Distribution and expression of GnRH 1, kiss receptor 2, and estradiol α and ß receptors in the anterior brain of females of Chirostoma humboldtianum.

Reproduction in vertebrates is a complex process regulated by many hormones, and by paracrine factors and their receptors. This study aimed to examine the expression of pjGonadotropin-releasing hormone (GnRH 1), the kisspeptin receptor 2 (kissr2), and estradiol receptors α and ß (ER α and ER ß) during different stages of the sexual cycle and their distribution within the anterior brain of females of Chirostoma humboldtianum. Among these molecules, the kissr2 showed the maximal variation in expression, while GnRH 1 showed minimal variation of expression, and ERß and ERα had intermediate variation of expression. The distribution of these molecules in the anterior brain was consistent with their levels of expression; kissr2 was widely distributed throughout the telencephalon and diencephalon, while ER and GnRH 1 showed more restricted distributions. No coexpression of kissr2 and ER in GnRH 1ergic neurons, suggesting that regulation of this GnRH variant is indirectly mediated by kisspeptin and estradiol.

Novel Inhaled Pan-JAK Inhibitor, LAS194046, Reduces Allergen-Induced Airway Inflammation, Late Asthmatic Response, and pSTAT Activation in Brown Norway Rats.

The Janus-activated kinase (JAK) family together with signal transducer and activator of transcription (STAT) signaling pathway has a key role in regulating the expression and function of many inflammatory cytokines. This has led to the discovery of JAK inhibitors for the treatment of inflammatory diseases, some of them already in the market. Considering the adverse effects associated with JAK inhibition by oral route, we wanted to explore whether JAK inhibition by inhaled route is enough to inhibit airway inflammation. The aim of this study was to characterize the enzymatic and cellular potency and the selectivity of LAS194046, a novel JAK inhibitor, compared with the reference compounds ruxolitinib and tofacitinib. The efficacy of this new JAK inhibitor is described in a model of ovalbumin (OVA)-induced airway inflammation in Brown Norway rats by inhaled administration. As potential markers of target engagement, we assessed the effect of LAS194046 on the STAT activation state. LAS194046 is a selective inhaled pan-JAK inhibitor that reduces allergen-induced airway inflammation, late asthmatic response, and phosphor-STAT activation in the rat OVA model. Our results show that topical inhibition of JAK in the lung, without relevant systemic exposure, is sufficient to reduce lung inflammation and improve lung function in a rat asthma model. In summary, JAK-STAT pathway inhibition by inhaled route constitutes a promising therapeutic option for lung inflammatory diseases.

A novel inhaled Syk inhibitor blocks mast cell degranulation and early asthmatic response.

Spleen tyrosine kinase (Syk) is essential for signal transduction of immunoreceptors. Inhibition of Syk abrogates mast cell degranulation and B cell responses. We hypothesized that Syk inhibition in the lung by inhaled route could block airway mast cells degranulation and the early asthmatic response without the need of systemic exposure. We discovered LAS189386, a novel Syk inhibitor with suitable properties for inhaled administration. The aim of this study was to characterize the in vitro and in vivo profile of LAS189386. The compound was profiled in Syk enzymatic assay, against a panel of selected kinases and in Syk-dependent cellular assays in mast cells and B cells. Pharmacokinetics and in vivo efficacy was assessed by intratracheal route. Airway resistance and mast cell degranulation after OVA challenge was evaluated in an ovalbumin-sensitized Brown Norway rat model. LAS189386 potently inhibits Syk enzymatic activity (IC50 7.2 nM), Syk phosphorylation (IC50 41 nM), LAD2 cells degranulation (IC50 56 nM), and B cell activation (IC50 22 nM). LAS189386 inhibits early asthmatic response and airway mast cell degranulation without affecting systemic mast cells. The present results support the hypothesis that topical inhibition of Syk in the lung, without systemic exposure, is sufficient to inhibit EAR in rats. Syk inhibition by inhaled route constitutes a promising therapeutic option for asthma.

CBP gene transfer increases BDNF levels and ameliorates learning and memory deficits in a mouse model of Alzheimer's disease.

