The relaxin peptide family–potential future hope for neuroprotective therapy? A short review

Since its discovery in the 1920’s the relaxin peptide hormone family has not only grown in number to now seven members （relaxin-1, relaxin-2, relaxin-3, insulin-like peptide （INSL） 3, INSL4, INSL5 and INSL6）, but ever more effects, suchs as vasodilatory, angiogenic, anti-apoptopic, anti-fibriotic and anti-inflammatory, have been linked to them. While relaxin-2 has mainly been investigated in the context of cardiac protection, most comprehensively in the RELAX-AHF and RELAX AHF2 studies, a small number of studies have furthermore assessed the potential neuroprotective effects of especially relaxin-2 and other members of the relaxin family. In this short review we summarise and discuss recent efforts to utilize relaxin hormones for neuroprotection and point out potential future fields of research and translational applications. While many questions still need to be answered, the promising results of the available studies definitely warrant future well-designed studies on neuroprotection by relaxin peptides.

蚯蚓组织中硫氧还蛋白还原酶抑制剂初探

目的研究蚯蚓组织成份对硫氧还蛋白系统的影响。方法乙酸盐缓冲液抽提蚯蚓组织成份 ,不同处理的蚯蚓提取液与硫氧还蛋白系统反应。在 340nm波长处 ,用NADPH作为被监测的反应底物来动态监测硫氧还蛋白还原酶 (TrxR)的催化活性。结果蚯蚓提取液与TrxR单独作用后 ,监测底物NADPH的吸光值几乎不发生变化。蚯蚓提取液的溶剂及煮沸后的上清液不具有以上作用。结论蚯蚓组织中含有能够抑制TrxR活性的物质 ,该物质的化学本质为蛋白质。

Wide transcriptional investigation unravel novel insights of the on-tree maturation and postharvest ripening of‘Abate Fetel’pear fruit

To decipher the transcriptomic regulation of the on-tree fruit maturation in pear cv.‘Abate Fetel’,a RNA-seq transcription analysis identified 8939 genes differentially expressed across four harvesting stages.These genes were grouped into 11 SOTA clusters based on their transcriptional pattern,of which three included genes upregulated while the other four were represented by downregulated genes.Fruit ripening was furthermore investigated after 1 month of postharvest cold storage.The most important variation in fruit firmness,production of ethylene and volatile organic compounds were observed after 5 days of shelf-life at room temperature following cold storage.The role of ethylene in controlling the ripening of‘Abate Fetel’pears was furthermore investigated through the application of 1-methylcyclopropene,which efficiently delayed the progression of ripening by reducing fruit softening and repressing both ethylene and volatile production.The physiological response of the interference at the ethylene receptor level was moreover unraveled investigating the expression pattern of 12 candidate genes,initially selected to validate the RNA-seq profile.This analysis confirmed the effective role of the ethylene competitor in downregulating the expression of cell wall(PG)and ethylene-related genes(ACS,ACO,ERS1,and ERS2),as well as inducing one element involved in the auxin signaling pathway(Aux/IAA),highlighting a possible cross-talk between these two hormones.The expression patterns of these six elements suggest their use as molecular toolkit to monitor at molecular level the progression of the fruit on-tree maturation and postharvest ripening.

Mitogenomes of historical type specimens unravel the taxonomy of sportive lemurs(Lepilemur spp.)in Northwest Madagascar

Accurate information on name-bearing types,including corresponding type localities,is essential for proper taxonomy.However,such geographic information is often missing or unreliable.The localities of type specimens collected 100–200 years ago can be difficult to trace due to changes in local names or simple inaccuracies.Such a case can be found for the gray-backed sportive lemur(Lepilemur dorsalis),with its type locality imprecisely fixed as Northwest Madagascar.In recent years,eight species have been newly described for the Inter-River-Systems(IRSs)of this region,however the designation of L.dorsalis remains controversial due to a lack of a precise type locality.Here,we sequenced the complete mitochondrial genomes(mitogenomes)of type specimens of L.dorsalis and L.grandidieri,which is currently recognized as a synonym of L.dorsalis and compared their sequences with those of samples of known provenance from different IRSs.Results showed that the two type specimens of L.dorsalis and L.grandidieri had identical mitogenome sequences and clustered closely with samples collected in IRS V,indicating that the type locality could be fixed to IRS V.Consequently,L.dorsalis occurs in IRS V,and L.grandidieri and L.mittermeieri are junior synonyms of L.dorsalis.This finding demonstrates the value of type specimens for clarifying phylogeographic and taxonomic questions and clarifies the taxonomy of sportive lemurs in Northwest Madagascar.

