentiated care based on prognostic factors they present (age, comorbidities, TNM status, HPV status, etc.), conditions of implementation, and quality criteria for indicated surgery (operability, resectability, margin quality, mutilation, salvage surgery), as well as quality criteria for radiotherapy (target volume, implementation time, etc.). The role of medical and postoperative treatments was also evaluated based on specific criteria. Finally, supportive care must be organized from the beginning and throughout the patients' care journey., Conclusion: All collected data have led to the development of a comprehensive framework aimed at harmonizing practices nationally, facilitating decision-making in multidisciplinary consultation meetings, promoting equality in practices, and providing a state-of-the-art and reference practices for assessing the quality of care. This new framework is intended to be updated every 5 years to best reflect the latest advances in the field., (Copyright © 2024 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.)

Oligometastases are defined as a number of detectable metastases less or equal to 5. In castrate-resistant oligo metastatic prostate Cancer (CR oligoM PC), Metastases-Directed Ablative radiotherapy (MDRT) is poorly investigated. Our study retrospectively reviewed the cases of CR oligoM PC treated with MDRT in 8 French high-volume radiotherapy centers. OS and PFS are defined as the delay between the first day of MDRT and death (OS) or progression according to PCWG criteria (PFS). OS and PFS are evaluated according to Kaplan Meyer, curves are compared with log rank test. Logistic regression was used to identify predictive factors for outcome: bone versus node metastasis, ISUP grade, PSA doubling Time (PSADT) at the time of MDRT, time to castration resistance. 107 patients were included in the study, among those 197 metastases received MDRT. For the overall population, the median follow-up was 25.2 months (1,4-145). OS was 93 % at 2 years and 81,4% at 3 years. At 2 years, 100 % of patients with node-only metastasis were alive versus 88,7% among those who have bone metastases (p = 0,72). The median PFS was 12,6 months (IC 95 % [9,6; 17]), with no difference among patients with node only disease versus the rest of the cohort. The PFS was 18,2 months (10,0; 32,4) in patients with PSADT >6 months versus 10,7 months (8,9; 14,3) when PSADT was inferior to 6 months. However, this difference did not reach significant. We did not find a correlation neither between ISUP grade (1-2 versus 3-4-5) and PFS, nor between hormone-sensitivity duration and PFS. Patients receiving MDRT for CR oligoM PC have a good prognosis with 81,6% OS at 3 years. PSA DT longer than 6 months could be related to better PFS. MDRT strategy could postpone the onset of new systemic treatment with median PFS >1 year., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Author(s).)

A palladium-catalyzed synthesis of 2-SF 5 -indenols has been developed by reacting commercially available boronic acid derivatives and readily accessible SF 5 -alkynes. The present methodology is fully regioselective thanks to the intrinsic polarization of SF 5 -alkynes. A selection of downstream functionalizations has been performed to highlight the versatility of 2-SF 5 -indenols and indenones as platforms for the design of more complex SF 5 -containing molecules., (© 2023 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

Objective: To describe the use, efficacy and safety profile of follitropin delta in women undergoing IVF/ICSI in routine clinical practice after one treatment cycle., Study Design: This was a French multicenter, prospective, observational study conducted in 14 fertility centers between June 2020 and June 2021. During this period, 248 women undergoing IVF or ICSI were treated with follitropin delta for the first time. Women were followed up to 10-11 weeks after the first fresh or frozen embryo transfer. The main outcomes were use of dosing algorithm, follitropin delta dosing patterns, ovarian response, pregnancy, and adverse drug reactions in routine clinical practice., Results: The analyzable population consisted of 223 patients with mean ± SD age of 33.0 ± 4.4 years, body weight of 65.7 ± 11.8 kg, and the median (IQR) AMH level was 2.6 (1.5-4.0) ng/mL. For 193 patients (86.5 %) it was the first IVF/ICSI cycle and for 30 (13.5 %) the second. The algorithm was used for the calculation of the starting dose for 88.3 % of the patients. The mean daily starting dose of follitropin delta was 11.4 ± 4.1mcg for the whole analyzable population and 14.4 ± 5.2 mcg for the sub-group of 26 patients dosed without the algorithm. The mean duration of stimulation with follitropin delta was 10.8 ± 5.2 days. The mean total dose of follitropin delta administered was 122.2 ± 80.0 mcg. An antagonist protocol was used in 90.3 % of patients. The mean ± SD number of oocytes retrieved among patients that started stimulation was 11.3 ± 6.8 and 46.1 % of patients achieved the targeted response of the algorithm of 8-14 oocytes retrieved. A fresh transfer was performed for 77.6 % of patients; the mean ± SD number of embryos transferred was 1.3 ± 0.5. The implantation rate was 36.0 %. Per started cycle, clinical pregnancy was reported in 35.0 % of the patients and ongoing pregnancy in 29.6 %. In total, 5 patients (2.2 %) reported an event of OHSS., Conclusion: Clinical results as collected in routine clinical practice are promising, showing a favorable effectiveness-safety profile of follitropin delta for a very varied patient population (including anovulatory PCOS, very poor responders, or non-IVF naïve patients). These real-world data complement results from clinical trials and provide useful information for usual clinical practice within a heterogeneous population group., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

The chloropentafluorosulfanylation of alkynes is a delicate but crucial operation for accessing SF 5 -alkynes that serve as substrates in numerous transformations. Dolbier's procedure using Et 3 B/O 2 was the most efficient approach, while recent efforts make use of other initiators and light activation. We found that THF, as a single stimulus, is sufficient to trigger the reaction of SF 5 Cl with alkynes. We determined the configuration of Cl/SF 5 products and clarified the structure of side-products.

Aim: The adrenal gland is a common site of metastasis with a rate of up to 27% in autopsy series. The incidence of these metastases is increasing due to greater use of Positron Emission Tomography scans and improved overall survival of patients with metastatic cancers. Stereotactic body radiation therapy (SBRT) is a non-invasive treatment option for metastasis. The aim of this study is to assess prognostic factors influencing local control, progression-free and overall survival in oligometastatic patients treated with SBRT for an adrenal metastasis., Methods: In this multicentric retrospective study, we included patients with adrenal metastases treated with SBRT between 2010 and 2021 in eleven french centers. All primary tumors were included., Results: A total of 110 patients treated for 121 adrenal lesions were included. Non-small-cell lung cancer was the predominant histologic type (55.4 %). Eighty-two percent of patients had at least 2 metastatic sites. The median Planning Target Volume was 70 cm 3 with a median prescription dose of 40 Gray (Gy). The mean Biologically Effective Dose (BED) 10 dose was 74.2 Gy. Local control at 1 and 2 years was 85.9 % and 72.5 % respectively. The median overall survival and progression-free survival were 31.6 and 8.5 months respectively. Local control was significantly improved by systemic treatment one month before or after SBRT (p = 0.009) and by a BED10 greater than or equal to 50 Gy (p = 0.003).In multivariate analysis, oligometastatic presentation (p = 0.009) and a metachronous metastatic presentation (p = 0.008) were independent factors for progression-free survival.Tolerance was excellent, no grade 3 and 4 toxicities were described due to SBRT., Conclusion: Stereotactic radiotherapy of adrenal metastases makes possible a local control of more than 85% at one year and was well tolerated. The factors influencing survival in oligometastatic patients still need to be found in order to better select those who benefit the most from this type of treatment., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors. Published by Elsevier B.V. on behalf of European Society for Radiotherapy and Oncology.)

