Expected impact of applying new 2013 AHA/ACC cholesterol guidelines criteria on the recommended lipid target achievement after acute coronary syndromes.

BACKGROUND: 2013 AHA/ACC guidelines on the treatment of cholesterol advised to tailor high-intensity statin after ACS, while previous ATP-III recommended titration of statin to reach low-density lipoprotein cholesterol (LDL-C) targets. We simulated the impact of this change of paradigm on the achievement of recommended targets. METHODS: Among a prospective cohort study of consecutive patients hospitalized for ACS from 2009 to 2012 at four Swiss university hospitals, we analyzed 1602 patients who survived one year after recruitment. Targets based on the previous guidelines approach was defined as (1) achievement of LDL-C target < 1.8 mmol/l, (2) reduction of LDL-C ≥ 50% or (3) intensification of statin in patients who did not reach LDL-C targets. Targets based on the 2013 AHA/ACC guidelines approach was defined as the maximization of statin therapy at high-intensity in patients aged ≤75 years and moderate- or high-intensity statin in patients >75 years. RESULTS: 1578 (99%) patients were prescribed statin at discharge, with 1120 (70%) at high-intensity. 1507 patients (94%) reported taking statin at one year, with 909 (57%) at high-intensity. Among 482 patients discharged with sub-maximal statin, intensification of statin was only observed in 109 patients (23%). 773 (47%) patients reached the previous LDL-C targets, while 1014 (63%) reached the 2013 AHA/ACC guidelines targetsone year after ACS (p value < 0.001). CONCLUSION: The application of the new 2013 AHA/ACC guidelines criteria would substantially increase the proportion of patients achieving recommended lipid targets one year after ACS. Clinical trial number, NCT01075868.

A semi-grand canonical Monte Carlo simulation model for ion binding to ionizable surfaces: proton binding of carboxylated latex particles as a case study

In this paper, we present a computer simulation study of the ion binding process at an ionizable surface using a semi-grand canonical Monte Carlo method that models the surface as a discrete distribution of charged and neutral functional groups in equilibrium with explicit ions modelled in the context of the primitive model. The parameters of the simulation model were tuned and checked by comparison with experimental titrations of carboxylated latex particles in the presence of different ionic strengths of monovalent ions. The titration of these particles was analysed by calculating the degree of dissociation of the latex functional groups vs. pH curves at different background salt concentrations. As the charge of the titrated surface changes during the simulation, a procedure to keep the electroneutrality of the system is required. Here, two approaches are used with the choice depending on the ion selected to maintain electroneutrality: counterion or coion procedures. We compare and discuss the difference between the procedures. The simulations also provided a microscopic description of the electrostatic double layer (EDL) structure as a function of p H and ionic strength. The results allow us to quantify the effect of the size of the background salt ions and of the surface functional groups on the degree of dissociation. The non-homogeneous structure of the EDL was revealed by plotting the counterion density profiles around charged and neutral surface functional groups.

Exploring the effect of aminoglycoside guanidinylation on ligands for Tau exon 10 splicing regulatory element RNA

We describe the effect of guanidinylation of the aminoglycoside moiety on acridine-neamine-containing ligands for the stem-loop structure located at the exon 10-5′-intron junction of Tau pre-mRNA, an important regulatory element of tau gene alternative splicing. On the basis of dynamic combinatorial chemistry experiments, ligands that combine guanidinoneamine and two different acridines were synthesized and their RNA-binding properties were compared with those of their amino precursors. Fluorescence titration experiments and UV-monitored melting curves revealed that guanidinylation has a positive effect both on the binding affinity and specificity of the ligands for the stemloop RNA, as well as on the stabilization of all RNA sequences evaluated, particularly some mutated sequences associated with the development of FTDP-17 tauopathy. However, this correlation between binding affinity and stabilization due to guanidinylation was only found in ligands containing a longer spacer between the acridine and guanidinoneamine moieties, since a shorter spacer produced the opposite effect (e.g. lower binding affinity and lower stabilization). Furthermore, spectroscopic studies suggest that ligand binding does not significantly change the overall RNA structure upon binding (circular dichroism) and that the acridine moiety might intercalate near the bulged region of the stem->loop structure (UV-Vis and NMR spectroscopy).

Low TCR avidity and lack of tumor cell recognition in CD8(+) T cells primed with the CEA-analogue CAP1-6D peptide.