Mitogenomic phylogeny of the Asian colobine genus Trachypithecus with special focus on Trachypithecus phayrei(Blyth, 1847) and description of a new species

Trachypithecus,which currently contains 20 species divided into four groups,is the most speciose and geographically dispersed genus among Asian colobines.Despite several morphological and molecular studies,however,its evolutionary history and phylogeography remain poorly understood.Phayre’s langur(Trachypithecus phayrei) is one of the most widespread members of the genus,but details on its actual distribution and intraspecific taxonomy are limited and controversial.Thus,to elucidate the evolutionary history of Trachypithecus and to clarify the intraspecific taxonomy and distribution of T.phayrei,we sequenced 41 mitochondrial genomes from georeferenced fecal samples and museum specimens,including two holotypes.Phylogenetic analyses revealed a robustly supported phylogeny of Trachypithecus,suggesting that the T.pileatus group branched first,followed by the T.francoisi group,and the T.cristatus and T.obscurus groups most recently.The four species groups diverged from each other 4.5-3.1 million years ago(Ma),while speciation events within these groups occurred much more recently(1.6-0.3 Ma).Within T.phayrei,we found three clades that diverged 1.0-0.9 Ma,indicating the existence of three rather than two taxa.Following the phylogenetic species concept and based on genetic,morphological,and ecological differences,we elevate the T.phayrei subspecies to species level,describe a new species from central Myanmar,and refine the distribution of the three taxa.Overall,our study highlights the importance of museum specimens and provides new insights not only into the evolutionary history of T.phayrei but the entire Trachypithecus genus as well.

SYNGR4 and PLEKHB1 deregulation in motor neurons of amyotrophic lateral sclerosis models: potential contributions to pathobiology

Amyotrophic lateral sclerosis is the most common adult-onset neurodegenerative disease affecting motor neurons. Its defining feature is progressive loss of motor neuron function in the cortex, brainstem, and spinal cord, leading to paralysis and death. Despite major advances in identifying genes that can cause disease when mutated and model the disease in animals and cellular models, it still remains unclear why motor symptoms suddenly appear after a long pre-symptomatic phase of apparently normal function. One hypothesis is that age-related deregulation of specific proteins within key cell types, especially motor neurons themselves, initiates disease symptom appearance and may also drive progressive degeneration. Genome-wide in vivo cell-type-specific screening tools are enabling identification of candidates for such proteins. In this minireview, we first briefly discuss the methodology used in a recent study that applied a motor neuron-specific RNASeq screening approach to a standard model of TAR DNA-binding protein-43(TDP-43)-driven amyotrophic lateral sclerosis. A key finding of this study is that synaptogyrin-4 and pleckstrin homology domain-containing family B member 1 are also deregulated at the protein level within motor neurons of two unrelated mouse models of mutant TDP-43 driven amyotrophic lateral sclerosis. Guided by what is known about molecular and cellular functions of these proteins and their orthologs, we outline here specific hypotheses for how changes in their levels might potentially alter cellular physiology of motor neurons and detrimentally affect motor neuron function. Where possible, we also discuss how this information could potentially be used in a translational context to develop new therapeutic strategies for this currently incurable, devastating disease.

Expanding through the Emerald Isle:exploration and spatial orientation of non-native bank voles in Ireland

Whether introduced into a completely novel habitat or slowly expanding their current range,the degree to which animals can effciently explore and navigate new environments can be key to survival,ultimately determining population establishment and colonization success.We tested whether spatial orientation and exploratory behavior are associated with non-native spread in free-living bank voles(Myodes glareolus,N=43)from a population accidentally introduced to Ireland a century ago.We measured spatial orientation and navigation in a radial arm maze,and behaviors associated to exploratory tendencies and risk-taking in repeated open-feld tests,at the expansion edge and in the source population.Bank voles at the expansion edge re-visited unrewarded arms of the maze more,waited longer before leaving it,took longer to start exploring both the radial arm maze and the open feld,and were more risk-averse compared to conspecifcs in the source population.Taken together,results suggest that for this small mammal under heavy predation pressure,a careful and thorough exploration strategy might be favored when expanding into novel environments.

