In addition, highly proliferative normal cells, such as T cells during activation, perform aerobic glycolysis while inhibiting mitochondrial pyruvate import8. Suppressed activity of the pyruvate dehydrogenase (PDH) complex, attributed to its phosphorylation, reduced free coenzyme A (CoA) levels and a decreased NAD+/NADH ratio, limits the mitochondrial metabolism of glycolysis-generated pyruvate, promoting its catabolism by LDH in the cytosol9,10. Frequent upregulation of LDHA expression in cancer cells drives lactate production from pyruvate, with reduced reversible conversion of lactate back to pyruvate. This process regenerates NAD+ from NADH, allowing glycolysis to persist11,12.

Mechanistically, lactate increases histone acetylation,

H3K9/27me3 MMP-2, MMP-9 Human placenta Related to trophoblasts motility and invasion

morula

This signalling cascade is one of the most obvious explanations of how outer cells of the mor­ula become biased towards a TE fate, whereas the inner, apolar and CDX2– cells are more likely to adopt an ICM fate.

This interaction is particularly impor­tant for successful placentation; impairment of decid­ualization in mice through genetic manipulation or as a consequence of maternal ageing frequently results in placental failur

Focusing on the low-est 20 percentile of Hi-C PC1 values, TSCs displayedstrong B-to-B compartment interactions, as did differenti-ated ESCs and MEFs (Fig. 3B,C; Miura et al. 2019). Interest-ingly, TSCs also showed a high A-to-A interaction, whiledifferentiated ESCs and MEFs did not (Fig.

xpectedly, human TSCs—whether derivedfrom blastocyst cells or CT cells—showed an H3K9me3distribution pattern similar to that of human ESCs, indi-cating that human TSCs most likely lose trophoblast-spe-cific H3K9me3 enrichment during their establishment,unlike mouse TSCs (see Fig. 1B).

. This was further confirmed by thedensity of each repeat within the H3K9me3 domains;thus, the number of LINE/L1 in TSC-defined H3K9me3domains was significantly higher than in ESC-defined do-mains, but the distribution of ERVK showed the oppositetenden

As expected, TSCs displayed higher expressions ofthe genes encoding H3K9me3 methyltransferases Setdb1and Suv39h2, and lower expressions for H3K9me3 deme-thylases Kdm4b/c/d, when compared with ESCs andMEF

Consistent with these findings, immunostainingfor H3K9me3 and H3.1/H3.2 revealed their colocalizationin the TSC nuclear foci, but not in the ESCs

H3K9me3

The global abun-dances of H3K4me3, H3K9me3, and H3.3 were indistin-guishable between ESCs and TSCs

Moreover, low oxygen tensions limit differentiation of cultured trophoblasts from uncomplicated pregnancies, as reflected by reduced formation of differentiated syncytiotrophoblasts and lower secretion of human chorionic gonadotropin and human placental lactogen compared to trophoblasts exposed to standard condition

novel isoform of NADPH oxidase in villi of preeclamptic pregnancy has recently been identified to contribute to the increased oxidative stress found in these placentas

activates transcription factors while generating reactive oxygen species (7

These results suggest that hypoxia induced changes in trophoblast secretion may yield a stimulus, such as increased thromboxane production, that limits the ability of villi to compensate for injury, by altering trophoblast turnover and limiting the differentiation of syncytiotrophoblasts during repai

ally at syncytial knots where clusters of nuclei with condensed chromatin reside

Such debris may incite part, if not all, of the increased maternal inflammatory response associated with the preeclamptic syndrome.

villous cytotrophoblasts

syncytial knots

denudations

lesion that mimics an arteriosclerotic plaque in an ad

The histopathology of placentas complicated by preeclampsia is commonly characterized by incomplete invasion of maternal blood vessels by trophoblasts and inadequate modification of the spiral arterioles in the decidua and superficial myometrium

Importantly, preeclampsia occurs with increased frequency when trophoblast mass is excessive, such as in multi-fetal gestations, molar pregnancies, gestational diabetes, and hydrops fetalis

The disorder is unique to human pregnancy, and the placenta is a prerequisite for development of the syndrome.