The use of "altered peptide ligands" (APL), epitopes designed for exerting increased immunogenicity as compared with native determinants, represents nowadays one of the most utilized strategies for overcoming immune tolerance to self-antigens and boosting anti-tumor T cell-mediated immune responses. However, the actual ability of APL-primed T cells to cross-recognize natural epitopes expressed by tumor cells remains a crucial concern. In the present study, we show that CAP1-6D, a superagonist analogue of a carcinoembriyonic antigen (CEA)-derived HLA-A*0201-restricted epitope widely used in clinical setting, reproducibly promotes the generation of low-affinity CD8(+) T cells lacking the ability to recognized CEA-expressing colorectal carcinoma (CRC) cells. Short-term T cell cultures, obtained by priming peripheral blood mononuclear cells from HLA-A*0201(+) healthy donors or CRC patients with CAP1-6D, were indeed found to heterogeneously cross-react with saturating concentrations of the native peptide CAP1, but to fail constantly lysing or recognizing through IFN- gamma release CEA(+)CRC cells. Characterization of anti-CAP1-6D T cell avidity, gained through peptide titration, CD8-dependency assay, and staining with mutated tetramers (D227K/T228A), revealed that anti-CAP1-6D T cells exerted a differential interaction with the two CEA epitopes, i.e., displaying high affinity/CD8-independency toward the APL and low affinity/CD8-dependency toward the native CAP1 peptide. Our data demonstrate that the efficient detection of self-antigen expressed by tumors could be a feature of high avidity CD8-independent T cells, and underline the need for extensive analysis of tumor cross-recognition prior to any clinical usage of APL as anti-cancer vaccines.

The DNA-binding domain (DBD) is essential for NR2E3 dimerization and interaction with Crx

Purpose:NR2E3 (PNR) is an orphan nuclear receptor essential for proper photoreceptor determination and differentiation. In humans, mutations in NR2E3 have been associated with the recessively inherited enhanced short wavelength sensitive (S-) cone syndrome (ESCS) and, more recently, with autosomal dominant retinitis pigmentosa (adRP). NR2E3 acts in concert with the transcription factors Crx and Nrl to repress cone-specific genes and activate rod-specific genes. NR2E3 and Crx have been shown to physically interact by their DNA-binding domain (DBD), which may also be implicated in the dimerization process of the nuclear receptor. However, neither NR2E3 homodimerization nor NR2E3/Crx complex formation has been investigated in detail. Methods:In this present work, we analyzed the dimerization of the NR2E3 protein and its interaction with Crx by bioluminescence resonance energy transfer (BRET2) which utilizes Renilla luciferase (hRluc) protein and its substrate DeepBlueC as an energy donor and a mutant green fluorescent protein (GFP2) as the acceptor. We investigated, on whole intact cells, the role of NR2E3 DBD-mutations in dimerization and association with Crx. Results:We clearly showed that NR2E3 formed homodimers in HEK-293T cells. Moreover, all causative NR2E3 mutations present in the DBD of the protein showed an alteration in dimerization, except for the R76Q and the R104W mutants. Interestingly, the adRP-linked G56R mutant was the only DBD-NR2E3 mutant that showed a correct interaction with Crx. Finally, we observed a decrease in rhodospin gene transactivation for all DBD-NR2E3 mutants tested and no potentiation for the adRP-linked G56R mutant. In addition, the p.G56R mutant enhanced the transrepression of M-opsin promoter, while all other DBD-NR2E3 mutants did not repress M-opsin transactivation. Conclusions:A defect, either in the dimer formation or in the interaction of NR2E3 with Crx, leads to abnormal transcriptional activity on rhodopsin and M-opsin promoter and to an atypical retinal development; while the titration of Crx by p.G56R-NR2E3 leads to low levels of rhodopsin and M-opsin expression and may be responsible for the strong adRP phenotype.