In the vibrant field of SF 5 chemistry, SF 5 X reagents (X=F, Cl, Br) are at the heart of current investigations in radical pentafluorosulfanylation reactions. SF 5 I is the missing link whose existence has not been reported despite its potential as SF 5 donor. This study reports the formal addition of the hitherto unknown SF 5 I reagent to alkynes by means of a combination of SF 5 Cl/KI/18-crown-6 ether. The exclusive regio- and stereoselective synthesis of unprecedented (E)-1-iodo-2-(pentafluoro-λ 6 -sulfanyl) alkenes was achieved. A consensus was reached through computational and mechanistic studies for the realistic formation of SF 5 - anion but not SF 5 I in solution and the rational involvement of SF 5 ⋅ and iodine radicals in the iodo pentafluorosulfanylation reaction., (© 2023 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH.)

Pyrazines are reactive 4π partners in intermolecular Diels-Alder cycloaddition with exceptionally activated dienophiles or in an intermolecular version at elevated temperatures. Herein, it is shown that an intramolecular cascade could occur even at room temperature, delivering a collection of 6- or 7-aza-indazoles. An interesting substituent effect of the cycloaddition precursor on the product distribution was uncovered, and in situ NMR studies were conducted to gain insights into this unexpected selectivity.

Cyanamides possess both nucleophilic and electrophilic centers, and their arylation reactions are known to proceed at N(sp 3 ) and C(sp) sites, leading to N -aryl cyanamides or amidines. N(sp) selectivity has also been reported only in the presence of amines, thus leading to guanidines. Herein, we report a general copper-catalyzed ligand-controlled Chan-Lam-Evans arylation of cyanamides proceeding regioselectively at the N(sp 3 ) or N(sp) atoms and leading to either N -aryl cyanamides or dissymmetric carbodiimides. The nature of the ligand, either a bipyridine or a diamine, controls the product distribution and thus offers a divergent entry to useful building blocks from readily available cyanamides.

The Sec61 complex forms a protein-conducting channel in the endoplasmic reticulum membrane that is required for secretion of soluble proteins and production of many membrane proteins. Several natural and synthetic small molecules specifically inhibit Sec61, generating cellular effects that are useful for therapeutic purposes, but their inhibitory mechanisms remain unclear. Here we present near-atomic-resolution structures of human Sec61 inhibited by a comprehensive panel of structurally distinct small molecules-cotransin, decatransin, apratoxin, ipomoeassin, mycolactone, cyclotriazadisulfonamide and eeyarestatin. All inhibitors bind to a common lipid-exposed pocket formed by the partially open lateral gate and plug domain of Sec61. Mutations conferring resistance to the inhibitors are clustered at this binding pocket. The structures indicate that Sec61 inhibitors stabilize the plug domain in a closed state, thereby preventing the protein-translocation pore from opening. Our study provides the atomic details of Sec61-inhibitor interactions and the structural framework for further pharmacological studies and drug design., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Toxoplasma gondii is responsible for toxoplasmosis, a disease that can be serious when contracted during pregnancy, but can also be a threat for immunocompromised individuals. Acute infection is associated with the tachyzoite form that spreads rapidly within the host. However, under stress conditions, some parasites can differentiate into cyst-forming bradyzoites, residing mainly in the central nervous system, retina and muscle. Because this latent form of the parasite is resistant to all currently available treatments, and is central to persistence and transmission of the parasite, specific therapeutic strategies targeting this developmental stage need to be found. T. gondii contains a plastid of endosymbiotic origin called the apicoplast, which is an appealing drug target because it is essential for tachyzoite viability and contains several key metabolic pathways that are largely absent from the mammalian host. Its function in bradyzoites, however, is unknown. Our objective was thus to study the contribution of the apicoplast to the viability and persistence of bradyzoites during chronic toxoplasmosis. We have used complementary strategies based on stage-specific promoters to generate conditional bradyzoite mutants of essential apicoplast genes. Our results show that specifically targeting the apicoplast in both in vitro or in vivo-differentiated bradyzoites leads to a loss of long-term bradyzoite viability, highlighting the importance of this organelle for this developmental stage. This validates the apicoplast as a potential area to look for therapeutic targets in bradyzoites, with the aim to interfere with this currently incurable parasite stage.

Synthesis of high quality colloidal Cerium(III) doped yttrium aluminum garnet (Y 3 Al 5 O 12 :Ce 3+ , "YAG:Ce") nanoparticles (NPs) meeting simultaneously both ultra-small size and high photoluminescence (PL) performance is challenging, as generally a particle size/PL trade-off has been observed for this type of nanomaterials. The glycothermal route is capable to yield ultra-fine crystalline colloidal YAG:Ce nanoparticles with a particle size as small as 10 nm but with quantum yield (QY) no more than 20%. In this paper, the first ultra-small YPO 4 -YAG:Ce nanocomposite phosphor particles having an exceptional QY-to-size performance with an QY up to 53% while maintaining the particle size ≈10 nm is reported. The NPs are produced via a phosphoric acid- and extra yttrium acetate-assisted glycothermal synthesis route. Localization of phosphate and extra yttrium entities with respect to cerium centers in the YAG host has been determined by fine structural analysis techniques such as X-ray diffration (XRD), solid state nuclear magnetic resonance (NMR), and high resolution scanning transmission electron microscopy (HR-STEM), and shows distinct YPO 4 and YAG phases. Finally, a correlation between the additive-induced physico-chemical environment change around cerium centers and the increasing PL performance has been suggested based on electron paramagnetic resonance (EPR), X-ray photoelectron spectrometry (XPS) data, and crystallographic simulation studies., (© 2023 The Authors. Small published by Wiley-VCH GmbH.)

Background: Child sexual abuse (CSA) can have detrimental, long-lasting consequences but effects are diverse, and resilience, or attainment of better-than-expected outcomes, is possible., Objective: This systematic review synthesises qualitative research findings about lived experiences of resilience processes used by women who had been subjected to CSA., Methods: A comprehensive search was undertaken of major and minor article databases (e.g., PsychInfo, Medline, CINAHL, Web of Science, Scopus) and Google Scholar, with hand searching of reference lists and forward searching of retrieved articles. Eight studies met the inclusion criteria (peer-reviewed qualitative or mixed methods studies written in English about experiences of resilience by women who had experienced CSA). Data extraction, quality appraisal, and thematic analysis were performed., Results: Thematic analysis generated several process-related resilience themes: distancing oneself from sexual abuse; building healthy interpersonal, community, and cultural connections; drawing on spiritual belief systems; reframing the sexual abuse; placing blame with the perpetrator; reclaiming self-worth; taking control of one's life; and pursuing meaningful goals. For some, it involved forgiveness of self and others, reclaiming one's sexuality, and/or fighting against diverse forms of oppression. There was much evidence that resilience was a dynamic, personal and social-ecological phenomenon., Conclusion: Counsellors and other professionals can use these findings to help women affected by CSA explore, develop, and strengthen factors that support resilience. Future research could explore the experiences of resilience for women with different cultural backgrounds, socioeconomic status, religious and/or spiritual affiliations., (Copyright © 2023. Published by Elsevier Ltd.)

