The role of GPCRs in bone diseases and dysfunctions

The superfamily of G protein-coupled receptors (GPCRs) contains immense structural and functional diversity and mediates a myriad of biological processes upon activation by various extracellular signals.Critical roles of GPCRs have been established in bone development,remodeling,and disease.Multiple human GPCR mutations impair bone development or metabolism,resulting in osteopathologies.Here we summarize the disease phenotypes and dysfunctions caused by GPCR gene mutations in humans as well as by deletion in animals.To date,92 receptors (5 glutamate family,67 rhodopsin family,5 adhesion,4 frizzled/taste2 family,5 secretin family,and 6 other 7TM receptors) have been associated with bone diseases and dysfunctions (36 in humans and 72 in animals).By analyzing data from these 92 GPCRs,we found that mutation or deletion of different individual GPCRs could induce similar bone diseases or dysfunctions,and the same individual GPCR mutation or deletion could induce different bone diseases or dysfunctions in different populations or animal models.Data from human diseases or dysfunctions identified 19 genes whose mutation was associated with human BMD:9 genes each for human height and osteoporosis;4 genes each for human osteoarthritis (OA) and fracture risk;and 2 genes each for adolescent idiopathic scoliosis (AIS),periodontitis,osteosarcoma growth,and tooth development.Reports from gene knockout animals found 40 GPCRs whose deficiency reduced bone mass,while deficiency of 22 GPCRs increased bone mass and BMD;deficiency of 8 GPCRs reduced body length,while 5 mice had reduced femur size upon GPCR deletion.Furthermore,deficiency in 6 GPCRs induced osteoporosis;4 induced osteoarthritis;3 delayed fracture healing;3 reduced arthritis severity;and reduced bone strength,increased bone strength,and increased cortical thickness were each observed in 2 GPCR-deficiency models.The ever-expanding number of GPCR mutation-associated diseases warrants accelerated molecular analysis,population studies,and investigation of phenotype correlation with SNPs to elucidate GPCR function in human diseases.

Loss of Aβ-nerve endings associated with the Merkel cell-neurite complex in the lesional oral mucosa epithelium of lichen planus and hyperkeratosis

The Merkel cell-neurite complex initiates the perception of touch and mediates Ap slowly adapting type I responses. Lichen planus is a chronic inflammatory autoimmune disease with T-cell-mediated inflammation, whereas hyperkeratosis is characterized with or without epithelial dysplasia in the oral mucosa. To determine the effects of lichen planus and hyperkeratosis on the Merkel cell-neurite complex, healthy oral mucosal epithelium and lesional oral mucosal epithelium of lichen planus and hyperkeratosis patients were stained by immunohistochemistry （the avidin-biotin-peroxidase complex and double immunofluorescence methods）using pan cytokeratin, cytokeratin 20 （K20, a Merkel cell marker）, and neurofilament 200 （NF200, a myelinated Aβ- and Aδ-nerve fibre marker） antibodies. N F200-immunoreactive （ir） nerve fibres in healthy tissues and in the lesional oral mucosa epithelium of lichen planus and hyperkeratosis were counted and statistically analysed. In the healthy oral mucosa, K20-positive Merkel cells with and without close association to the intraepithelial NF200-ir nerve fibres were detected. In the lesional oral mucosa of lichen planus and hyperkeratosis patients, extremely rare NF200-ir nerve fibres were detected only in the lamina propria. Compared with healthy tissues, lichen planus and hyperkeratosis tissues had significantly decreased numbers of NF200-ir nerve fibres in the oral mucosal epithelium. Lichen planus and hyperkeratosis were associated with the absence of Aβ-nerve endings in the oral mucosal epithelium. Thus, we conclude that mechanosensation mediated by the Merkel cell-neurite complex in the oral mucosal epithelium is impaired in lichen planus and hvperkeratosis.