Cognitive dysfunction and memory loss are common features of Alzheimer's disease (AD). Abnormalities in the expression profile of immediate early genes that play a critical role in memory formation, such as the cAMP-response element binding protein (CREB), have been reported in the brains of AD patients. Here we show that amyloid-ß (Aß) accumulation, which plays a primary role in the cognitive deficits of AD, interferes with CREB activity. We further show that restoring CREB function via brain viral delivery of the CREB-binding protein (CBP) improves learning and memory deficits in an animal model of AD. Notably, such improvements occur without changes in Aß and tau pathology, and instead are linked to an increased level of brain-derived neurotrophic factor. The resulting data suggest that Aß-induced learning and memory deficits are mediated by alterations in CREB function, based on the finding that restoring CREB activity by directly modulating CBP levels in the brains of adult mice is sufficient to ameliorate learning and memory. Therefore, increasing CBP expression in adult brains may be a valid therapeutic approach not only for AD, but also for various brain disorders characterized by alterations in immediate early genes, further supporting the concept that viral vector delivery may be a viable therapeutic approach in neurodegenerative diseases.

Weight Gain After 12 Months of Switching to Bictegravir/Emtricitabine/Tenofovir Alafenamide in Virologically Suppressed HIV Patients.

Recent studies suggest that the introduction of antiretroviral agents such as integrase strand transfer inhibitors (INSTI) may lead to weight gain in people living with HIV (PLHIV). In this retrospective observational study, we report the weight changes observed in virologically suppressed HIV patients after 12 months of switching to bictegravir/emtricitabine/tenofovir alafenamide (BIC/F/TAF) due to a national change in public policy in Mexico. Patients on prior regimens based on TDF/FTC or ABC/3TC plus non-nucleoside retrotranscriptase inhibitor, INSTI, or protease inhibitor were included. In the 399 patients analyzed, a significant weight increase was found, as well as an increase in body mass index (BMI), total cholesterol, low-density lipoprotein cholesterol (LDL-C), glucose, creatinine, and CD4+ cells after 12 months of switching treatment (all p ≤ .001). Mean weight gain was 1.63 kg [confidence interval (95% CI): 1.14-2.11], whereas the average percentage of weight gained was 2.5% (95% CI: 1.83-3.17). After considering the confounding effect of baseline weight status, the change in weight and BMI did not present significant differences between any of the prior treatment schemes. In conclusion, PLHIV switching to BIC/F/TAF therapy experienced weight gain after the first year of switching treatment. Although this weight gain could be due to the switch in treatment regimen, it cannot be excluded that it was caused by other factors since no comparable control group could be used for comparison.

Naturally secreted amyloid-beta increases mammalian target of rapamycin (mTOR) activity via a PRAS40-mediated mechanism.

Reducing the mammalian target of rapamycin (mTOR) activity increases lifespan and health span in a variety of organisms. Alterations in protein homeostasis and mTOR activity and signaling have been reported in several neurodegenerative disorders, including Alzheimer disease (AD); however, the causes of such deregulations remain elusive. Here, we show that mTOR activity and signaling are increased in cell lines stably transfected with mutant amyloid precursor protein (APP) and in brains of 3xTg-AD mice, an animal model of AD. In addition, we show that in the 3xTg-AD mice, mTOR activity can be reduced to wild type levels by genetically preventing Aß accumulation. Similarly, intrahippocampal injections of an anti-Aß antibody reduced Aß levels and normalized mTOR activity, indicating that high Aß levels are necessary for mTOR hyperactivity in 3xTg-AD mice. We also show that the intrahippocampal injection of naturally secreted Aß is sufficient to increase mTOR signaling in the brains of wild type mice. The mechanism behind the Aß-induced mTOR hyperactivity is mediated by the proline-rich Akt substrate 40 (PRAS40) as we show that the activation of PRAS40 plays a key role in the Aß-induced mTOR hyperactivity. Taken together, our data show that Aß accumulation, which has been suggested to be the culprit of AD pathogenesis, causes mTOR hyperactivity by regulating PRAS40 phosphorylation. These data further indicate that the mTOR pathway is one of the pathways by which Aß exerts its toxicity and further support the idea that reducing mTOR signaling in AD may be a valid therapeutic approach.

Pyrazine-based Syk kinase inhibitors.

A series of aminopyrazines as inhibitors of Syk kinase activity and showing inhibition of LAD2 cells degranulation is described. Optimization of the carboxamide motif with aminomethylpiperidines provided high potency inhibiting Syk but low cellular activity. Amides of cis and trans adamantanol showed good inhibitory activity against Syk as well as remarkable activity in LAD2 cells degranulation assay.