Blood-brain barrier (BBB) breakdown and immune cell infiltration into the central nervous system (CNS) are early hallmarks of multiple sclerosis (MS). High numbers of CD8 + T cells are found in MS lesions, and antigen (Ag) presentation at the BBB has been proposed to promote CD8 + T cell entry into the CNS. Here, we show that brain endothelial cells process and cross-present Ag, leading to effector CD8 + T cell differentiation. Under physiological flow in vitro, endothelial Ag presentation prevented CD8 + T cell crawling and diapedesis resulting in brain endothelial cell apoptosis and BBB breakdown. Brain endothelial Ag presentation in vivo was limited due to Ag uptake by CNS-resident macrophages but still reduced motility of Ag-specific CD8 + T cells within CNS microvessels. MHC class I-restricted Ag presentation at the BBB during neuroinflammation thus prohibits CD8 + T cell entry into the CNS and triggers CD8 + T cell-mediated focal BBB breakdown., (© 2023. The Author(s).)

Herein is described a fully regio- and stereoselective hydroelementation reaction of SF 5 -alkynes with N, O and S-nucleophiles and further functionalization of the corresponding Z-(hetero)vinyl-SF 5 intermediates, a suitable platform to access α-SF 5 ketones and esters, β-SF 5 amines and alcohols under mild reaction conditions. Experimental and computational comparative studies between SF 5 - and CF 3 -alkynes have been performed to highlight and explain the difference of reactivity and selectivity observed between these two fluorinated motifs., (© 2023 Wiley-VCH GmbH.)

Repeated embryo implantation failures (RIF) is a source of distress and frustration for patients and clinicians alike. Today's approaches for treating RIF are largely empirical and have limited effectiveness. The main causes of RIF are poor endometrial receptivity and poor-quality embryos. Recent studies have suggested the involvement of immune dysregulation due to an imbalance between T-helper (Th) 1 and Th2 cytokines; this opens up perspectives for treating women with RIF and increasing the implantation rate. We conducted an interventional, longitudinal, prospective cohort study of the impact of correcting the cytokine imbalance on the clinical pregnancy rate in women with RIF. Seventy-seven women with RIF underwent an endometrial biopsy during the implantation window. The cytokine profile was evaluated by studying the activation and maturation of uterine natural killer (uNK) cells, the IL-15/Fn-14 mRNA ratio (a biomarker of uNK activation/maturation), and the IL-18/TWEAK mRNA ratio (a marker of angiogenesis and the Th1/Th2 balance). Personalized treatment was initiated for women with an abnormal endometrial cytokine profile (hyper-activation or hypo-activation). We documented the clinical pregnancy rate after subsequent embryo transfers. In total, 72.7% (56/77) of patients had an abnormal endometrial cytokine profile (hyper-activation in 68.8% (n = 53) and hypo-activation in 3.9% (n = 3). After treatment (or not) as a function of the endometrial profile, the overall clinical pregnancy rate was 30.2%. Our results indicated a potential positive effect of appropriate treatment on the ongoing pregnancy rate in women with RIF, despite the small number of cases analyzed. The results must now be validated in randomized studies with larger numbers of well-characterized patients. By applying a previously published decision tree, this treatment approach could be implemented in clinics worldwide.

In this study, the atomic and chemical structure and the optical response of A x B 1- x bimetallic nanoparticles (BNPs) combining gold or silver (A) with aluminium or indium (B) were investigated at various stoichiometries in order to examine if stable alloyed phases could exist and promote the emergence of localized surface plasmon resonance (LSPR) in the UV range. The structure and morphology of BNPs of a few nanometres, produced by laser vaporization, were analysed by transmission electron microscopy (TEM) and optical absorption measurements were performed on matrix-embedded BNPs. Information about the oxidation state of the BNPs can be inferred from a comparison between experimental optical spectra and Mie calculations in the dipolar approximation. The BNPs' internal structures were further investigated by additional characterization techniques. Firstly, in situ X-ray photoelectron spectroscopy provided information about the chemical state of the constituent elements and their evolution with time. Secondly, synchrotron-based X-ray scattering techniques were performed on Ag-Al BNPs in a wide-angle configuration under grazing incidence, giving complementary information about structural and morphological heterogeneities in the BNPs. Finally, the restructuring of the partially oxidized Au 0.33 Al 0.67 BNPs annealed in a reducing atmosphere was also attempted by environmental TEM. The complementary techniques of characterization show that silver-based Ag-In and Ag-Al BNPs form metallic silver-rich alloyed cores surrounded by an indium or aluminium oxide shell. The initial LSPR is in the UV range for both systems, but the difference in the kinetics of oxidation between indium and aluminium involves less blue-shifted LSPR for Ag-Al BNPs. In the case of gold-based BNPs, we show evidence of ordered nanoalloys just after air exposure and the appearance of gold and indium (or aluminium) demixing during oxidation. The initial LSPR of Au-In BNPs is the one the most in the UV range among the four systems, with an LSPR peak centred at 254 nm, which may be a sign of the formation of the Au 0.33 In 0.67 alloy. Nevertheless, strategies to preserve BNPs from oxidation have to be developed.

Task-unrelated thought (TUT), commonly referred to as mind wandering, is a mental state where a person's attention moves away from the task-at-hand. This state is extremely common, yet not much is known about how to measure it, especially during dyadic interactions. We thus built a model to detect when a person experiences TUTs while talking to another person through a computer-mediated conversation, using their keystroke patterns. The best model was able to differentiate between task-unrelated thoughts and task-related thoughts with a kappa of 0.363, using features extracted from a 15 second window. We also present a feature analysis to provide additional insights into how various typing behaviors can be linked to our ongoing mental states., (© The Author(s), under exclusive licence to Springer Nature B.V. 2022, Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

