The pleiotropic effects of tissue plasminogen activator in the brain:implications for stroke recovery

Tissue plasminogen activator （tPA） use in the treatment of isch- emic stroke： tPA is a serine protease that catalyzes the breakdown of blood dots. Because of its thrombolytic properties, tPA is used to treat specific types of stroke, including ischemia, but is contra- indicated for treatment of hemorrhagic stroke or head trauma. Although a life saving and powerful ＇dot buster＇, tPA has a short therapeutic window. When administered outside of this prescribed timeframe, research suggests that tPA can produce neurotoxic ef- fects in the brain, due in part to activation of several signalling pro- cesses associated with cell apoptosis, degradation of the extracel- lular matrix, and increase in the permeability of the neurovascular unit （Yepes et al., 2009）. Concerted research has been dedicated to- ward understanding the mechanisms mediating the impact of tPA on the brain, using both in vivo and in vitro animal models.

Validation and Characterization of Ghd7.1, a Major Quantitative Trait Locus with Pleiotropic Effects on Spikelets per Panicle, Plant Height, and Heading Date in Rice (Oryza sativa L.)

A quantitative trait locus （QTL） that affects heading date （HD） and the number of spikelets per panicle （SPP） was previously identified in a small region on chromosome 7 in rice （Oryza sativa L.）. In order to further characterize the QTL region, near isogenic lines （NILs） were quickly obtained by self-crossing recombinant inbred line 189, which is heterozygous in the vicinity of the target region. The pleiotropic effects of QTL Ghd7.1 on plant height （PH）, SPP, and HD, were validated using an NIL-F2 population. Ghd7.1 explained 50.2%, 45.3%, and 76.9% of phenotypic variation in PH, SPP, and HD, respectively. Ghd7.1 was precisely mapped to a 357-kb region on the basis of analysis of the progeny of the NIL-F2 population. Day-length treatment confirmed that Ghd7.1 is sensitive to photoperiod, with long days delaying heading up to 12.5 d. Identification of panicle initiation and development for the pair of NILs showed that Ghd7.1 elongated the photoperiod-sensitive phase more than 10 d, but did not change the basic vegetative phase and the reproductive growth phase. These findings indicated that Ghd7.1 regulates SPP by controlling the rate of panicle differentiation rather than the duration of panicle development.

Sodium-glucose cotransporter 2 inhibitors’ mechanisms of action in heart failure

Three major cardiovascular outcome trials(CVOTs)with a new class of antidiabetic drugs-sodium-glucose cotransporter 2(SGLT2)inhibitors(EMPAREG OUTCOME trial with empagliflozin,CANVAS Program with canagliflozin,DECLARE-TIMI 58 with dapagliflozin)unexpectedly showed that cardiovascular outcomes could be improved possibly due to a reduction in heart failure risk,which seems to be the most sensitive outcome of SGLT2 inhibition.No other CVOT to date has shown any significant benefit on heart failure events.Even more impressive findings came recently from the DAPA-HF trial in patients with confirmed and well-treated heart failure:Dapagliflozin was shown to reduce heart failure risk for patients with heart failure with reduced ejection fraction regardless of diabetes status.Nevertheless,despite their possible wide clinical implications,there is much doubt about the mechanisms of action and a lot of questions to unravel,especially now when their benefits translated to nondiabetic patients,rising doubts about the validity of some current mechanistic assumptions.The time frame of their cardiovascular benefits excludes glucoselowering and antiatherosclerotic-mediated effects and multiple other mechanisms,direct cardiac as well as systemic,are suggested to explain their early cardiorenal benefits.These are:Anti-inflammatory,antifibrotic,antioxidative,antiapoptotic properties,then renoprotective and hemodynamic effects,attenuation of glucotoxicity,reduction of uric acid levels and epicardial adipose tissue,modification of neurohumoral system and cardiac fuel energetics,sodiumhydrogen exchange inhibition.The most logic explanation seems that SGLT2 inhibitors timely target various mechanisms underpinning heart failure pathogenesis.All the proposed mechanisms of their action could interfere with evolution of heart failure and are discussed separately within the main text.

