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Homeowners often have a toolkit ready for repair jobs around the house. A handy homeowner can easy take care of simple, uncomplicated problems such as clogged drains or burst pipe. Home plumbing skills are easily acquired over time. Tradie Hotline Plumbers are the best when it comes to all the plumbing issues. You can save some money and time by doing some of the repair jobs at home.
Critical info
Plumbing jobs for Home Plumbers
If you want a technical job that is varied and allows you to move up and about, then this is the right career for you. As a professional, your services will be needed in different areas such as the kitchen, bathroom, ventilation, air conditioning, gas servicing and heating. Plumbing is very critical in any home. Plumbing systems are known to fail from time to time.
SKILLS required to BE A GOOD PLUMBER
- A good plumber needs problem-solving skills as there are new challenges every day that require you to be a quick thinker.
- Following through with technical plans is another skill that a plumber should have. This type of job needs a keen person who can see every small detail with precision and care to get the job well done.
- You should understand the value of safety and health. As this job deals with homes, there is a great need for attention to health and safety matters so as not to endanger the residents of the home.
- You will be walking into many homes and premises and dealing with different personalities. You will, therefore, need to have excellent customer care skills.
- The ability to work well alone or in a team is very crucial as you may find yourself in a situation where you are required to collaborate with others.
- A good approach to work is also required as you will have to deal with functional objects that should be handled carefully and in a certain order.
- Physical fitness, though not necessary, may prove helpful as plumbing is practical work that requires muscle and a handy person. While any individual can easily navigate around the plumbing areas, it would benefit you if you can work and move around with ease.
- Install water heaters, water supplies, and drainage.
- Repair faults in systems and equipment
- Service boilers and heaters
- Install domestic appliances such as cookers, gas fires, washing machines, and showers
- Service ventilation units and air conditioners
- Fix leaks
To become the best home plumber, you will need to complete technical education in a recognized institution and acquire the right qualifications. Some prefer to get this knowledge via apprenticeship.


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A JANUARY meeting on a freezing football pitch led to 50 years of marriage for a Marsden couple.
Robert and Evelyn Lambert, of Netherley Drive, have just celebrated their golden wedding.
They were married at St Bartholomew's Church in Marsden.
Mrs Lambert, who was born in Marsden, met Mr Lambert, from Gorple, near Hebden Bridge, while he was playing football at Marsden.
The couple lived with Mr Lambert's parents at Milnsbridge, before moving to Outlane. In 1956, they moved to Netherley Drive, before building their current house, just yards away, in 1991.
Mrs Lambert was a mender at a Linthwaite mill and was a warden for the elderly. Mr Lambert ran the family firm, Lambert's Haulage, for 25 years.
The couple celebrated their anniversary with two surprises organised by their four children.
Mrs Lambert had to decipher a puzzle - which led to the couple having a week's holiday at a hotel. Later they were treated to a surprise meal.

subset: commoncrawl


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Orthodoxy (from Greek ὀρθός, orthos ("right", "true", "straight") and δόξα, doxa ("opinion" or "belief", related to dokein, "to think"),[1]) is adherence to accepted norms, more specifically to creeds, especially in religion.[2] In the Christian sense the term means "conforming to the Christian faith as represented in the creeds of the early Church".[1]
- History 1
- Christianity 2
- Related concepts 3
- See also 4
- References 5
The earliest (first) recorded use of the term "orthodox" is in the Codex Iustinianus of 529-534,[3] but "heterodoxy" was in use from the beginning of the first century of Christianity.[4]
The concept of orthodoxy is prevalent in many forms of organized monotheism. However, orthodox belief is not usually overly emphasized in polytheistic or animist religions, in which there is often little or no concept of dogma, and varied interpretations of doctrine and theology are tolerated and sometimes even encouraged within certain contexts. Syncretism, for example, plays a much wider role in non-monotheistic (and particularly, non-scriptural) religion. The prevailing governing idea within polytheism is often orthopraxy ("right practice") rather than "right belief".
In classical Christian usage, the term orthodox refers to the set of doctrines which were believed by the early Christians. A series of Ecumenical Councils, also known as the First seven Ecumenical Councils, were held over a period of several centuries to try to formalize these doctrines. The most significant of these early decisions was that between the Homoousian doctrine of Athanasius and Eustathius (which became Trinitarianism) and the Heteroousian doctrine of Arius and Eusebius (called Arianism). The Homoousian doctrine, which defined Jesus as both God and man with the hypostatic union of the 451 Council of Chalcedon, won out in the Church and was referred to as orthodoxy in most Christian contexts, since this was the viewpoint of the majority. (The minority nontrinitarian Christians object to this terminology).
Following the 1054 Great Schism, both the Western and Eastern Churches continued to consider themselves uniquely orthodox and catholic. Over time the Western Church gradually identified with the "Catholic" label and people of Western Europe gradually associated the "Orthodox" label with the Eastern Church (in some languages the "Catholic" label is not necessarily identified with the Western Church).
Today, the two largest "Orthodox" Christian communions are the Eastern Orthodox Church (often simply "Orthodoxy") and Oriental Orthodoxy.
Related concepts
Orthodoxy is opposed to heterodoxy ("other teaching") or heresy. People who deviate from orthodoxy by professing a doctrine considered to be false are called heretics, while those who, perhaps without professing heretical beliefs, break from the perceived main body of believers are called schismatics. The term employed sometimes depends on the aspect most in view: if one is addressing corporate unity, the emphasis may be on schism; if one is addressing doctrinal coherence, the emphasis may be on heresy.
Apostasy is a violation of orthodoxy that takes the form of complete abandonment of the faith. A deviation lighter than heresy is commonly called error, in the sense of not being grave enough to cause total estrangement, while yet seriously affecting communion. Sometimes error is also used to cover both full heresies and minor errors.
See also
- Belief in Jesus
- Catholic Christianity
- Council of Nicaea
- Council of Chalcedon
- Chalcedonian Christianity
- Neo-orthodoxy
- Orthodox Christianity
- Orthodox Judaism
- Orthodox Islam
- Orthopraxy
- Paleo-orthodoxy
- Proto-orthodox Christianity
- Rule of Faith
- Theology
- ^ a b orthodox. Dictionary.com. Online Etymology Dictionary. Douglas Harper, Historian. Dictionary Definition (accessed: March 03, 2008).
- ^ orthodox. Dictionary.com. The American Heritage Dictionary of the English Language, Fourth Edition. Houghton Mifflin Company, 2004. Dictionary definition (accessed: March 03, 2008).
- ^ Liddell & Scott; Code of Justinian: "We direct that all Catholic churches, throughout the entire world, shall be placed under the control of the orthodox bishops who have embraced the Nicene Creed."
- ^ (Mohr Siebeck 2005 ISBN 978-316148561-9), p. 342The Formation of the Early ChurchJostein Ådna (editor),


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'Disheartening, Divisive': 9/11 Widower Answers Cruz's 'NY Values' Criticism
Trump Goes After Cruz: 'Everybody Hates Him, He Won't Get Any Deals Done'
Judge Jeanine Slams GOP Establishment for Subverting Trump: 'Support Your Frontrunner!'
A retired NYPD officer and 9/11 widower hit back at Sen. Ted Cruz (R-TX) for his recent remarks about "New York values," calling them disheartening and divisive.
In an interview on Fox News Sunday, Cruz doubled down on his criticism of Donald Trump's "New York values," which drew a sharp rebuke from Trump at last week's GOP debate.
"That formulation didn't come from me. It came from Donald Trump. Donald Trump, when he was being interviewed by Tim Russert, when he was explaining his views a number of years ago," Cruz said.
Cruz has argued that Trump and others from New York City do not share the same conservative values as Iowans.
Speaking to Ashley Webster on Fox Business Network, former NYPD officer James Smith followed up on his recent Facebook post in which he invited Cruz to visit the 9/11 Memorial and "see for yourself, and perhaps learn something about, the values of New Yorkers."
Dear Senator Cruz,I was disappointed by your disparaging remarks about New York values somehow being different from...
Posted by James Smith on Thursday, January 14, 2016
Smith's wife, Moira, was the only female NYPD officer killed in the attacks on the World Trade Center on 9/11.
He said he believes Cruz's comments are "divisive" and that America needs the next president to bring the country together.
"We all believe in the same things. We all want the same things for our kids," said Smith.
