Hello everyone and welcome to the next edition of the BioExcel webinar series. My name is Rosson Apostolouf and I will be the host of today's talk. Today we will have Vanya Kalandrini who will tell us about some methods for hybrid molecular mechanics and coarse-grained approaches to modeling of proteins. Before we start, I have to let you know that this webinar is being recorded. And we will publish a recording of the webinar on the BioExcel website and also on our YouTube channel which you can watch later at your convenience. And you are welcome to share the recording with your colleagues or friends. A very brief overview of BioExcel which is the European Centre of Excellence for Computational Bio Molecular Research and we are the organizers of this series. A few words about our work. For those of you who are not familiar with it. We work with several very important applications in the area of molecular modeling simulations such as ROMAX, for anti-simulations, HALO, for integrative modeling and doki, and CPMD for hybrid QMM methodology for enzymatic reactions present. We also work a lot on usability with devices of different workflows. With associated data integration, we use several platforms and we develop, we work on a number of use cases and pilot projects about which you can read more on our website that make it very easy for people to build on. We also put a lot of effort into training and consultancy. We have an extensive training program with various workshops, hands-on, bring your own workflow sessions, etc. that we believe will be of interest to the community. So have a look at our website for the upcoming events. Next year we have quite a few workshops that you might be interested in attending. One more activity that we do is we run a number of interest groups which focus on specific areas that we have expertise in. We have, for example, integrative modeling focused on doki around HADOC, free energy calculations, which are also very important nowadays for drug design. What's most probably of interest to you is the hybrid methods for biomolecular systems where we look at things that you will hear about today. So visit our website and you can subscribe to some of these use groups. We have also forums called Repositories in the chat channel which you are very welcome to use. One more thing, at the end of today's presentation we will have a questions and answers session where you can speak directly with Vania and ask any questions you have regarding the material. I will encourage you to write your questions in the control panel section to the right. You can see it as their own points. So type your question there during the talk and at the end I will give you the microphone to speak up. If you don't have a microphone or if you have promised without you, I will read the question on your behalf. And later you can join discussions at our forums, dusk.bioxcel.edu. And now it's my pleasure to introduce our today's presenter, Dr. Vania Calandrini, who is a researcher at the Computational Biomedicine Institute at the Ulich Research Center in Germany. After she got her habilitation in Physics at the University of Orleans in France, she continued working on physiochemical processes, shaping the signaling processes at sub-neural level. Now she's working on the development of models and computational methods, describing the internal protein dynamics and transport phenomena. So it's my pleasure now to change to Vania to continue with the presentation. Okay, so thanks Ross for the introduction and thanks also for this invitation. So today I will talk about an hybrid molecular mechanics cost-grain scheme, which has been proved to be especially useful to characterize ligand binding to proteins with unknown 3D structure and low sequence identity, which is mostly the case of many big families of membrane proteins, such as for instance, G-protein-caplet receptors. Actually, hybrid methods are in general the method of choice when both fast processes on a small spatial scale and slow processes on larger spatial scales are relevant, and you want to keep at the same time the minimum number of degrees of freedom of the problem. For instance, in the case of ligand-protein binding, cost-grain approaches could be a priori adapted, but if you are interested in the intrinsic atomistic features of the recognition process, you need to maintain an atomistic resolution at least on the binding site. So exploiting the fact that the important high-resolution details are specially localized, you can couple different resolutions keeping at the same time the minimum number of degrees of freedom of the problem. But there is something more and on top of this reduction of degree of freedom, and in this webinar I will try to show you that in some biologically relevant cases, such as for instance membrane proteins or GPCRs, a big family of membrane proteins, because of the intrinsic characteristic of the problem, hybrid methods are really strategic, if not unique. Not only for the simple reduction of the degree of freedom. To target this important class of membrane proteins, our group started to develop a molecular mechanics cost-grain approach several years ago, and this is also the reason why I put here so many people who contributed to this evolution. And so I will describe the methods as it is in its current implementation, and I'll describe also some recent developments to further improve the method in order to allow reliable estimation of ligand-protein binding energetics. So if the structural determinants of a pharmaceutical target, a receptor or an enzyme are experimentally known or reliable structural predictions, or you can make reliable structural predictions, usually you can get highly accurate ligand poses by using standard bioinformatics-based approaches, docking, homology modeling, docking. However, when these conditions are not verified, for instance this is the case for membrane proteins that represent as much as 60% of the overall proteins targeted by FDA-approved drugs. The application of these approaches is not so straightforward. So this, why it's so difficult in the case of membrane proteins, applies standard approaches. And why hybrid molecular mechanics cost-grain approach can be used to circumvent the problem. Actually, for membrane proteins we know the 3D structures are in about 2.5% of the cases of the proteins and for GPCRs in particular around 5%. And moreover, the average sequence identity between members of large families of these membrane proteins, such as G protein in a couple of receptors or voltage-gated ion channels, is often below 20%. This means that the template selection and the alignment for homology modeling is far from trivial. The probability to end up with side-chains orientation, inaccurate side-chains orientation is quite high. And so the docking protocols are very difficult to be used in this condition. Even running extensive plain MD simulation or enhanced sampling methods on different initial models may require very long time to allow side-chains to relax to a correct free energy minimum. And moreover, this may again end up with wrong orientations impacting the predicting power of the docking procedures. An alternative is represented by cost-grain simulations, but again they cannot describe the atomistic features of the recognition between proteins and other ligands. So this was for us the main motivation to develop an hybrid molecular mechanics cost-grain approach, specifically conceived to predict the ligand poses in membrane proteins with lower resolution models. In this scheme, the atomistic molecular mechanics region corresponds to the region of interest, for instance the receptor binding site along with the ligand and the solvent around. In the cost-grain region, far from the binding site, each residue is represented by a single CG bead centered on the C-alpha atom. And in order to ensure the backbone