Prospects for 3D bioprinting of organoids

Three-dimensional(3D)organoids derived from pluripotent or adult tissue stem cells seem to possess excellent potential for studying development and disease mechanisms alongside having a myriad of applications in regenerative therapies.However,lack of precise architectures and large-scale tissue sizes are some of the key limitations of current organoid technologies.3D bioprinting of organoids has recently emerged to address some of these impediments.In this review,we discuss 3D bioprinting with respect to the use of bioinks and bioprinting methods and highlight recent studies that have shown success in bioprinting of stem cells and organoids.We also summarize the use of several vascularization strategies for the bioprinted organoids,that are critical for a complex tissue organization.To fully realize the translational applications of organoids in disease modeling and regenerative medicine,these areas in 3D bioprinting need to be appropriately harnessed and channelized.

Promise of metformin for preventing age-related cognitive dysfunction

The expanded lifespan of people,while a positive advance,has also amplified the prevalence of age-related disorders,which include mild cognitive impairment,dementia,and Alzheimer's disease.Therefore,competent therapies that could improve the healthspan of people have great significance.Some of the dietary and pharmacological approaches that augment the lifespan could also preserve improved cognitive function in old age.Metformin,a drug widely used for treating diabetes,is one such candidate that could alleviate age-related cognitive dysfunction.However,the possible use of metformin to alleviate age-related cognitive dysfunction has met with conflicting results in human and animal studies.While most clinical studies have suggested the promise of metformin to maintain better cognitive function and reduce the risk for developing dementia and Alzheimer's disease in aged diabetic people,its efficacy in the nondiabetic population is still unclear.Moreover,a previous animal model study implied that metformin could adversely affect cognitive function in the aged.However,a recent animal study using multiple behavioral tests has reported that metformin treatment in late middle age improved cognitive function in old age.The study also revealed that cognitionenhancing effects of metformin in aged animals were associated with the activation of the energy regulator adenosine monophosphate-activated protein kinase,diminished neuroinflammation,inhibition of the mammalian target of rapamycin signaling,and augmented autophagy in the hippocampus.The proficiency of metformin to facilitate these favorable modifications in the aged hippocampus likely underlies its positive effect on cognitive function.Nonetheless,additional studies probing the outcomes of different doses and durations of metformin treatment at specific windows in the middle and old age across sex in nondiabetic and non-obese prototypes are required to substantiate the promise of metformin to maintain better cognitive function in old age.

A combination therapy for KRAS-mutant lung cancer by targeting synthetic lethal partners of mutant KRAS

The KRAS gene is frequently mutated in multiple cancer types,but it fell off the drug discovery radar for many years because of its inherent "undruggable" structure and undefined biological properties.As reported in the paper entitled "Suppression of KRas-mutant cancer through the combined inhibition of KRAS with PLK1 and ROCK" in Nature Communications,we performed a synthetic lethal screening with a combinatorial strategy on a panel of clinical drugs;we found that combined inhibition of polo-like kinase 1 and RhoA/Rho kinase markedly suppressed tumor growth in mice.An increase in the expression of the tumor suppressor P21^(WAF1/CIP1) contributed to the synergistic mechanism of the combination therapy.These findings open a novel avenue for the treatment of KRAS-mutant lung cancer.

Does endurance training improve red blood cell aging and hemorheology in moderate-trained healthy individuals?

Objective:To examine the impact of a 6-week endurance training on red blood cell(RBC)aging and deformability of healthy participants to detect possible improved hemorheological and performance-related adaptations.Methods:A total of 31 participants(17 females and 14 males)performed a 6-week moderate training protocol(three 1-h running sessions per week at 70%of maximal heart rate).Blood was sampled before and after the training.RBCs from each participant were fractioned according to density and age into 4 RBC subfractions.Subfractions were examined for changes of RBC properties,including aging distribution,RBC deformability,RBC microparticles,and phosphatidylserine concentrations.RBC and plasma nitrite levels were measured as indicators of nitric oxide metabolism.Results:Aerobic performance,peak oxygen consumption,ventilatory thresholds,velocity at the aerobic-anaerobic threshold,and lactate at exhaustion improved after training.The relative amount of both young RBCs and old RBCs increased,and the amount of the main RBC fraction decreased.Phosphatidylserine externalization and RBC-derived microparticles decreased.Overall deformability expressed as shear stress required to achieve half-maximum deformation to theoretical maximal elongation index at infinite shear stress improved in unfractioned RBCs(p<0.001).Nitrite decreased in total(p=0.001),young(p<0.001),main(p<0.001),and old(p=0.020)aged RBCs and in plasma(p=0.002),but not in very old RBCs.Conclusion:These results indicate that non-endurance-trained healthy participants benefit from a regular moderate running training program because performance-related parameters improve and a younger RBC population with improved RBC properties is induced,which might support oxygen supply in the microcirculation.