Smith disputed that New Yorkers have values that are any different from anywhere else.
"Maybe we do things a little differently here, maybe we're a little more tolerant, but our values are the same. It was disheartening to see," said Smith.
Watch the interview above, and watch "Varney & Co." weekdays on FBN at 9a ET.
Police Desperately Searching for Missing 2yo Boy in TN
WATCH: Grandma's Unimpressed Reaction to 'Yeezy' Sneakers Goes Viral
'Donald Is Dismayed': Cruz, Trump Exchange Fire Over Birther Claims


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After 13 years and six full-length releases, Terror has earned widespread respect and established the model for consistency, authenticity and intensity. Rougher and tougher than its predecessors, "The 25th Hour" is 14 tracks of punishing, no-filler hardcore guaranteed to trigger pile-ons, stage dives and mosh pits at a venue near you.
1. The 25th Hour
2. No Time For Fools
3. Bad Signs
4. Feed The Rats
5. The Solution
6. Blinded By The Lights
7. Trust No Face
8. Why?
9. Mind At War
10. Snap
11. Sick And Tired
12. Life Goes On
13. Both Of You
14. Deep Rooted


text:
January 2014
Cyprus Banks Continue To Issue Proceedings Against UK Buyers
Clients receive Writs of Summons at their UK residences
29 January 2014
Can't decide whether to buy a property in the UK or abroad?
If you are toying between buying a property in Portugal, the Canaries or southern Spain or staying right here in Blighty, A Place in the Sun: Home or Away? needs you.
28 January 2014
Holiday rental ideas for February
If you haven't yet decided where to buy your overseas home, then renting a holiday home allows you to test the water and live like a local. Here we suggest some destinations ideal for rentals during the month of February.
28 January 2014
Time to invest in Tampa?
As our TV series heads to Tampa Bay area, we bring you the low down on the place
27 January 2014


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- Research article
- Open Access
Correct anteroposterior patterning of the zebrafish neurectoderm in the absence of the early dorsal organizer
- Máté Varga1, 2Email author,
- Shingo Maegawa1, 3 and
- Eric S Weinberg1Email author
© Varga et al; licensee BioMed Central Ltd. 2011
- Received: 4 January 2011
- Accepted: 16 May 2011
- Published: 16 May 2011
The embryonic organizer (i.e., Spemann organizer) has a pivotal role in the establishment of the dorsoventral (DV) axis through the coordination of BMP signaling. However, as impaired organizer function also results in anterior and posterior truncations, it is of interest to determine if proper anteroposterior (AP) pattern can be obtained even in the absence of early organizer signaling.
Using the ventralized, maternal effect ichabod (ich) mutant, and by inhibiting BMP signaling in ich embryos, we provide conclusive evidence that AP patterning is independent of the organizer in zebrafish, and is governed by TGFβ, FGF, and Wnt signals emanating from the germ-ring. The expression patterns of neurectodermal markers in embryos with impaired BMP signaling show that the directionality of such signals is oriented along the animal-vegetal axis, which is essentially concordant with the AP axis. In addition, we find that in embryos inhibited in both Wnt and BMP signaling, the AP pattern of such markers is unchanged from that of the normal untreated embryo. These embryos develop radially organized trunk and head tissues, with an outer neurectodermal layer containing diffusely positioned neuronal precursors. Such organization is reflective of the presumed eumetazoan ancestor and might provide clues for the evolution of centralization in the nervous system.
Using a zebrafish mutant deficient in the induction of the embryonic organizer, we demonstrate that the AP patterning of the neuroectoderm during gastrulation is independent of DV patterning. Our results provide further support for Nieuwkoop's "two step model" of embryonic induction. We also show that the zebrafish embryo can form a radial diffuse neural sheath in the absence of both BMP signaling and the early organizer.
- Zebrafish Embryo
- Vegetal Pole
- Morpholino Antisense Oligonucleotide
- Dorsal Organizer
- Spemann Organizer
The body plan of developing animal embryos is initially generated by establishment of the anteroposterior (AP) and dorsoventral (DV) axes. The dorsal organizer (i.e., Spemann organizer and homologous structures) is clearly important in formation of the DV axis (reviewed in [1–3]), but its role in AP axis development has been controversial (reviewed in [4, 5]). Failure to form the Spemann organizer in frogs and fish [6–8] results not only in the absence of dorsal tissues, but also in the loss of anterior regions of the embryo. Nevertheless, there is also evidence that at least some degree of proper AP patterning occurs with surgical removal or genetic ablation of the organizer in mouse, chick, and zebrafish embryos [9–17]. In zebrafish and Xenopus embryos unable to form a dorsal organizer, head neurectodermal markers are still expressed in proper relative AP order if BMP signaling is absent [8, 18, 19]. The orientation of the AP axis with respect to the animal/vegetal (AnVeg) axis has also been disputed. Some have argued for the equivalence of the AP axis with the "classic" DV axis of anamniotes [20–22], while others have proposed a concordance of the AP and AnVeg axes in these groups [5]. As the function of the organizer may obscure an underlying mechanism that establishes AP pattern, we chose to further study the control of AP axis formation in embryos genetically blocked in the ability to form a dorsal organizing center.
Embryos bred from females homozygous for the ich mutation (ich embryos) show a reduction of maternal β-catenin-2 expression. Furthermore, treatment of wild-type embryos with a morpholino antisense oligonucleotide (MO) targeting β-catenin-2 causes a failure of organizer formation and loss of anterior tissues, whereas loss of β-catenin-1 alone has no ventralizing or posteriorizing effects [8]. Using a TOP-GFP Wnt-reporter line, we showed that while the MO against β-catenin-2 (βcat2MO) could eliminate the dorsal marginal expression of the transgene in shield stage embryos, a MO against β-catenin-1 (βcat1MO) had no effect in this region [23]. In contrast, the germ-ring transgene expression was abolished only when the two MOs were administered together, showing that this domain of expression was mediated redundantly by both β-catenins [23]. Injection of both MOs into wild-type embryos, or of βcat1MO to ich embryos already deficient in β-catenin-2 expression, caused the ectopic induction of chordin (chd) and noggin1 (nog1) around the blastodermal margin of the embryo [8, 23]. Such embryos deficient in both β-catenins develop a distinctive phenotype at 24 hpf (termed 'ciuffo'), in which a protrusion of tissue from the vegetal end of the yolk expresses neurectodermal markers in an apparently proper AP pattern. This expression is dependent on chd [8, 23]. The massive expression of chd in βcat1MO + βcat2MO-treated embryos would be expected to result in a marked inhibition of BMP signaling due to the direct binding of Chd to BMP ligand [24].
In the work presented here, we first show that ich embryos injected with βcat1MO + βcat2MO or with bmp2bMO alone both exhibit loss of BMP signaling and upregulate chd. Previously, we demonstrated that in 'ciuffo' embryos, key specific markers of the early organizer are never induced [8] and expression of goosecoid (gsc) [25] and chd are dependent on the endogenous, germ-ring expression of Nodal homologues [23].
Here we provide definitive evidence that the upregulation of chd in bmp2bMO-treated ich embryos is not due to the ectopic induction of organizer tissue, since other typical markers of the early and late dorsal signaling center are not induced. The ectopic expression of chordin appears to be a consequence of downregulation of BMP signaling, and not due to radialization of an early dorsal organizing center. Using embryos at several developmental stages, we show that both anterior and posterior neurectodermal markers are expressed with correct AP pattern, even in the absence of the organizer, as long as BMP signaling is inhibited. We then show that the same pathways that are involved in setting up the AP neurectodermal pattern in wild-type embryos - Wnt-, Nodal-, and FGF signaling - are required for elaboration of the full AP pattern in the absence of BMP and organizer signals. Finally, we examined the morphology of the neurectodermal tissue in 'ciuffo' embryos and found that cells with neuronal identity are organized in a sheath of mesoderm and endoderm, similar to the neural net present in cnidarians. We speculate that during the evolution of bilaterian precursors, the establishment of a DV-oriented BMP signaling gradient during embryogenesis resulted in the transformation of an outer radially organized, AP-patterned neural sheath, into the stereotypical vertebrate neural tube. This view extends the recent analysis of Meinhardt [5], which regards the generation of AP pattern of the vertebrate brain as an organizer-independent, ancestral, radially symmetric system.