integrity, there is an intermediate region that couples the two regions at different resolutions. In this way, we can get rid of potentially wrong information coming from atomistic modeling of side-chains. So this is the potential energy function of the protein frame. So there is the eMM contribution is the potential energy function of the molecular mechanics region. ECG is the potential term for the cost-grain region. EI is that of the interface bridging the two resolution regions. EIMM and ECGI describe the interaction energies between the interface and the molecular mechanics region and that between the interface and the cost-grain region. EMM, EI and EMM, I are currently represented by Grommos 96 force field. ECGI and ECGI are represented in terms of a go-like, let's say, model. Specifically, you see there is this term that represents the bonded interaction between consecutive beads. And this part represents the non-bonded interaction in terms of more potential. And then you see here there is the ECGI bonded term that ensures the integrity of the protein backbone. And you see here you have the bonded interactions between CG beads and the consecutive C-alpha atoms in the interface as well as you see here the non-bonded interactions between the CG beads and the C-alpha and the CBIT atoms in the interface. In the first implementation, we tested this potential for two cytosolic proteins, HIV type 1 virus aspartic proteins. And the human secretase BAC, so before to move to receptors to membrane proteins, we first tested this scheme for cytosolic proteins and we tuned the parameters, the cut-off, the interface region thickness in order to reproduce the rhythmic square fluctuations calculated with plane MD simulations. And we further tested the accuracy of the model calculating the covariance matrix of the C-alpha position fluctuations. And you see here that if you calculate the agent vectors corresponding to the plane MD simulations and MMCG simulations, you see that the most relevant agent vectors almost coincide which means that basically with MMCG we are able to essentially recover the main aspect, the main features of the dynamics. And then, okay, we are very happy with this, but in order to proper model membrane proteins, we need something more. Specifically, we have to take into account the solvation around the binding site and also we have to take into account the membrane protein interactions. So we added five walls, two hemispheres at the extracellular and cytoplasmatic region of the protein to prevent water evaporation is P3 and P4 in the sketch, two planar walls at the lipid head and a wall enveloping the transmembrane portion of the protein to mimic the membrane. And specifically, water evaporation from the atomistic region around the binding site is prevented by a softened lenar-johns-like potential whose minimum is at a distance rp from the hemispherical boundary of the water droplet. And as for water, water penetration in the transmembrane space is prevented by a responsive potential proportional to 1 over d where d is the distance from the planar walls. And the protein membrane interaction is mimicked by a softened lenar-johns-like potential with the minimum at a distance rp from this virtual wall enveloping the transmembrane portion of the protein. So this frame, we tested this model on the human beta-2 adrenergic receptor, which is a GPCR, a G-protein-capled receptor in complex with its inverse agonist as carazolol for which the X-ray structure of the complex and MD simulations are available. And you see here the root-me-square fluctuation and the comparison between plain MD simulations and MMCG simulations. In gray here the residues corresponding to the molecular mechanics region and you see in blue the MD and in black the MMCG and you see there is a fair agreement at least for the atoms in the molecular mechanics part. Still there are some differences that can be expected due to the different force fields applied, number 99 in the case of MD simulation and grommos in the case of molecular mechanics coarse-grain simulation. You see here a snapshot of the binding site obtained from MMCG trajectory of the complex and you see also the superimposed positions of the ligand along the trajectories. The structural determinants of the active site are well maintained. You see here in the panel here the distribution of the distances between the ligand and some key residues involved in the binding with the ligand. Apart from this specific hydrogen bond the agreement is quite good between plain MD simulation and MMCG. After the calibration through the beta-drinergic receptor we have also applied our MMCG scheme to other GPCRs. In particular the beta-test receptors 38 and 46 and again the aim was to determine the binding poses of their agonists. This is a very challenging application because again for these GPCRs we don't have any structural information and the sequence identity with the template is less than 20%. Nevertheless our MMCG models were consistent with almost all site-directed mutagenesis experiments available and we were also able to find an intermediate binding site in addition to the standard binding site which again is compatible with experiments so let's say that at least so far with this method we are quite confident to be able to determine at least the main features of the binding from the structural point of view of the binding of the ligands to these membrane proteins. But despite all the improvement in the system due to the addition of the hydration water of the membrane and so on and so forth still some artifacts may be introduced in the solvent dynamics because of the boundary potential added to prevent water evaporation from the binding site. So for this sound alternative could be the implementation of dual-resolution modeling for the solvent such as the so-called Hamiltonian-based adaptive-resolution scheme which has been recently proposed by Raffaello Potestillo and Kurt Kramer. Within this scheme water is described with full atomistic resolution in the molecular mechanics region and a cost-grain representation outside the molecular mechanics region. The interface between these two sub-domains again consists of a hybrid-resolution region where water molecules change on the fly their resolution so they freely diffuse in and out of the molecular mechanics region removing this way possible artifacts introduced by the confining potential. And to couple the atomistic and the cost-grain potentials at the interface each address interpolates the Hamiltonians of the two regions. And we are very happy with this because each address preserves by construction the Hamiltonian framework which a priori allows a rigorous ligand binding free energy calculations. So let's say toward the implementation of this scheme in our MMCG method in collaboration with Raffaello Potestillo we have applied for the first time the HRD scheme to cytosolic proteins in water. For this first application the proteins is fully atomistic so only the solvent is treated with this dual resolution scheme based on each address and the aim of this work was to demonstrate the applicability of the method also to water sorbetting complex biological systems because so far the method was only tested for water in water basically. And so for this we compare the structural and dynamical properties of proteins in solvent computed with both each address simulation and fully atomistic simulations. And as a test case we use the etox one and cyclophiline two globular proteins without some differences for the folding is a bit different for these two proteins. And you see here in the scheme DAT indicates the radius of the atomistic region and we override the thickness of the atomistic region in order to determine the optimal thickness of the molecular mechanics part in order to reproduce correctly all the properties all dynamical and structural properties of