Leptospirosis is a globally prevalent zoonotic disease, and is caused by pathogenic spirochetes from the genus Leptospira. LipL21 and LipL41 are lipoproteins expressed strongly on the outer membrane ...of pathogenic Leptospira spp. Many studies have shown that both proteins are interesting targets for vaccines and diagnosis. However, their role in host-pathogen interactions remains underexplored. Therefore, we evaluated the capacity of LipL21 and LipL41 to bind with glycosaminoglycans (GAGs), the cell receptors and extracellular matrix, and plasma components by ELISA. Both proteins interacted with collagen IV, laminin, E-cadherin, and elastin dose-dependently. A broad-spectrum binding to plasma components was also observed. Only LipL21 interacted with all the GAG components tested, whereas LipL41 presented a concentration-dependent binding only for chondroitin 4 sulfate. Although, both proteins have the ability to interact with fibrinogen, only LipL21 inhibited fibrin clot formation partially. Both proteins exhibited a decrease in plasminogen binding in the presence of amino caproic acid (ACA), a competitive inhibitor of lysine residues, suggesting that their binding occurs via the kringle domains of plasminogen. LipL41, but not LipL21, was able to convert plasminogen to plasmin, and recruit plasminogen from normal human serum, suggesting that the interaction of this protein with plasminogen may occur in physiological conditions. This work provides the first report demonstrating the capacity of LipL21 and LipL41 to interact with a broad range of host components, highlighting their importance in host-Leptospira interactions.
Effect of Mg content on age-hardening response, tensile properties, and microstructures of a T5-treated thixo-cast Al–7wt.%Si–0.01wt.%Sr alloy has been investigated. The strengths of the T5-treated ...alloy increase with increasing the Mg content due to the dispersion of high density of needle-like precipitates (β” phases). Also, the addition of 1.0wt.% Mg results in the formation of evenly distributed fine Mg2Si phases and Fe-rich compounds in the eutectic Si regions, and therefore, the Al–7wt.%Si–1.0wt.%Mg–0.01wt.%Sr alloy exhibits high 0.2% proof stress of 241 MPa and moderate elongation to failure of 5.1%, which are comparable to those of T6-treated gravity-cast Al–7wt.%Si–0.3wt.%Mg (ASTM A356) alloys. Although the addition of 1.5wt.% Mg or more further improves the strengths, the excess additions of Mg lead to the formation of coarse Mg2Si phases. This causes significant loss of ductility, and the alloys show poor elongation to failure of ~2%.
This study examined 1) the clinical relevance of trunk movement asymmetry, which was evaluated using a trunk-mounted inertial measurement unit (IMU), and 2) the relationship between trunk movement ...asymmetry and lower limb muscle strength asymmetry in individuals with knee osteoarthritis (OA).
One-hundred-thirty-one participants (mean age, 74.2 years; 71.8% female; Kellgren and Lawrence K&L grade ≥1) underwent gait analysis at their preferred pace for IMU-based measurement of trunk movement asymmetry (harmonic ratio HR and improved HR). The isometric strength of quadriceps and hip abductors was evaluated using a hand-held dynamometer. Pain and disability level were evaluated using a validated self-reported questionnaire. Multiple regression analyses with covariate adjustment were performed to examine the relationship between trunk movement asymmetry (independent variable) and pain, disability level, or muscle strength asymmetry (dependent variables).
Individuals with severe knee OA (K&L grade ≥3) had increased trunk movement asymmetry in the medio-lateral axis compared to those with a K&L grade of 1. Increased trunk movement asymmetry was associated with a greater knee pain and disability. The increased trunk movement asymmetry was significantly associated with an increase in the asymmetry of quadriceps strength, but not with asymmetry in the strength of hip abductor.
Our findings indicate that increased medio-lateral trunk movement asymmetry may be an indicator of impairment, rather than adaptation, in individuals with knee OA. This preliminary finding warrants validation by future study. Paying close attention to medio-lateral trunk movement asymmetry may be key to our understanding of OA-related pain and disability.
To test the hypothesis that the interaction between low back pain (LBP) and knee pain intensity contributes to the disability level of individuals with knee osteoarthritis (OA).
Community-dwelling ...participants with knee OA (Kellgren/Lawrence K/L grade ≥1) were enrolled. LBP and its severity were identified using questionnaires. Knee pain severity and disability level were evaluated using the Japanese Knee Osteoarthritis Measure (JKOM) subscale. Multiple linear regression analyses were performed to examine the effect of the LBP–knee pain interaction, an independent variable, on disability, a dependent variable.
A total of 260 participants (age, 48–88 years; 77.7% women) were included. Of them, 151 (58.1%) had LBP. The LBP–knee pain interaction was significantly associated with disability after the adjustment for covariates. A post-hoc subgroup analysis revealed that the relationship between knee pain intensity and disability level was higher in individuals with LBP (beta: 0.621 points; 95% confidence interval CI: 0.511 to 0.731 points) than in those without LBP (beta: 0.402 points; 95% CI: 0.316 to 0.487 points).