Highly potent aminopyridines as Syk kinase inhibitors.

A novel class of potent Syk inhibitors has been developed from rational design. Highly potent aminopyridine derivatives bearing a 4-trifluoromethyl-2-pyridyl motif and represented by compound 13b IC(50): 0.6 nM were identified. Substitution by a 2-pyrazinyl motif and SAR expansion in position 4 of the central core provided diverse potent non-cytotoxic Syk inhibitors showing nanomolar activity inhibiting human mast cell line LAD2 degranulation.

Medical education and mental health during COVID-19: a survey across 9 countries.

OBJECTIVES: To investigate students' experience with medical education alongside their mental and physical health since the onset of the COVID-19 pandemic across nine countries. METHODS: A cross-sectional online survey was distributed by local collaborators to 2,280 medical students across 148 medical schools in Brazil, Chile, Colombia, Germany, Italy, Japan, Mexico, Spain, and Venezuela using non-probability convenience sampling from June 22 to July 24, 2020. Students answered questions regarding teaching, internet use, COVID-19, physical and mental well-being. A multivariate logistic regression examined factors associated with depressed mood, insomnia, and headache. RESULTS: Academic teaching shifted to a virtual (67%, n=1,534) or hybrid environment (23%, n=531), whilst bedside teaching was suspended or cancelled (93%, n=2,120). Across all countries students were equally satisfied with the teaching modality, quantity, quality, and the evaluation system of in-person, hybrid, and online curricula. Negative changes in mental (40% (n=912) insomnia, 57% (n=1,300) emotional irritability, 47% (n=1,072) emotional instability, 41% (n=935) anhedonia, 40% (n=912) depressed mood) and physical (36% (n=821) headache, 57% (n=1,299) ocular tiredness, 49% (n=1,117) backache) health symptoms were frequently observed. Positive associations between the number of daily screen hours and depressed mood (adjusted odds ratio (AOR)=1.09, 95%CI: 1.05-1.12, p<.001), insomnia (AOR=1.08, 95%CI: 1.05-1.11, p<.001), and headache (AOR=1.11, 95%CI: 1.07-1.14, p<.001) were identified. CONCLUSIONS: Students' experience with digital and hybrid medical curricula was diverse during the pandemic. Education modality, quantity, and quality were positively evaluated. However, students' mental and physical health worsened. Besides bedside teaching, faculties ought to digitalize and strengthen social communities and extend support services for students.

[Blood supply during disasters: the experience of Chile in 2010]. / Abastecimiento de sangre durante desastres: la experiencia de Chile en 2010.

A review of the management of blood supply and its administration during disasters was conducted based on the experience of several events that occurred primarily from 2000-2010, particularly the earthquake that measured 8.8 on the Richter scale that struck central and southern Chile on 27 February 2010. The objective was to provide information that could be useful in improving response plans and strategies during potential future disasters. The descriptive information on response procedures was obtained from interviews, internal reports, and the computer database from the Maule regional blood production center. The results lead to the conclusion that to respond efficiently and effectively to the need for blood in the immediate wake of a disaster it is essential to have both a centralized management system that facilitates the supply and administration of blood and volunteers with competence in health that are willing to swiftly arrive during these events. A change in the profile of blood donors during such emergencies was also observed. In Chile, for example, during the two weeks after the earthquake, the ratio of male/female donors was reversed. There was 61.1% participation by women, whereas in the week before the event women accounted for only 37%.

Lifestyle Changes Among Medical Students During COVID-19 Pandemic: A Multicenter Study Across Nine Countries.

The global pandemic caused by coronavirus disease-2019 (COVID-19) disrupted both public and private life for many. Concerning medical students, practical teaching and classrooms were substituted with a virtual curriculum. However, how this new academic environment has affected students' health and lifestyles has yet to be studied. In this study, we surveyed 2,776 students from nine different countries about changes in their university curricula and potential alterations in their daily habits, physical health, and psychological status. We found negative changes across all countries studied, in multiple categories. We found that 99% of respondents indicated changes in their instruction delivery system, with 90% stating a transition to online education, and 93% stating a reduction or suspension of their practical activities. On average, students spent 8.7 hours a day in front of a screen, with significant differences among countries. Students reported worsened studying, sleeping, and eating habits with substantial differences in Latin American countries. Finally, the participants frequently expressed onset and increase in both mental and physical health symptoms: backache, asthenopia, irritability, and emotional instability. Altogether, these results suggest a potential risk in the health and academic performance of future doctors if these new academic modalities are maintained.