Pulmonary arterial hypertension (PAH) is a progressive, devastating disease, and its main histological manifestation is an occlusive pulmonary arteriopathy. One important functional component of PAH is aberrant endothelial cell (EC) function including apoptosis-resistance, unchecked proliferation, and impaired migration. The mechanisms leading to and maintaining physiologic and aberrant EC function are not fully understood. Here, we tested the hypothesis that in PAH, ECs have increased expression of the transmembrane protein integrin-β5, which contributes to migration and survival under physiologic and pathological conditions, but also to endothelial-to-mesenchymal transition (EnMT). We found that elevated integrin-β5 expression in pulmonary artery lesions and lung tissue from PAH patients and rats with PH induced by chronic hypoxia and injection of CD117 + rat lung EC clones. These EC clones exhibited elevated expression of integrin-β5 and its heterodimerization partner integrin-αν and showed accelerated barrier formation. Inhibition of integrin-ανβ5 in vitro partially blocked transforming growth factor (TGF)-β1-induced EnMT gene expression in rat lung control ECs and less in rat lung EC clones and human lung microvascular ECs. Inhibition of integrin-ανβ5 promoted endothelial dysfunction as shown by reduced migration in a scratch assay and increased apoptosis in synergism with TGF-β1. In vivo , blocking of integrin-ανβ5 exaggerated PH induced by chronic hypoxia and CD117 + EC clones in rats. In summary, we found a role for integrin-ανβ5 in lung endothelial survival and migration, but also a partial contribution to TGF-β1-induced EnMT gene expression. Our results suggest that integrin-ανβ5 is required for physiologic function of ECs and lung vascular homeostasis., Competing Interests: The authors declares no conflict of interest., (© 2022 The Authors. Pulmonary Circulation published by Wiley Periodicals LLC on behalf of the Pulmonary Vascular Research Institute.)

Background: Individuals living with a rheumatic pain condition can face delays in accessing pain clinics, which prevents them from receiving timely treatment. Little is known regarding their specific healthcare utilization in order to alleviate pain while waiting to obtain services in pain clinics. Hence, the aim of this study was to explore the perceptions and experiences of persons living with rheumatic conditions regarding healthcare utilization while waiting to access a pain clinic., Methods: In this qualitative descriptive study, semi-structured interviews were conducted with adults living with a painful rheumatic condition that reported either being waiting for admission in a pain clinic, having been referred but then denied pain clinic services, or having received services during the previous six months, in the province of Quebec, Canada. The interviews were transcribed verbatim, and an inductive thematic analysis was performed., Results: Twenty-six individuals were interviewed (22 women and 4 men; mean age 54 ± 10 years). Three themes were identified: 1) lacking guidance in identifying solutions to their complex and multidimensional needs, 2) struggling to obtain and maintain services due to systemic access barriers, and 3) displaying resilience through a search for accessible and sustainable self-management strategies., Conclusions: The current approaches and structures of health services fail to adequately answer the service needs of individuals experiencing painful rheumatic conditions. Important shifts are required in pain education, in increasing access to multidisciplinary approaches at the primary care level and in breaking down barriers individuals with chronic pain face to receive appropriate and timely care., (© 2022. The Author(s).)

Introduction: Narcolepsy is a chronic and rare hypersomnia of central origin characterized by excessive daytime sleepiness and a complex array of symptoms as well as by several medical comorbidities. With growing pharmacological options, polytherapy may increase the possibility of a patient-centered management of narcolepsy symptoms. The aims of our study are to describe a large cohort of Italian patients with narcolepsy who were candidates for pitolisant treatment and to compare patients' subgroups based on current drug prescription (drug-naïve patients in whom pitolisant was the first-choice treatment, switching to pitolisant from other monotherapy treatments, and adding on in polytherapy)., Methods: We conducted a cross-sectional survey based on Italian data from the inclusion visits of the Post Authorization Safety Study of pitolisant, a 5-year observational, multicenter, international study., Results: One hundred ninety-one patients were enrolled (76.4% with narcolepsy type 1 and 23.6% with narcolepsy type 2). Most patients (63.4%) presented at least one comorbidity, mainly cardiovascular and psychiatric. Pitolisant was prescribed as an add-on treatment in 120/191 patients (62.8%), as switch from other therapies in 42/191 (22.0%), and as a first-line treatment in 29/191 (15.2%). Drug-naive patients presented more severe sleepiness, lower functional status, and a higher incidence of depressive symptoms., Conclusion: Our study presents the picture of a large cohort of Italian patients with narcolepsy who were prescribed with pitolisant, suggesting that polytherapy is highly frequent to tailor a patient-centered approach., (© 2022. The Author(s).)

Background: Human sperm chromatin condensation is a sum of epigenetic events that allows for the near-complete replacement of histones with protamines. Under high-magnification microscopy, nuclear vacuoles have been described as thumbprints with poor chromatin condensation. The objective of this study is to examine whether vacuolated spermatozoa carry specific epigenetic marks, which may influence embryo development. Methods: The presence and three-dimensional distribution of ten epigenetic marks (protamine-P2, histone-H3, H3K4me1/me2/me3, H3K9me1/me2/me3, H3K27me3, H4k20me2) were evaluated and compared in morphometrically normal spermatozoa according to the presence or absence of a large vacuole occupying more than 15% of the head surface (n = 4193). Results: Vacuolated spermatozoa were significantly more frequently labelled with H3 and H3K4me3 than normal spermatozoa (88.1% ± 2.7 and 78.5% ± 5.2 vs. 74.8% ± 4.8 and 49.1% ± 7.4, respectively; p = 0.009 and p < 0.001) and significantly less marked by P2 and H3K27me3 (50.2% ± 6.2 and 63.9% ± 6.3 vs. 82.1% ± 4.4 and 73.6% ± 5.1, respectively; p < 0.001 and p = 0.028). In three dimensions, vacuoles are nuclear concavities filled with DNA carrying the H3K4me3 marker. Conclusion: High-magnification microscopy is a simple tool to estimate in real time the sperm epigenetic profile. The selection of normal spermatozoa without vacuoles and the deselection of spermatozoa with vacuoles appear to be epigenetically favorable to embryo development and safe offspring.