Is the speed of adjusting to environmental change condition dependent?An experiment with house mice(Mus musculus)

Environmental conditions change constantly either by anthropogenic perturbation or naturally across space and time.Often,a change in behavior is the frst response to changing conditions.Behavioral fexibility can potentially improve an organism’s chances to survive and reproduce.Currently,we lack an understanding on the time-scale such behavioral adjustments need,how they actually affect reproduction and survival and whether behavioral adjustments are suffcient in keeping up with changing conditions.We used house mice(Mus musculus)to test whether personality and life-history traits can adjust to an experimentally induced food-switch fexibly in adulthood or by intergenerational plasticity,that is,adjustments only becoming visible in the offspring generation.Mice lived in 6 experimental populations of semi-natural environments either on high or standard quality food for 4 generations.We showed previously that high-quality food induced better conditions and a less risk-prone personality.Here,we tested whether the speed and/or magnitude of adjustment shows condition-dependency and whether adjustments incur ftness effects.Life-history but not personality traits reacted fexibly to a food-switch,primarily by a direct reduction of reproduction and sloweddown growth.Offspring whose parents received a food-switch developed a more active stress-coping personality and gained weight at a slower rate compared with their respective controls.Furthermore,the modulation of most traits was condition-dependent,with animals previously fed with high-quality food showing stronger responses.Our study highlights that life-history and personality traits adjust at different speed toward environmental change,thus,highlighting the importance of the environment and the mode of response for evolutionary models.

Janus-faced Mitofusin 2 (MFN2): mitochondria-endoplasmic reticulum shaping and tethering functions unveiled

In a recently published study in Science,Naòn et al.report two uncharacterized splice variants of Mitofusin 2(MFN2)that specifically shape and tether the endoplasmic reticulum(ER)to mitochondria.1 This work sheds new light on the pleiotropic effects previously ascribed to MFN2 loss-of-function mutations,and has important implications for associated metabolic and neurological diseases.

Health risk ranking of antibiotic resistance genes in the Yangtze River

Antibiotic resistance is an escalating global health concern,exacerbated by the pervasive presence of antibiotic resistance genes(ARGs)in natural environments.The Yangtze River,the world's third-longest river,traversing areas with intense human activities,presents a unique ecosystem for studying the impact of these genes on human health.Here,we explored ARGs in the Yangtze River,examining 204 samples from six distinct habitats of approximately 6000 km of the river,including free-living and particle-associated settings,surface and bottom sediments,and surface and bottom bank soils.Employing shotgun sequencing,we generated an average of 13.69 Gb reads per sample.Our findings revealed a significantly higher abundance and diversity of ARGs in water-borne bacteria compared to other habitats.A notable pattern of resistome coalescence was observed within similar habitat types.In addition,we developed a framework for ranking the risk of ARG and a corresponding method for calculating the risk index.Applying them,we identified water-borne bacteria as the highest contributors to health risks,and noted an increase in ARG risks in particle-associated bacteria correlating with heightened anthropogenic activities.Further analysis using a weighted ARG risk index pinpointed the ChengdueChongqing and Yangtze River Delta urban agglomerations as regions of elevated health risk.These insights provide a critical new perspective on ARG health risk assessment,highlighting the urgent need for strategies to mitigate the impact of ARGs on human health and to preserve the ecological and economic sustainability of the Yangtze River for future human use.