protein and solvent as well. You see here the Hamiltonian of the system so you have the kinetic energy then you have this term for all atom bonded and non-bonded interactions internal to the protein and the all atom non-bonded protein water interactions and here you have this term that represents the hybrid non-bonded potential energy contribution of each water molecule VMM represents the SPC force field so the atomistic force field and VUCG the coarse grain potential and this term is derived from an independent all atom simulation on pure water through an iterative Boltzmann inversion procedure. And then you have this correction term called Gibbs free energy compensation term before to move to the correction term you see here in the hybrid part you see there is this lambda function that smoothly couples the two level of description the molecular mechanics part and the CG part you see here the function going from one for the molecular mechanics part to zero for the CG part. So in this this this correction term contains basically two contribution a contribution that to compensate the so-called drift force that arises from the coupling of the coarse grain and the MM Hamiltonians and a second term that compensates for the so-called thermodynamic force and you see here some comparison between all atoms simulations and H address simulation so the secondary structure elements are maintained and if you look at the root mean square fluctuations there is a very good agreement and also if you look for instance at the power spectrum of the dipole-dipole correlation dipole-dipole time correlation function again the agreement between all atoms and H address simulation is very good. Now if you look at the solvent you see here the radial density profile of water from the center of the atomistic region to the coarse grain region and you see here for H address simulations the density profile is almost flat so you have basically the same density in all of the region of the system and if you look also at the mean square displacement of water both for the bulk and for the hydration layers again H address is in good agreement with all atoms MD simulations. So in general we do not see an important variation in the protein dynamics or flexibility or structure by reducing the atomistic radius of the molecular mechanics part. The same is true for water structural properties and for translational diffusion whilst the reorientational dynamics of water is quite sensitive to the atomistic thickness and for instance you see here in this plot for thickness of the atomistic part of the order of 1.6 nanometer you have a discrepancy between MD and H address of the order of 10% and of course if you decrease the thickness of the atomistic part this discrepancy increases more and more. So the next step for us is to implement this H address scheme together with our MMCG potential for membrane protein and this is part of the work of one of our PhD students, Thomas Torenzi and this work will be done in collaboration with Raffaello Potestillo. So thank you for your attention and I think now I have to move to the question and answer session. Yes, thank you Vanya for the very nice presentation. Now we start our questions and answer session from the listeners. So everyone please use the chat channel, on the control panel there is the chat section where don't chat actually the questions. You can also use the chat, I'm not even involved to ask your question. So the first question we have is from Luca Maghi and I will now see if we can hear each other. Luca, could you say something? I'm not sure whether your audio works. Okay, can you hear me? There you are, yes. So microphone is off so you can ask your question directly. Hi Vanya, thank you for your presentation. And then I was wondering if you are planning to use a different force field in the MMCG scheme. Yeah, this is one of the future developments. Specifically we are working to implement amber force field. So yes. Yeah, okay. I guess I found that using ligands sometimes it's very difficult to use grommets because you have problems. Yeah, absolutely. Yes, this amber seems to be at least the standard for this kind of problem. And this is for us the main motivation to implement. Actually we are already working on this and we are doing right now preliminary tests. And of course all the parameters of the force field to be tuned for the coarse grain part in order to couple in the proper way the coarse grain part with the atomistic region, let's say. Okay, thank you. Thank you Luca. Our next question is from Alberto Duipietre. Unfortunately his audio doesn't work so I will read the question on his behalf. And he would like to know if you could comment on the correction of the thermodynamics force. Yes, so let's say that with the first correction you remove on average the drift force. But you cannot, let's say, remove the density imbalance originating from the different virial pressure on the CG and MM subsystems. So in terms of the ground potential PV means that the ground potential is for identical volumes is different in the CG and in the MM part while the compressibility for instance remain unchanged because you tune the CG potential to match the radial distribution function of the atomistic water. So by construction the compressibilities are unchanged. But this is not true for the virial pressure. So in order to enforce a uniform density you have to introduce compensating force, this second term. And basically you can show that the integral of this force across the hybrid region, so the work performed by this force on a molecule crossing the hybrid interface can be approximated by the ratio between the local pressure profile and the reference target density. So this is the origin of this second correction term and the form of this correction term. Thank you. I'll go to if you have further comments please write them in the question box. Our next question is from Anna Pociccio, if I pronounce correctly. So Anna let's see. So now you'll be able to ask a question directly. Hello, can you hear me? Yes. Okay, okay. So thank you for the nice talk. I have a curiosity let's say. So when you tested the MMCG on the beta-alphanergic you started from the x-ray structure if I'm not mistaken. Right. So the ligand is already in the good binding force. But did you test what might happen when you start from a wrong binding force or conformation? Yes. So we did also some tests in this direction. So we started with let's say wrong binding poses. So with the ligand very far from the binding site. And on average after 100, 200 nanoseconds the ligand migrates to the good binding pose. So it's let's say that we are quite confident that also starting in from very quite wrong configuration. So we are more or less able to recover the correct binding poses. Okay. Thank you. Thank you. And we have a question from John. Okay. So you can speak up. Can you hear us? Okay, maybe there is some problem with W. I will read the question on your behalf. John is asking to learn more about the main applications of this hybrid method. In other words, which are the biological processes that allow us to study in comparison with only molecular mechanical codes? This is a special interesting. So in general, as I said, hybrid molecular mechanics course grain methods are interesting to, for instance, to reduce the degree of freedom. If you need a high resolution only in a specific region of your system. Assuming that you have a good way to couple the high resolution region with the course resolution region. This is a good way, let's say to reduce the degree of freedom. So a priori you could increase the size or the complexity of your system just because you are on the other side, you are reducing the degree of freedom of the system. For us, in the case of GPCRs, the interest in using these hybrid methods in particular molecular mechanics course grain part is intrinsic