Kinetics of selective oxidation of lactose to lactobionic acid over Pd-active carbon catalyst

Laktoosi eli maitosokeri on tärkein ainesosa useimpien nisäkkäiden tuottamassa maidossa. Sitä erotetaan herasta, juustosta ja maidosta. Laktoosia käytetään elintarvike- ja lääketeollisuuden raaka-aineena monissaeri tuotteissa. Lääketeollisuudessa laktoosia käytetään esimerkiksi tablettien täyteaineena. Hapettamalla laktoosia voidaan valmistaa laktobionihappoa, 2-keto-laktobionihappoa ja laktuloosia. Laktobionihappoa käytetään biohajoavien pintojen ja kosmetiikkatuotteiden valmistuksessa, sekä sisäelinten säilöntäliuoksissa, joissa laktobionihappo estää happiradikaalien aiheuttamien kudosvaurioiden syntymistä. Tässä työssä laktoosia hapetettiin laktobionihapoksi sekoittimella varustetussa laboratoriomittakaavaisessa panosreaktorissa käyttäenkatalyyttinä palladiumia aktiivihiilellä. Muutamissa kokeissa katalyytin promoottorina käytettiin vismuttia, joka hidastaa katalyytin deaktivoitumista. Työn tarkoituksena oli saada lisää tietoa laktoosin hapettamisen kinetiikasta. Laktoosin hapettumisessa laktobionihapoksi havaittiin selektiivisyyteen vaikuttavan muunmuassa reaktiolämpötila, paine, pH ja käytetyn katalyytin määrä. Katalyyttiä kierrättämällä eri kokeiden välillä saatiin paremmat konversiot, selektiivisyydet ja saannot. Parhaat koetulokset saatiin hapetettaessa synteettisellä ilmalla 60 oC lämpötilassa ja 1 bar paineessa. Tehdyissä kokeissa pH:n säätö tehtiin manuaalisesti, joten pH ei pysynyt koko ajan haluttuna. Laktoosin konversio oli parhaimmillaan 95 %. Laktobionihapon suhteellinen selektiivisyys oli 100% ja suhteellinen saanto 100 %. Kinetiikan matemaattinen mallinnus tehtiin Modest-ohjelmalla käyttäen kokeista saatuja mittaustuloksia.Ohjelman avulla estimoitiin parametreja ja saatiin matemaattinen malli reaktorille. Tässä työssä tehtiin kineettinen mallinnus myös ravistelureaktorissa tehdyille laktoosin hapetuskokeille, missä pH pysyi koko ajan haluttuna 'in-situ' titrauksen avulla. Työn yhteydessä selvitettiin myös mahdollisuutta käyttää monoliittikatalyyttejä laktoosin hapetusreaktiossa.

Pyridyyliryhmän sisältävien erotusmateriaalien ominaisuudet ja soveltaminen hydrometallurgiassa

Diplomityössä tutkittiin silikarunkoisen, pyridyyliryhmän sisältävän erotusmateriaalin kykyä erottaa selektiivisesti kuparia, nikkeliä, kobolttia ja kadmiumia sinkkisulfaattiliuoksista. Erotuskykyä verrattiin kolonnikokein toiseen kaupalliseen polystyreenidivinyylibentseenirunkoiseen (PS-DVB) erotusmate-riaaliin, jonka funktionaalinen ryhmä on samantyyppinen. Silikarunkoisen erotusmateriaalin happo-emäsominaisuuksia selvitettiin titrauksin. Metallien sitoutumisen kinetiikkaa ja eluointia verrattiin PS-DVB-runkoisen erotus-materiaalin kirjallisuudessa esitettyihin tuloksiin. Lisäksi määritettiin kummankin erotusmateriaalin partikkelikokojakaumat. Silikarunkoisen materiaalin havaittiin turpoavan noin 4 % muutettaessa se vapaastaemäsmuodosta happomuotoon. Turpoaminen oli huomattavasti vähäisempää kuin PS-DVB-runkoisella materiaalilla. Silikarunkoisen erotus-materiaalin titrauksen tuloksena voitiin todeta, että se oli heikosti emäksinen. Titrauskäyrä muistutti PS-DVB-runkoisen erotusmateriaalin titrauskäyrää, vaikka erotusmateriaalien protonoitumisalueet olivat hieman erilaiset. Tämä johtuu siitä, että silikarunkoisen materiaalin funktionaaliset ryhmät poikkeavat rakenteeltaan hieman PS-DVB-runkoisesta materiaalista. Tasapainokokeet osoittivat, että silikarunkoinen erotusmateriaali adsorboi tutkituista metalleista eniten kuparia ja nikkeliä ja vähiten sinkkiä. Kaikkien tutkittujen metallien eluointi silikarunkoisesta erotusmateriaalista onnistui rikkihapolla toisin kuin PS-DVB-runkoisesta erotusmateriaalista, jonka regenerointiin tarvitaan rikkihappoa tai ammoniumhydroksidia riippuen siitä, mitä metalleja siihen on ladattu.