Study Question: Could whole-exome sequencing (WES) be useful in clinical practice for men with maturation arrest (MA) after a first testicular sperm extraction (TESE)?, Summary Answer: WES in combination with TESE yields substantial additional information and may potentially be added as a test to predict a negative outcome of a recurrent TESE in patients with MA., What Is Known Already: At present, the only definitive contraindications for TESE in men with non-obstructive azoospermia (NOA) are a 46,XX karyotype and microdeletions in the azoospermia factor a (AZFa) and/or AZFb regions. After a first negative TESE with MA, no test currently exists to predict a negative outcome of a recurrent TESE., Study Design, Size, Duration: In a cohort study, we retrospectively included 26 patients with idiopathic NOA caused by complete MA diagnosed after a first TESE., Participants/materials, Setting, Methods: Twenty-six men with MA at the spermatocyte stage in all seminiferous tubules, according to a histopathological analysis performed independently by two expert histologists, and a normal karyotype (i.e. no AZF gene microdeletions on the Y chromosome) were included. Single-nucleotide polymorphism comparative genomic hybridization array and WES were carried out. The results were validated with Sanger sequencing. For all the variants thought to influence spermatogenesis, we used immunohistochemical techniques to analyse the level of the altered protein., Main Results and the Role of Chance: Deleterious homozygous variants were identified in all seven consanguineous patients and in three of the 19 non-consanguineous patients. Compound heterozygous variants were identified in another 5 of the 19 non-consanguineous patients. No recurrent variants were identified. We found new variants in genes known to be involved in azoospermia or MA [including testis expressed 11 (TEX11), meiotic double-stranded break formation protein 1 (MEI1), proteasome 26s subunit, ATPase 3 interacting protein (PSMC3IP), synaptonemal complex central element protein 1 (SYCE1) and Fanconi anaemia complementation group M (FANCM) and variants in genes not previously linked to human MA (including CCCTC-binding factor like (CTCFL), Mov10 like RISC complex RNA helicase 1 (MOV10L1), chromosome 11 open reading frame 80 (C11ORF80) and exonuclease 1 (EXO1)]., Large Scale Data: Data available on request., Limitations, Reasons for Caution: More data are required before WES screening can be used to avoid recurrent TESE, although screening should be recommended for men with a consanguineous family background. WES is still a complex technology and can generate incidental findings., Wider Implications of the Findings: Our results confirmed the genetic aetiology of MA in most patients: the proportion of individuals with at least one pathologic variant was 50% in the overall study population and 100% in the consanguineous patients. With the exception of MEI1 (compound heterozygous variants of which were identified in two cases), each variant corresponded to a specific gene-confirming the high degree of genetic heterogeneity in men with MA. Our results suggest that WES screening could help to avoid recurrent, futile TESE in men with MA in general and in consanguineous individuals in particular, but these results need to be confirmed in future studies before clinical implementation., Study Funding/competing Interest(s): The study was funded by the Fondation Maladies Rares (Paris, France), Merck (Kenilworth, NJ, USA), IRSF (Montigny le Bretonneux, France) and Agence de la Biomédecine (Saint Denis, France). There are no competing interests., Trial Registration Number: N/A., (© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology.)

Dendritic cells are the most powerful antigen-presenting cells of the immune system. They present exogenous antigens associated with Major Histocompatibility Complex (MHC) Class II molecules through the classical pathway to stimulate CD4+ T cells, or with MHC-I to activate CD8+ T lymphocytes through the cross-presentation pathway. DCs represent one of the main cellular targets during infection by Toxoplasma gondii . This intracellular parasite incorporates essential nutrients, such as cholesterol, to grow and proliferate inside a highly specialized organelle, the parasitophorous vacuole (PV). While doing so, T. gondii modulates the host immune response through multiple interactions with proteins and lipids. Cholesterol is an important cellular component that regulates cellular physiology at the structural and functional levels. Although different studies describe the relevance of cholesterol transport for exogenous antigen presentation, the molecular mechanism underlying this process is not defined. Here, we focus our study on the inhibitor U18666A, a drug widely used to arrest multivesicular bodies biogenesis that interrupts cholesterol trafficking and changes the lipid composition of intracellular membranes. Upon bone marrow-derived DC (BMDC) treatment with U18666A, we evidenced a drastic disruption in the ability to present exogenous soluble and particulate antigens to CD4+ and CD8+ T cells. Strikingly, the presentation of T. gondii -associated antigens and parasite proliferation were hampered in treated cells. However, neither antigen uptake nor BMDC viability was significantly affected by the U18666A treatment. By contrast, this drug altered the transport of MHC-I and MHC-II molecules to the plasma membrane. Since U18666A impairs the formation of MVBs, we analyzed in T. gondii infected BMDCs the ESCRT machinery responsible for the generation of intraluminal vesicles. We observed that different MVBs markers, including ESCRT proteins, were recruited to the PV. Surprisingly, the main ESCRT-III component CHMP4b was massively recruited to the PV, and its expression level was upregulated upon BMDC infection by T. gondii . Finally, we demonstrated that BMDC treatment with U18666A interrupted cholesterol delivery and CHMP4b recruitment to the PV, which interfered with an efficient parasite replication. Altogether, our results highlight the importance of cholesterol trafficking and MVBs formation in DCs for optimal antigen presentation and T. gondii proliferation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Croce, Garrido, Dinamarca, Santi-Rocca, Marion, Blanchard, Mayorga and Cebrian.)

It is well established that by modulating various immune functions, host infection may alter the course of concomitant inflammatory diseases, of both infectious and autoimmune etiologies. Beyond the major impact of commensal microbiota on the immune status, host exposure to viral, bacterial, and/or parasitic microorganisms also dramatically influences inflammatory diseases in the host, in a beneficial or harmful manner. Moreover, by modifying pathogen control and host tolerance to tissue damage, a coinfection can profoundly affect the development of a concomitant infectious disease. Here, we review the diverse mechanisms that underlie the impact of (co)infections on inflammatory disorders. We discuss epidemiological studies in the context of the hygiene hypothesis and shed light on the sometimes dual impact of germ exposure on human susceptibility to inflammatory disease. We then summarize the immunomodulatory mechanisms at play, which can involve pleiotropic effects of immune players and discuss the possibility to harness pathogen-derived compounds to the host benefit., Competing Interests: The authors have declared that no competing interests exist.

Mycolactone is a diffusible lipid toxin produced by Mycobacterium ulcerans, the causative agent of Buruli ulcer disease. Altough bacterially derived mycolactone has been shown to traffic from cutaneous foci of infection to the bloodstream, the mechanisms underpinning its access to systemic circulation and import by host cells remain largely unknown. Using biophysical and cell-based approaches, we demonstrate that mycolactone specific association to serum albumin and lipoproteins is necessary for its solubilization and is a major mechanism to regulate its bioavailability. We also demonstrate that Scavenger Receptor (SR)-B1 contributes to the cellular uptake of mycolactone. Overall, we suggest a new mechanism of transport and cell entry, challenging the dogma that the toxin enters host cells via passive diffusion., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Tello Rubio, Bugault, Baudon, Raynal, Brûlé, Morel, Saint-Auret, Blanchard, Demangel and Guenin-Macé.)

The host lymphocyte response is decisive in Pneumocystis pneumonia (PCP) pathophysiology but little is known of the specific roles of lymphocyte subpopulations in this fungal infection. Peripheral NK, NKT, B, TCD4+ and TCD8+ subpopulations were compared by immunophenotyping between 20 patients diagnosed with PCP (PCP(+)] and 20 uninfected immunosuppressed patients (PCP(-)). Among PCP(+) subjects, the lymphocyte populations were also compared between surviving and deceased patients. Low B cell count (<40 cells/µL) was more frequent in PCP(+) than in PCP(-) patients ( p = 0.03), while there was no difference for the TCD4 count. Among the PCP(+) group, the 7 deceased patients had lower Th1 ( p = 0.02) and Tc1 ( p = 0.03) populations, higher Th2 response ( p = 0.03), higher effector TCD8 ( p < 0.01), lower central memory TCD8 ( p = 0.04) and reduced NK cells ( p = 0.02) compared with the 13 survivors. Th1/Th2 ratio < 17, CD8 Tc1 < 44%, effector TCD8 < 25%, central memory TCD8 < 4%, NK cells < 50 cells/µL and total lymphocytes < 0.75 G/L were associated with a higher risk of mortality ( p = 0.003, p = 0.007, p = 0.0007, p = 0.004, p = 0.02 and p = 0.019, respectively). The traditional analysis of TCD4 and TCD8 populations may be insufficient in the context of PCP. It could be completed by using B cells to predict the risk of PCP, and by using lymphocyte subpopulations or total lymphocyte count, which are easy to obtain in all health care facilities, to evaluate PCP prognosis.

