Focus: Zoonotic Disease: New Series of Imidazoles Showed Promising Growth Inhibitory and Curative Potential Against Trypanosoma Infection

The Trypanosoma spp. cause animal and human trypanosomiasis characterized with appreciable health and economic burden mostly in developing nations. There is currently no effective therapy for this parasitic disease, due to poor drug efficacy, drug resistance, and unwanted toxicity, etc. Therefore, new anti-Trypanosoma agents are urgently needed. This study explored new series of imidazoles for anti-Trypanosoma properties in vitro and in vivo. The imidazoles showed moderate to strong and specific action against growth of T. congolense. For example, the efficacy of the imidazole compounds to restrict Trypanosoma growth in vitro was ≥ 12-fold specific towards T. congolense relative to the mammalian cells. Additionally, the in vivo study revealed that the imidazoles exhibited promising anti-Trypanosoma efficacy corroborating the in vitro anti-parasite capacity. In particular, three imidazole compounds (C1, C6, and C8) not only cleared the systemic parasite burden but cured infected rats after no death was recorded. On the other hand, the remaining five imidazole compounds (C2, C3, C4, C5, and C7) drastically reduced the systemic parasite load while extending survival time of the infected rats by 14 days as compared with control. Untreated control died 3 days post-infection, while the rats treated with diminazene aceturate were cured comparable to the results obtained for C1, C6, and C8. In conclusion, this is the first study demonstrating the potential of these new series of imidazoles to clear the systemic parasite burden in infected rats. Furthermore, a high selectivity index of imidazoles towards T. congolense in vitro and the oral LD₅₀ in rats support anti-parasite specific action. Together, findings support the anti-parasitic prospects of the new series of imidazole derivatives.     

Corticosterone predicts foraging behavior and parental care in macaroni penguins

Corticosterone has received considerable attention as the principal hormonal mediator of allostasis or physiological stress in wild animals. More recently, it has also been implicated in the regulation of parental care in breeding birds, particularly with respect to individual variation in foraging behavior and provisioning effort. There is also evidence that prolactin can work either inversely or additively with corticosterone to achieve this. Here we test the hypothesis that endogenous corticosterone plays a key physiological role in the control of foraging behavior and parental care, using a combination of exogenous corticosterone treatment, time-depth telemetry, and physiological sampling of female macaroni penguins (Eudyptes chrysolophus) during the brood-guard period of chick rearing, while simultaneously monitoring patterns of prolactin secretion. Plasma corticosterone levels were significantly higher in females given exogenous implants relative to those receiving sham implants. Increased corticosterone levels were associated with significantly higher levels of foraging and diving activity and greater mass gain in implanted females. Elevated plasma corticosterone was also associated with an apparent fitness benefit in the form of increased chick mass. Plasma prolactin levels did not correlate with corticosterone levels at any time, nor was prolactin correlated with any measure of foraging behavior or parental care. Our results provide support for the corticosterone-adaptation hypothesis, which predicts that higher corticosterone levels support increased foraging activity and parental effort.     

Effect of pre-treatment with St John's Wort on nephrotoxicity of cisplatin in rats

An herbal health care supplement, St John's Wort (SJW, Hypericum perforatum) has become widely used in the treatment of depression, and is known to interact with therapeutic drugs. Here we report a preventive effect of SJW on cisplatin nephrotoxicity in rats. Rats were given SJW (400 mg/kg/day, p.o.) for 10 consecutive days, and were injected with cisplatin (5 mg/kg, i.v.) on the day after the final SJW treatment. Cisplatin treatment increased the serum creatinine level, which is an index of nephrotoxicity, to 1.51+/-0.22 mg/dl (mean+/-SE) from 0.28+/-0.05 mg/dl (control) on day 5 after the cisplatin injection. This increase fell significantly to 0.86+/-0.13 mg/dl by pre-treatment with SJW. Cisplatin-induced histological abnormality of the kidney was blocked by pre-treatment with SJW. When SJW was administered for 10 days, the amounts of renal metallothionein (MT) and hepatic multidrug resistance protein 2 (Mrp2) were increased to 164.8+/-13.0% and 220.8+/-39.3% (mean+/-SE) of controls, respectively. GSH levels in the kidney and liver were not changed. Total and free cisplatin concentration in serum was not influenced by SJW treatment. In conclusion, the results suggest that pre-treatment with SJW may diminish cisplatin nephrotoxicity.     

The novel F-box protein Mfb1p regulates mitochondrial connectivity and exhibits asymmetric localization in yeast

Although it is clear that mitochondrial morphogenesis is a complex process involving multiple proteins in eukaryotic cells, little is known about regulatory molecules that modulate mitochondrial network formation. Here, we report the identification of a new yeast mitochondrial morphology gene called MFB1 (YDR219C). MFB1 encodes an F-box protein family member, many of which function in Skp1-Cdc53/Cullin-F-box protein (SCF) ubiquitin ligase complexes. F-box proteins also act in non-SCF complexes whose functions are not well understood. Although cells lacking Mfb1p contain abnormally short mitochondrial tubules, Mfb1p is not essential for known pathways that determine mitochondrial morphology and dynamics. Mfb1p is peripherally associated with the mitochondrial surface. Coimmunoprecipitation assays reveal that Mfb1p interacts with Skp1p in an F-box-dependent manner. However, Mfb1p does not coimmunoprecipitate with Cdc53p. The F-box motif is not essential for Mfb1p-mediated mitochondrial network formation. These observations suggest that Mfb1p acts in a complex lacking Cdc53p required for mitochondrial morphogenesis. During budding, Mfb1p asymmetrically localizes to mother cell mitochondria. By contrast, Skp1p accumulates in the daughter cell cytoplasm. Mfb1p mother cell-specific asymmetry depends on the F-box motif, suggesting that Skp1p down-regulates Mfb1p mitochondrial association in buds. We propose that Mfb1p operates in a novel pathway regulating mitochondrial tubular connectivity.     