to the system. Because, as I said, the system, we don't know for most of these proteins, we don't know the structure, the 3D structures. The sequence identity, if you try with homology modeling, the sequence identity is very low. So the models that you can obtain with standard bioinformatics approaches are, let's say, not reliable. For instance, we also tried in our institute to run MD simulations, standard plain MD simulations, starting from these models. But it's almost impossible to infer any information because you may experience unfolding or very strange behavior because the orientation of the side chains is very, maybe is wrong. And so it's really difficult to converge to the good orientation to some meaningful free energy minimum. But on top of this, in most of the case, you see really unfolding, so very strange behavior. Instead, with this MMCG approach, let's say that we remove all the potentially wrong information that is not essential to the problem. So we keep the minimum amount of information. For instance, in the part far from the binding site, we use a coarse grain representation just to have the essential flexibility and to transmit this flexibility also to the binding site. But no more than this because basically we need only this and at least so far this was the best strategy, let's say, in our experience to address binding, ligand binding problems to GPCRs or membrane proteins without unknown 3D structures and low sequence identity. Thank you, Vanya. I hope this was sufficient. If you have additional questions, please write it in the box. I was wondering, Vanya, I have a question to what are the maximum sizes that you have, sizes of systems that you have worked with? What is the limit of the method given the computers that we have at the moment? So far, we don't have any special limitation in the sense that this MMCG approach is embedded in GROMACS, so the engine is GROMACS. So it performs quite well, let's say, at least the same performance of GROMACS. The size of our system, at least so far, is quite small because we started with the binding of small ligand to the binding to GPCRs. But in principle, you can imagine to increase the size of the system or increase the complexity of your systems, adding other, following along the same lines, adding other proteins or whatever, or larger ligands or whatever. Thanks. One of our participants, Dike Osmario, is raising his hand, so can we hear each other? Would you like to ask a question? Hello. Can you hear me? Yes. Yes, very good. Oh, that's great. It's the first time I use this, so I'm a little bit confused. Well, thank you very much for this very interesting talk. I finally see after decades that people realize what I was doing in the 80s, namely the coarse-grained business. Because you can't be the world policeman that follows all the motions of all the particles in the world. You have to represent the solvent, especially in the biggest part of the system, by coarse-graining. And I have introduced the PMF approach for that that explains things that have not been explained by MD, by all atomic MD, up to date. So I predicted in 84, I predicted with very rough structural model for ions and water, the transition between left-handed DNA, right-handed DNA, left-handed DNA, the busy transition. Nobody working in the area of the brute force simulations that are pervading all science nowadays has ever been able to predict this because their DNAs, they disappear. They are poly ions and they dissociate. You cannot hold them together. But they keep supporting the brute force methods at the finitum, forget everything that has been done in the last 30 years, and now fortunately young people come in and they start to refine this business. And a final comment I have is that you don't need the coupling between, with the grain canonical ensemble and the in-between and all the stuff. You don't need all this if, if, a big if, if the relaxation times involved in relaxing the water which are obtainable from nuclear spring resonance or whatever, if these are fast compared to your motions, then you just need my PMF approach, nothing else for the water, for the ions, for whatever you have. If you are interested to collaborate with me, I'm retired, I don't have a group, I don't have funding, but I am still doing active science. If you are interested to collaborate with me, please contact me. Yes, yes, of course. You can left on the chat or maybe you can, no, you have also my address email so you can send me your article and of course you can contact me. No, it's not an article, it's 60 articles. I have the last, the last week, you know, it's impossible. People do not know the literature before the introduction of the scanning and all the stuff. If you want to collaborate with me, I would very much like to do this because I see that finally my concepts are being realized at this partly, but in a very obscure and awkward way, you don't need all this. You will gain a lot, you will gain a lot by contacting me, believe me. My name is Dikeos Mario Sumpases, Sumpases, S-O-U-M-P-A-S-I-S. You can find me in the research gate, you can find me in Google, you can find me in some places, but I'm not connected with some groups, etc. I'm just doing my work alone now because I'm retired. Okay, it would be a pleasure. Could you please say again the spelling of your name? My name is S, S like Siena. S, S-O-U-M-P-A-S-I-S, S-O-U-M-P-A-S-I-S. I have the name of Dikeos Mario here. Oh, correct. I can send you both email, like, foot through the search. Thank you very much for the talk though because this question you know with the relaxation times is very important for me for other reasons too. So if you have from your simulations where you will try to do this with the Grand Canonical I know the stuff you know. If you have some data on times involved, so what are the characteristic times of your ligand of your protein science compared to water distribution relaxation times? I think at least for the hydration water I think that they are not so different because you know in the for the hydration water you have this sub-diffusive phenomena so the timescale can be very very slow. But at least so far we are testing only mainly let's say the structural properties of the system. Of course the next step is to characterize the dynamics and to compare in a quantitative way. But of course I get the point of course if you have a big if the timescales are well separated let's say you don't need you don't need all this relation with different ensembles that's it you know so this was the strategy I introduced as I tell you beginning 1984 for all biopolymers whether they are poly ions whether they are DNA proteins or whatever you have you can use it in docking you can use protein interactions everywhere and it gives you very good results compared to experiments. Yeah so I don't know this method so I have to I have to admit so I have to go to the literature. Please take take a little bit of time to look at it and then you can you can contact me by you can contact me in the research gauge or link. Thank you this is a this is a very interesting discussion I'm afraid we are approaching the hour and yes thank you too we're approaching the hour and with which we will finish our webinar I want to remind you that our forums at asbelbergs.eu you're very welcome to post any questions and continue with topics of your interest and yes thank you again Vanya for the great talk. Thanks for the invitation. Yes and everybody have a great time over the upcoming holidays next year we'll prepare a bunch of very exciting talks in our webinar series so stay tuned. We will add you to our newsletter meeting this so that you can learn about the new talks that might be very interesting for you and your colleagues. So with this we are finishing and we will get again together next year. Have a good evening everybody. Thank you. Thanks. Good evening.