Interestingly, pregnant women at high altitude have maternal systemic blood pO2 values in the 50-60 mm Hg range and a frequency of preeclampsia about four-fold higher compared to women at sea level (22)

Research in both humans and rodents has demonstrated that low oxygen tension directs trophoblast stem cell differentiation toward a phenotype that is associated with the junctional zone

3Tripathi V, Popescu NC, Zimonjic DB. DLC1 induces expression of E-cadherin in prostate cancer cells through Rho pathway and suppresses invasion. Oncogene 2014; 33:724-33; PMID:23376848; http://dx.doi.org/10.1038/onc.2013.7 [Crossref], [PubMed], [Web of Science ®], [Google Scholar] Notch-1 expression is reduced in placentas with preeclampsia.44Cobellis L, Mastrogiacomo A, Federico E, Schettino MT, De Falco M, Manente L, Coppola G, Torella M, Colacurci N, De Luca A. Distribution of Notch protein members in normal and preeclampsia-complicated placentas. Cell Tissue Res 2007; 330:527-34; PMID:17955263; http://dx.doi.org/10.1007/s00441-007-0511-6 [Crossref], [PubMed], [Web of Science ®], [Google Scholar] Similar to the role of Notch-1 in human trophoblasts, inactivation of Notch-2 in human trophoblast lineages also affects intrauterine trophoblastic migration, reducing trophoblastic invasion of the maternal uterine spiral arteries

trophoblastic giant cells

Hemochorial placental development is characterized by close contact between maternal and fetal tissues and occurs in humans and rodents such as the rat and mouse.

EOMES, a gene whose expression is completely lacking in both preimplantation human TE and early post-implantation human trophoblast

Studies using human endometrial epithelial monolayers have shown that, in contrast to mouse embryos, the initial attachment of human embryos occurs via the polar TE, cells located adjacent to the inner cell mass

In addition, several lines of evidence, including a prolonged period during which the pluripotency marker POU5F1/OCT4 and the TE marker CDX2 are co-expressed in the TE layer, suggest that human TE is not specified until at least the late blastocyst stage

cells is another mechanism of trophoblast invasion during earlypregnancy. Matrix metalloproteinases are a family of endopepti-dases that degrade different components of extracellular matrix(Vegh et al., 1999; Sternlicht and Werb, 2001; Singh et al., 2011).

There is no mention of it in the internationally acceptedTerminologia Embryologica.

Hormones such as progesterone and human chorionic gonadotropin (hCG) areimportant regulators.

head involution defective(hid) gene (UAS-hid) (electronic supplementary material,figure S1). An autoregulated tetracycline transactivator (tTA)transgene has been widely used as a conditional lethalsystem in insects [5,16]. Death is thought to be due to a generalinterference in gene expression due to high levels of the tTAtranscription factor. Similarly, we reasoned that the overexpres-sion of Gal4 would be lethal. The activation of hid expressionby Gal4 would cause lethality due to induction of apoptosis[17]. For the R, a single UAS-Gal80 construct was made. Con-sequently, all genes (Gal80, Gal4 and hid) have multiple copiesof the UAS sequence upstream of a core promoter and are thusactivated by binding of Gal4 to UAS.As the core promoter can have a significant impact on thelevel of gene activation by Gal4 [18], we evaluated differentcore promoters with the Gal4/UAS binary system. Usingdifferent core promoters, we were able to modulate theexpression of Gal4 and optimize the lethal system. Thestrong core promoter from the D. melanogaster hsp70 gene(DmHsp70) has been widely used since the development ofthe Gal4/UAS binary system in Drosophila [13,18]. The Droso-phila synthetic core promoter (DSCP) contains optimizedversions of the motifs (TATA, Inr, MTE and DPE) that arethought to be important for function [19]. Indeed, the DSCPcore promoter has been found to promote robust expressionwith a broad range of enhancers that bind different activator

as9 was expressedunder the control of nanos regulatory sequences, which drive ex-pression in the male and female germline

n ≥ 43). Using wild type (wt) as a comparator, we saw no significant differences (‘ns’) in any genotype other than dsxF−/− females, which were unable to feed on

the violence experienced

In situations where a paper requires additional authors, cats have been credited as co-authors (McGaw & Twitchit, 2012, Hetherington & Willard, 1975)