Structural diversity in heterocyclic chemistry is key to unlocking new properties and modes of action. In this regard, heterocycles embedding emerging fluorinated substituents hold great promise. Herein is described a strategy to access 2-SF 5 -(aza)indoles for the first time. The sequence relies on the radical addition of SF 5 Cl to the alkynyl π-system of 2-ethynyl anilines followed by a cyclization reaction. A telescoped sequence is proposed, making this strategy very appealing and reproducible on a gram scale. Downstream functionalizations are also demonstrated, allowing an easy diversification of N- and C3-positions. Ames test, p K a , log P , and differential scanning calorimetry measurements of several fluorinated 2-Rf-indoles are also disclosed. These studies highlight the strategic advantages that a C2-pentafluorosulfanylated motif impart to a privileged scaffold such as an indole., Competing Interests: The authors declare no competing financial interest., (© 2021 The Authors. Published by American Chemical Society.)

Background: Uveal melanoma (UM) is the most common intraocular tumor in adults. Despite good primary tumor control, up to 50% of patients develop metastasis, which is lethal. UM often presents asymptomatically and is usually diagnosed by clinical examination and imaging, making it one of the few cancer types diagnosed without a biopsy. Hence, alternative diagnostic tools are needed. Circulating tumor DNA (ctDNA) has shown potential as a liquid biopsy target for cancer screening and monitoring. The aim of this study was to evaluate the feasibility and clinical utility of ctDNA detection in UM using specific UM gene mutations., Methods: We used the highly sensitive digital droplet PCR (ddPCR) assay to quantify UM driver mutations (GNAQ, GNA11, PLCβ4 and CYSTLR2) in cell-free DNA (cfDNA). cfDNA was analyzed in six well established human UM cell lines with known mutational status. cfDNA was analyzed in the blood and aqueous humor of an UM rabbit model and in the blood of patients. Rabbits were inoculated with human UM cells into the suprachoroidal space, and mutated ctDNA was quantified from longitudinal peripheral blood and aqueous humor draws. Blood clinical specimens were obtained from primary UM patients (n = 14), patients presenting with choroidal nevi (n = 16) and healthy individuals (n = 15)., Results: The in vitro model validated the specificity and accuracy of ddPCR to detect mutated cfDNA from UM cell supernatant. In the rabbit model, plasma and aqueous humor levels of ctDNA correlated with tumor growth. Notably, the detection of ctDNA preceded clinical detection of the intraocular tumor. In human specimens, while we did not detect any trace of ctDNA in healthy controls, we detected ctDNA in all UM patients. We observed that UM patients had significantly higher levels of ctDNA than patients with nevi, with a strong correlation between ctDNA levels and malignancy. Noteworthy, in patients with nevi, the levels of ctDNA highly correlated with the presence of clinical risk factors., Conclusions: We report, for the first time, compelling evidence from in vitro assays, and in vivo animal model and clinical specimens for the potential of mutated ctDNA as a biomarker of UM progression. These findings pave the way towards the implementation of a liquid biopsy to detect and monitor UM tumors.

Purpose: Management of head and neck cancers of unknown primary (HNCUP) combines neck dissection (ND) and radiotherapy, with or without chemotherapy. The prognostic value of ND has hardly been studied in HNCUP., Methods: A retrospective multicentric study assessed the impact of ND extent (adenectomy, selective ND, radical/radical-modified ND) on nodal relapse, progression-free survival (PFS) or survival, taking into account nodal stage., Results: 53 patients (16.5%) had no ND, 33 (10.2%) had lymphadenectomy, 116 (36.0%) underwent selective ND and 120 underwent radical/radical-modified ND (37.3%), 15 of which received radical ND (4.7%). With a 34-month median follow-up, the 3-year incidence of nodal relapse was 12.5% and progression-free survival (PFS) 69.1%. In multivariate analysis after adjusting for nodal stage, the risk of nodal relapse or progression was reduced with lymphadenectomy, selective or radical/modified ND, but survival rates were similar. Patients undergoing lymphadenectomy or ND had a better PFS and lowered nodal relapse incidence in the N1 + N2a group, but the improvement was not significant for the N2b or N2 + N3c patients. Severe toxicity rates exceeded 40% with radical ND., Conclusion: In HNCUP, ND improves PFS, regardless of nodal stage. The magnitude of the benefit of ND does not appear to depend on ND extent and decreases with a more advanced nodal stage.

The unfolded protein response (UPR) has emerged as a central regulator of immune cell responses in several pathologic contexts including infections. However, how intracellular residing pathogens modulate the UPR in dendritic cells (DCs) and thereby affect T cell-mediated immunity remains uncharacterized. Here, we demonstrate that infection of DCs with Toxoplasma gondii (T. gondii) triggers a unique UPR signature hallmarked by the MyD88-dependent activation of the IRE1α pathway and the inhibition of the ATF6 pathway. Induction of XBP1s controls pro-inflammatory cytokine secretion in infected DCs, while IRE1α promotes MHCI antigen presentation of secreted parasite antigens. In mice, infection leads to a specific activation of the IRE1α pathway, which is restricted to the cDC1 subset. Mice deficient for IRE1α and XBP1 in DCs display a severe susceptibility to T. gondii and succumb during the acute phase of the infection. This early mortality is correlated with increased parasite burden and a defect in splenic T-cell responses. Thus, we identify the IRE1α/XBP1s branch of the UPR as a key regulator of host defense upon T. gondii infection., (© 2021 The Authors.)

Background: Extensive waiting times before receiving services is a major barrier to adequate pain management. Waiting times may have a detrimental impact on patients' conditions and quality of life. However, there remains a lack of knowledge on the actual experiences of patients waiting to receive services, especially for those with rheumatic conditions. The present study aimed to gain an in-depth understanding of perceptions and experiences of patients with rheumatic conditions regarding access to pain clinic services. The secondary objective was to identify possible solutions to improve this access according to patients' perspectives., Methods: This qualitative study based on semi-structured interviews was conducted with adults with rheumatic conditions waiting to access pain clinics in the province of Quebec, Canada. Interviews were transcribed verbatim and analyzed using thematic content analysis., Results: Twenty-six participants were interviewed (22 women and 4 men; mean age 54 ± 10 years). Four main themes were identified: 1) the perception that waiting time is unacceptably long; 2) how the lack of information affects patients' experiences of waiting; 3) patients' various expectations towards the pain clinic, from high hopes to disillusionment and 4) carrying an emotional, physical and financial burden resulting from the wait. Participants reported several solutions to improve the experience of waiting, including providing information to patients, increasing resources, improving prioritization processes and care coordination, and providing alternative interventions to patients during the wait., Conclusions: For patients with rheumatic conditions, access to pain clinic services is challenging due to extensive waiting times. The burden it imposes on them adds to the existing challenge of living with a chronic rheumatic condition. The solutions identified by participants could serve as building blocks to develop and implement measures to improve patients' experience of accessing pain-related services.