Prolonged existence of SARS-CoV-2 RNAs in the extracellular vesicles of respiratory specimens from patients with negative reverse transcription-polymerase chain reaction

Background and aim:Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)is primarily in the respiratory tract,particularly in patients with underlying comorbidities.This study aimed to investigate the presence of the virus inside the extracellular vesicles(EVs)in patients with and without chronic liver disease(CLD).Methods:Eighty patients with positive SARS-CoV-2,including twenty-four patients with CLD and fiftysix patients without CLD,and five healthy controls with negative SARS-CoV-2 were enrolled.Nasal swab specimens were tested for the detection of SARS-CoV-2 using reverse transcription-polymerase chain reaction(RT-PCR).Patients with coronavirus disease 2019(COVID-19)were followed up on days 7 and 14.Nasal swab,collected in viral transport media(VTM),and plasma samples were investigated at each time point.EVs were isolated from the nasal swabs(collected in VTM)and plasma using differential ultracentrifugation and estimated at each time point.The transmission or replication by the EVs was assessed in Vero E6 cells.Results:In patients with baseline RT-PCR positive,SARS-CoV-2 RNAs inside the EVs were found in 68/80(85%)patients with higher viral load in the nasal swabs than in the EVs(cycle threshold(Ct)value,23.4±5.7 vs.30.3±5.0,P<0.001).On follow-up at day 7,of the 32 patients negative for COVID-19,15(46.9%)had virus persistence in the EVs(Ct value,30.7±2.7),and on day 14,of the 56 patients with negative SARS-CoV-2,16 patients(28.6%)had positive SARS-CoV-2 RNAs in the EVs(Ct value,31.4±3.0).The mean viral load decreased on days 7 and 14 compared to baseline in the nasal swabs(P<0.001)but not in the EVs.Additionally,SARS-CoV-2 RNAs were undetectable in the plasma,but 12.5% of patients were positive in the plasma EVs.Significantly prolonged and high viral load was found in the EVs on day 14 in COVID-19 patients combined with CLD compared with COVID-19 patients(P?0.0004).We found significant higher levels of EV-associated with endothelial cells and hepatocytes in the COVID-19 t CLD group than COVID-19 group(P?0.032 and P?0.002,respectively),suggesting more endothelial cells and hepatocytes cellular injury in liver disease patients with COVID-19.Interestingly,we also found EVs could transmit SARS-CoV-2 RNAs into Vero E6 cells at 24 h post-infection.Conclusions:The identification of SARS-CoV-2 RNAs in the EVs in patients with negative RT-PCR indicates the persistence of infection and likely recurrence of the infection.It is suggestive of another route of transmission as EVs harbor SARS-CoV-2 RNAs.EV-associated RNAs may determine the ongoing inflammation and clinical course of subjects with undetectable SARS-CoV-2 virus and this may have relevance to better management of patients with CLD.

Ailanthone:a new potential drug for castration-resistant prostate cancer

Prostate cancer (PCa) is the most common male cancer [1, 2]. PCa initially depends on androgen receptor (AR) signaling for growth and survival. Androgen deprivation therapy causes a temporary reduction in PCa tumor burden, but the tumor eventually develops into castrationresistant prostate cancer (CRPC) with the ability to grow again in the absence of androgens [3]. Mechanisms of CRPC progression include AR amplification and overexpression [4], AR gene rearrangement promoting synthesis of constitutively-active truncated AR splice variants (ARVs) [4], and induction of intracrine androgen metabolic enzymes [3]. Current anti-androgen therapies including MDV3100 (Enzalutamide) and abiraterone have focused on the androgen-dependent activation of AR through its ligand-binding domain (LBD), but do not provide a continuing clinical benefit for patients with CRPC and presumably fail due to multiple mechanisms including the expression of AR-Vs lacking the LBD [5]. These AR-Vs signal in the absence of ligand and are therefore resistant to LBD-targeting AR antagonists or agents that repress androgen biosynthesis [6].