Embryos deficient in canonical Wnt signaling show loss of BMP signaling
Ectopic expression of chd is also correlated with the repression of epidermal markers, as posited by the "neural default model" [34]. The ubiqitous expression of the epidermal marker p63 [35] observed in ich embryos (Figure 1L) is reduced upon the injection βcatMOs (Figure 1N), and completely abolished when bmp2bMO is used alone or in combination with the other MOs (Figure 1M,O). This latter result shows that in the absence of BMP signaling ectodermal cells can not acquire epidermal fates.
In summary, two different methods - injection of ich embryos with bmp2bMO or with βcat1MO + βcat2MO (i.e., 'ciuffo' embryos) - can be utilized to obtain embryos lacking the organizer and BMP signaling.
Impairment of BMP-signaling does not result in ectopic organizer formation
Unlike some other components of the early DV transcriptional network (e.g. squint (sqt) [15] and fgf8 [39]) that are first expressed dorsally at sphere stage and then followed by a pan-germ-ring upregulation at ~30% epiboly, boz and gsc are exclusively expressed in the dorsal side of developing wild type embryos, and are thus more definitive markers of the early dorsal signaling center and organizer. Furthermore, while the ectopic expression of these genes can induce a complete axis in zebrafish [40, 41], the overexpression of chd alone cannot do so, neither in wild type [41], nor in ich embryos (our unpublished observations). As is the case also in Xenopus [42], coinjection of chd mRNA with a Wnt-antagonist can induce anterior neural structures and notochord (our unpublished observations). But, unlike Xenopus, where chd is found to be necessary for the induction of a complete secondary axis [43], in zebrafish chd is dispensable for gsc-induced secondary axis formation [41]. These results offer clear evidence that the ectopic expression of chd in bmp2bMO-injected ich embryos is due to a global de-repression of its transcription in the absence of BMP signaling [44], and is not the consequence of ectopic induction of organizer tissue.
Inhibition of BMP signaling reveals normal AP neurectodermal patterning in the absence of the organizer
When injection of bmp2bMO is used to inhibit BMP signaling in these embryos, all four neurectodermal markers are expressed robustly in correct relative AP order in approximately the same AP position as in wild-type embryos (Figures 3G-I). The width of the expression domains is almost identical to those of wild-type embryos, but the expression is radial, extending completely around the embryo, rather than restricted to the dorsal side. (Similar results were observed with two other markers, otx1, expressed in the prospective forebrain and midbrain [48], and gbx1, expressed from the midbrain/hindbrain boundary posterior towards rhombomere 2 [49] (Additional file 1, Figure S1A-I)).
When βcat1MO + βcat2MO injection is used to inhibit BMP signaling, the results are similar in that all four markers are expressed in correct AP order (Figure 3J-L, Additional file 1, Figure S1J-L). The major difference is that expression is shifted towards the posterior of the embryo. The anterior cyp26 domain and the otx1 and gbx domains are wider, and the area of hoxb1b is restricted to a more posterior region of the embryo than is the case in wild-type or in bmp2bMO-injected ich embryos. We also tested the effects of injecting all three MOs on expression of the four markers (Figure 3M-O, Additional file 1, Figure S1M-O). Results for the more posterior markers gbx1 and hoxb1b are similar to the embryos treated with the two βcatMOs alone, while the expression of otx1 and the anterior domain of cyp26 is expanded to encompass the whole anterior 60% of the neurectoderm. Treatment with bmp2bMO, but not with the two βcatMOs, eliminates BMP signaling in the animal pole region (Figure 1C-E), thus permitting expression of these anterior markers in the former, but not latter, embryos. The expansion of expression of the anterior markers toward the vegetal pole in the triple MO-treated embryos, compared to embryos treated with bmp2bMO alone, is evidence for a posteriorizing role of Wnt/β-catenin signaling. When this signaling is eliminated by MO treatment, there is a marked posterior expansion of the zone of anterior identity.
A comparison of AP patterning in the neurectoderm of βcatMO-injected ich ('ciuffo') embryos and bmp2b morphant embryos cannot easily be carried out at later stages. After 11 hpf, bmp2bMO-injected ich embryos, like swr/bmp2b embryos [30], begin to burst and die as a consequence of severe constriction movements. The 24 hpf βcat1MO-injected ich embryos do survive and we already had good indication that their neurectoderm exhibited correct patterning [8, 23]. Two-color in situ hybridizations with four probes (emx1, krox20, val, hoxb6b) showing distinct restricted expression along the AP axis confirm and extend these results (Additional file 2, Figure S2). While none of these markers were expressed in ich embryos (Additional file 2, Figure S2B,E,H), they were all expressed in correct relative spatial order in embryos co-injected with βcat1MO and βcat2MO. The more anterior markers (emx1 in Additional file 2, Figure S2A-C', krox20 in Additional file 2, Figure S2D-I') were detected proximal to the yolk, while the posterior markers (krox20 in Additional file 2, Figure S2A-C', val in Additional file 2, Figure S2D-F' and hoxb6b in Additional file 2, Figure S2G-I') were expressed distal to the yolk. These results, along with the data presented on 10 hpf and 11 hpf embyos, indicate that the patterning pathways necessary to establish major neuroectodermal territories (forebrain, hindbrain and neural tube) are functional in 'ciuffo' embryos, and that these regions are demarcated with correct relative AP pattern.
We also tested ich embryos injected with βcatMO1 or bmp2bMO for expression of the more posterior hox genes hoxb6b, hoxb8a, hoxa9a, hoxd12, and hoxc13a at 24 hpf. (The majority of bmp2bMO-injected embryos die during earlier stages of development, but ~ 2% survive to 24 hpf.) Although we were unable to obtain good signals by in situ hybridization, and thus, were not able to determine if these genes were expressed in a proper relative AP pattern, RT-PCR assays did indicate the relative level of their expression in these embryos (Additional file 3, Figure S3). A signal was obtained for hoxb6b, hoxb8a, hoxa9a and hoxd12, but not for hoxc13a, in βcatMO1-injected ich embryos (Additional file 3, Figure S3 - lane 3), and for all five of these genes in bmp2bMO-injected ich embryos (Additional file 3, Figure S3 - lane 8). These results show that embryos lacking both organizer and BMP signaling have the potential to express not only anterior neurectodermal markers, but also trunk posterior markers. We also tested for expression of these genes in untreated ich embryos (Additional file 3, Figure S3 - lane 2) and found that the four most posterior markers were robustly expressed. This result is consistent with the finding that ich mutant embryos do express the earlier posterior neurectodermal markers sox3 and zic2.2, which are involved in tail neural tube formation [47].
AP patterning in the absence of the organizer is modulated by the same factors as in wild-type embryos
Wnt, Nodal, and FGF signaling pathways are all known to be involved in the posteriorization of neural tissue [45, 54–56], an effect they achieve by epistatic interactions between themselves and the retinoic acid (RA) pathway [45, 57]. As noted above, the absence of canonical Wnt/β-catenin activity in ich embryos injected with bmp2bMO expands cyp26 and otx1-expressing anterior neurectoderm towards the vegetal pole in comparison with embryos treated with bmp2bMO alone (Figure 3G,J,M; Additional file 1, Figure S1G,J,M). The posterior expansion can also be seen in the comparison of rx3 expression in ich embryos injected with the three MOs and embryos injected solely with bmp2bMO (Figure 4G,M). Also consistent with a posteriorizing role for Wnt signaling is the finding that the more posterior neurectoderm, as indicated by regions of hoxb1b, gbx1, and fkd3 expression, is shifted markedly to a more vegetal position when ich embryos are treated either with βcatMOs alone or with βcatMOs + bmp2bMO compared to embryos injected with bmp2bMO alone (Figure 3H,K,N; Additional file 1, Figure S1H,K,N; Figure 4H,K,N). These results show that the posteriorizing role of Wnt/β-catenin signaling is completely independent of BMP signaling. That there is still ample expression of the hindbrain markers hoxb1b and gbx1 in ich embryos injected with both βcatMOs suggests that other factors must act independently (or perhaps upstream of Wnt8 signaling) as posteriorizing agents. Supporting this idea is that 'ciuffo' embryos still express at least four posterior hox genes (Additional file 3, Figure S3).