A Capra hircus chromosome 19 locus linked to milk production influences mammary conformation

Background:Economically important milk production traits including milk volume,milk fat and protein yield vary considerably across dairy goats in New Zealand.A significant portion of the variation is attributable to genetic variation.Discovery of genetic markers linked to milk production traits can be utilised to drive selection of highperformance animals.A previously reported genome wide association study across dairy goats in New Zealand identified a quantitative trait locus(QTL)located on chromosome 19.The most significantly associated single nucleotide polymorphism(SNP)marker for this locus is located at position 26,610,610(SNP marker rs268292132).This locus is associated with multiple milk production traits including fat,protein and volume.The predicted effect of selection for the beneficial haplotype would result in an average production increase of 2.2 kg fat,1.9 kg protein and 73.6 kg milk yield.An outstanding question was whether selection for the beneficial allele would co-select for any negative pleiotropic effects.An adverse relationship between milk production and udder health traits has been reported at this locus.Therefore,a genome wide association study was undertaken looking for loci associated with udder traits.Results:The QTL and production associated marker rs268292132 was identified in this study to also be associated with several goat udder traits including udder depth(UD),fore udder attachment(FUA)and rear udder attachment(RUA).Our study replicates the negative relationship between production and udder traits with the high production allele at position 19:26,610,610(SNP marker rs268292132)associated with an adverse change in UD,FUA and RUA.Conclusions:Our study has confirmed the negative relationship between udder traits and production traits in the NZ goat population.We have found that the frequency of the high production allele is relatively high in the NZ goat population,indicating that its effect on udder conformation is not significantly detrimental on animal health.It will however be important to monitor udder conformation as the chromosome 19 locus is progressively implemented for marker assisted selection.It will also be of interest to determine if the gene underlying the production QTL has a direct effect on mammary gland morphology or whether the changes observed are a consequence of the increased milk volume.

Statins in risk-reduction and treatment of cancer

Statins,which are competitive inhibitors of 3-hydroxy-3-methyl-glutarylcoenzyme A reductase,reduce cholesterol blood levels and the risk of developing cardiovascular diseases and their related complications.In addition to this main activity,statins show pleiotropic effects such as antioxidant,anti-inflammatory and antiproliferative properties,with applications in many pathologies.Based on their antiproliferative properties,in vitro and in vivo studies have investigated their effects on various types of cancer(i.e.,breast cancer,prostate cancer,colorectal cancer,ovarian cancer,lung cancer)with different genetic and molecular characteristics.Many positive results were obtained,but they were highly dependent on the physiochemical properties of the statins,their dose and treatment period.Combined therapies of statins and cytotoxic drugs have also been tested,and synergistic or additive effects were observed.Moreover,observational studies performed on patients who used statins for different pathologies,revealed that statins reduced the risk of developing various cancers,and improved the outcomes for cancer patients.Currently,there are many ongoing clinical trials aimed at exploring the potential of statins to lower the mortality and the disease-recurrence risk.All these results are the foundation of new treatment directions in cancer therapy.

The domestication-associated L1 gene encodes a eucomic acid synthase pleiotropically modulating pod pigmentation and shattering in soybean

Pod coloration is a domestication-related trait in soybean,with modern cultivars typically displaying brown or tan pods,while their wild relative,Glycine soja,possesses black pods.However,the factors regulating this color variation remain unknown.In this study,we cloned and characterized L1,the classical locus responsible for black pods in soybean.By using map-based cloning and genetic analyses,we identified the causal gene of L1 and revealed that it encodes a hydroxymethylglutaryl-coenzyme A(CoA)lyase-like(HMGL-like)domain protein.Biochemical assays showed that L1 functions as a eucomic acid synthase and facilitates the synthesis of eucomic acid and piscidic acid,both of which contribute to coloration of pods and seed coats in soybean.Interestingly,we found that L1 plants are more prone to pod shattering under light exposure than l1 null mutants because dark pigmentation increases photothermal efficiency.Hence,pleiotropic effects of L1 on pod color and shattering,as well as seed pigmentation,likely contributed to the preference forl1 alleles during soybean domestication and improvement.Collectively,our study provides new insights into the mechanism of pod coloration and identifies a new target for future de novo domestication oflegume crops.

