Lean mass increased sig-nificantly in the exercise group compared with baseline (P # .01)and the usual care group (P , .001). At follow-up, all body com-position variables remained significantly improved in the exercisegroup compared with baseline (P , .001

After 5 minutes of quiet sitting, blood pressurewas measured by using the arm contralateral to the affected breastwith an automated sphygmomanometer

Exercise improves individual components ofmetabolic syndrome in survivors of breast cancer7-9;however, consensus is lacking that it improvesmetabolic syndrome as a collective entity, partic-ularly in high-risk survivors of breast cancer—racial and/or ethnic minorities with obesity

sarcopenic obesity

Fig. 3.

Fig. 2.

Fig. 1.

Usewar metaphors with caution; they are an ethical minefield

we havenow demonstrated for the first time that patients with PTSD ex-hibit greater vascular a1AR sensitivity, as evidenced by a lowerED50 for the selective a1AR agonist PE.

elective a1AR agonist, phenylephrine

11

7

Wheninvestigating the transition between the twoarchitectures, we noted that mosquitoes, whichdisplay type-I features

ig. 1

Early studies focused on histonepost-translational modifications(Barski et al. and Mikkelsen et al.) andtranscription factors (Johnson et al.and Robertson et al.

Our method is currently limited by the inability to identify candi-dates that contain introns but can be expanded to include modelsof introns in fungi.

test the ability to identify novel phero-mones, we verified that deletion of all copies of the candidate far-nesylated pheromone of Yarrowia lipolytica (whose last commonancestor with S. cerevisiae existed more than 300 million yearsago) prevented mating of the a cells of this species.

Overall,we find known or candidate pheromone genes in 241 of332 mined genome

We built a computational pipeline to identify farnesylatedfungal pheromones in sequenced genomes.

look forhomologs of known pheromones in sequenced fungal ge-nomes

Since then, pheromones have beenbiochemically isolated and characterized in laboratory yeasts,filamentous fungi, and crop pathogens by isolation from extra-cellular medium, 2,9,17,18 but this approach depends on discov-ering the environmental conditions that stimulate mating and ob-taining sufficient material to determine the pheromone’s peptidesequence

Finding thepheromones of economically important yeast will help to under-stand and control their mating as well as shed light on the evolu-tion of these molecules and the receptors that recognize them

we identified strong candidate pheromone genes in241 genomes, covering 13 clades that are each separated from each other by at least 100 million years,the time required for evolution to remove detectable sequence homology among small pheromone genes.For one small clade, the Yarrowia, we demonstrated that our algorithm found the a-factor genes: deletingall four related genes in the a-mating type of Yarrowia lipolytica prevents mating

overcome this problem

) Project is to enable the scientific and medical communities tointerpret the human genome sequence and apply it to understand human biology and improve health. T

GC (%)

Thus, we reasonedthat low-cost de novo WGS can be applied directly after ITS sequencing.

Together, these data indicateda differential reliance on ASCT2 activity across breast cancer celllines, whereby only basal-like cells required ASCT2-mediatedglutamine uptake for cell growth.

levels of glycolytic metabolite

AR-C155858 (SR13801)

Myc directly and selectively activates MCT1 tran-scription and that elevated MCT1 levels are a hallmark ofhuman malignancies with MYC or MYCN involvement. Notably,we show that blocking MCT1 function rapidly disables glycol-ysis, leading to reductions in ATP and glutathione (GSH) levels,and that cotreatment with metformin, which forces the gly-colytic phenotype, augments the in vivo efficacy of MCT1inhibitors against MYC-expressing malignances.

nude mice

xenograft growth

All these data indicate that WZB117, a novel Glut1inhibitor, is effective both in vitro and in vivo in inhibitingcancer cell growth and can serve as a prototypicalcompound for the further development of Glut1 andglucose transport inhibitors as a new group of anticancertherapeutics.