Aging is the major risk factor for the development of chronic diseases. After decades of research focused on extending lifespan, current efforts seek primarily to promote healthy aging. Recent advances suggest that biological processes linked to aging are more reliable than chronological age to account for an individual's functional status, i.e. frail or robust. It is becoming increasingly apparent that biological aging may be detectable as a progressive loss of resilience much earlier than the appearance of clinical signs of frailty. In this context, the INSPIRE program was built to identify the mechanisms of accelerated aging and the early biological signs predicting frailty and pathological aging. To address this issue, we designed a cohort of outbred Swiss mice (1576 male and female mice) in which we will continuously monitor spontaneous and voluntary physical activity from 6 to 24 months of age under either normal or high fat/high sucrose diet. At different age points (6, 12, 18, 24 months), multiorgan functional phenotyping will be carried out to identify early signs of organ dysfunction and generate a large biological fluids/feces/organs biobank (100,000 samples). A comprehensive correlation between functional and biological phenotypes will be assessed to determine: 1) the early signs of biological aging and their relationship with chronological age; 2) the role of dietary and exercise interventions on accelerating or decelerating the rate of biological aging; and 3) novel targets for the promotion of healthy aging. All the functional and omics data, as well as the biobank generated in the framework of the INSPIRE cohort will be available to the aging scientific community. The present article describes the scientific background and the strategies employed for the design of the INSPIRE Mouse cohort., Competing Interests: All authors of the paper “Towards a large-scale assessment of relationship between biological and chronological aging: The INSPIRE Mouse cohort” declare no conflict of interest related to this manuscript

Mycobacterium ulcerans, the causative agent of Buruli ulcer (BU) disease, is unique amongst human pathogens in its capacity to produce a lipid toxin called mycolactone. While previous studies have demonstrated that bacterially-released mycolactone diffuses beyond infection foci, the spatiotemporal distribution of mycolactone remained largely unknown. Here, we used the zebrafish model to provide the first global kinetic analysis of mycolactone's diffusion in vivo, and multicellular co-culture systems to address the critical question of the toxin's access to the brain. Zebrafish larvae were injected with a fluorescent-derivative of mycolactone to visualize the in vivo diffusion of the toxin from the peripheral circulation. A rapid, body-wide distribution of mycolactone was observed, with selective accumulation in tissues near the injection site and brain, together with an important excretion through the gastro-intestinal tract. Our conclusion that mycolactone reached the central nervous system was reinforced by an in cellulo model of human blood brain barrier and a mouse model of M. ulcerans-infection. Here we show that mycolactone has a broad but heterogenous profile of distribution in vivo. Our investigations in vitro and in vivo support the view that a fraction of bacterially-produced mycolactone gains access to the central nervous system. The relative persistence of mycolactone in the bloodstream suggests that assays of circulating mycolactone are relevant for BU disease monitoring and treatment optimization., Competing Interests: The authors have declared that no competing interests exist.

Infections of the nervous system elicit neuroimmune responses and alter neurotransmission, affecting host neurological functions. Chronic infection with the apicomplexan parasite Toxoplasma correlates with certain neurological disorders in humans and alters behavior in rodents. Here, we propose that the crosstalk between neurotransmission and neuroinflammation may underlie some of these cognitive changes. We discuss how T. gondii infection suppresses noradrenergic signaling and how the restoration of this pathway improves behavioral aberrations, suggesting that altered neurotransmission and neuroimmune responses may act in concert to perturb behavior. This interaction might apply to other infectious agents, such as viruses, that elicit cognitive changes. We hypothesize that neurotransmitter signaling in immune cells can contribute to behavioral changes associated with brain infection, offering opportunities for potential therapeutic targeting., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

As the world energy crisis remains a long-term challenge, development and access to renewable energy sources are crucial for a sustainable modern society. Electrochemical energy conversion devices are a promising option for green energy supply, although the challenge associated with electrocatalysis have caused increasing complexity in the materials and systems, demanding further research and insights. In this field, scanning probe microscopy (SPM) represents a specific source of knowledge and understanding. Thus, our aim is to present recent findings on electrocatalysts for electrolysers and fuel cells, acquired mainly through scanning electrochemical microscopy (SECM) and other related scanning probe techniques. This review begins with an introduction to the principles of several SPM techniques and then proceeds to the research done on various energy-related reactions, by emphasizing the progress on non-noble electrocatalytic materials., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Trypanosoma cruzi , the cause agent of Chagas disease, is transmitted mainly by blood-feeding insects of the subfamily Triatominae. The T. cruzi life cycle alternates between triatomines and mammalian hosts, excluding birds and reptiles. Triatomines of Mepraia genus are wild vectors of T. cruzi in Chile. Mepraia specimens infected with T. cruzi have been detected in Pan de Azúcar and Santa María islands. The most common vertebrates that inhabit these islands are birds and reptiles, and it is unknown whether small mammals are present. Consequently, it is relevant to know whether there are any T. cruzi -infected small mammals on those islands to elucidate the T. cruzi cycle. To clarify this crossroads, islands of northern Chile were explored to determine if T. cruzi -infected triatomines and rodents co-occur in islands of northern Chile. T. cruzi DNA was detected by conventional and real-time PCR in three islands: on Santa María and Pan de Azúcar islands T. cruzi was detected in Mepraia sp samples, while on Pan de Azúcar (6.1%) and Damas islands (15%) was detected in the rodent Abrothrix olivacea . We show for the first time in Chile the occurrence of insular rodents infected with T. cruzi , and a complete T. cruzi life cycle in a coastal island. Our results provide new insights to understand the T. cruzi infection in the wild cycle., Competing Interests: The authors declare there are no competing interests., (©2020 Campos-Soto et al.)

Ynamides are fascinating small molecules with complementary reactivities under radical, ionic, and metal-catalyzed conditions. We report herein synthetic and DFT investigations of palladium-catalyzed ligand-controlled regiodivergent hydrometalation reactions of ynamides. Germylated and stannylated enamides are obtained with excellent α, E - or β, E -selectivities and a broad functional group tolerance. Such a regiodivergent palladium-catalyzed process is unique in ynamide chemistry and allows for the elaboration of metalated enamides that are useful building blocks for cross-coupling reactions or heterocyclic chemistry. DFT calculations fully support the experimental data and demonstrate the crucial roles of the trans -geometry of the [H-Pd(L)-Ge] complex, as well as of the steric requirements of the phosphine ligand. In addition, these calculations support the prevalence of a hydro-palladation pathway over a metal palladation of the π system of the ynamide.