Experimental evidence for root competition effects on community evenness in one of two phytometer species

Aims Plant-plant interactions,being positive or negative,are rec-ognized to be key factors in structuring plant communities.However,it is thought that root competition may be less impor-tant than shoot competition due to greater size symmetry below-ground.Because direct experimental tests on the importance of root competition are scarce,we aim at elucidating whether root competition may have direct or indirect effects on commu-nity structure.Indirect effects may occur by altering the overall size asymmetry of competition through root-shoot competitive interactions.Methods We used a phytometer approach to examine the effects of root,shoot and total competition intensity and importance on evenness of experimental plant communities.Thereby two different phytom-eter species,Festuca brevipila and Dianthus carthusianorum,were grown in small communities of six grassland species over three levels of light and water availability,interacting with neighbouring shoots,roots,both or not at all.Important Findings We found variation in community evenness to be best explained if root and shoot(but not total)competition were considered.However,the effects were species specific:in Dianthus communities increasing root competition increased plant community evenness,while in Festuca communities shoot competition was the driving force of this evenness response.Competition intensities were influenced by environmental conditions in Dianthus,but not in Festuca phytometer plants.While we found no evidence for root-shoot interactions for neither phytom-eter species root competition in Dianthus communities led to increased allocation to shoots,thereby increasing the potential ability to perform in size-asymmetric competition for light.Our experiment demonstrates the potential role of root competition in structuring plant communities.

finDr:A web server for in silico D-peptide ligand identification

In the rapidly expanding field of peptide therapeutics,the short in vivo half-life of peptides represents a considerable limitation for drug action.D-peptides,consisting entirely of the dextrorotatory enantiomers of naturally occurring levorotatory amino acids(AAs),do not suffer from these shortcomings as they are intrinsically resistant to proteolytic degradation,resulting in a favourable pharmacokinetic profile.To experimentally identify D-peptide binders to interesting therapeutic targets,so-called mirror-image phage display is typically performed,whereby the target is synthesized in D-form and L-peptide binders are screened as in conventional phage display.This technique is extremely powerful,but it requires the synthesis of the target in D-form,which is challenging for large proteins.Here we present finDr,a novel web server for the computational identification and optimization of D-peptide ligands to any protein structure(https://findr.biologie.uni-freiburg.de/).finDr performs molecular docking to virtually screen a library of helical 12-mer peptides extracted from the RCSB Protein Data Bank(PDB)for their ability to bind to the target.In a separate,heuristic approach to search the chemical space of 12-mer peptides,finDr executes a customizable evolutionary algorithm(EA)for the de novo identification or optimization of D-peptide ligands.As a proof of principle,we demonstrate the validity of our approach to predict optimal binders to the pharmacologically relevant target phenol soluble modulin alpha 3(PSMα3),a toxin of methicillin-resistant Staphylococcus aureus(MRSA).We validate the predictions using in vitro binding assays,supporting the success of this approach.Compared to conventional methods,finDr provides a low cost and easy-to-use alternative for the identification of D-peptide ligands against protein targets of choice without size limitation.We believe finDr will facilitate D-peptide discovery with implications in biotechnology and biomedicine.

A Shelter for the Future:How WUSCHEL Protects the Shoot Apical Meristem from Viral Infection

Plant development in its majority occurs post-embryonically through the activity of local meristems that provide daughter cells for the development of new organs.It has long been acknowledged that the shoot apical meristem(SAM),which holds the stem cells that will form above-ground organs,is recalcitrant to infection by multiple pathogens,a crucial strategy to safeguard normal devel-opment and subsequent generations.However,the molecular mechanisms underlying SAM immunity remain largely unknown.

Multimodal 4-arylchromene derivatives with microtubule-destabilizing,anti-angiogenic,and MYB-inhibitory activities

Aim:Efficient and readily available anticancer drugs are sought as treatment options.For this reason,chromene derivatives were prepared using the one-pot reaction and tested for their anticancer and anti-angiogenic properties.Methods:2-Amino-3-cyano-4-(aryl)-7-methoxy-4H-chromene compounds(2A-R)were repurposed or newly synthesized via a three-component reaction of 3-methoxyphenol,various aryl aldehydes,and malononitrile.We performed assays to study the inhibition of tumor cell growth[3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromid(MTT)assay],effects on microtubules(immunofluorescence),cell cycle(flow-activated cell sorting analysis),angiogenesis(zebrafish model),and MYB activity(luciferase reporter assay).Fluorescence microscopy was applied for localization studies via copper-catalyzed azide-alkyne click reaction of an alkyne-tagged drug derivative.Results:Compounds 2A-C and 2F exhibited robust antiproliferative activities against several human cancer cell lines(50%inhibitory concentrations in the low nanomolar range)and showed potent MYB inhibition.The alkyne derivative 3 was localized in the cytoplasm after only 10 min of incubation.Substantial microtubule disruption and G2/M cell-cycle arrest were observed,where compound 2F stood out as a promising microtubule-disrupting agent.The study of anti-angiogenic properties showed that 2A was the only candidate with a high potential to inhibit blood vessel formation in vivo.Conclusion:The close interplay of various mechanisms,including cell-cycle arrest,MYB inhibition,and anti-angiogenic activity,led to identifying promising multimodal anticancer drug candidates.