Both ATPreduction and senescence were described for the first timeas potential anticancer mechanisms of Glut1 inhibitors

enescence

Additional but presently unknown mechanism may beinvolved in the regulation of pRb and cell-cycle arrest inA549 cells treated with WZB117.

other cellgrowth, survival, and cell death processes were examinedin WZB117-treated cancer cells to identify molecular par-ticipants and consequences of the treatment.

fter identifying and characterizing some of the bio-logic and biochemical changes in cancer cells related toglucose transport and glucose metabolism

Oligomycin, a specific mitochondrial inhibitor, didnot reduce cell proliferation rate at a concentration of50 nmol/L (data not shown)

The possibility of theinvolvement of other mechanisms such as AMP-activatedprotein kinase (AMPK)/mTOR signaling–mediated arrestof protein synthesis cannot be ruled out

Fig. 3B and C)

RBC

Fig. 1C

Figure 1

sizes of the compound-treated tumors were onaverage more than 70% smaller than those of themock (PBS/DMSO)-treated tumors

whether WZB117 inhibits cancer growth in animal tumormodels

showing the anticancer activity of WZB117 incultured cancer cells

This study was done to determine the anticancerefficacy in vivo and identify the anticancer mechanism ofthe inhibitors using the compound WZB117.

RBC and RBC-derived vesicles were prepared usingpublished protocols (22) with minor modifications

Protein target studies II: docking studies

Anaerobe Gas Generating Pouch System with indicator(BD GasPak EZ). The pouch formed an oxygen-free envi-ronment in which the compound-treated cells were incu-bated for 24 hours.

Caspase

The effect of BCH and the mechanism of BCH on cell growth suppressionin cancer cells

(A)

Placental mammals may have therefore evolved random X inactivation to alleviate the burden of maternal X-chromosome mutations.

In Rett's syndrome, for instance, females that carry a mutated copy of the MECP2 gene on the maternal X are able to survive (although with variable symptoms), because the paternal X has a normal copy that remains active in some cells

ecreased expression of SOX9

Transfec-tion

responds rapidly and strongly to Kdm6b knock-down at the very beginning of the temperature-sensitive period

Kdm6b was up-regulated at 26°C

ong half-life greater than 12 h

tress response correlates with changes in alternative splicingof Jumonji-family histone modifiers, suggesting a relationshipbetween cellular stress and sex-specific gene expressionchanges

central to environmental sex determination and sex changein reef fishe

hanges in methylation at Dmrt1caused by temperature exposure were heritable and capableof over-riding chromosomal sex in the next generation

TSD

theca/Leydig

granulosa/Sertoli

future oogonia or spermatogonia

mammals seems to be to maintain male fate

threshold is reached sufficient to maintain andstabilize one pathway and repress the alternative pathway.

how a sex determination pathwaycan be engaged and stabilized without an inherited genetic determinant.

sex determination is a synthesis of manymolecular events that drives a community of cells towards a coordinatedtissue fate.

Due to the infertility of human females heterozy-gous for FOXL2 mutations, the homozygous loss-of-functionphenotype has not yet been reported

As shown here, the maintenance of female gonadal sexrequires continuous expression of FOXL2 to suppress maledevelopment

Like Yin and Yang,

Foxl2/

cell typ

Why Dmrt1 mutants are feminized only after birthremains unclear.

oestrogens, which are essential for ovariandevelopment in many vertebrates;

Sex determination can be viewed as a battle for primacy in thefetal gonad between a male regulatory gene network in whichSryactivatesSox9 and a female network involving WNT/b-catenin sig-nalling

Giventhe importance of R-spondin1 and Wnt4acting via β-catenin in establishing theembryonic ovary, it would be of inter-est to conditionally delete this path-way in adult ovaries to see whether thegonads also show ovary to testis trans-differentiation. In other words, is thiseffect solely mediated by Foxl2, or areother factors of equal importance alsoinvolved?

deletion of Foxl2 in the adultovary is sufficient to induce transdiffer-entiation of the ovary into a testis

activation of Sox9 bySry leads to the differentiation of thesupporting cell lineage into pre-Sertolicells.

ovar-ian development occurs in the absenceof Sry,

In all mammalianembryos, the gonad is “bipotential,”that is, it can form either an ovary ora testis.

he germ-line theory had experimentalsupport from a large number of different or-ganisms.