TGFβ proteins also act as posteriorizing factors during normal zebrafish development. Injection into wild-type embryos of mRNA for antivin, a potent antagonist of Nodals and Activins, results in dramatic anteriorization, with the most severely affected embryos losing all parts of the neural tube except telencephalic tissue [54]. To determine if ligands inhibited by antivin are posteriorizing factors in the absence of BMP signaling and organizer, we co-injected antivin mRNA and bmp2bMO into ich embryos. These embryos exhibited complete anteriorization of the neuroectoderm, as indicted by ubiquitous expression of the anterior markers cyp26 and otx1 (compare Figure 3G with 3S; Additional file 1, Figure S1G with S1S) and complete loss of the more posterior markers otx1 and gbx1 (compare Figure 3H with 3T; Additional file 1, Figure S1H with S1T). The lack of expression of the anterior markers at the vegetal pole itself is not due to an absence of expression in vegetal neurectoderm; rather, it is a consequence of a failure to complete gastrulation by those embryos co-injected with both antivin mRNA and bmp2bMO (arrowheads in Figure 3S-U and Additional file 1, Figure S1S-U indicate the vegetal extent of the germ-ring at 10 hpf), an observation consistent with a role of activin in gastrulation movements shown in Xenopus [58, 59]. We also used an alternative method of inhibiting TGFβ signaling, the application of SB431542, a compound that inhibits Smad2/3-mediated TGFβ-signaling [60]. Embryos grown in SB431542 also exhibited a concentration-dependent anteriorization, and also stalled during gastrulation (Additional file 1, Figure S4). Interestingly, the posteriorizing effects appear not to be entirely due to Nodal signals, as inhibiting expression of these ligands by co-injection of MOs against squint (sqt) and cyclops (cyc), the two zebrafish Nodal homologues known to be expressed during these gastrulation stages [61–64], showed much less posterior expansion of cyp26 expression compared to antivin treatment (compare Figures 2G,S to Additional file 4, Figure S4M) and dramatically less reduction of hoxb1b expression (compare Figure 3H,T and Additional file 4, Figure S4N).
FGF signaling is yet a third signal transduction pathway known to posteriorize neurectoderm in wild-type embryos [16, 45, 65, 66]. To check if this signaling pathway also functions in embryos devoid of organizer and BMP signaling, we treated ich embryos inhibited in BMP signaling with SU5402, a small molecule inhibitor of FGF receptor activity [67]. Treatment with this compound caused the expansion of cyp26 and otx1 anterior marker domains (compare Figure 3G with 3Y; Additional file 1, Figure S1G with S1Y) and elimination of expression of hoxb1b and gbx1 posterior markers (compare Figure 3H with 3Z; Additional file 1, Figure S1H with S1Z). However, as SU5402 treatment itself appears to reduce the intensity of cyp26 and hoxb1b expression, we also employed other methods of inhibiting FGF signaling (the reduction in staining intensity might be due to a role of early FGF signaling in neural capacitation [T. Kudoh, personal communication]). Injections of mRNAs encoding a dominant negative FGF receptor (XFD) [68] or the MAPK-pathway antagonist mkp3 [69] yielded a similar expansion of the cyp26 domain (Additional file 5, Figure S5M,S compared with Figure 4G), but was less effective in eliminating the hoxb1b domain (Additional file 5, Figure S5N,T compared with Figure 4H). These latter results, however, are complicated by obvious effects on gastrulation movements that result in asymmetry of staining around the circumference of the embryo. All three FGF signaling inhibitors do, however, have dramatic anteriorizing effects on expression of neurectodermal markers.
In summary these observations show not only that embryos that fail to exhibit an early dorsal organizer show correct relative AP patterning in the absence of BMP signaling, but that this patterning is under posteriorizing control of Wnt-, TGFβ-, and FGF-signaling, just as is the case in wild-type embryos.
Diffuse neurectoderm surrounds mesoderm and endoderm in embryos lacking canonical Wnt signaling and impaired in BMP signaling
Correct anteroposterior patterning in the absence of the organizer and BMP signaling
The work described here adds to extensive evidence suggesting that an early dorsal organizer is not required for proper AP patterning of the vertebrate embryo. Surgical removal of the organizer in mouse, Xenopus, chick, and fish [9, 11–13, 70], transplantation experiments in zebrafish [16, 71], and genetic "ablations" of organizer tissue in mouse [10, 14] and zebrafish [15, 17, 72] all strongly suggested that the organizer is not required for generation of AP pattern.
However, these earlier experiments were not definitive. The ablation experiments in chick and mice were often followed by an almost complete restoration of the organizer [11], or did not completely eliminate the expression of all organizer-related genes [13]. In the zebrafish embryo, most genes with organizer activity are expressed before the shield becomes visible; thus, physical removal of this structure can not eliminate organizer activity completely [12]. Zebrafish embryos impaired in the Nodal signaling pathway display defective shield formation [15, 17], but dorsal expression of several organizer markers (e.g. chd, gsc, boz) can be observed during the development of mutant embryos [17, 73], and axis formation is not completely abolished even in sqt;cyc;boz triple mutants [72].
In the zebrafish embryo, a true genetic ablation of the dorsal organizer resulting in failure to induce any dorsal markers is really only achieved by the severe reduction of maternal β-catenin-2 in mutant ich embryos, or in embryos treated with MOs against β-catenin-2 [7, 8]. However, as ich embryos fail to form head, trunk, and most neurectodermal tissues, their phenotype is not informative for determining if loss of dorsal organizer results in altered A-P pattern.
The lack of importance of the organizer in generating neurectodermal A-P pattern dramatically revealed only when BMP signaling is inhibited in embryos lacking the organizer. The first indication of this was the outcome of an experiment of Ober and Schulte-Merker [18] in which vegetal yolk was removed from wild-type zebrafish embryos just after fertilization. Such embryos were completely ventralized with lack of organizer (embryonic shield) and neurectoderm formation, indicating that determinants of organizer formation are localized at or near the vegetal pole. However, when this vegetal yolk removal was performed on swr/bmp2b embryos (which lack BMP signaling) neural tissue did form and at least two neural markers appeared with appropriate AP pattern, but were expressed radially. A similar result was obtained by comparing double boz;chd embryos, unable to form an organizer and neurectoderm, with triple boz;chd;swr embryos, in which the ectoderm is neuralized and markers of the midbrain hindbrain boundary and rhombomeres are correctly patterned [74]. In the experimental work we have presented above, we can explain the restoration of correct A-P neurectodermal pattern found in embryos inhibited in expression of both β-catenins [8] as a consequence of the inhibition of BMP signaling due to the massive ectopic expression of chd in these embryos [23]. Our results show that this patterning is equivalent to embryos lacking maternal β-catenin-2 that have been inhibited in BMP signaling by injection with bmp2bMO.
We also provide the first report that simultaneous inhibition of BMP signaling and organizer formation results in proper neurectodermal patterning even during gastrula stages. In Xenopus, neurectodermal markers were expressed radially in proper relative AP order in the brain of embryos lacking both organizer and BMP signaling was shown at later neurula stages, but not during gastrulation [19]. In this case, the knockdown of BMP signaling was obtained by administration of MOs against three BMPs and organizer functions were eliminated by UV treatment or administration of a β-catenin MO. Thus, the consequence of simultaneous elimination of both BMP signaling and organizer formation in both zebrafish and Xenopus is robust formation of radially organized neurectoderm, including all regions of the brain, with proper relative AP pattern.
It is interesting that the pattern of embryonic neurectodermal AP domains is highly conserved between chordates and the radially organized hemichordates [75, 76], suggesting that the deuterostome ancestor had the same AP pattern and that generation of the AP axis is independent of the organizer. Moreover, the independence of the AP and DV axis, previously recognized in hemichordates [77], is also clearly shown in the zebrafish embryo when dorsal organizer formation is eliminated along with a reduction in BMP signaling.
Multiple organizer-independent signaling pathways posteriorize the neurectoderm
It is well established that one of the major posteriorizing signals during vertebrate embryogenesis is the canonical Wnt pathway, which acts as a morphogen along the AP axis of the neural plate to regulate the expression of patterning genes [55]. Zebrafish mutants which upregulate the pathway, such as masterblind/axin1 (mbl) [79] or headless/tcf3 (hdl) [80] exhibit a loss of anterior neural structures, whereas impairment of Wnt signaling results in the expansion of anterior neural compartments [45, 56]. Our results provide evidence that this posteriorizing effect of Wnt signaling is independent of the dorsal organizer. Injection of bmp2bMO alone into ich embryos clearly does not result in formation of organizer tissue (Figure 2C,F). Yet, inhibition of all detectable Wnt-signaling by the additional co-injection of the two β-catMOs [23] results in a marked expansion of anterior neuroectoderm (Figure 2M,O, Figure 3M,O). It should be noted as well that the persistence of considerable amounts of posterior markers under these conditions (Figure 2N, 3N) suggests that Wnts are not the only posteriorizing signals and that other, parallel-acting pathways function as well.