Recognizing that the system is flawed, some research groups have used unconventional methods to draw attention to the problematic nature of the process. For example, author order has been decided by competitions that involve skill, such as games of: Scramble (Belyea & Lancaster, 2002); tennis (Griffiths & Anderson, 1978); or a brownie bake-off (Young & Young, 1992). Others participate in games of chance, such as: rock, paper, scissors (Kupfer et al., 2004) and coin-toss (Miller & Ballard, 1992).

To date, no Arg demethylases have been conclusively identified

It should be noted that genetic evidence in vivo for MBD function is complicated by redundancy between the proteins.

methyl- CpG-binding protein 2 (MeCP2).

By preventing the binding of such transcription factors, DNA methylation can therefore impede transcription activation of CGI promoters that contain their sequence- recognition motifs. Using the same principle, methyl-ated cytosines can also serve as binding modules for transcription activators

Moreover, DNMT- deficient mice exhibit severe developmental abnormalities, culminating in early embryonic lethality2

In fact, cytosine methylation comes at a cost: 5mC is inherently mutagenic because it can spontane-ously undergo deamination, leading to C → T transi-tions17

However, someshortcomings of TGS (like the requirement for higher nucleic acid concentrations andhigher error rates than other platforms) should be properly addressed, to reach its fullpotential [

may also arise in repetitive stretches (including homopolymers) and CG-rich regions, dueto enzymatic limitations of DNA polymerases. Besides, the typical short-readings of SGSmay pose insurmountable hindrances, since they may be difficult, if not impossible, tobe accurately assembled, mainly in the absence of a reference genome. The rationale isthat similar or identical short fragments may be located at different genome sites. So, itmay become impossible to map a particular short sequence to any specific site, amongstthe multiple potential targets available in the genome [3]. Also, as with FGS, SGS can beapplied to sequence DNA, but cannot directly sequence RNA molecules

However, FGS approaches are expensive, time consumingand with low throughput. Therefore, they are not practical to sequence full genomes ortranscriptomes. Indeed, the Human Genome Project using such a platform took 15 years,at a cost of three million milliard USD, even after optimizations that increased readinglengths and reduced errors, allowing researchers to finish it in half the time than previouslyexpected at the time

The genetic characteristicsand evolution of invasive species, which reflects howinvasive species arrive, overcome small populationdynamics, and rapidly adjust to novel environments inthe introduced range, enhances our ability to predictwhether an introduced species establishes and spreads.

As an alternative to these methods, here weshow that yeast cell surface expression of an engineered proteinwith affinity for iron oxide can be used for efficient magnet-ization of yeast

. However, it has been arguedthat the observed correlation between recom-bination and the efficiency of selection couldbe an artefact of GC-biased gene conversion(gBGC) (25).

we used conservativecut-offs for calling var-iants, and we recovered similar patterns afterexcluding variants more likely to have resultedfrom damage

We found that low genetic di-versity regions of the passenger pigeon genomeare generally in the centers of macrochromo-somes, whereas the edges of macrochromosomesand microchromosomes have higher diversity

greater in passenger pigeons (averagep= 0.008)than in band-tailed pigeons (averagep=0.004),but this difference is less than expected giventheir population sizes [it suggests thatNe/Ncwas0.0002 for passenger pigeons compared to 0.2for band-tailed pigeons; (14)]

We applied a Bayesian skyline model of an-cestral population dynamics to the mitochondrialgenomes of 41 passenger pigeons from acrosstheirformerbreedingrange

Within some countries individuals are strongly differentiated alongthe principal component (PC) axes, suggesting that in some cases theresolution of the genetic data may exceed that of the available geo-graphic information.