I am Dr. Rajasekar C. Jaka, consultant surgical oncologist and robotic surgeon, working in multi-manipal hospital since last 15 years. I do all complicated high-end oncosurgical cases in multi-manipal hospital.  Everything can be managed here. We have done many number of complicated high-end surgeries very successfully here and the results are very good. We have a backup support to manage here with a medical oncologist so anything can be managed in this hospital with regard to medical and surgical oncology.


We've harvested the rice. Now we're at the business end where we mill the rice into a product to eat. So the first thing that happened after we harvested the rice is we took it to dry. It was at a moisture content of about 21% from memory. And we took it and dried it in a flatbed dryer down to a moisture of about 14%. So Martin's going to measure the moisture content of a sample before our eyes and hopefully it's what I claim it is. So I can't actually measure the sample that has been in the mill because it's already milled. But I have another sample here and the ideal moisture content for milling is between 13 and 14%. And so the first step would basically be to measure the moisture content. And this is an example for a moisture meter, the eerie moisture meter. You put a small sample of grains in there and then you crush them. And then by measuring the resistance, it gives you the moisture content. And this basically tells you that the sample that we have is still too wet. We couldn't use that for milling. So that's more than 16%. It's more than 14% in this case. And basically this would also tell us if it's right for milling between 14% or whether it's right for seeds. What happens if you mill it when it's wetter than 14%? If you mill it wetter than the grain is very soft and we get a lot of damage in the rice mill. By basically the machines crushing the grains. So your milling yield would be a lot lower. And what if it's too dry? If it's too dry, then it's too brittle. And again because of mechanical stress you get more cracking because it's so brittle and again you get more losses. And for the drying there are different options. This grain was dried in the flatbed dryer. But the flatbed dryer is a very simple technology that can be locally produced and produces reasonably good quality. But then there are also more sophisticated dryers like we have run over there, which is a so-called recirculating batch dryer which allows us to produce really the optimum quality of the paddy before we do the milling. Okay, okay. So when we were growing the crop, particularly when we were harvesting the crop, the goal was to harvest the crop at about 20-21% moisture and then dry it down because that will give us the greatest grain quality and yield, whole grain yield through the mill. Now what do I mean by whole grain yield if we come over to our little demonstration bench over here? It's to start with the paddy to remove the husk, to remove the bran layer which is just underneath the husk and that's what brown rice still has the brown layer and to get whole grain and broken grain. There's not much we can do to manipulate the quantity of husk we have. Likewise there's not much we can do to manipulate the amount of bran we have but the whole idea of the management in the field and in the drying process and the milling process itself is to get as much whole grain as possible and as little broken grain. The whole grain is worth a lot, the broken grain isn't worth so much. So in most markets the rice is traded according to different quality stand nuts and one of the stand nuts for example looks at the percentage of broken grains. So you would have typically stand nuts that say for example rice is 5% broken so there would be 95% whole grains and 5% broken. Similarly there's rice is 10% broken and also it's 25% broken and one of the objectives of rice milling is then also basically to produce according to that stand nuts and there are different equipments in the rice mill that help us doing that. After the grain has been dried to the appropriate moisture content it's then delivered to the mill and the first stage is the de-hulling where we have two rubber rollers set at a very close clearance to each other and one roller is travelling just a little bit slower than the other roller and that abrasion motion, that pincer motion removes the husk from the rice it then goes on to a gravity table which then in a horizontal reciprocating motion it's on a slight angle and that successfully removes the hulled rice the hulled brown rice from the rice that was not successfully hulled and the rice that was not successfully hulled goes back to be de-hulled again. After that it goes through three stages of polishing an abrasion stone polisher, a friction polisher and then you also have a choice of a mist polisher if you want that final shall I call it sheen for a really quality, high quality product that really looks as desirable as it tastes and there's one final process after the polishing process it's then graded for size both through a rotary sifter and through a length grader and that separates the hulled rice from the broken rice ironically then the broken rice is often then mixed back into the hulled rice but at a known percentage it's typically 5% more there are very different standards the best quality is usually has 5% broken and the worst quality 25% broken and then beyond that local markets often don't implement those standards so there you might find 60% broken or even more depending on the quality of the raw material and also the performance of the rice. So it is usually broken grains are mixed back into the whole grains at a known standard typically 5% to 25%. The final stage in a sophisticated rice mill is the colour sorter there's an ingenious piece of technology that runs streams of milled rice grain in a single grain stream there's sensors that sense the colour of individual grains and if the colour is not white enough basically that could be from poor milling it could be because it's a foreign object like a stone there's nothing as much fun as a stone in your rice a short sharp jet of compressed air will remove the grain and so those final high standard sorting processes is quite a common process in high standard rice mills and then hence you have the finished product whole grain well milled rice with a known quantity of broken in it and that's really the objective of the whole process So there we have it the business end this is where the white rice that we know and enjoy is produced and we've covered off on the processes before the milling and during the milling that allow us to produce as much quality white rice as possible and a minimum of everything else and the objective is really to sort of use the potential of the paddy and get the maximum amount of whole grains and the minimum amount of broken and also basically presented in a way that the consumers really like it