FGFs and activin-type TGFβ signals have also been implicated in AP patterning [54, 65]. Accordingly, injection of inhibitors of FGF and Nodal/Activin signaling into zebrafish embryos results in dramatic anteriorization of neural tissue [16, 45, 54]. By blocking these pathways in bmp2bMO-injected ich embryos, we were also able to induce dramatic reduction in posterior neuroectoderm and expansion of anterior neuroectodermal markers (Figure 3S-U,3Y-A', Additional file 1, Figure S1S-U,Y-A').
An alternative explanation for the observed shift in the position of the posterior markers in embryos treated with β-catMOs might be an altered posterior movement of mesodermal cells. By regulating cell-cell adhesion, the BMP gradient across the DV axis controls convergence and extension movements of lateral mesodermal cells in wild type embryos [81]. In 'ciuffo' embryos, we have demonstrated that an ectopic gradient forms between cells with active BMP signaling at the animal pole and the chd expressing cells of the germ-ring (Figure 1). This gradient is likely responsible for the excessive migration of cells towards the vegetal pole and the formation of the characteristic protrusions at 24 hpf. However, as triple morphant (bmp2bMO and the two β-catMOs) embryos show an almost identical posteriorization as 'ciuffo' embryos, without any sign of abnormal posterior cell movements, we think it unlikely that the posteriorization in 'ciuffo' embryos is due to such movements. We followed the post-gastrulation development of untreated and morphant ich embryos and although excess tissue can be readily observed at the vegetal pole of 'ciuffo' embryos at 12.5-13.5 hpf, the triple morphants resemble ich embryos treated with bmp2bMO alone, with tissue accumulation at both animal and vegetal sides (Additional file 6, Figure S6).
The "two step model" provides a comprehensive explanation for our observations (Figure 6). When the "activating", BMP-antagonist signals are absent, the effects of the "transformative" signals, although present, are masked by the lack of the neuroectoderm. This is the case in ich embryos, which lack expression of BMP antagonists and in which presence of BMPs is ubiquitous (Figure 6B). In contrast, the removal of BMP-signaling transforms the complete ectoderm to neuroectodermal fate, and patterning domains in ich embryos appear as circumferential rings (Figure 6E). The normal "transformative" posteriorizing signals clearly operate in these embryos but are not restricted by the ventral cues that would have functioned in the wild-type state. Under such conditions an impairment in the level of posteriorizing factors can be easily observed as a vegetal "shift" (anteriorization) in the position of neuroectodermal expression domains in ich embryos. The shift can be caused by inhibition of germ-ring Wnt8 signaling by treatment with both β-catMOs (Figure 6F), or by inhibition of Nodal/Activin with antivin or SB431542, or by inhibition of FGF signaling with SU5402 or mkp3 or XFD (Figure 6G). However, in the case of ich embryos treated with these Nodal/Activin or FGF inhibitors, the anteriorization is only observed in embryos also inhibited in BMP signaling (Figure 6G) as, otherwise, the ubiquitous expression of BMPs prevents formation of any neurectoderm at all (Figure 6D). 'Ciuffo' (i.e., βcat1MO-treated ich) embryos (Figure 6C) present a state quite similar to bmp2bMO-treated ich embyros, as the lack of canonical Wnt signaling induces large amounts of BMP-antagonists in a wide band extending from the germ-ring, allowing the "transformative" Nodal/Activin and FGF signals to operate. However, such embryos still retain BMP signaling in the animal pole region of the embryos and thus, neurectodermal markers are not expressed in the animal-most fourth of the embryo.
This model (which is similar to the one proposed earlier by Meinhardt based on theoretical considerations [5], and more recently by Niehrs based on the review of the existing literature [82]) also offers an explanation for multiple aspects of the dorsalized and ventralized phenotypes described in several zebrafish mutants. For example, the progressive loss of anterior neural tissue observed in embryos with different degrees of ventralization, such as less severe ich embryos (C2,C3,C4) [7] or chd and nog1 double deficient embryos (CI,CII) [83], is due to the smaller size of the ''activation" domain and not to a change in the "transformative" signal (Figure 6H,I). As anti-BMP signals fail to reach the animal-most region of the gastrula, markers of the forebrain (and often midbrain) will not be turned on. Similarly, in mutants of the BMP pathway, such as swr, somitabun (sbn) and snailhouse (snh) [30], the oversized BMP-absent area results in laterally expanded, but otherwise correctly positioned, expression domains during gastrulation (Figure 4J) [32, 84], indicating that the "transformative" signal is not perturbed in such embryos.
Our observations clearly refute the argument that the zebrafish AP and "classical" DV axes are equivalent [20, 21], as it is clear from work presented here that the prospective AP axis of the embryo coincides with the early animal-vegetal axis of the zygote. As Xenopus embryos deficient both in organizer formation and BMP signaling also express AP patterning markers circumferentially [19], we propose that the concordance of the AP and animal-vegetal axis is a general feature of the anamniote embryos.
'Ciuffo' embryos may reveal ancestral anteroposterior radial neurectoderm patterning
Two striking features of the neurectoderm of 24 hr 'ciuffo' embryos are the radial organization along the full AP extent of the embryo, and the location of cells of neuronal identity in a diffuse network close to the outer surface, while tissues of mesodermal and endodermal identity reside within the embryo. This organization is reminiscent of the supposed pre-Urbilaterian, proto-Eumetazoan ancestor. Comparative studies suggest that the Eumetazoan ancestor had a diffuse nerve net [85] and members of Cnidaria, the sister clade of Eumetazoa, still possess such a primitive nervous system. Although it is yet unclear how exactly the patterning of this structure occurs, it has been suggested that FGF and TGFβ signaling pathways play an active role in specifying the neuronal identities observed in Nematostella vectensis, an anthozoan cnidarian [86]. This view coincides with the evolutionary scenario suggested by Arendt et al. [87] in which BMP signaling was originally involved in the patterning of neuronal cell types and it was only adapted later to control formation of a centralized nervous system. Indeed, in several anthozoan species, asymmetric expression of BMPs and BMP antagonists has been observed, suggesting both that the origins of the bilaterian DV patterning system predate the Cnidarian - Eumetazoan split and that the system was originally not involved in driving nervous system centralization [88–91]. Strikingly, in Nematostella most BMP-components are expressed in the endoderm [90] and recent functional data indicates a major role in endoderm patterning (and a lesser role in neural differentiation) for the BMP pathway [92]. It is noteworthy that chordin and different bmp/dpp genes are expressed on the same side of the directive axis in Nematostella, suggesting a patterning center with functional similarities to the chd/admp-expressing vertebrate organizer [92]. Such a center alone is sufficient to create a BMP gradient in the embryo [93], most likely through the shuttling of Chd/BMP complexes [94]. As a similar system was recently described for sea urchins as well [95], we suggest that this might constitute a prototypical BMP signaling paradigm, which later evolved into the scalable BMP signaling system observed in some Bilaterians.
Interestingly, some larval hemichordates (which together with echinoderms form the sister group of vertebrates in Deuterostoma) also possess a diffuse, epidermal neural network (reviewed in Gerhart et al. [96]). New research, however, suggests that this feature is not homologous with the vertebrate neural plate (as has been previously suggested [77]), but is a transient larval adaptation of certain hemichordate species [97]. As whenever a CNS is present in Bilateria, it develops on the side of BMP antagonism [87], it can be inferred that a centralized nervous system, regulated by BMP signals, is the ancestral state for all bilaterians. In echinoderms and certain hemichordates, where centralization is not observed, a secondary loss might have occurred during the evolution of these lineages [98]. By eliminating Wnt signaling and greatly reducing BMP signaling in 'ciuffo' embryos, we can observe the lack of restriction of neurectoderm to a particular DV level. That the potential for such a "diffuse nerve net" exists in a chordate species suggests that the evolutionary transition between a centralized and diffuse nervous system might have involved only a quite limited number of steps.