In addition, the results are relevant tothe prospects of genetic ancestry testing6; an individual’s DNA canbe used to infer their geographic origin with surprising accuracy—often to within a few hundred kilometres.

Increased genetic variation resultingfrom sexual reproduction is widelythought to counteract this cost, but simpleproof-of-concept models quickly revealedboth a flaw in this verbal logic and anunexpected outcome: sex need not in-crease variation, and even when it does,the increased variation need not increasefitness

Proof-of-concept models, used in manyfields, test the validity of verbal chains oflogic by laying out the specific assumptionsmathematically. The results that followfrom these assumptions emerge throughthe principles of mathematics, whichreduces the possibility of logical errors atthis step of the process.

Darwin’s [22]theory of natural selection represents onesuch model, and many others havefollowed since; for example, Mullerproposed that genetic recombinationmight evolve to prevent the buildup of

Thus, neutraldiversity patterns will depend not only on the rate of genetic drift,but also on the rate at which variation is lost due toselection at linkedsites;

Undersimplifying assumptions, the rate of genetic drift is inverselyproportional to the population size.

Efforts to address such questions spurred therise of modern population genetics and contributed to thedevelopment of theneutral theory of molecular evolution—the nullhypothesis for much of evolutionary genetics and comparativegenomics [1–3]

Whereaspsychoanalysis posited that anxiety resulted from early-life developmentswith mothers and fathers, later mapped onto husbands and wives, mepro-bamate worked on the thalamus, the alimentary tract and other sexedstructures that functioned independent of gender.69

‘The Business of Running a Home’.40In 1956, Look magazine celebrated the housewife as ‘this wondrouscreature’ who ‘marries younger than ever, bears more babies, and looksand acts far more feminine than the emancipated girls of the 1920s oreven the 30s ... she gracefully concedes the top job rungs to men’.41

chemists

This then allows the conscious, structured by the laws ofthe superego, to build a civilisation. When the ‘maternal’ returns and pro-gress halts, as Irigaray argues in the end of Speculum, ‘man turns awayfrom his fears and projects them onto the woman’.

How-ever, the child does not entirely give up the desire for mother – instead heplaces the emotions and memories that constitute the notion of motherbelow the radar of consciousness, and in this act of repression the uncon-scious is formed.

In Inhibitions, Symptoms, and Anxiety,anxiety is defined as an uncanny alarm reaction that causes a subject tore-experience briefly the apperception of vulnerability

Left untreated, symptoms diagnosed in these mothers causedloneliness and suffering – in men. Yet, after taking ‘the drug’, as Cosmo-politanexplained in January 1956, ‘frigid women who abhorred maritalrelations reported they responded more readily to their husbands’ advances’.

Emphasis on the Valium craze of the 1970s, however, has caused manyscholars to overlook the 1950s as a decade in which key links were forgedbetween ‘mothers’ and psychopharmacological medications.

I’d like to propose a consideration of the temporalities of the states of debility and disability (alongside the more commonplace processes of aging and daily rest) as potentially resistive to capitalism and other forces of oppression

This project is grounded in an understanding that “wellness” culture is fundamentally a capitalist enterprise, which aims to sell our bodies back to us amidst a scarcity of resources and language to address new environmentally caused and chronic illnesses that are rapidly unfolding

. I want to valorize my time in ways that have nothing to do with work,to say a big “fuck you” to every person at a dinner party who has ever pointedly asked me,“So...what do you do?” because I haven’t “done” much in a long time. The story I’m telling hereis equal parts a processing of the trauma of illness and an exploration of how the body istreated under the regime of capitalism.