He obtained DNAsamples from unusual clinical cases in whichindividuals with two X chromosomes hadbeen designated as males (XX males) andones with an XY chromosomal constitutionhad been designated as females (XY fe-males)

can the nucleus of a fully differen-tiated cell, if placed in an undivided egg cell,direct the development of a complete andwell-formed new organism, or as they say inthe trade, do nuclei from differentiated cellsremain totipotent?

We are vertebrates because our motherswere vertebrates and produced eggs of thevertebrate pattern; but the color of ourskin and hair and eyes, our sex, statureand mental peculiarities were determinedby the sperm as well as by the egg fromwhich we came

The nucleusmay contain genes, but if all cells contain thesame set of genes, how indeed could differ-ent cell types arise during embryonic devel-opment?

he relative roles of the cellnucleus and cytoplasm in heredity.

The potential applications to humans cannotbe that far off.

specific base sequences in aDNA molecule, which is in higher organismsorganized into complex arrangements of pro-tein and nucleic acid called chromosomes.

The essay is divided into three parts

The basic assumption of scholars in this areais that scientific research forms an integralpart of our cultural, social, and political sys-tems.

I will discuss the devel-opment of two central concepts in develop-mental biology - differential gene expressionand the continuity of the germ line; I arguethat social and political factors combinedwith particular experimental results to shapethe ideas which have come now, in the lasthalf of the 1980sto be accepted into the bio-logical canon.

Now finally the father'sheirs, the "hip, young gunslingers of moderndevelopmental biology" have returned to res-cue the stunted offspring and help it, withthe heavenly blessing of the Father, to growto manhood.

(A)

Our analysis shows that DMRT1 is the key sex determinationswitch in birds and that it is essential for testis development, butthat production of estrogen is also a key factor in primary sexdetermination in chickens, and that this production is linked toDMRT1 expression

applied CRISPR/Cas9 to isolatedchicken germ cells that were injected intosurrogate embryos. Those embryos hadbeen genetically modified such that theylacked their own germ cells, and this greatlyenhanced the rate of germline transmission,in itself a highlight of the pape

using genome editing to pre-cisely inactivate one copy of DMRT1 inotherwise genetically male (ZZ) chickens

and expression of ovary marker proteins,such as FOXL2 and aromatase

his resulted in‘feminisation’ of the gonads in genetic maleembryos, featuring ovarian-like structure

romosomal sex directs theembryonic gonads to form ovaries ortestes, which then secrete hormones tofeminise or masculinise the rest of thebody.

The mole

B) Volcano plo

(A) Strategy used to identify genes withaltered 3D chromatin organization as aresult of species-specific rearrangements.

Fig. 1D

caf-folded using Hi-C data

Genome assembly

tissue

intersexuality

B) Strategy used to assign regulatoryelements to candidate genes. Number ofactive enhancers is correlated to geneexpression levels for each tissue

androgen synthesis

A positive correla-tion between active enhancers and gene ex-pression was found for 10 genes. Among thetop-ranked candidates, we selected those dis-playing higher expression for subsequent func-tional validation: the androgen-related geneCYP17A1 and the pro-testicular growth fac-tor gene FGF9

GO terms

predicted to gain de novo interactionwith regions containing active enhancers

AD predictions,to delimit a potential region of new interac-tions for each candidate gene and determinethe number of active regulatory elements con-tained within

Using our functional datasets, we thensearched for footprints of altered gene regu-lation that might be the consequence of mole-specific rearrangements

To identify mole-specific rearrangements, we compared themole genomes (T. occidentalis and C. cristata)with full-chromosome assemblies from human,mouse, and shrew, as the closest taxonomicaloutgroup with normal ovarian development

no relevant candidates were found,we searched for changes in 3D chromatinorganization, on the basis of the hypothesisthat rearrangements can alter regulatory do-mains and affect gene expression

Our anal-ysis confirms moles as a distinct family in theorder Eulipotyphla, with shrews and hedge-hogs being the most closely related species(15) (supplementary text)

investigate the molecular origins of moleovotestes,

nexception to this paradigm occurs in moles(family Talpidae), in which XX-genotypic fe-males have an intersex phenotype in at leasteight species

Our results highlight how integrative genomicapproaches can reveal the phenotypic impact of noncoding sequence changes

non-cod-ing, cis-acting gene regulatory elements and discuss howthey may control transcriptional programmes that underpinsex determination in the context of the 3-dimensional fold-ing of chromatin.