The organizer apparently arose in a chordate ancestor, as a signaling center homologous to the vertebrate organizer has been found in the cephalochordate (amphioxus) Branchiostoma floridae [99]. As tunicates are now considered the sister group of vertebrates, and amphioxus is more distantly related, it is likely that the organizer was lost in tunicates [99]. Chordate embryos have evolved the organizer to provide among other signaling functions, a specialized temporal and spatial program of BMP antagonist expression which acts on a pre-existing, extremely highly conserved pattern of AP tissue specification. As the AP pattern of gene expression appears to be widely conserved throughout the animal kingdom, it will be of interest to test whether the same pattern-generating "transformative" signals operate in hemichordates and non-vertebrate chordates. Wnt signals have already been shown in cephalochordates (amphioxus) to be expressed posteriorly, around the germ-ring, very much as in fish and amphibians, indicating that Wnts are a posterior "transformative'" signal characteristic of chordates [99–101]. In amphioxus, the effects of this signal appear to be strongest at the posterior end of the embryo, while retinoic acid has a more important role in determining AP identity elsewhere [100]. Wnt signaling is an extremely ancient mechanism of patterning the body axis [82, 102], as it operates to specify position along the main body axis of the cnidarian Nematostella vectensis (a sea anemone) [103, 104]. There is virtually nothing known, however, about FGF and Nodal signaling as potential "transformative" signals in non-vertebrate embryos.
Our work provides evidence for the organizer-independent AP patterning of the neuroectoderm in the developing zebrafish gastrula. We observed correctly located AP neurectodermal domains in the organizer-less ich mutant embryos when BMP-signaling was inhibited. The position and size of these domains depends mainly on the action of Wnt-, FGF- and Nodal signaling, originating from the germ-ring of the gastrula. These observations can be easily interpreted within the framework of Nieuwkoop's "two step model": the observed neurectodermal pattern in wild type fish is the result of the concerted action of "activating" and "transformative" signals (in the case of the zebrafish, BMP-antagonists and germ-ring-derived morphogens, respectively).
Our results also clearly refute recent proposals about the equivalency of the AP and "classical" DV axes in anamniotes, as the concordance of the AP axis with the AnVeg axis of the early embryo is evident.
When both Wnt- and BMP-signaling was inhibited in ich embryos, they developed into a well patterned tube-like structure, where a neurectodermal sheet envelopes inner mesodermal and endodermal tissues. In this neurectodermal domain scattered neuronal progenitors can be detected. Therefore, we speculate that vertebrates still retain the genetic program to form an ancient radially-organized diffuse neural net, and that only a limited number of changes in this program may have been necessary to form a neural-tube type of organization.
Zebrafish strains and husbandry
Zebrafish were maintained under standard conditions [105]. Wild-type embryos were derived from AB parents, while ichabod p1 (ich) embryos were obtained by breeding homozygous ich females with brass or ich males. Only those ich females that reproducibly yielded severely ventralized Class 1 (or Class 1a) phenotypes (for details see [7, 40]) were used. All animal work described here was carried out under Protocols 700433 and 801973 approved by the Institutional Animal Care and Use Committee (IACUC) of the University of Pennsylvania. This committee approves animal work only if it follows internationally recognized ethical and experimental guidelines.
Morpholino antisense oligonucleotide and mRNA injections
β-catenin-1-MO (βcat1MO) [8], β-catenin-2-MO (βcat2MO) [8], bmp2bMO [26], sqtMO [106], and cycMO [107] were manufactured by Gene Tools (Philomath, OR) and the sequences of each are as published. Clones used to prepare sense mRNA were as follows: mkp3 in pCS2+ [69] and antivin (lefty1) in pCS2+ [108]. mRNAs were synthesized and capped using an mMessage mMachine Kit (Ambion), following the manufacturer's protocol. RNAs and morpholinos were stored in dH2O at -20°C and injection solutions were prepared by diluting a 2 × stock of reagent in dH2O with an equal volume of Dulbecco's modified phosphate-buffered saline containing 5% phenol red (Sigma). Approximately 1 nl of solution was injected into the yolk at the base of blastomeres of 1-4 cell embryos. The concentration of these antisense and sense reagents that were injected per embryo were as follows: βcat1MO and βcat2MO (β catMOs) (3 mM each), bmp2bMO (0.4 mM), sqtMO and cycMO (0.6 mM each), and antivin (atv) mRNA (200 ng/μl).
Small molecule treatments
SB431542 (Sigma) and SU5402 (Calbiochem) were used at indicated concentrations to block TGF β-activin and FGF signaling, respectively. The reagents were dissolved in DMSO and added to the culture medium at the 1000-cell stage. Embryos were kept in the dark until fixed.
RT-PCR experiments
Total RNA isolated from pooled samples of 10 embryos was used to generate cDNA using the SuperScript II kit (Invitrogen), following the manufacturer's protocol. The primers used in the experiment were as follows (all shown in 5'-3' orientation): krox20-F: CTGCCAGCCTCTGTGACTA, krox20-R: CCATGGTGCAGCTGAGAGT, hoxb6b-F: CTGACCGCTCGTGCGCTAT, hoxb6b-R: ATCTTCCTCATCGCTGACCTT, hoxb8a-F: GCAGAGTCCATGTGCGGTAA, hoxb8a-R: CAATCCGACGCTTGCGTGTT, hoxa9a-F: AACTGAGCCACCGACGGTTA, hoxa9a-R: TCTTCATCCTGCGGTTTTGGA, hoxd12-F: GTCACTGAGCGCCCAGAAT, hoxd12-R: CAGTTCCAATCTGTCCGAAA, hoxc13a-F: CCACGTCACGATGCATTGAT, hoxc13a-R: TAACTTGACGTTCTGAGAGGTT, ef1a-F: ACCGGCCATCTGATCTACAA and ef1a-R: CAATGGTGATACCACGCTCA.
Whole mount in situhybridizations and immunohistochemistry
The following clones were used to prepare antisense probes for hybridization: p63 [35], krox20 [53], emx1 [109], val (D. Grunwald, cDNA library), cyp26 [45], hoxb1b [46], hoxb6b [110], otx1 [48], gbx1 [49], rx3 [50], boz [38], gsc [25], chd [111] and fkd3 [51]. Antisense RNA probes were synthesized and two color in situ hybridization was carried out as previously described [23]. For embryos older than 24 hpf (Figure 5; Additional file 1, Figure S1) NBT/BCIP was used as primary chromogen, as it gave better results. Whole mount embryos were imaged with a Leica MZ12 stereomicroscope, using a Roper Scientific Photometrics RGB Vision MS-C digital camera system (CRI, Inc, Boston, MA).
For manual sections (Figure 5) embryos subjected to whole-mount in situ hybridisation were cleared in serial incubations of glycerol (25, 50, 75 and 95%). Sections were placed in a drop of glycerol, cover-slipped, and imaged with 40 × (0.8 NA) water-immersion lens using a Nikon E1000 microscope connected to a digital camera (Jenoptik) operated by Openlab (Improvision) software.
For immunohistochemistry, embryos were fixed in 4% PFA, blocked in standardized blocking solution (10% fetal bovine serum, 1% DMSO, 0.8% Triton-X in PBS), incubated overnight at 4 C° with a 1:100 dilution of anti-phospho-Smad1/5/8 antibody (Cell Signaling Technology), followed by a 1:200 dilution of goat anti-rabbit Alexa Fluor 488-conjugated antibody (Invitrogen). To visualize the nuclei, embryos were incubated in 1:1000 dilution of TO-PRO®-3 iodide (Invitrogen) DNA stain in PBST. After several washes the specimens were mounted in 1% low melting point agarose, and imaged on a Leica TCS SP Confocal Microscope using ×10 objectives. Image reconstruction was performed using Volocity (Improvison) software.
All figures were composed using Adobe Photoshop and Illustrator (CS3).
We thank Joshua Bradner for fish care and technical help, Gianfranco Bellipanni for helpful and stimulating discussions and Steve Wilson and Jon Clarke for gifts of SB431542 and SU5402. This work was supported by NIH grant R01 HD39272 to E.S.W.
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This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


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Slashfilm reports that the running time of Logan has been extended. Worry not for reshoots, it seems the runtime has been increased for a far more sinister purpose, showcasing future Fox Films. A buddy who works at the theater was kind enough to help me copyt/paste a description of the trailer from Slashfilm's website, although it wasn't easy. Be forewarned there are spoilers below!