This is true, but I was willing to listen to the suggestions of peoplewho actually lived with the disease over advice from those who merely studied it

The doctors insisted on a risky treatment of biologic drugs, either Humira or Remicade. Bothare immune suppressants with the potential for terrifying side effects. Humira is self­injectedevery two weeks and Remicade is given as an infusion in a chemo center every other month.They told me there was no alternative, but I’d heard that there were other drugs worth trying. Irefused to believe that the treatment they offered was my only option. I insisted on a secondopinion and asked to be discharged. They sent in medical students, nurses, residents, interns,and doctors to tell me that biologics were the only way. I was eventually taken off of theineffective anti­inflammatory steroids

Both areautoimmune in nature. Crohn’s is a disease of the intestinal tract, while AS affects the spineand peripheral joints. The doctors were sparing in their emotional presence. Of cours

Would Christian faith, she asks suddenly, give its believers enough conviction “to leap straight into Heaven off Beachy Head?” (a well-known suicide spot).

They won’t accept the “co-operative” conventions. They blurt things out. They turn sym- pathisers away. They won’t go to work. They lie down. They waste time. They fantasise. They don’t go to Church or believe in Heaven.

Besides, illness really prefers solitude. “Here we go alone, and like it better so.” The ill have dropped out of the army of workers and become deserters. This gives them time to do things normal people can’t do, like looking at the clouds or the flowers. And what they find comforting about clouds and flowers is not their sympathy, but their indifference.

Her fan- tasy, in On Being Ill, of a secular, literary after-life consisting of gossip, conversation, and play-acting, is enacted in the tone of the essay itself

She tinkered considerably, too, with the wording about lines of poetry which speak to us in illness, cutting phrases about words which “spread their bright wings, swim like coloured fish in green waters,” words which “ripple like leaves, and chequer us with light and shadow.” It’s as if, on re-reading, this eloquent, mysterious passage seemed too fanciful to her.

Absence and distance are themes in both essay and novel.

the whole landscape of life lies remote and fair, like the shore seen from a ship far out at sea.” Cam, in the boat going to the lighthouse, will echo this: “All looked distant and peaceful and strange.

Their letters became more intimate, and Woolf noted in her diary that “The best of these ill- nesses is that they loosen the earth about the roots. They make changes. People express their affec- tion.”* Just so, in On Being Ill, “illness often takes on the disguise of love...” wreathing “the faces of the absent...with a new significance” and creating “a childish outspokenness.”

“The Dr has sent me to bed: all writ- ing forbidden.” “Can’t make the Dr. say when I can get up, when go away, or anything.” “I feel as if'a vulture sat on a bough above my head, threatening to descend and peck at my spine, but by blandish- ments I turn him into a kind red cock.

But, in her writings about illness—as here—there is also a repeated emphasis on its creative and liberating effects. “I believe these illnesses are in my case— how shall I express it?—partly mystical. Something happens in my mind.”* On Being Ii] tracks that “something” in the “undiscovered countries,” the ‘virgin forest,” of the experience of the solitary invalid.

It seems possible, though unprovable, that she might have had some chronic febrile or tubercu- lar illness. It may also be possible that the drugs she was taking, for both her physical and mental symp- toms, exacerbated her poor health.

At the begin- ning of 1922, these symptoms got so bad that she consulted a heart specialist who diagnosed a “tired” heart or heart murmur. Teeth-pulling (unbeliev- ably) was recommended as a cure for persistent high temperature—and also for “neurasthenia.” (So the visit to the dentist in On Being I// is not a change of subject.)

By its sleight- of-hand and playfulness, and its appearance of having all the “space and leisure” in the world for allusion and deviation, it gallantly makes light of dark and painful experiences.

It “treats” not only illness, but language, religion, sympathy, solitude, and reading.

‘The centuries old practice of farmer saved seed isreally a gross disadvantage to third world farmers who inadver-tently become locked into obsolete varieties because of theirtaking the ‘easy road’ and not planting newer, more productivevarieties’.