Low-dose Thymoglobulin vs Basiliximab Induction Therapy in Low-Risk Living Related Kidney Transplant Recipients: A Prospective Randomized Trial.

CONTEXT: Thymoglobulin is used effectively as induction agent in kidney transplantation but the optimal dose is not well established. OBJECTIVE: Demonstrate that low-dose thymoglobulin (3 mg/kg) has similar efficacy and safety compared to basiliximab induction in low-risk kidney transplantation under standard maintenance immunosuppression DESIGN, SETTING, PARTICIPANTS: Prospective randomized study in kidney transplant patients (12/2016-05/2018). INCLUSION CRITERIA: Recipients > 18 years, first living donor transplant. EXCLUSION CRITERIA: Second and multiorgan transplant, ABO incompatibility, positive cross-match, panel reactive antibodies (PRA) > 30%, positive donor-specific antibody, human immunodeficiency virus, hepatitis B surface antigen, hepatitis C virus positive, white blood cells < 2000 cells/mm3, platelets < 75,000 cells/mm3 and malignancy. INTERVENTION: Group A: basiliximab (20 mg D0 and D4). Group B: thymoglobulin (3 mg/kg total). Maintenance immunosuppression: tacrolimus, mycophenolate mofetil, and steroids. MAIN OUTCOME MEASURES: Biopsy-proven acute rejection (BPAR), delayed graft function, slow graft function, leukopenia, infections, adverse events, graft loss, estimated glomerular filtration rate, and death within 12 months. RESULTS: 100 patients (basiliximab, n = 53) (thymoglobulin, n = 47) were included. Donor and recipient characteristics were similar except for longer dialysis (basiliximab), PRA class I (1.2% basiliximab, 4.5% thymoglobulin), HLA match (basiliximab 2.8, thymoglobulin 2.2), and cytomegalovirus status. BPAR rate was basiliximab 3.8% and thymoglobulin 6.4% (P = ns). Delayed graft function (basiliximab 3.8%; thymoglobulin 4.3%), slow graft function, and 12-month leukopenia (basiliximab 11.3%, thymoglobulin 21.3%) were similar between groups (P = ns). There was no difference in infections and adverse events between groups. Patient and graft survival were as follows: basiliximab 98.1% and 92.5%, thymoglobulin 100% and 93.6% (P = ns). CONCLUSION: Low-dose thymoglobulin induction (3 mg/kg) can be used effectively and safely in low-risk kidney transplantation with good results during the first year post-transplant.

Remodeling the brain with behavioral experience after stroke.

BACKGROUND AND PURPOSE: Behavioral experience can drive brain plasticity, but we lack sufficient knowledge to optimize its therapeutic use after stroke. METHODS: We outline recent findings from rodent models of cortical stroke of how experiences interact with postinjury events to influence synaptic connectivity and functional outcome. We focus on upper extremity function. RESULTS: After unilateral cortical infarcts, behavioral experiences shape neuronal structure and activity in both hemispheres. Experiences that matter include interventions such as skill training and constraint-like therapy as well as unguided behaviors such as learned nonuse and behavioral compensation. Lateralized behaviors have bihemispheric influences. Ischemic injury can alter the sensitivity of remaining neocortical neurons to behavioral change and this can have positive and negative functional effects. CONCLUSIONS: Because experience is ongoing in stroke survivors, a better understanding of its interaction with brain reorganization is needed so that it can be manipulated to improve function and prevent its worsening.

Identification of 2-Imidazopyridine and 2-Aminopyridone Purinones as Potent Pan-Janus Kinase (JAK) Inhibitors for the Inhaled Treatment of Respiratory Diseases.

Janus kinases (JAKs) have a key role in regulating the expression and function of relevant inflammatory cytokines involved in asthma and chronic obstructive pulmonary disease. Herein are described the design, synthesis, and pharmacological evaluation of a series of novel purinone JAK inhibitors with profiles suitable for inhaled administration. Replacement of the imidazopyridine hinge binding motif present in the initial compounds of this series with a pyridone ring resulted in the mitigation of cell cytotoxicity. Further systematic structure-activity relationship (SAR) efforts driven by structural biology studies led to the discovery of pyridone 34, a potent pan-JAK inhibitor with good selectivity, long lung retention time, low oral bioavailability, and proven efficacy in the lipopolysaccharide-induced rat model of airway inflammation by the inhaled route.