F42:F4Eva Trailer Description Below:
The scene opens on a picture of a desolate planet. The wind picks up, blowing a cloud of dust across the alien world. A metallic rasp is heard as a metallic faceplate is revealed. Dramatic music begins playing.
Title card reads 'It took four people to save the world.' Fade.
Interior Baxter Building. Ben's voice says "Reed, you have to cure me." Fade.
'But some of them paid a higher price than others.'
Miles Teller looks imploringly at the camera. "Ben, It's too risky. It could kill you." The half-blooded child of a turd and a Rock-Biter looks resolute. "I have to try Reed. I have to try." Fade.
'And some weren't done paying.' Fade to ben with his humanity restored, dying in a hospital bed of radiation poisoning. Cut to his Funeral. Everyone looks sad except for Kate Mara, who has the same wooden expression on her face. The human torch was recast as Marlon Wayans.
'But when the world is threatened again...' Fade.
A shadow slowly spreads across the funeral possession as something blocks out the sun. People take off sunglasses and look up in fear. Kate Mara looks... Hungry? Bored? I can't tell. Marlon trips over a chair when he tries to flame on. There's a purple Borg Sphere in the sky. You can almost see the string.
'By an enemy from the past' Fade.
Famous video blogger and arch-nemesis Doctor doom cackles as he takes over the TV. "I will have my revenge on reed Richards with the help of my new alley Kang!" Kang sounds like John Leguizamo, and his costume makes him look like a lilac-colored Power-Ranger.
Lots of flashes of scenes of explosions, Marlon's flaming comic relief, the worst costumes you have ever seen. "Oh no. How will we ever find someone tough enough to replace ben?"
' How will they ever find someone tough enough to replace ben?' Fade.
"Hello, you've Reached Wade Wilson." Wade Wilson answers the phone. "Uh-huh. Uh-huh. Aliens you say. Uh-huh. From the future? Okay. Hold on one Sec." Miles cringes as he hears gunshots in the background. "Okay, I'm back. Visa or MasterCard?"
'But will it be enough?' Fade.
At this point the trailer goes insane with the rapid-fire scenes and the dramatic music. More Explosions. Wade in costume. DR Doom monologuing with cloven hooves. Wade in a hoody. Wade in a Fantastic 4 Costume. Alien invaders coming down in their space ships. Kang monologuing. Doctor Doom Exploding heads. Wade shooting a lot of aliens. Wade playing space invaders using one of Reed's death rays. A lot of scenes of the other three of them standing around while Wade
Coming in 2018, F42:F4EVA
And just when we thought we were safe, the threat suddenly becomes very real. Run. Run while you still can. See the trailer when Logan hits theaters on March 3rd.


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19 militants killed in clashes with Pak army
At least 19 militants including five commanders and seven soldiers were killed during a clash in Pakistan's North Waziristan tribal region, said the military on Monday.
A statement by Pakistan military's Inter Services Public Relations (ISPR) said, "19 terrorists were killed, including five of their commanders, in an intense exchange of fire with security forces last night in an unclear pocket along the North Waziristan-Afghan border. When being chased and cordoned, one militant exploded himself killing seven soldiers." The suicide bomber exploded himself on the Laddha-Shawal axis on the boundary between North and South Waziristan tribal regions.
North Waziristan is one of seven tribal districts of Pakistan bordering Afghanistan and Pakistan military has launched a comprehensive operation against the foreign and local militants in the region.


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Kathy C. Lynn Md
- Macon US-GA
- [email protected]
Rheumatologist Kathy C. Lynn, M.D., works as an Assistant Professor of internal medicine and rheumatology at the Mercer University School of Medicine in Macon and teaches medical students and residents at The Medical Center of Central Georgia. Kathy C. Lynn, M.D., serves as one of more than 278 faculty members of the Mercer University School of Medicine, which boasts an enrollment of 350 students and grants several kinds of medical degrees. Kathy C. Lynn, M.D., also teaches medical students and residents at Georgia's second largest hospital, The Medical Center of Central Georgia, a full-service hospital that houses more 600 beds and serves an estimated population of 750,000. In addition, she works on case reports and publications as a member of the faculty there. In addition to her role as an instructor, Kathy C. Lynn, M.D., works in a private practice focusing on rheumatology, an internal medicine sub-specialty that focuses on treating diseases in the joints, muscles, and bones. Kathy C. Lynn, M.D., also serves as an Attending Physician at the Anderson Health Care Rheumatology Clinic. She graduated from the Mercer University School of Medicine and completed a two-year rheumatology fellowship at Emory University School of Medicine in Atlanta. When not working, Kathy C. Lynn, M.D., enjoys reading books from a diverse range of authors that includes Barbara Kingsolver, Lauretta Hannon, Jane Walker, Raleigh Kirby Godsey, Ferrol Sams, Janisse Ray, and Nancy Grace. Kathy C. Lynn, M.D., also likes to garden, water ski, and kayak. She is a member of the environmental group, the Altamaha Riverkeeper, and Georgia Wilderness Society, a group of outdoor enthusiasts who travel throughout the southeastern United States to enjoy hiking, canoeing, and other activities.


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Focus on good health with this week's meetings and events.
Arthritis. Members of Arthritis Self-Help (MASH) meet for gentle exercise. Kaiser Permanente Medical Center Conference Center, Conference Room E, 25825 S. Vermont Ave., Harbor City, 3 to 4 p.m. Thursdays. All are welcome to attend. Call 310-548-3040.
Bereavement. The Good Grief support group is a free program of the Stephen Ministry. The group is open to all members of the church and the community who have experienced the death of a loved one. The Neighborhood Church, 415 Paseo del Mar, Palos Verdes Estates. A new six-week session, 7 to 8:30 p.m. Thursdays, starts today and continues weekly through Dec. 17. (No meeting on Thanksgiving Day.) This is not a walk-in group. You must call 310-378-9353 to register.
Cancer support. Walk with Sally needs mentors and volunteers are needed to help children who have a parent or sibling with cancer. An introductory meeting will explain the program. 23133 Hawthorne Blvd., Suite B-15, Torrance, 7 to 8 p.m. the first Thursday of the month. Call 310-378-5843 or e-mail firstname.lastname@example.com to RSVP.
Weight Control. T.O.P.S. No. 1383 meets at King's Way Community Church, 1748 W. 251st St., Lomita, 5:30 to 7 p.m. Thursdays. Call 310-325-6664.
Weight control. T.O.P.S. Chapter 2139 meets at St. Lawrence Church, 1900 S. Prospect Ave., Redondo Beach, 9:30 to 11 a.m. Saturdays. Call 310-316-4350.
Bereavement. Torrance Memorial Home Health & Hospice drop-in bereavement support group. Health Conference Center, 3330 Lomita Blvd., Torrance, 6 to 7:30 p.m. Mondays. Call 310-784-3754.
Overeaters Anonymous. A support group for those suffering from compulsive eating. 2222 Artesia Blvd., Redondo Beach, 6 p.m. Mondays. No dues or fees. Call 310-374-8533.
Refugio support group. A Spanish-speaking support group for breast cancer survivors, sponsored by the YWCA and the Susan G. Komen Foundation. Harbor-UCLA Medical Center, Trailer N-24, 1124 W. Carson St., Torrance, 9 a.m. to noon the second and fourth Tuesday of the month.
Health lecture. Providence Little Company of Mary Medical Center presents a lecture on knee replacement with a surgeon, physical therapist and an occupational therapist. LCM Medical Center, 4101 Torrance Blvd., Torrance, 6:30 to 8:30 p.m. Tuesday. Admission is free but reservations are requested by calling 800-618-6659.
Stress seminar. Taylor Chiropractic and Laser Center is offering a seminar titled "Stress Less Through the Holidays." South End Tennis & Racquet Club, 2800 Skypark Drive, Torrance, 12:30 p.m. Tuesday and 6:30 p.m. Nov. 12. RSVP by calling 310-891-0102.
Multiple Sclerosis. Harbor/South Bay MS support group meeting. The Neighborhood Center, McMasters Park, 3612 Artesia Blvd., Torrance, 1 p.m. the second and fourth Tuesday of the month. Call 310-769-0694.
T.O.P.S. Chapter 148. Take Off Pounds Sensibly. Harbor City Recreation Center, 24901 S. Frampton Ave., Harbor City, 9:30 to 11 a.m. Tuesdays. Call 310-532-8795.