Metabolomics-assisted refinement of the pathways of steroidal glycoalkaloid biosynthesis in the tomato clade

Steroidal glycoalkaloids（SGAs） are nitrogen-containing secondary metabolites of the Solanum species,which are known to have large chemical and bioactive diversity in nature.While recent effort and development on LC/MS techniques for SGA profiling have elucidated the main pathways of SGA metabolism in tomato,the problem of peak annotation still remains due to the vast diversity of chemical structure and similar on overlapping of chemical formula.Here we provide a case study of peak classification and annotation approach by integration of species and tissue specificities of SGA accumulation for provision of comprehensive pathways of SGA biosynthesis.In order to elucidate natural diversity of SGA biosynthesis,a total of 169 putative SGAs found in eight tomato accessions（Soianum lycopersicum, S.pimpinellifolium, S.cheesmaniae, S.chmielewskii, S.neorickii,S.peruvianum,S.habrochaites,S.pennellii） and four tissue types were used for correlation analysis.The results obtained in this study contribute annotation and classification of SGAs as well as detecting putative novel biosynthetic branch points.As such this represents a novel strategy for peak annotation for plant secondary metabolites.

Wnt/β-catenin signaling in heart regeneration

The ability to repair damaged or lost tissues varies significantly among vertebrates.The regenerative ability of the heart is clinically very relevant,because adult teleost fish and amphibians can regenerate heart tissue,but we mammals cannot.Interestingly,heart regeneration is possible in neonatal mice,but this ability is lost within 7 days after birth.In zebrafish and neonatal mice,lost cardiomyocytes are regenerated via proliferation of spared,differentiated cardiomyocytes.While some cardiomyocyte turnover occurs in adult mammals,the cardiomyocyte production rate is too low in response to injury to regenerate the heart.Instead,mammalian hearts respond to injury by remodeling of spared tissue,which includes cardiomyocyte hypertrophy.Wnt/β-catenin signaling plays important roles during vertebrate heart development,and it is re-activated in response to cardiac injury.In this review,we discuss the known functions of this signaling pathway in injured hearts,its involvement in cardiac fibrosis and hypertrophy,and potential therapeutic approaches that might promote cardiac repair after injury by modifying Wnt/β-catenin signaling.Regulation of cardiac remodeling by this signaling pathway appears to vary depending on the injury model and the exact stages that have been studied.Thus,conflicting data have been published regarding a potential role of Wnt/β-catenin pathway in promotion of fibrosis and cardiomyocyte hypertrophy.In addition,the Wnt inhibitory secreted Frizzled-related proteins(sFrps)appear to have Wnt-dependent and Wnt-independent roles in the injured heart.Thus,while the exact functions of Wnt/β-catenin pathway activity in response to injury still need to be elucidated in the non-regenerating mammalian heart,but also in regenerating lower vertebrates,manipulation of the pathway is essential for creation of therapeutically useful cardiomyocytes from stem cells in culture.Hopefully,a detailed understanding of the in vivo role of Wnt/β-catenin signaling in injured mammalian and non-mammalian hearts will also contribute to the success of current efforts towards developing regenerative therapies.