Pathogen Risk Analysis for Wild Amphibian Populations Following the First Report of a Ranavirus Outbreak in Farmed American Bullfrogs (Lithobates catesbeianus) from Northern Mexico.

Ranaviruses are the second deadliest pathogens for amphibian populations throughout the world. Despite their wide distribution in America, these viruses have never been reported in Mexico, the country with the fifth highest amphibian diversity in the world. This paper is the first to address an outbreak of ranavirus in captive American bullfrogs (Lithobates catesbeianus) from Sinaloa, Mexico. The farm experienced high mortality in an undetermined number of juveniles and sub-adult bullfrogs. Affected animals displayed clinical signs and gross lesions such as lethargy, edema, skin ulcers, and hemorrhages consistent with ranavirus infection. The main microscopic lesions included mild renal tubular necrosis and moderate congestion in several organs. Immunohistochemical analyses revealed scant infected hepatocytes and renal tubular epithelial cells. Phylogenetic analysis of five partial ranavirus genes showed that the causative agent clustered within the Frog virus 3 clade. Risk assessment with the Pandora⁺ protocol demonstrated a high risk for the pathogen to affect amphibians from neighboring regions (overall Pandora risk score: 0.619). Given the risk of American bullfrogs escaping and spreading the disease to wild amphibians, efforts should focus on implementing effective containment strategies and surveillance programs for ranavirus at facilities undertaking intensive farming of amphibians.

Motor skill training, but not voluntary exercise, improves skilled reaching after unilateral ischemic lesions of the sensorimotor cortex in rats.

BACKGROUND AND PURPOSE: Exercise and rehabilitative training each have been implicated in the promotion of restorative neural plasticity after cerebral injury. Because motor skill training induces synaptic plasticity and exercise increases plasticity-related proteins, we asked if exercise could improve the efficacy of training on a skilled motor task after focal cortical lesions. METHODS: Female young and middle-aged rats were trained on the single-pellet retrieval task and received unilateral ischemic sensorimotor cortex lesions contralateral to the trained limb. Rats then received both, either, or neither voluntary running and/or rehabilitative training for 5 weeks beginning 5 days postlesion. Motor skill training consisted of daily practice of the impaired forelimb in a tray-reaching task. Exercised rats had free access to running wheels for 6 h/day. Reaching function was periodically probed using the single-pellet retrieval task. RESULTS: In young adults, motor skill training significantly enhanced skilled reaching recovery compared to controls. However, exercise did not significantly enhance performance when administered alone or in combination with skill training. There was also no major benefit of exercise in older rats. Additionally, there were no effects of exercise in a measure of coordinated forelimb placement (the foot-fault test) or in immunocytochemical measures of several plasticity-related proteins in the motor cortex. CONCLUSIONS: In young and middle-aged animals, exercise did not improve motor skill training efficacy following ischemic lesions. Practicing motor skills more effectively improved recovery of these skills than did exercise. It remains possible that an alternative manner of administering exercise would be more effective.

The vermicelli handling test: a simple quantitative measure of dexterous forepaw function in rats.

Loss of function in the hands occurs with many brain disorders, but there are few measures of skillful forepaw use in rats available to model these impairments that are both sensitive and simple to administer. Whishaw and Coles previously described the dexterous manner in which rats manipulate food items with their paws, including thin pieces of pasta [Whishaw IQ, Coles BL. Varieties of paw and digit movement during spontaneous food handling in rats: postures, bimanual coordination, preferences, and the effect of forelimb cortex lesions. Behav Brain Res 1996;77:135-48]. We set out to develop a measure of this food handling behavior that would be quantitative, easy to administer, sensitive to the effects of damage to sensory and motor systems of the CNS and useful for identifying the side of lateralized impairments. When rats handle 7 cm lengths of vermicelli, they manipulate the pasta by repeatedly adjusting the forepaw hold on the pasta piece. As operationally defined, these adjustments can be easily identified and counted by an experimenter without specialized equipment. After unilateral sensorimotor cortex (SMC) lesions, transient middle cerebral artery occlusion (MCAO) and striatal dopamine depleting (6-hydroxydopamine, 6-OHDA) lesions in adult rats, there were enduring reductions in adjustments made with the contralateral forepaw. Additional pasta handling characteristics distinguished between the lesion types. MCAO and 6-OHDA lesions increased the frequency of several identified atypical handling patterns. Severe dopamine depletion increased eating time and adjustments made with the ipsilateral forepaw. However, contralateral forepaw adjustment number most sensitively detected enduring impairments across lesion types. Because of its ease of administration and sensitivity to lateralized impairments in skilled forepaw use, this measure may be useful in rat models of upper extremity impairment.