Reflexology demo. Wellness Coach and Certified Reflexologist Linda Chollar will demonstrate foot reflexology as a self-care technique for pain, stress and fatigue. Call for Redondo Beach location. 5 to 6:30 p.m. Wednesdays. RSVP by calling 310-318-3353 or log on to www.PainFreePath.com.
Mental/emotional health. Beach Cities Alliance for the Mentally Ill support group meeting. Church of the Brethren, 2761 W. 190th St., Redondo Beach, 10 a.m. to noon the second Wednesday of the month. Free. Call 310-378-6565.
Al-Anon. A support group for families and friends of alcoholics. Various dates, times and locations throughout the South Bay. Call 310-544-9668 for a list of times and locations.
– Sandy Gerety
Send Health Calendar items items two weeks in advance to: Sandy Gerety c/o the Daily Breeze, 21250 Hawthorne Blvd., Suite 170, Torrance, CA 90503. Fax to: 310-540-6272 or e-mail: firstname.lastname@example.com (without attachments).


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I heard a quote the other day that I just love: "Anyone can love a rose, but it takes a great deal to love a leaf. It is ordinary to love the beautiful, but it is beautiful to love the ordinary."
I have a conch shell on my bathroom windowsill that is impossible to dust. No one would think it was anything special, just at a glance. It is thickly coated in some sort of white crust, and into the crust is embedded all these tiny little shells that no doubt belonged to tiny sea creatures who wandered up looking for a spot to land. I'm guessing they finally just left their shells there after fruitlessly trying to disconnect from the muck. One can only hope they found a safe harbor before being eaten by something … probably the thing that lived in my conch shell. As unlovely as it is now, it was actually a slimy mossy green when I got it, and I bleached it and scrubbed it until it is now its white crusty, spiderweb catching self. I think it's beautiful.
Just so you don't get the wrong idea, I do not have an artistic eye, though I'm working on it. I usually last about 12 minutes in an art gallery. I look long and hard at sculptures that appear to have been dropped, then glued back together, and I see no deeper meaning.
I always wind up thinking, "My five year old could make that, and then we'd really be banking!" Those kinds of things are worth a fortune. So I spend my obligatory 12 minutes working my way through the art I understand and then, once I've passed the Norman Rockwell and Grandma Moses stuff I'm all, "So, someone mentioned going for pizza after this? Is anyone else starving?"
America has a strange idea of beauty now. Have you noticed? Beauty is only attributed to young, smooth, perfect sorts of things. I mean, we seem to like weird artwork, don't get me wrong, but when it comes to other stuff or people, we miss the boat a lot. Not all Americans, but mainstream folks, even Christians seem to place a higher value on that which is fun to look at. Just try finding a popular Christian musician that isn't pretty. I'm telling you, IF they exist, they are super rare!
Not just Christians though, of course. Hollywood is kind of low on talent, but ridiculously high in the beauty category. It is full of gorgeous, young, smooth women who are twenty pounds underweight, and full of people of ordinary size who are all grocery store clerks in movies. I feel bad for Hollywood women. They only have a shelf life of approximately three months. Then they develop a wrinkle that can't be airbrushed out and their career is shot, unless you're Betty White who is adorable, or Meryl Streep who is just too fabulous to be shunted away. Still it's pretty hard to get a job in Hollywood, even for a guy, if you don't have just the perfect look. I guess if they feel you're worth the trouble, they might also try to give you just the perfect look. Heaven forbid people just look normal. It might give people the impression that they are worthy of attention just like they are.
Anyone watching the night Susan Boyle debuted on "Britain's Got Talent" knows exactly what I'm talking about. You should watch it on Youtube if you didn't see it live. People's reactions to her were incredible. The obvious, not just distaste, but utter lack of respect shown to her before she started singing will blow your mind. Also, everyone's reaction AFTER she started singing will blow your minds. How could someone with slightly crooked teeth, who doesn't fall in the 16-22 age range and isn't a stick figure possibly be talented? An anomaly of the first order no doubt. Someone completely forgot to tell her that she was worthless because she wasn't a super model. I think we should all use a little less plastic and paint.
Here is my thought about my conch shell, and unbeautiful people (I learned that word from a five-year-old. It's so awesome that every word processor underlines it with a red squiggly line). I don't think my conch shell is beautiful because I bought it at a shell shop somewhere in Missouri a thousand miles from an actual beach. You can find shells in places like that. It's just weird. I guess they're there for people who spend money to have perfectly polished and beautiful things to decorate their house. I am obviously not one of those people. If you added up everything I've spent on my home decor, it probably wouldn't equal what one of those pretty conch shells would cost you.
But I ask you this: Was your pretty and polished conch shell fished out of the sea for you on a mission trip to Belize? Was it handed to you with love by one of the sweetest teenagers in existence? Was it smuggled, somewhat illegally, through customs wrapped artfully in dirty clothes in your luggage? I'm just sayin. My story is cooler. Just so you know, I have nothing against spending money on your house … but I have nothing against my way either.
Everything in my house is either a token of an experience that I loved, or given to me by someone I love. I hate those random psych questions that ask, "If your house was on fire and your family was safe and you knew you could save one thing, what would you save?" I usually sit for a moment and mentally run through every picture, book, bottle of sand (yes, sand is a decoration at my house) and then flee the room in tears. I would want to save all of it. It all has meaning to me. That query is even more bizarre when they tell you you can only save one family member. My husband refers to a Captain Kirkism as an answer. "I don't believe in a no win scenario. I would save them all." I refuse to answer altogether. I don't think Jason or I would do very well on a psyche evaluation.
It is my personal opinion that people are more beautiful the longer they live and the less they botox. If you will sit and share your life story with a kid for an hour, or if you can describe what it was like to huddle in a foxhole, or fearlessly march onto a beach in Normandy under constant German fire, or you still knit, sew or crochet, you are a beautiful person. If you sag somewhere because you've had three children, or your skin is puckered from surgery, or your hands are calloused from years of using them for your livelihood, that's all because life has happened to you. If you're a single or foster parent, don't even get me started on your level of amazingness.
The greatest beauty lies in reality: in the depth of our experiences. Smile lines are a mark of a life spent finding joy in trials. Not the mark of a perfect life.
So, we should expand our definition of beauty a little bit, right? At least enough to include ourselves, for pete's sake! It isn't because we're humble that we don't think we're beautiful, it's because we've been lied to, we're insecure, we're inundated with plastic figurines all painted to perfect specifications by toddlers in China. So forget the Walmart version of you, or the Dillards version if you happen to have more money. We are my conch shell. We have a story that is worth being a bit banged up for. We are real people, with real purpose in life. We are loved by God. Jesus would rather die than live without us. If nothing else in this entire world is beautiful, that is beautiful. End of story.


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> >description { color: red } > >:link { color: green !important } > > > >:not(:link) { link: url(ref); } > I would say green, but as you point out, that would "violate a > fundamental design constraint of CSS -- property values cannot affect > what rules apply to an element." It also violates the definition of :not. The same node is being matched by :link and :not(:link) if you're insisting that it's a link that's colored green. > There are probably good reasons for that, I suppose. Yes. Like the fact that to figure out what the property values are you have to know what rules apply. If the former can affect the latter, the problem is not solvable, is it? > But when we something like the 'link' property would exist, all elements that > are links would be expressed, in a UA that supports CSS, with that particular > property. That's even worse, because the UA will probably be using :link (or some equivalent) for its default link styling too. So now we're back to the problem of having rules in the UA sheet applying or not based on the values of properties. > That would be a UA style sheet (minimized of course, leaving out > @namespace etc.). A document author style sheet could then match all > unvisited links using ':link'. I'm not sure why you're drawing this weird distinction between UA and author sheets... Is there a basis for this? > It was just to point out that "Does it make sense to have links that :link > does not match" doesn't make sense. That was merely a proposal to resolve the logical contradiction. The precise proposal was "Whether :link matches or not is independent of the value of the 'link' property." This does lead to sub-optimal behavior. But the alternative (having it depend on the value of the property) is not viable within the constraints of the logical system that is CSS. If you can propose an alternate logical system that applies rules to nodes, handles this case, and is identical to CSS in the cases where CSS is defined, please do so. Boris -- The study of non-linear physics is like the study of non-elephant biology.Received on Thursday, 11 March 2004 13:26:54 UTC
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