Such surgery is contro-versial because it is usually performed on babies, who are too youngto consent, and risks assigning a sex at odds with the child’s ultimategender identity

uncover the mechanisms

A study in 1996 recorded womenwith fetal cells in their blood as many as 27 yearsafter giving birth13; another found that maternalcells remain in children up to adulthood14. Thistype of work has further blurred the sex divide,because it means that men often carry cells fromtheir mothers, and women who have been preg-nant with a male fetus can carry a smattering ofits discarded cells.

A DSD called congenital adrenal hyperplasia(CAH), for example, causes the body to produceexcessive amounts of male sex hormones; XXindividuals with this condition are born withambiguous genitalia (an enlarged clitoris andfused labia that resemble a scrotum).

In 1990,researchers made headlines when they uncovered the identity of thisgene3,4, which they called SRY

“I think there’s much greater diversity within male or female,and there is certainly an area of overlap where some people can’t easilydefine themselves within the binary structure,”

The function of this vascularization is notknown.

ovigerous cords

ovarian follicle

endothelial cells, fibroblasts, andblood-derived cells such as macrophages, lymphocytes,plasma cells, monocytes, and mast cells.

these cells secrete a hormone that plays a role in estab-lishing and maintaining the secondary male sex charac-teristics

Moreover, it is unclearwhether a single factor induces the migration of one ormore precursor cell types that subsequently differentiateinto the different testicular cell populations by direct

expressed in Sertoli cells, or more accurately thepre-Sertoli cells

rganizing center of the male gonad and or-chestrate the differentiation of all other cell types

meso-derm.

The initial phase is characterized by theemergence of the so-called indifferent, bipotential gonad,or genital ridge, which is identical in males and females.

owever, varia-tions in mammalian sexual differentiation are known toexist, and this needs to be kept in mind when extrapolat-ing from one species to another.

determined by environment during a sensitiveperiod of embryonic development

sex is de-termined by genes at conception

describessubsequent steps in developmental pathways, dur-ing which the male and female phenotypes are pro-gressively built up, according to the initial decision

meant to designate thedevelopmental step at which an individual fate isirremediably directed towards either the male orthe female condition

a single eggis more costly to produce than a single sperm cell,female fecundity is limited mainly by her ability toproduce eggs, while male reproductive success islimited by the number of females he can insemin-ate.

anisogamy

haplodiploidy

separate sexes, biparentalism, parental controlover sex ratios, Mendelian segregation of sex-ratioalleles, random mating in an infinite population,and no environmentally induced sex differencesin fitness

gene capture

sexes’ or ‘genders’

diatoms

homologous re-combination between non-sister co-linear chro-mosome pairs, maintained as templates

To what extent repair still plays a role in main-taining meiotic sex is a matter of debate

Such damaging changes cannot be repairedin unicellular haploid organisms; if non-lethal, theywill be transmitted to daughter cells and progres-sively accumulate through generations.

Given its early origin in eukaryotes and near-ly universal distribution, it might seem that sexshould provide large and obvious evolutionary ad-vantages. However, it turns out that costs are mucheasier to identify than are benefits

so that sex actually halvesthe number of individuals.

volutionarilyrelated enzymes

diploid

haploid

parthenogenesis

the paternal sperm cell that fertilized thematernal ovum contributed an X or a Y chromo-some

X’ chromosome

sex to be determined bythe mother’s nutrition during the first three monthsof pregnancy; a poor diet was thought to result inmales, and a better diet in females

epigenetic theories of sex determinationhave actually prevailed until recently

Aristotle proposed that males are character-ized by an abundance of fire (the superior element),and for this reason are hot and dry, while females,with an abundance of water, are rather cold andwet

The dispute about theexact nature of spermatozoa was settled in 1841 bythe Swiss embryologist Albert von Kölliker