Role of Toll-like receptors in regulatory functions of T and B cells

Pathogens can find their ways to most sites in the host. Pathogen sensors, such as Toll-like receptors (TLRs), must be equally and broadly distributed on immune cells to combat them through innate and adaptive immunity. Most classes of TLRs are found in innate immune cells to obtain an immediate re- sponse against pathogens, but recent studies indicate that a number of TLRs are wildly expressed in T and B cells, suggesting TLRs also directly regulate adaptive immune responses. Due to the rapid in- crease of new information on the multiple roles of TLRs, in this paper we aim to review several main properties of TLRs and their direct role in T and B cells. This review consists of 6 parts: (i) Characteris- tics of Toll-like receptors (TLRs) and signaling; (ii) signalling pathways of TLRs; (iii) TLR expressions on human leukocytes; (iv) TLR expressions and functions in the Th1, CD4+CD45RO+ memory T cells and regulatory/suppressor T as well as B cell populations; (v) therapeutic potential of TLR agonists; (Vi) discussion and perspective. The latest findings and potential therapeutic applications are discussed. There is growing evidence supporting the concept that TLR activation contributes not only to innate immunity but also to adaptive immunity, including direct regulation of both T and B lymphocytes by TLRs.

Genomic analyses of metal resistance genes in three plant growth promoting bacteria of legume plants in Northwest mine tailings, China

To better understand the diversity of metal resistance genetic determinant from microbes that survived at metal tailings in northwest of China, a highly elevated level of heavy metal containing region, genomic analyses was conducted using genome sequence of three native metal-resistant plant growth promoting bacteria（PGPB）. It shows that： Mesorhizobium amorphae CCNWGS0123 contains metal transporters from P-type ATPase, CDF（Cation Diffusion Facilitator）, Hup E/Ure J and CHR（chromate ion transporter） family involved in copper, zinc, nickel as well as chromate resistance and homeostasis. Meanwhile, the putative Cop A/Cue O system is expected to mediate copper resistance in Sinorhizobium meliloti CCNWSX0020 while Znt A transporter, assisted with putative Czc D, determines zinc tolerance in Agrobacterium tumefaciens CCNWGS0286. The greenhouse experiment provides the consistent evidence of the plant growth promoting effects of these microbes on their hosts by nitrogen fixation and/or indoleacetic acid（IAA） secretion,indicating a potential in-site phytoremediation usage in the mining tailing regions of China.

Experiment meets biogeography:plants of river corridor distribution are not more stress tolerant but benefit less from more benign conditions elsewhere

Aims Factors limiting distributions of species are fundamental to ecology and evolution but have rarely been addressed experimentally for multiple species.The conspicuous linear distribution patterns of plant species confined to river corridors in the Central European lowlands constitute an especially long-standing distribution puzzle.We experimentally tested our novel hypothesis that the tolerance of species to river corridor conditions is independent of the degree of confinement to river corridor habitats,but that species not confined to river corridors are better able to take advantage of the more benign non-river corridor conditions.Methods We grew 42 herbaceous species differing in their confinement to river corridors in a common garden experiment on loamy soil typical for river corridor areas and sandy soil typical for non-river corridor areas,and with and without a flooding period.For a subset of species,we grew plants of both river corridor and non-river corridor origin to test for adaptation to river corridor conditions.Important findings Species more confined to river corridor areas benefited less from the more benign non-flooded and non-river corridor soil conditions than species of wider distributional range did.For subsets of 7 and 12 widespread species,the response to flooding and soil origin,respectively,did not differ between plants from river corridor sites and plants from other sites,suggesting that the habitat tolerance of widespread species is due to phenotypic plasticity rather than to local adaptation.Overall,we found clear support for our novel hypothesis that species not confined to river corridors are more able to take advantage of the more benign non-river corridor conditions.Our study provides a general hypothesis on differences between species confined to stressful habitats and widespread species out for test in further multispecies comparative experiments.

Investigation of epididymal immunology

Immunology is the study of the structure and function of the immune system. The immune system consists of an earlier-stage innate immunity and a later-stage adap-tive immunity. The task of the immune system is to efficiently respond to non-self antigens and the invasion of pathogens, thereby protecting the host’s homeostasis. This review article discusses the structure and function of the epididymis, in-cluding the composition of the epithelial cells of the epidi-dymis and their relationship to the immune system, through the assessment of alterations in the immune cells of the epididymis. The review also shows the anti-inflammatory properties of rat epididymal defensin and the description of the blood-epididymis barrier, immune barrier, epididymitis and pathological mechanisms of infertility in males. Taken together, we see that the epididymis possesses a close link with immunology. Finally, this review discusses the future of studies involving epididymal immunology.