Genetic Architecture of Natural Variation in Rice Chlorophyll Content Revealed by a Genome-Wide Association Study

Chlorophyll content is one of the most important physiological traits as it is closely related to leaf photo- synthesis and crop yield potential. So far, few genes have been reported to be involved in natural variation of chlorophyll content in rice （Oryza sativa） and the extent of variations explored is very limited. We con- ducted a genome-wide association study （GWAS） using a diverse worldwide collection of 529 O. sativa accessions. A total of 46 significant association loci were identified. Three F2 mapping populations with parents selected from the association panel were tested for validation of GWAS signals. We clearly demon- strated that Grain number, plant height, andheading date7 （GhdT） was a major locus for natural variation of chlorophyll content at the heading stage by combining evidence from near-isogenic lines and transgenic plants. The enhanced expression of Ghd7 decreased the chlorophyll content, mainly through down- regulating the expression of genes involved in the biosynthesis of chlorophyll and chloroplast. In addition, Narrow leaf1 （NAL1） corresponded to one significant association region repeatedly detected over two years. We revealed a high degree of polymorphism in the 5＇ UTR and four non-synonymous SNPs in the cod- ing region of NAL1, and observed diverse effects of the major haplotypes. The loci or candidate genes iden- tified would help to fine-tune and optimize the antenna size of canopies in rice breeding.

Immunological Aspects of the Statins' Function in Patients with Heart Failure:A Report from the Annual Conference of ESC-Heart Failure 2005

The annual meeting of the Heart Failure Association of ESC in Lisbon, in June 2005, was exceptionally successful. There were many very interesting presentations and workshops with the unique rifle： Statins in heart failureCholesterol-lowering is not the only goal. Heart failure （HF） is a progressive disease with coronary artery disease （CAD） as the most often underlying etiology. Treatment to prevent progression of heart failure has been targeted to reverse the consequences of HF and to a less extent the cause - the atherosclerotic plaque itself. On the average 50% of patients with heart failure are treated with lipid intervention. Lipid-lowering treatment with statins clearly reduces morbidity and mortality of patients with documented CAD. Since the prevalent etiology of heart failure is CAD, its prevention may reduce heart failure progression. However, recent studies suggest that pleiotropic effects of statins are more important than the influence related to their cholesterol lowering mechanism. Furthermore it is suggested that low levels of circulating lipoproteins and cholesterol may be independent predictors of impaired outcome in patients with heart failure. There are some possible explanations for this finding. High levels of cholesterol can be beneficial to heart failure patients; cholesterol-rich serum lipoproteins are able to modulate inflammatory immune function because they bind and detoxify bacterial lipopolysaccharide, a very strong stimulator of the release of proinflammatory cytokines that promote heart failure progression and death. So current recommendations strongly emphasize that the aim of treatment of HF is not to lower cholesterol. Cellular ＆ Molecular Immunology. 2005;2（6）：433-437.

Nature’s marvels endowed in gaseous molecules Ⅰ:Carbon monoxide and its physiological and therapeutic roles

Nature has endowed gaseous molecules such as O_(2),CO_(2),CO,NO,H2 S,and N2 with critical and diverse roles in sustaining life,from supplying energy needed to power life and building blocks for life ’s physical structure to mediating and coordinating cellular functions.In this article,we give a brief introduction of the complex functions of the various gaseous molecules in life and then focus on carbon monoxide as a specific example of an endogenously produced signaling molecule to highlight the importance of this class of molecules.The past twenty years have seen much progress in understanding CO’s mechanism(s) of action and pharmacological effects as well as in developing delivery methods for easy administration.One remarkable trait of CO is its pleiotropic effects that have few parallels,except perhaps its sister gaseous signaling molecules such as nitric oxide and hydrogen sulfide.This review will delve into the sophistication of CO-mediated signaling as well as its validated pharmacological functions and possible therapeutic applications.

Additive and additive × additive interaction make important contributions to spikelets per panicle in rice near isogenic (Oryza sativa L.) lines

Epistasis plays an important role in the genetic basis of rice yield traits. Taking interactions into account in breeding programs will help the development of high-yielding rice varieties. In this study, three sets of near isogenic lines （NILs） targeting three QTLs for spikelets per panicle （SPP）, namely qSPP1, qSPP2 and qSPP7, which share the same Zhenshan 97 genetic background, were used to produce an F 2 population in which the three QTLs segregated simultaneously. The genotypes of the individual F 2 plants at the three QTLs were replaced with three markers that are closely linked to the corresponding QTLs. These QTLs were validated in the F 2 and F 3 populations at the single marker level. qSPP7 exhibited major pleiotropic effects on SPP, plant height and heading date. Multifactor analysis of variance was performed for the F 2 population and its progeny. Additive × additive interaction between qSPP2 and qSPP7 had significant effects on SPP in both the F 2 population and its progeny. Both additive and additive × additive interactions could explain about 73% of the total SPP phenotypic variance. The SPP performance of 27 three-locus combinations was ranked and favorable combinations were rec- ommended for rice breeding in different ecosystems.