Dysregulation of CDK8 and Cyclin C in tumorigenesis

Appropriately controlled gene expression is fundamental for normal growth and survival of all living organisms. In eukaryotes, the tran- scription of protein-coding mRNAs is dependent on RNA polymerase II （Pol II）. The multi-subunit transcription cofactor Mediator complex is proposed to regulate most, if not all, of the Pol II-dependent transcription. Here we focus our discussion on two subunits of the Mediator complex, cyclin-dependent kinase 8 （CDK8） and its regulatory partner Cyclin C （CycC）, because they are either mutated or amplified in a variety of human cancers. CDK8 functions as an oncoprotein in melanoma and colorectal cancers, thus there are considerable interests in developing drugs specifically targeting the CDK8 kinase activity. However, to evaluate the feasibility of targeting CDK8 for cancer therapy and to understand how their dysregulation contributes to tumorigenesis, it is essential to elucidate the in vivo function and regulation of CDKS-CycC, which are still poorly understood in multi-cellular organisms. We summarize the evidence linking their dysregulation to various cancers and present our bioinformatics and computational analyses on the structure and evolution of CDK8. We also discuss the implications of these observations in tumorigenesis. Because most of the Mediator subunits, including CDK8 and CycC, are highly conserved during eukaryotic evolution, we expect that investigations using model organisms such as Drosophila will provide important insights into the function and regulation of CDK8 and CycC in different cellular and developmental contexts.

ULTRASHORT PULSE MULTISPECTRAL NON-LINEAR OPTICAL MICROSCOPY

Ultrashort pulse,multispectral non-linear optical microscopy(NLOM)is developed and used to image,simultaneously,a mixed population of cells expressing different fluorescent protein mutants in a 3D tissue model of angiogenesis.Broadband,sub-10-fs pulses are used to excite multiple fluorescent proteins and generate second harmonic in collagen.A 16-channel multispectral detector is used to delineate the multiple non-linear optical signals,pixel by pixel,in NLOM.The ability to image multiple fluorescent protein mutants and collagen,enables serial measurements of cell-cell and cell-matrix interactions in our 3D tissue model and characterization of fundamental processes in angiogenic morphogenesis.

Increasing targeting scope of adenosine base editors in mouse and rat embryos through fusion of TadA deaminase with Cas9 variants

Dear Editor, The clustered regularly interspaced short palindromic repeat （CRISPR） system has been widely adapted to genome editing to either introduce or correct genetic mutations （Wang et al., 2016）. However, due to competition with the dominant non-homologous end-joining （NHEJ） pathway, precise genome modifications through Cas9-stimulated homologous recombination （HR） is inefficient. Through fusion of cytidine deaminases, APOBEC1 （apolipoprotein B editing complex 1） or AID （activation-induced deaminase）, with Cas9 variants, several groups have developed the cytidine base editor （BE） systems （Komor et al., 2016; Li et al., 2018; Nishida et al., 2016）. The BE system achieves programmable conversion of C-G base pairs to T.A without double-stranded DNA cleavage （Zhou et al., 2017）. More recently, adenine base editors （ABEs）, which efficiently convert A-T base pairs to G-C in genomic DNA, have been developed via fusion of an engineered tRNA adenosine deaminase （ecTadA from Escherichia coh） with nCas9 （Gaudelli et al., 2017）. The ABE system has quickly been adapted to generate disease models and correction of genetic disease in mice （Ryu et al., 2017; Liu et al, 2018）. However, whether the editing efficiency and the targeting scope of ABE could be improved is largely unexplored. In this study, we describe the efficient generation of base-edi- ted mice and rats modeling human diseases through ABEs with highest efficiency up to 100%. We also demonstrate an increase of ABE activity through injection of chemically modified tracrRNA and crRNA in mouse zygotes, and the expansion of editing scope by fusion of an ecTadA mutant to SaCas9n-KKH and Casgn-VQR variants in both cells and embryos. Our study suggests that the ABE system is a powerful and convenient tool to introduce precise base conversions in rodents.