LBP interacts with knee pain intensity and contributes to disability level in individuals with knee OA. Coexisting LBP and knee pain had a stronger impact on disability level than LBP or knee pain alone. These findings highlight the potential deteriorative effects of the LBP–knee interaction on disability. Maximal treatment effects for disability might be achieved when LBP and knee pain are targeted simultaneously, rather than separately.
Using hourly data from a three‐year simulation based on a gravity‐wave resolving general circulation model, we have first inferred a global view of gravity wave sources and propagation affecting ...significantly the momentum balance in the mesosphere. The meridional cross section of momentum fluxes suggests that there are a few dominant propagation paths originating from the subtropics in summer and the middle to high latitudes in winter. These gravity waves are focused into the mesospheric jets in their respective seasons, acting effectively to decelerate the jets. The difference in the source latitudes likely contributes to the hemispheric asymmetries of the jets. The horizontal distribution of the momentum fluxes indicates that the dominant sources are steep mountains and tropospheric westerly jets in winter and vigorous monsoon convection in summer. The monsoon regions are the most important window to the middle atmosphere in summer because of the easterlies associated with the monsoon circulation.
Tyrosine kinase inhibitor (TKI)-sensitive and TKI-resistant mutations of epidermal growth factor receptor (EGFR) are associated with lung adenocarcinoma. EGFR mutants were previously shown to exhibit ...ligand-independent activation. We have previously demonstrated that pulmonary surfactant protein D (SP-D, SFTPD) suppressed wild-type EGFR signaling by blocking ligand binding to EGFR. We herein demonstrate that SFTPD downregulates ligand-independent signaling in cells harboring EGFR mutations such as TKI-sensitive exon 19 deletion (Ex19del) and L858R mutation as well as TKI-resistant T790M mutation, subsequently suppressing cellular growth and motility. Lectin blotting and ligand blotting in lung cancer cell lines suggested that EGFR mutants express oligomannose-type N-glycans and interact with SFTPD directly. Cross-linking assay indicated that SFTPD inhibits ligand-independent dimerization of EGFR mutants. We also demonstrated that SFTPD reduced dimerization-independent phosphorylation of Ex19del and T790M EGFR mutants using point mutations that disrupted the asymmetric dimer interface. It was confirmed that SFTPD augmented the viability-suppressing effects of EGFR-TKIs. Furthermore, retrospective analysis of 121 patients with lung adenocarcinoma to examine associations between serum SFTPD levels and clinical outcome indicated that in TKI-treated patients with lung cancer harboring EGFR mutations, including Ex19del or L858R, high serum SFTPD levels correlated with a lower number of distant metastases and prolonged overall survival and progression-free survival. These findings suggest that SFTPD downregulates both TKI-sensitive and -resistant EGFR mutant signaling, and SFTPD level is correlated with clinical outcome. These findings illustrate the use of serum SFTPD level as a potential marker to estimate the efficacy of EGFR-TKIs.
Emotionally salient information activates orexin neurons in the lateral hypothalamus, leading to increase in sympathetic outflow and vigilance level. How this circuit alters animals' behavior remains ...unknown. Here we report that noradrenergic neurons in the locus coeruleus (NA
neurons) projecting to the lateral amygdala (LA) receive synaptic input from orexin neurons. Pharmacogenetic/optogenetic silencing of this circuit as well as acute blockade of the orexin receptor-1 (OX1R) decreases conditioned fear responses. In contrast, optogenetic stimulation of this circuit potentiates freezing behavior against a similar but distinct context or cue. Increase of orexinergic tone by fasting also potentiates freezing behavior and LA activity, which are blocked by pharmacological blockade of OX1R in the LC. These findings demonstrate the circuit involving orexin, NA
and LA neurons mediates fear-related behavior and suggests inappropriate excitation of this pathway may cause fear generalization sometimes seen in psychiatric disorders, such as PTSD.
High emissions of air pollutants from Northeast Asia are strongly influenced by air quality as well as by ecosystems. This study investigated the spatiotemporal variations in the sulfur isotopic ...ratio (δ34S) in atmospheric deposition at eleven monitoring stations in Japan from 2011 to 2016 and estimated the amount of transboundary transported anthropogenic sulfate (TRB) deposition using mass balance calculations. The δ34S of sulfate in precipitation ranged from −0.42 to +22.7‰. Sea salt (SS), TRB, and domestic anthropogenic sources (DOM) were the dominant sources of sulfate deposition in Japan. TRB sulfate deposition was largest on the Sea of Japan side, with an annual average value of 1.5 ± 0.3–6.9 ± 0.5 mg m−2 d−1 (36–44%), followed by Mt. Happo (4.5 ± 0.1 mg m−2 d−1; 88%), the Pacific Ocean side (1.5 ± 0.8, 4.3 ± 0.9 mg m−2 d−1; 24–50%), and the remote islands in the North Pacific Ocean (1.1 ± 0.2, 2.0 ± 0.8 mg m−2 d−1; 19–32%). TRB sulfate deposition on the Sea of Japan side was 2–12 times higher in winter and 1–2 times higher in summer than that of DOM. In contrast, TRB sulfate deposition on the Pacific Ocean side was 1.5–3 times higher in summer than in winter due to high precipitation levels. In Tokyo, the annual contribution from DOM sulfate deposition is approximately three times higher than that from TRB. Annual TRB sulfate deposition is lowest at Ogasawara at 1.1 ± 0.2 mg m−2 d−1, and the annual oceanic DMS contribution to sulfate deposition is high, accounting for 1.3 mg m−2 d−1 (20 ± 6%). The contribution of Asian dust was estimated to be 1–5.2 mg m−2 d−1(3–6%), which occurred in a single Asian dust event on the Sea of Japan side.