Hello students! There are a few questions bubbling in the head of every net aspirant who is trying to prepare and give their best in the last few days of net exam. A lot of students are worried and they are really tensed about how they should prepare. Is it the right way in which they are preparing? What were the mistakes that they did last time due to which they were not able to qualify this exam and how should they channelize their last few days so that they can prepare even if they have not made any previous preparation? If all these questions are going in your head as well then you are at the right video because in this video I'm going to line up all the dos and don'ts that you should follow if you are preparing for UGC net and the tips that I'm going to give is going to be relevant for paper one and paper two both. Now it is important here for you to note that all these tips I'm giving they are actually tested. I have applied them during my net preparation and I qualified net in first attempt. In this video I'm going to show you my notes and how I prepared my notes in last few days which helped me clear net. So if you are really looking forward to follow a strategy or right path which can actually help you qualify net then this is the video for you and do watch it till the end. If you're ready to do the incredible then take a pen and paper and start jotting down the most important points I'm going to mention right here. I have seen a lot of students who are always looking forward for good books. They are always asking people which book they should buy which can help them qualify net. Guys I can tell you very clearly here there's no one book which can make you qualify net. If that would have been the case then everyone would have got that book and have cleared net. Why net is so difficult to achieve because you need to use your mind along with good books. Every book is good and bad at the same time. If you don't use your brain then that book can be a bad book for you because that book will not help you achieve net. Don't go after books. Go after what your brain says. Go after smart work. This is the time when you don't need to refer to any one book. This is the time when you need to make handy notes like one page notes for each topic. I'm going to show you my notes for paper one. These are my notes for paper one and if you look very clearly you will find that for each topic I just made one page notes. I refer to a few books and then I just made one page notes and if you go through this entire copy you will find out that my notes have a proper format. I keep on highlighting the mistakes that I was making. I kept on highlighting the most important point which I saw in the previous year papers. So this is the right way to make notes. It's not just going through the books again and again. Your brain would not be able to absorb the facts so easily. You need to give him little material and that little material should be very clear. So don't go after books. Go after a smart strategy which can actually help you qualify in it and that smart strategy is to make handy reference notes. A note paper should not exceed more than one page per topic. So for example suppose you're making notes on tools of research which is a paper one topic. If you look at my notes I have clearly mentioned few important things and that's it. I did not go beyond it. I did not like write paragraphs. I just write quick pointers which can help me remember the correct fact on the day of the net exam. A lot of students question me how many hours should we study in last 20 days to clear a net. Now this is a really really bad question because see there's no particular hours that I can tell you which can help you qualify in it. It's not how many hours. It's about what you do in those hours that can determine whether you've cleared net or you do not clear net. I have seen a lot of students who sit for like 16 hours and then don't clear net and I've seen those smart students who sit for not more than six hours and they clear and achieve their targets. How is this possible? It is possible because the students who are sitting for six hours they know how to manage time. They know how our brain works. Okay if you want to bake a cake you need to know the procedure right. If you don't know the procedure you cannot bake a cake in a right manner. Similarly if you want to qualify in it if you want to feed data in your brain you need to know what is the mechanism of the brain and it's very simple. Our brain's attention span is 50 minutes. So only for 50 minutes our brain can concentrate on the work and then beyond that time if you keep on working if you keep on studying our brain does not retain anything. So after every 50 minutes make it a point that you give yourself a five minute break. Be it going to washroom just stretching or talking to a friend on phone for five minutes just distract yourself so that you can come back and again attract your brain to study that topic. So managing time is very important. It's not how much hours you are studying it's about what you're doing in those hours and that is how you can qualify in it. So if you are ready to give your best in this exam then I'm telling you best is going to come back to you. Only the thing that you need to remember is that the time that you are studying make sure that is the time when you're concentrating. It's not