Chagas disease is one of the main zoonoses mediated by vectors in America. The etiological agent is the protozoan Trypanosoma cruzi, transmitted mainly by hematophagous insects of the subfamily Triatominae. Mepraia species are triatomines endemic to Chile that play an important role in T. cruzi transmission in the wild cycle and are potential vectors for humans. In addition to the continental distribution, populations of Mepraia genus have been reported inhabiting islands of northern Chile. The presence of individuals of Mepraia in insular areas might be explained through passive dispersion by marine birds or by vicariance of an ancestral widespread population. To clarify the biogeographic origin and phylogenetic relationships of island individuals of Mepraia, mitochondrial COI and cyt b genes were sequenced in individuals from island and continental areas. Gene sequences were used to estimate phylogenetic relationships, divergence dates and migration rates between insular and continental populations. The dates of divergence estimates are congruent with sea level and tectonic changes that originated the islands during Pleistocene. Migration rates suggest symmetric historical island-continent gene flow. We suggest that the origin of island triatomines can be explained by both vicariance and dispersion. Phylogenetic relationships show that individuals from Santa María Island and the continent clustered in a clade different from those previously reported, indicating a new lineage of Mepraia genus. This study will contribute to understand the origin of the T. cruzi infection in coastal islands of northern Chile., Competing Interests: The authors have declared that no competing interests exist.

Coinfections shape immunity and influence the development of inflammatory diseases, resulting in detrimental or beneficial outcome. Coinfections with concurrent Plasmodium species can alter malaria clinical evolution, and malaria infection itself can modulate autoimmune reactions. Yet, the underlying mechanisms remain ill defined. Here, we demonstrate that the protective effects of some rodent malaria strains on T cell-mediated inflammatory pathologies are due to an RNA virus cohosted in malaria-parasitized blood. We show that live and extracts of blood parasitized by Plasmodium berghei K173 or Plasmodium yoelii 17X YM, protect against P. berghei ANKA-induced experimental cerebral malaria (ECM) and myelin oligodendrocyte glycoprotein (MOG)/complete Freund's adjuvant (CFA)-induced experimental autoimmune encephalomyelitis (EAE), and that protection is associated with a strong type I interferon (IFN-I) signature. We detected the presence of the RNA virus lactate dehydrogenase-elevating virus (LDV) in the protective Plasmodium stabilates and we established that LDV infection alone was necessary and sufficient to recapitulate the protective effects on ECM and EAE. In ECM, protection resulted from an IFN-I-mediated reduction in the abundance of splenic conventional dendritic cell and impairment of their ability to produce interleukin (IL)-12p70, leading to a decrease in pathogenic CD4 + Th1 responses. In EAE, LDV infection induced IFN-I-mediated abrogation of IL-23, thereby preventing the differentiation of granulocyte-macrophage colony-stimulating factor (GM-CSF)-producing encephalitogenic CD4 + T cells. Our work identifies a virus cohosted in several Plasmodium stabilates across the community and deciphers its major consequences on the host immune system. More generally, our data emphasize the importance of considering contemporaneous infections for the understanding of malaria-associated and autoimmune diseases. IMPORTANCE Any infection modifies the host immune status, potentially ameliorating or aggravating the pathophysiology of a simultaneous inflammatory condition. In the course of investigating how malaria infection modulates the severity of contemporaneous inflammatory diseases, we identified a nonpathogenic mouse virus in stabilates of two widely used rodent parasite lines: Plasmodium berghei K173 and Plasmodium yoelii 17X YM. We established that the protective effects of these Plasmodium lines on cerebral malaria and multiple sclerosis are exclusively due to this virus. The virus induces a massive type I interferon (IFN-I) response and causes quantitative and qualitative defects in the ability of dendritic cells to promote pathogenic T cell responses. Beyond revealing a possible confounding factor in rodent malaria models, our work uncovers some bases by which a seemingly innocuous viral (co)infection profoundly changes the immunopathophysiology of inflammatory diseases., (Copyright © 2020 Hassan et al.)

Toxoplasma gondii is a ubiquitous parasitic protist found in a wide variety of hosts, including a large proportion of the human population. Beyond an acute phase which is generally self-limited in immunocompetent individuals, the ability of the parasite to persist as a dormant stage, called bradyzoite, is an important aspect of toxoplasmosis. Not only is this stage not eliminated by current treatments, but it can also reactivate in immunocompromised hosts, leading to a potentially fatal outcome. Yet, despite its critical role in the pathology, the bradyzoite stage is relatively understudied. One main explanation is that it is a considerably challenging model, which essentially has to be derived from in vivo sources. However, recent progress on genetic manipulation and in vitro differentiation models now offers interesting perspectives for tackling key biological questions related to this particularly important developmental stage.

Discovery of antibiotics of a novel mode of action is highly required in the fierce battlefield with multi-drug resistant bacterial infections. Previously we have validated the protein-protein interaction between bacterial NusB and NusE proteins as an unprecedented antimicrobial target and reported the identification of a first-in-class inhibitor of bacterial ribosomal RNA synthesis with antimicrobial activities. In this paper, derivatives of the hit compound were rationally designed based on the pharmacophore model for chemical synthesis, followed by biological evaluations. Some of the derivatives demonstrated the improved antimicrobial activity with the minimum inhibitory concentration (MIC) at 1-2 μg/mL against clinically significant bacterial pathogens. Time-kill kinetics, confocal microscope, ATP production, cytotoxicity, hemolytic property and cell permeability using Caco-2 cells of a representative compound were also measured. This series of compounds were named "nusbiarylins" based on their target protein NusB and the biaryl structure and were expected to be further developed towards novel antimicrobial drug candidates in the near future., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Toxoplasma gondii (Tg), an obligate intracellular parasite of the phylum Apicomplexa, infects a wide range of animals, including humans. A hallmark of Tg infection is the subversion of host responses, which is thought to favor parasite persistence and propagation to new hosts. Recently, a variety of parasite-secreted modulatory effectors have been uncovered in fibroblasts and macrophages, but the specific interplay between Tg and dendritic cells (DCs) is just beginning to emerge. In this review, we summarize the current knowledge on Tg-DC interactions, including innate recognition, cytokine production, and antigen presentation, and discuss open questions regarding how Tg-secreted effectors may shape DC functions to perturb innate and adaptive immunity., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Pyrimidines are almost unreactive partners in Diels-Alder cycloadditions with alkenes and alkynes, and only reactions under drastic conditions have previously been reported. We describe how 2-hydrazonylpyrimidines, easily obtained in two steps from commercially available 2-halopyrimidines, can be exceptionally activated by trifluoroacetylation. This allows a Diels-Alder cycloaddition under very mild reaction conditions, leading to a large diversity of aza-indazoles, a ubiquitous scaffold in medicinal chemistry. This reaction is general and scalable and has an excellent functional group tolerance. A straightforward synthesis of a key intermediate of Bayer's Vericiguat illustrates the potential of this cycloaddition strategy. Quantum mechanical calculations show how the simple N -trifluoroacetylation of 2-hydrazonylpyrimidines distorts the substrate into a transition-state-like geometry that readily undergoes the intramolecular Diels-Alder cycloaddition.