评价四氢喋呤(BH_4)作为勃起功能障碍治疗药物的可能性(英文)

Aim： Nitric oxide （NO）-mediated smooth muscle relaxation causes penile erections. The endothelial NO synthase （eNOS） coenzyme tetrahydrobiopterin （BH4） converts eNOS-mediated catalytic activity from oxygen radical to NO production, improving endothelial function and vascular smooth muscle relaxation. Methods： Using quantitative immunohistochemistry, 8-isoprostane and nitrotyrosine concentrations were compared in cavernosal tissue from 17 potent and 7 impotent men, and the effect of single oral doses of BH4 on penile rigidity and tumescence was investigated. The pharmacodynamic effect of single oral doses of BH4 on penile rigidity and tumescence was investigated in a randomized, placebo-controlled, double-blind cross-over fashion in 18 patients with erectile dysfunction （ED） while receiving visual sexual stimulation. Results： 8-isoprostane content in endothelium and smooth muscle was signifi- cantly higher in impotent patient samples; the level of nitrotyrosine was unchanged in ED patients. Relative to placebo, a single dose of 200 mg BH4 led to a mean increase in duration of 〉 60% penile rigidity （33.5 rain [95% confidence interval （CI）： 13.1-49.3] at base and 29.4 rain [95% CI： 8.9-42,2] at tip）. A 500-mg dose increased the relative duration of 〉 60% penile rigidity by 36. I rain （95% CI： 16.3-51.8） at the base and 33.7 rain （95% CI： 11.4-43.9） at the tip. Treatments were well tolerated. Conclusion： BH4 treatment is suggested to switch eNOS catalytic activity from super-oxide to NO formation, leading to a reduced formation of free radical reaction product 8-isoprostane without alteration of nitrotyrosine. The observed results make BH4 a suitable candidate as an ED treatment through reconstitution of altered catalytic activity of the eNOS. （Asian JAndro12006 Mar; 8： 159-167）

FTY720,a sphingosine analog,altered placentome histoarchitecture in ewes

Background:The lysosphingolipid,sphingosine-1-phosphate,is a well-described and potent pro-angiogenic factor.Receptors,as well as the sphingosine phosphorylating enzyme sphingosine kinase 1,are expressed in the placentomes of sheep and the decidua of rodents;however,a function for this signaling pathway during pregnancy has not been established.The objective of this study was to investigate whether sphingosine-1-phosphate promoted angiogenesis within the placentomes of pregnant ewes.Ewes were given daily jugular injections of FTY720(2-amino-2[2-(−4-octylphenyl)ethyl]propate-1,3-diol hydrochloride),an S1P analog.Results:FTY720 infusion from days 30 to 60 of pregnancy did not alter maternal organ weights nor total number or mass of placentomes,but did alter placentome histoarchitecture.Interdigitation of caruncular crypts and cotyledonary villi was decreased,as was the relative area of cotyledonary tissue within placentomes.Also,the percentage of area occupied by cotyledonary villi per unit of placentome was increased,while the thickness of the caruncular capsule was decreased in ewes treated with FTY720.Further,FTY720 infusion decreased the number and density of blood vessels within caruncular tissue near the placentome capsule where the crypts emerge from the capsule.Finally,FTY720 infusion decreased asparagine and glutamine in amniotic fluid and methionine in allantoic fluid,and decreased the crown rump length of day 60 fetuses.Conclusions:While members of the sphingosine-1-phosphate signaling pathway have been characterized within the uteri and placentae of sheep and mice,the present study uses FTY720 to address the influence of S1P signaling on placental development.We present evidence that modulation of the S1P signaling pathway results in the alteration of caruncular vasculature,placentome architecture,abundance of amino acids in allantoic and amniotic fluids,and fetal growth during pregnancy in sheep.The marked morphological changes in placentome histoarchitecture,including alteration in the vasculature,may be relevant to fetal growth and survival.It is somewhat surprising that fetal length was reduced as early as day 60,because fetal growth in sheep is greatest after day 60.The subtle changes observed in the fetuses of ewes exposed to FTY720 may indicate an adaptive response of the fetuses to cope with altered placental morphology.