Recurrent Macular Edema in Central Retinal Vein Occlusion Treated with Intravitreal Ranibizumab using a Modified Treat and Extend Regimen.

Background: The aim of this study was to evaluate the stability over time of the individually defined interval of intravitreal ranibizumab injection (IVR) for the treatment of recurrent macular edema (ME) in central retinal vein occlusion (CRVO). Patients and Methods: A case series of treatment naïve patients followed in the Jules Gonin Eye Hospital for macular edema due to central retinal vein occlusion is presented. Patients were treated monthly with IVR until complete absence of fluid on qualitative SD-OCT with a minimum of 5 monthly IVR. Thereafter, they were followed according to a modified treat and extend regimen (mTER). Results: Twelve eyes (12 patients) with ME due to CRVO were included. The mean follow-up period was 31.3 months. Analysis showed that best corrected visual acuity (BCVA), central macular thickness and qualitative spectral domain optical coherence tomography (SD-OCT) showed comparable results under monthly interval, after titration of an individualized interval and when performed in a series. 78 % of treating intervals were within ± 2 weeks of the first individually adjusted interval. The mean first defined interval was 4.3 weeks and the mean interval over time was 5.5 weeks (p = 0.003). There was a trend towards longer interval over time. Conclusion: The adjusted interval of retreatment of patients with ME due to CRVO showed a high stability with a trend toward longer duration over time. An mTER regimen seems to be valuable to follow patients with ME with good stabilization of VA.

A semi-grand canonical Monte Carlo simulation model for ion binding to ionizable surfaces: Proton binding of carboxylated latex particles as a case study

In this paper, we present a computer simulation study of the ion binding process at an ionizable surface using a semi-grand canonical Monte Carlo method that models the surface as a discrete distribution of charged and neutral functional groups in equilibrium with explicit ions modelled in the context of the primitive model. The parameters of the simulation model were tuned and checked by comparison with experimental titrations of carboxylated latex particles in the presence of different ionic strengths of monovalent ions. The titration of these particles was analysed by calculating the degree of dissociation of the latex functional groups vs. pH curves at different background salt concentrations. As the charge of the titrated surface changes during the simulation, a procedure to keep the electroneutrality of the system is required. Here, two approaches are used with the choice depending on the ion selected to maintain electroneutrality: counterion or coion procedures. We compare and discuss the difference between the procedures. The simulations also provided a microscopic description of the electrostatic double layer (EDL) structure as a function of pH and ionic strength. The results allow us to quantify the effect of the size of the background salt ions and of the surface functional groups on the degree of dissociation. The non-homogeneous structure of the EDL was revealed by plotting the counterion density profiles around charged and neutral surface functional groups. © 2011 American Institute of Physics.

Determination of the complexing capacity of synthetic and real wine for Zn using Absence of Gradients and Nerstian Equilibrium Stripping technique

The complexing capacity of synthetic (0.011 M tartrate in 13.5% ethanol) and real wine (Raimat Abadia) in titrations with added total Zn concentrations up to 0.03 M has been determined following the free Zn concentrations with AGNES (absence of gradients and Nernstian equilibrium stripping) technique. A correction to find the preconcentration factor or gain (Y1) really applied at each one of the ionic strengths reached due to Zn additions along the titration has been applied. The standard implementation of AGNES to real wine led to the observation of two anomalous behaviors: (a) an increasingly negative current in the deposition stage (labeled as “HER” effect) and (b) a minimum in the currents of the stripping stage plot (labeled as the “dip” effect). A practical strategy to apply AGNES avoiding the dip effect has been developed to quantify properly free Zn concentrations. The van den Berg–Ružic–Lee linearization method (assuming the existence of just 1:1 complexes) has been adapted to consider the dilution effect and the ionic strength changes. Aggregated stability constants and total ligand concentrations have been calculated from synthetic and wine titration data. The found complexing capacity in the studied wine (cT,L = 0.0179 ± 0.0007 M) indicates the contribution of ligands other than tartrate (which is confirmed to be the main one).