just that you're sitting with a book and nothing is going inside you. After every 50 minutes check how much you've retained is it that you were wasting time you've read so many pages and you still don't remember anything or have you worked smartly you've highlighted thing you have marked pointers you've remembered those pointers and now after 50 minutes you exactly know what you've done in 50 minutes. Don't waste time work smartly even with six hours of preparation you can qualify in it only when you know the right way to work. The third and the most important thing that is going to help you in the next few days of your preparation is solving previous year papers. Me de se aaj bhi jab students phone kar ke pujhtayin ki naam paper one ke liy kya kare is last time me. I always tell them the same thing. Sir, previous year papers ko refer karo, unni solve karo, apni galtiyo ko evaluate karo aur un mistakes ko correct karo because if you see all the previous year papers of paper one specifically you will see that concept is repeating year after year. Questions are not going to repeat but at least the concept is repeating and if you have understood the concept you know the method to solve that question then I can give you any question in the same concept and you will solve it. So it's as simple as that. Previous year papers ko solve karne se you become familiar to the paper pattern you become familiar to those mistakes that you're making. There are times when students make silly mistakes on the day of the exam because they've not solved previous year papers. Agar bahi galtiyo wo previous year papers ko solve karte wa kar dethe tab wo galtiyo ko wo correct kar sakte ther aur baad mein wo exam mein wo galtiyo wapis nahi doharate. Also, there are questions students ask me that abto paper pattern change oge hai, syllabus change oge hai, abhi kya previous year papers relevant hai? Yes, of course, 110% relevant hai because if you look at paper one, paper one ka purana syllabus bahin ka wahi hai, 10% new topics logical reasoning aur mathematical reasoning mein add hui hai. That's it, purane topics delete nahi hui hai. So, previous year papers ko agar aap refer karte to at least 90% topics ki preparation aapki arraam se hosate without using any book. And also understand the fact, sirf solve nahi karna hai, evaluate karna hai, dekhna hai ki galtiyo kaha huri hai, you have to study your mistakes. I have seen students jo sirf solve kar dethe hai apni galtiyo ko nahi dekhne. Solve karne se kya hoga? Agar aapne 50 mé se 30 marks le aaye to hoga kya ye jo 20 marks aapki loos hoi hai, in galtiyo ko wapis anko seekhi hai, dekhhi kaha galtiyo ho rahe hai jissi next time aapki 50 mé se 50 aaye, 50 mé se 30 na aaye. Also understand the fact, ki agar aap previous year papers solve kar rahe hai aur her paper solve karne ke baat evaluate kar rahe hai to un corrected cheezo ko apne dhyaan me rakhe aur unko apply kar ye next paper me. So that you know that ok, I am making progress. If you follow the same study pattern, you are going to get the same result. Aapne ek topic padha, question solve kare, galat hui. Aap aap bhaapise baise hi ho topic padhe hai phir question solve karte phir galat hota hai. Ye to ek endless chain hai jo hoti rahe hi. What is important is that you see the pattern, then you see the result. If the result is not appropriate, then change your pattern to change the result. Same pattern, same result. Change pattern, new result. It's very simple. So don't grip when you get low score in your previous year papers in your mock test because it's okay to get low score. Low score karna galti nahi hai. Galti tabh karte hai aap jab low score karne ke baavjut aap mahinat dehi karte. If you don't work on your mistakes so that you can get a better score next time, that is where you are lacking behind. And always remember, if winter comes, can spring be far behind, agar aaj apna low score raha hai aur aap mahinat karne hai, to kya kail bhi wahi low score raha? Bilkul nahi. Kail aapka bohda chha score banega. So I wish you all the very best for the next 10 days. And most of all, I wish you a very, very peaceful state of mind. I wish you a state of mind jis main aap bohot aapsis appreparation kar pahe aap apne aapko ek stable environment mein rakh pahe. And I wish you that this time you will qualify in that exam. Give your best shot and I'm pretty sure success is going to be on your side. Also don't forget to subscribe to this channel because we are posting some amazing videos on paper one preparation on this channel. And we are going to continue to post these videos for the next few weeks. Also I would like to tell you if you've not yet subscribed us on the social media platforms, I think it's time to do it because it's free. And you will get all the latest updates about net, when is the admit card releasing and when is the exam happening and what happened on the first day of the exam, how is the paper pattern. All these updates would be given to you on all my social media platforms. Apart from that, you can visit my website, to get all the previous year's sold papers so that you don't need to go anywhere else. You will get everything under one website. So that's it for this video lecture. We'll meet soon, very soon in the next video lecture. But till the time we meet next, happy learning, keep loving literature and stay tuned to arpathakarva.com.


Type 2 diabetes, T2DM, Alzheimer's disease, AD, and insulin resistance are all age-related conditions which have been linked by recent research. It has been found that insulin resistance and impaired insulin signalling may contribute to the progression of these diseases. Additionally, it has been discovered that Alzheimer's disease, AD, share similarities with Type 2 diabetes, T2DM. Both diseases are characterized by reduced insulin secretion and or action, leading to altered glucose and lipid metabolism and elevated levels of certain compounds in the blood. These findings suggest that there may be a shared underlying mechanism for the development and progression of both diseases. This article was authored by Giuseppe Verdal, Kevin N. Keane, Vinicius F. Creusat and others.