Discovery of a Novel Inhaled PI3Kδ Inhibitor for the Treatment of Respiratory Diseases.

Oral PI3Kδ inhibitors such as Idelalisib and Duvelisib have shown efficacy as anticancer agents and Idelalisib has been approved for the treatment of three B-cell cancers. However, Idelalisib has a black box warning on its product label regarding the risks of fatal and serious toxicities including hepatic toxicity, severe diarrhea, colitis, pneumonitis, infections, and intestinal perforation. Some of these side effects are mechanism-related and could hinder the development of Idelalisib for less severe conditions. For respiratory diseases, compounds administered by inhalation are delivered directly to the site of action and may improve the therapeutic index of a drug, minimizing undesired side effects. This work describes the discovery and optimization of inhaled PI3Kδ inhibitors intended for the treatment of severe asthma and COPD. Once the potency was in the desired range, efforts were focused on identifying the particular physicochemical properties that could translate into better lung retention. This medicinal chemistry exercise led to the identification of LAS195319 as a candidate for clinical development.

Ranavirus genotypes in the Netherlands and their potential association with virulence in water frogs (Pelophylax spp.).

Ranaviruses are pathogenic viruses for poikilothermic vertebrates worldwide. The identification of a common midwife toad virus (CMTV) associated with massive die-offs in water frogs (Pelophylax spp.) in the Netherlands has increased awareness for emerging viruses in amphibians in the country. Complete genome sequencing of 13 ranavirus isolates collected from ten different sites in the period 2011-2016 revealed three CMTV groups present in distinct geographical areas in the Netherlands. Phylogenetic analysis showed that emerging viruses from the northern part of the Netherlands belonged to CMTV-NL group I. Group II and III viruses were derived from the animals located in the center-east and south of the country, and shared a more recent common ancestor to CMTV-amphibian associated ranaviruses reported in China, Italy, Denmark, and Switzerland. Field monitoring revealed differences in water frog host abundance at sites where distinct ranavirus groups occur; with ranavirus-associated deaths, host counts decreasing progressively, and few juveniles found in the north where CMTV-NL group I occurs but not in the south with CMTV-NL group III. Investigation of tandem repeats of coding genes gave no conclusive information about phylo-geographical clustering, while genetic analysis of the genomes revealed truncations in 17 genes across CMTV-NL groups II and III compared to group I. Further studies are needed to elucidate the contribution of these genes as well as environmental variables to explain the observed differences in host abundance.

Tandem duplications of a degenerated GTP-binding domain at the origin of GTPase receptors Toc159 and thylakoidal SRP.

The evolutionary origin of some nuclear encoded proteins that translocate proteins across the chloroplast envelope remains unknown. Therefore, sequences of GTPase proteins constituting the Arabidopsis thaliana translocon at the outer membrane of chloroplast (atToc) complexes were analyzed by means of HCA. In particular, atToc159 and related proteins (atToc132, atToc120, and atToc90) do not have proven homologues of prokaryotic or eukaryotic ancestry. We established that the three domains commonly referred to as A, G, and M originate from the GTPase G domain, tandemly repeated, and probably evolving toward an unstructured conformation in the case of the A domain. It resulted from this study a putative common ancestor for these proteins and a new domain definition, in particular the splitting of A into three domains (A1, A2, and A3), has been proposed. The family of Toc159, previously containing A. thaliana and Pisum sativum, has been extended to Medicago truncatula and Populus trichocarpa and it has been revised for Oryza sativa. They have also been compared to GTPase subunits involved in the cpSRP system. A distant homology has been revealed among Toc and cpSRP GTP-hydrolyzing proteins of A. thaliana, and repetitions of a GTPase domain were also found in cpSRP protein receptors, by means of HCA analysis.