Unveiling the effect of estrogen receptors in alcoholic liver disease:A novel outlook

Alcoholic liver disease(ALD)has a multifaceted development,progressing from alcoholic steatosis to alcoholic hepatitis and ultimately to alcoholic cirrhosis,irreversible liver damage that can even result in hepatocellular carcinoma.The prevalence of ALD is increasing globally,particularly among middle-aged adults.Gender-based studies have revealed that ALD affects more men;however,disease progression differs between men and women.Despite this,the molecular understanding of alcohol-induced liver injury among genders and its association with changes in sex hormone metabolism,particularly with estrogen and estrogen receptors(ERs)in ALD,remains poor.This review focuses on experimental and human studies describing alcohol and its association with estrogen metabolism and signaling via ERs.Chronic alcohol consumption affects the immune response,and whether estrogen has any contributory effect remains inadequately studied.This review also discusses various therapeutic approaches currently in use and future approaches that can affect the response or progression via estrogen signaling.The role of gender on alcohol consumption and its association with steroid hormones must be elucidated for a better understanding of the pathogenesis of ALD,the development of effective therapeutic approaches,and better disease management in both men and women,as ALD remains a major public health concern.

Exercise precision medicine for type 2 diabetes:Targeted benefit or risk?

Concurrent exercise and metformin administration may reduce the acute and chronic effects of exercise on glucose metabolism in the patients with type 2 diabetes(T2D).However,several studies suggest that combing metformin and exercise treatment may have neither additive effect nor even cause adverse effects in T2D patients.This case report aimed to highlight the challenges associated with prescribing exercise to type 2 diabetes patients undergoing metformin treatment.A 67-years old woman was followed-up for five months,including assessment of the acute and chronic glucose and lactate metabolism induced by concomitant exercise and metformin.The findings were four-fold:1)During a high-intensity interval training bout,blood glucose systematically decreased,while blood lactate concentrations fluctuated randomly;2)Basal blood lactate levels were well above 2 mmol/L on days with medication only;3)Combined exercise and metformin administration induced additive effects on the normalization of glucose and 4)high levels of physical activity had a positive impact on the continuous glucose fluctuations,while decreased levels of physical activity induced a large fluctuation of glucose due to home confinement of an infectious disease caused by the SARS-CoV-2 virus.Our findings showed that when combined with exercise and metformin treatment for T2D patients,exercise may contribute to improving glycemic control while metformin may elevate lactate levels in the long term.The observed results underline the need to prescribe exercise and monitor lactate levels for reducing possible risks associated with metformin treatment and reinforce the importance of tailoring exercise therapy.

Generation of obese rat model by transcription activator-like effector nucleases targeting the leptin receptor gene

The laboratory rat is a valuable mammalian model organism for basic research and drug discovery. Here we demonstrate an efficient methodology by applying transcription activator-like effector nucleases(TALENs) technology to generate Leptin receptor(Lepr) knockout rats on the Sprague Dawley(SD) genetic background. Through direct injection of in vitro transcribed m RNA of TALEN pairs into SD rat zygotes, somatic mutations were induced in two of three resulting pups. One of the founders carrying bi-allelic mutation exhibited early onset of obesity and infertility. The other founder carried a chimeric mutation which was efficiently transmitted to the progenies. Through phenotyping of the resulting three lines of rats bearing distinct mutations in the Lepr locus, we found that the strains with a frame-shifted or premature stop codon mutation led to obesity and metabolic disorders. However, no obvious defect was observed in a strain with an in-frame 57 bp deletion in the extracellular domain of Lepr. This suggests the deleted amino acids do not significantly affect Lepr structure and function. This is the first report of generating the Lepr mutant obese rat model in SD strain through a reverse genetic approach. This suggests that TALEN is an efficient and powerful gene editing technology for the generation of disease models.