Molecular Functions of Oxygen-Evolving Complex Family Proteins in Photosynthetic Electron Flow

Oxygen-evolving complex (OEC) protein is the original name for membrane-peripheral subunits of photosystem (PS) Ⅱ. Recently,multiple isoforms and homologs for OEC proteins have been identified in the chloroplast thylakoid lumen, indicating that functional diversification has occurred in the OEC family. Gene expression profiles suggest that the Arabidopsis OEC proteins are roughly categorized into three groups: the authentic OEC group, the stressresponsive group, and the group including proteins related to the chloroplast NAD(P)H dehydrogenase (NDH) complex involved in cyclic electron transport around PSI. Based on the above gene expression profiles, molecular functions of the OEC family proteins are discussed together with our current knowledge about their functions.     

Reduced BMP Signaling Results in Hindlimb Fusion with Lethal Pelvic/Urogenital Organ Aplasia: A New Mouse Model of Sirenomelia

Sirenomelia, also known as mermaid syndrome, is a developmental malformation of the caudal body characterized by leg fusion and associated anomalies of pelvic/urogenital organs including bladder, kidney, rectum and external genitalia. Most affected infants are stillborn, and the few born alive rarely survive beyond the neonatal period. Despite the many clinical studies of sirenomelia in humans, little is known about the pathogenic developmental mechanisms that cause the complex array of phenotypes observed. Here, we provide new evidences that reduced BMP (Bone Morphogenetic Protein) signaling disrupts caudal body formation in mice and phenocopies sirenomelia. Bmp4 is strongly expressed in the developing caudal body structures including the peri-cloacal region and hindlimb field. In order to address the function of Bmp4 in caudal body formation, we utilized a conditional Bmp4 mouse allele (Bmp4^flox/flox) and the Isl1 (Islet1)-Cre mouse line. Isl1-Cre is expressed in the peri-cloacal region and the developing hindimb field. Isl1Cre;Bmp4^flox/flox conditional mutant mice displayed sirenomelia phenotypes including hindlimb fusion and pelvic/urogenital organ dysgenesis. Genetic lineage analyses indicate that Isl1-expressing cells contribute to both the aPCM (anterior Peri-Cloacal Mesenchyme) and the hindlimb bud. We show Bmp4 is essential for the aPCM formation independently with Shh signaling. Furthermore, we show Bmp4 is a major BMP ligand for caudal body formation as shown by compound genetic analyses of Bmp4 and Bmp7. Taken together, this study reveals coordinated development of caudal body structures including pelvic/urogenital organs and hindlimb orchestrated by BMP signaling in Isl1-expressing cells. Our study offers new insights into the pathogenesis of sirenomelia.     

Airway Wall Area Derived from 3-Dimensional Computed Tomography Analysis Differs among Lung Lobes in Male Smokers

Background

It is time-consuming to obtain the square root of airway wall area of the hypothetical airway with an internal perimeter of 10 mm (√Aaw at Pi10), a comparable index of airway dimensions in chronic obstructive pulmonary disease (COPD), from all airways of the whole lungs using 3-dimensional computed tomography (CT) analysis. We hypothesized that √Aaw at Pi10 differs among the five lung lobes and √Aaw at Pi10 derived from one certain lung lobe has a high level of agreement with that derived from the whole lungs in smokers.

Methods

Pulmonary function tests and chest volumetric CTs were performed in 157 male smokers (102 COPD, 55 non-COPD). All visible bronchial segments from the 3^rd to 5^th generations were segmented and measured using commercially available 3-dimensional CT analysis software. √Aaw at Pi10 of each lung lobe was estimated from all measurable bronchial segments of that lobe.

Results

Using a mixed-effects model, √Aaw at Pi10 differed significantly among the five lung lobes (R² = 0.78, P<0.0001). The Bland-Altman plots show that √Aaw at Pi10 derived from the right or left upper lobe had a high level of agreement with that derived from the whole lungs, while √Aaw at Pi10 derived from the right or left lower lobe did not.

Conclusion

In male smokers, CT-derived airway wall area differs among the five lung lobes, and airway wall area derived from the right or left upper lobe is representative of the whole lungs.     

Cross-linking Evidence for Multiple Interactions of the PsbP and PsbQ Proteins in a Higher Plant Photosystem II Supercomplex

The extrinsic subunits of membrane-bound photosystem II (PSII) maintain an essential role in optimizing the water-splitting reaction of the oxygen-evolving complex (OEC), even though they have undergone drastic change during the evolution of oxyphototrophs from symbiotic cyanobacteria to chloroplasts. Two specific extrinsic proteins, PsbP and PsbQ, bind to the lumenal surface of PSII in green plants and maintain OEC conformation and stabilize overall enzymatic function; however, their precise location has not been fully resolved. In this study, PSII-enriched membranes, isolated from spinach, were subjected to chemical cross-linking combined with release-reconstitution experiments. We observed direct interactions between PsbP and PsbE, as well as with PsbR. Intriguingly, PsbP and PsbQ were further linked to the CP26 and CP43 light-harvesting proteins. In addition, two cross-linked sites, between PsbP and PsbR, and that of PsbP and CP26, were identified by tandem mass spectrometry. These data were used to estimate the binding topology and location of PsbP, and the putative positioning of PsbQ and PsbR on the lumenal surface of the PSII. Our model gives new insights into the organization of PSII extrinsic subunits in higher plants and their function in stabilizing the OEC of the PSII supercomplex.