Koboltin ja nikkelin poisto sinkkisulfaattiliuoksesta ioninvaihdolla

Työssä tutkittiin kahden silikapohjaisen erotusmateriaalin soveltuvuutta nikkelin ja koboltin poistoon sinkkisulfaattiliuoksista. Suurin osa kokeista tehtiin ioninvaihtimella, jonka funktionaalinen ryhmä on iminodietikkahappo. Vertailuerotusmateriaalin toiminta perustui adsorptioon. Liuoksina käytettiin sekä autenttista prosessiliuosta että synteettistä ZnSO4-liousta. Ioninvaihtimen kestävyyskokeissa selvisi, että tutkittu ioninvaihdin kestää hyvin sekä 60 oC lämpötilan että happamia olosuhteita. Emäksisissä liuoksissa silikarunko ei kestä. Jo 0,1 M NaOH-liuos liuottaa merkittävästi hartsia vuorokauden aikana. Vaihtimen vetyionikapasiteetiksi saatiin titrauksella 2,3 mekv/g. Tasapainokokeilla saatiin selville, että ioninvaihdin on selektiivinen nikkelille sinkin suhteen ja että selektiivisyys kasvaa liuoksen pH:n laskiessa. Koboltille ioninvaihdin ei ole selektiivinen sinkin suhteen. Mikäli sinkin pitoisuus on tuhansia kertoja nikkelin pitoisuutta suurempi, ei ioninvaihtimen Ni-selektiivisyys riitä myöskään nikkelille. Synteettisillä ZnSO4-liuoksilla tehtyjen kolonnikokeiden perusteella havaittiin, että tutkitulla ioninvaihtimella voidaan laimeista ZnSO4-liuoksista poistaa nikkeliä selektiivisesti. Nikkelin eluointi onnistui helposti 1 M H2SO4:lla. Vertailukokeen perusteella oli ioninvaihtimen Ni/Zn-selektiivisyys referenssiadsorbentin Ni/Zn-selektiivisyyttä pienempi. Ioninvaihtokolonnin mallintaminen ei onnistunut riittävän hyvin kuvaamaan ioninvaihtimessa tapahtuvaa samanaikaista ioninvaihtoa ja adsorptiota. Sen sijaan kun kolonnissa oli vertailumateriaalina käytetty adsorbentti, saatiin kolonnikokeiden tulokset mallilla hyvin ennustettua.

Epäpuhtauksien poistaminen sinkkisulfaattiliuoksista käyttäen selektiivisiä ioninvaihtimia

Diplomityössä on tutkittu kuparin, koboltin, nikkelin ja kadmiumin poistamista sinkkisulfaattiliuoksista käyttäen uusia silikarunkoisia kelatoivia erotusmateriaaleja. Vertailukohteena on käytetty perinteisiä kaupallisia polymeerirunkoisia kelatoivia ioninvaihtohartseja. Laboratoriokokeissa selvitettiin erotusmateriaalien adsorptio- ja ioninvaihto-ominaisuuksia tasapaino- ja kolonnikokeilla. Silikarunkoisten erotusmateriaalien kemiallista kestävyyttä tutkittiin olosuhteissa, jotka vastaavat prosessisyklin eri vaiheita. Metallien adsorptiomekanismien selvittämiseksi erotusmateriaaleille tehtiin happo-emäs ja sulfaattititraukset. Tasapainokokeet osoittivat, että silikarunkoisilla erotusmateriaaleilla saatiin kupari erotettua väkevistä sinkkisulfaattiliuoksista polymeerirunkoisia kelatoivia ioninvaihtohartseja paremmin. Tutkituilla erotusmateriaaleilla ja ioninvaihtohartseilla ei havaittu merkittävää selektiivisyyttä koboltille, nikkelille tai kadmiumille sinkin ja kuparin läsnä ollessa. Kolonnikokeilla yritettiin löytää paras esikäsittely-lataus-eluointisykli kuparin talteenottoon väkevistä sinkkisulfaattiliuoksista silikarunkoisilla erotusmateriaaleilla. Kolonnikokeissa esikäsittely tehtiin laimealla NaOH:lla, jonka jälkeen petiin syötettiin hapanta sinkkisulfaattiliuosta. Eluointi onnistui hyvin laimealla rikkihapolla. Kolonnikokeiden tulokset osoittivat, että kupari on mahdollista erottaa väkevistä sinkkisulfaattiliuoksista. Silikarunkoisten erotusmateriaalien kemiallista kestävyyttä tutkittaessa havaittiin materiaalien kestävän hyvin happoja ja 60 oC:en lämpötilaa. Sitä vastoin alkaalisissa olosuhteissa tapahtui silikan liukenemista. Tutkituilla erotusmateriaaleilla havaittiin kuparin sitoutumista sekä ioninvaihtomekanismin avulla että sitoutuneena neutraalina suolana.