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•Spatiotemporal variations of the sulfur isotopic ratio in atmospheric deposition in Japan were investigated.•δ34S of sulfate in precipitation were seasonal variation with high in winter.•Contribution from transbundary transported sulfur deposition was larger than those of domestic sources.•Contribution from domestic sulfur deposition was larger in the Pacific Ocean site.
Introduction La lipodystrophie congénitale généralisée de Berardinelli-Seip (BSCL) est caractérisée par une absence quasi totale de tissu adipeux et une insulinorésistance sévère, et est fréquemment ...liée à la mutation du gène BSCL2 codant la seipine. Le défaut d’adipogenèse observé in vitro est en partie corrigé par les thiazolidinediones. L’objectif de ce travail est de déterminer si un traitement in vivo par de la pioglitazone (PIO) améliore le phénotype métabolique des souris Bscl2-/-. Matériels et méthodes Les souris mâles Bscl2-/- de 4 semaines ont été traitées par la PIO (45 mg/kg dans le régime) pendant 9 semaines. Résultats Le traitement par la PIO entraîne une baisse de l’insulinémie (0,22 ± 0,05 vs 5,8 ± 1,5 ng/mL chez les souris contrôles) et tend à améliorer la tolérance au glucose. Les souris Bscl2-/- traitées présentent une augmentation de la masse de tissu adipeux mésentérique (103 ± 13 vs 28,8 ± 6,6 mg) qui est associée avec une élévation des concentrations plasmatiques de leptine et d’adiponectine (respectivement 0,77 ± 0,10 vs 0,28 ± 0,03 ng/mL et 10,0 ± 3,1 vs 0,48 ± 0,09 μg/mL). De façon remarquable, la PIO est capable de corriger la stéatose hépatique : le contenu hépatique en triglycérides est diminué de plus de 50 %, et l’expression des gènes marqueurs de fibrose est réduite. Enfin, la sur-expression des gènes impliqués dans l’internalisation de lipides (LDLr, CD36) détectée chez les souris Bscl2-/- est corrigée par la PIO. Conclusion Nos résultats montrent qu’un traitement précoce par la PIO permet une réversion partielle du phénotype lipodystrophique des souris Bscl2-/- et de la stéatose et l’insulinorésistance associées.
Introduction La lipodystrophie congénitale de Berardinelli-Seip (BSCL) est un syndrome rare caractérisé par une absence généralisée de tissu adipeux et une insulino-résistance sévère. Les ...cardiomyopathies sont fréquentes chez les patients atteints de BSCL mais les mécanismes impliqués sont très mal caractérisés. Matériels et méthodes Nous avons étudié le métabolisme cardiaque chez des souris déficientes en seipine (Bscl2-/-) à l’aide de radiotraceurs. Parallèlement, une analyse structurale et fonctionnelle a été effectuée par échocardiographie. Résultats Précédemment, nous avions mis en évidence que le catabolisme des lipoprotéines riches en triglycérides (TRL) est accéléré chez les souris Bscl2-/-. Dans cette étude, l’utilisation de TRL radiomarquées a révélé une augmentation de l’internalisation cardiaque des acides gras chez les souris Bscl2-/- (2 230 ± 40 vs 1 430 ± 139 cpm chez les souris sauvages, p < 0,05). Cette accumulation lipidique est associée à une augmentation du poids du coeur des souris Bscl2-/- comparativement aux souris sauvages (230 ± 38 mg vs 178 ± 19 mg p < 0,05). Un suivi échocardiographique, de 2 à 8 mois, montre que ces souris ne présentent pas de remodelages structuraux significatifs. Cependant, l’augmentation des niveaux d’ARNm de l’isoforme β de la chaîne lourde de la myosine (β-MHC) chez les souris Bscl2-/- (+175 ± 4,9 % vs souris sauvages) suggère l’initiation d’un remodelage myocardique. En terme fonctionnel, l’analyse du flux mitral par sonde doppler révèle une dysfonction diastolique chez les souris Bscl2-/- avec une augmentation du temps de relaxation isovolumétrique (TRIV). Le traitement de ces animaux par la pioglitazone permet une normalisation du niveau d’expression de la β-MHC ainsi que des valeurs de TRIV. Conclusion Les souris Bscl2-/- présentent une augmentation de la capture des acides gras qui est associée à une dysfonction diastolique comparable à celle décrite pour la cardiomyopathie diabétique. Les souris Bscl2-/- constituent un nouveau modèle pour comprendre les mécanismes impliqués dans la lipotoxicité au niveau cardiaque.
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