On the Impact of Precursor Unfolding during Protein Import into Chloroplasts

Protein translocation across membranes is a fundamental cellular process. The majority of the proteins of organelles such as mitochondria and chloroplasts is synthesized in the cytosol and subsequently imported in a posttranslational manner. The precursor proteins have to be unfolded at least for translocation, but it has also been assumed that they are unfolded during transport to the organelle in the cytosol. Unfolding is governed by chaperones and the translocon itself. At the same time, chaperones provide the energy for the import process. The energetic properties of the chloroplast translocon were studied by import of the Ig-like module of the muscle protein titin fused to the transit peptide of the chloroplast targeted oxygen evolving complex subunit of 33 kDa （OE33）. Our results suggest that p（OE33）titin is folded prior to import and that translocation is initiated by unfolding after having bound to the translocon at the chloroplast surface. Using a set of stabilizing and destabilizing mutants of titin previously analyzed by atomic force microscopy and as passenger for mitochondrial translocation, we studied the unfolding force provided by the chloroplast translocon. Based on these results, a model for translocation is discussed.

GPR54 deficiency reduces the Treg population and aggravates experimental autoimmune encephalomyelitis in mice

GPR54 is highly expressed in the central nervous system and plays a crucial role in pubertal development. However, GRP54 is also expressed in the immune system, implying possible immunoregulatory functions. Here we investigated the role of GPR54 in T cell and immune tolerance. GPR54 deficiency led to an enlarged thymus, an increased number of thymocytes, and altered thymic micro-architecture starting around puberty, indicating GPR54 function in T-cell development through its regulatory effect on the gonadal system. However, flow cytometry revealed a significant reduction in the peripheral regulatory T cell population and a moderate decrease in CD4 single-positive thymocytes in prepubertal Gpr54^(-/-) mice. These phenotypes were confirmed in chimeric mice with GPR54 deficient bone marrow-derived cells. In addition, we found elevated T cell activation in peripheral and thymic T cells in Gpr54^(-/-) mice. When intact mice were immunized with myelin oligodendrocyte glycoprotein, a more severe experimental autoimmune encephalomyelitis(EAE) developed in the Gpr54^(-/-) mice. Interestingly, aggravated EAE disease was also manifested in castrated and bone marrow chimeric Gpr54^(-/-) mice compared to the respective wild-type control,suggesting a defect in self-tolerance resulting from GPR54 deletion through a mechanism that bypassed sex hormones. These findings demonstrate a novel role for GPR54 in regulating self-tolerant immunity in a sex hormone independent manner.

Understanding human diseases using Drosophila

One of the major goals of biomedical research is to elucidate the causal relationships of critical factors involved in the initiation and progression of human diseases at the molecular and cellular levels. This knowledge is required for developing effective treatments for major diseases including cancer, cardiovascular and metabolic diseases, as well as neurodegenerative diseases and neurological disorders. Because of their phylogenetic representations and relative ease of experimental manipulation, model organisms such as the budding yeast (Saccharomyces cerevisiae), the nematode worm (Caenorhabditis elegans), the fruit fly (Drosophila melanogaster'), the thale cress (Arabidopsis thaliana), the zebrafish (Danio rerio'), the frog (Xenopus laevis), and the mouse (Mus musculus}, have been extensively studied over the past century (Hedges, 2002;Muller and Grossniklaus, 2010;Dietrich et al., 2014).

Advanced Exercise Prescription for Cancer Patients and its Application in Germany

The scientific interest of exercise medicine for the treatment of cancer is ever expanding.Recently published and updated guidelines for exercise training in cancer patients by the American College of Sports Medicine(ACSM),the Clinical Oncol-ogy Society of Australia(COSA)or the Exercise and Sports Science Australia(ESSA)are leading the way towards an indi-vidualized approach for exercise prescription.These guidelines provide physicians and therapists with a comprehensive and detailed overview about the beneficial effects of exercise training and,more so,summarize the evidence on potential dose-response mechanisms,including pathways of exercise-induced stimuli to counteract tumour microenvironmental pathologies.However,the most optimal types and doses of exercise training across the cancer disease and treatment continuum are yet to be determined.Therefore,the purpose of this narrative review was to illustrate the current implications but also limitations of exercise training during the different stages of cancer therapy,as well as to discuss necessary future directions.As a second purpose,special attention will be given to the current role of exercise in the treatment of cancer in Germany.