Practical guidance and considerations for transitioning patients from oxcarbazepine or carbamazepine to eslicarbazepine acetate--Expert opinion.

There is currently a lack of guidance on methodology and special considerations for transitioning patients from oxcarbazepine (OXC) or carbamazepine (CBZ) to eslicarbazepine acetate (ESL), if deemed clinically necessary. An advisory panel of epilepsy experts was convened to share their experience on the use of adjunctive ESL in clinical practice and to provide practical recommendations to help address this gap. When changing over from OXC to ESL, an OXC:ESL dose ratio of 1:1 should be employed to calculate the ESL target dose, and the changeover can take place overnight. No changes to comedication are required. Since CBZ has a different mechanism of action to ESL and is a stronger inducer of cytochrome P450 (CYP) enzymes, the transitioning of patients from CBZ to ESL requires careful consideration on a patient-by-patient basis. In general, a CBZ:ESL dose ratio of 1:1.3 should be employed to calculate the ESL target dose, and patients should be transitioned over a minimum period of 1-2weeks. Special considerations include adjustment of titration schedule and target dose in elderly patients and those with hepatic or renal impairment and potential adjustment of comedications metabolized by CYP enzymes. In summary, due to structural distinctions between ESL, OXC, and CBZ, which affect mechanism of action and tolerability, there are clinical situations in which it may be appropriate to consider transitioning patients from OXC or CBZ to ESL. Changing patients over from OXC to ESL is generally more straightforward than transitioning patients from CBZ to ESL, which requires careful consideration.

Synthesis of Janus compounds for the recognition of G-U mismatched nucleobase pairs

The design and synthesis of two Janus-type heterocycles with the capacity to simultaneously recognize guanine and uracyl in G-U mismatched pairs through complementary hydrogen bond pairing is described. Both compounds were conveniently functionalized with a carboxylic function and efficiently attached to a tripeptide sequence by using solid-phase methodologies. Ligands based on the derivatization of such Janus compounds with a small aminoglycoside, neamine, and its guanidinylated analogue have been synthesized, and their interaction with Tau RNA has been investigated by using several biophysical techniques, including UV-monitored melting curves, fluorescence titration experiments, and 1H NMR. The overall results indicated that Janus-neamine/guanidinoneamine showed some preference for the +3 mutated RNA sequence associated with the development of some tauopathies, although preliminary NMR studies have not confirmed binding to G-U pairs. Moreover, a good correlation has been found between the RNA binding affinity of such Janus-containing ligands and their ability to stabilize this secondary structure upon complexation.

Competition in notch signaling with cis enriches cell fate decisions

Notch signaling is involved in cell fate choices during the embryonic development of Metazoa. Commonly, Notch signaling arises from the binding of the Notch receptor to its ligands in adjacent cells driving cell-to-cell communication. Yet, cell-autonomous control of Notch signaling through both ligand-dependent and ligand-independent mechanisms is known to occur as well. Examples include Notch signaling arising in the absence of ligand binding, and cis-inhibition of Notch signaling by titration of the Notch receptor upon binding to its ligands within a single cell. Increasing experimental evidences support that the binding of the Notch receptor with its ligands within a cell (cis-interactions) can also trigger a cell-autonomous Notch signal (cis-signaling), whose potential effects on cell fate decisions and patterning remain poorly understood. To address this question, herein we mathematically and computationally investigate the cell states arising from the combination of cis-signaling with additional Notch signaling sources, which are either cell-autonomous or involve cell-to-cell communication. Our study shows that cis-signaling can switch from driving cis-activation to effectively perform cis-inhibition and identifies under which conditions this switch occurs. This switch relies on the competition between Notch signaling sources, which share the same receptor but differ in their signaling efficiency. We propose that the role of cis-interactions and their signaling on fine-grained patterning and cell fate decisions is dependent on whether they drive cis-inhibition or cis-activation, which could be controlled during development. Specifically, cis-inhibition and not cis-activation facilitates patterning and enriches it by modulating the ratio of cells in the high-ligand expression state, by enabling additional periodic patterns like stripes and by allowing localized patterning highly sensitive to the precursor state and cell-autonomous bistability. Our study exemplifies the complexity of regulations when multiple signalng sources share the same receptor and provides the tools for their characterization.