Hello and welcome back to the craft box. My name is sprint and today We're in episode 96 of the was a one-on-one death walkthrough last episode if you haven't checked it out already We came into Zafaria and we defeated a couple of things and the the Baobab marker which is there um And yeah, I've actually never seen this before that's kind of cool But yeah, so that's basically what we did So this episode we're starting by talking to Resek prideful Why do you bother me? I have no time for trifles. I thought we were rid of all you wizard city nuisances. I Have no time for you now the day is dying and the shadows go long No bother someone else Counselor Kakinya broken fang is toothless and weak. He's right over there Okay Hey Who are you? Yes, I gave permission for the students to travel to the savannah, but now they are lost in probably dead The savannah is too dangerous a place for outsiders Dead runs on quick legs and the weak fall beneath tooth and spear You would get lost in die from hunger or thirst if I let you go. You don't even have a map Where would you get the map? You are persistent aren't you there is probably a map in the student dormitory? Very well, then if you can find a map in the dormitory. I will give you permission to enter the savannah Okay, then sounds easy just a map and then we're in the savannah Perfect. I feel like it's way too quiet Like everything is way too quiet. I don't know why Because like it used to be kind of loud, but now it doesn't I don't know why it's kind of worrying me But anyway, we're into here And see what we can find Collect fleshling Okay, then you crazy person We are going to put you in and you are a boss a rank 10 boss.  Yep, this should be fun. If not, we've got reshuffle. So, oh well, we can always try again Let's do that start off with a a nice wee Prism What are you doing? Prisming me? Haha, you're fizzling. That's what you're doing boy. Oh Fizzling as well. Okay boy. Oh, I think you're cool, huh? Hmm, we'll see how you like being cool now Okay, we're gonna draw. What do we get one of you? Okay Yep, basically, we're just gonna next blade and then hit man. We should be fine. I didn't put feint in Maybe I should have. Oh well. It's fine Oops, Gecko. Hello Should probably have put feint in. Oh well, that's fine. I didn't actually check how much healthy he has I always do that like halfway through but I'm like, oh, I wonder how much healthy he actually has Try some. Hello I've seen you on waterworks a bit. Geez Getting down to like half health in the first round of battle. Like what the hell? Waterworks. Geez man 4,200. Okay Draw again. We should hopefully get in single blade. We did. Perfect. We will do This might help if I actually click on myself Yeah Yum Okay And what do we have next? We have one of these. I mean, we're just gonna continue to blade Just gonna keep blading man Just keep blading just keep blading Blading blading blading blading Storms are like, hello I mean, we've actually not lost too much health, which is kind of good Um, I was more worried than I should have been for this battle Um Okay, half health finally or just over Um, okay another blade Max blades there now, which is good four blades prism If I had a feint I would have used it But you know what? We're just gonna hurt and get some health back because we're kind of nearly dying No, not too bad. Not too bad bolt. It's gonna do max and kill me That's happened before don't judge Oh, hello that did quite a lot Quite a lot more than I was expecting Um Let's do this And we're probably not gonna crit, but if we do though, it'd be nice Again and again Nope, not for it. That's unfortunate. No, well We should still do a lot Okay, yeah, we're gonna go Don't know either. Okay Don't worry. He has a bit more health. That's why we have wraith Yes Okay We're just going to enshrine you because we can do we get a yes, we got a single blade, which is good Yum And next round we'll wraith and hopefully kill Yum Okay, how much health does he have like 1,000? Great. Ah, even less. That's perfect.  Thanks game I need some more accuracy. That's the only thing that I'm lacking in this year is accuracy Um, which is kind of annoying But I have so many power pips which is good But accuracy is kind of annoying because I fizzle more Um, but it's fine. I think I've got like two accuracy or something something pathetic Why not Zinae show us how it's done Really? Okay game. I see how it is max folding.  Nope Min Oh, not min mid You know, we're just gonna do this Cause it's the only thing that we have currently Thanks game Did either way but it's still kind of annoying Okay Yeah, it was why are you here boyo? Lucky you showed up before that horrible bug ate me. I knew this place was dangerous the moment we arrived I thought I'd be safe by skipping this advantage trip and staying in baobab I never knew they had such giant bugs here the other students No, I haven't seen anybody since they left. I've been hiding uh studying here a map Sure. I have a map of the savannah. You can have it. I'm getting out of this place Simone brightlands hands you the map. You should take it back to counsellor kakenya broken fang Yeah, there's one that was losey wasn't it? Ha ha ha ha Yep only gets harder from here Um, but yeah, we find quite a few in the savannah and then we go elsewhere for I don't even know why but we go elsewhere Um to do things and yeah That's what happens Um, I think it's actually in search of the elephant which takes forever, but you know, that's fine We're just gonna do what it says And that's probably the best way to play the game Okay That map will do Yay level up. You are foolish for still wanting to go into the savannah. It is a bad time there for my people However, I told you I would give you my leave. So go to your death if you must You will need permission from the other counsellors to speak to counsellor unati narana and convince her You are another wizard city wizard Yes, I am You want to visit the savannah kakenya broken fang already gave you his permission Can you even wield a spear? I won't send you directly to your death If you can prove you can handle yourself You can earn my permission too. The baobab market has become a rough and violent place Gangs of thugs harass the good merchants Show me that you can survive by defeating some of these wild spear fang slashers and giving the merchants some peace Then we're drunk Okay, I'll be back once I've defeated spear fang slashers Okay, I am back Just finished off that and now nightrunner. Hello Better than I expected I will say All right, as you are so insistent I'll grant you my permission to travel into the savannah still before the guards will open the gate for you You must get counsellor rassic pride falls approval. Hmm. He was just here I wonder where he went. He's a lazy loud I see his assistant over there. Their good heart is a weakling and a groveller He'll bend to you if you are forceful enough Okay, let us Talk to their good heart Hello Oh, hello. What do you need me for? You need the counsellor's approval to open the savannah gate Why would you want to do that? It's not safe out there Oh, I see you're looking for the missing students. That is important and brave counsellor pride fall hard to return home on pressing business Oh as acting counsellor I could grant you permission But you see some of our merchants have been victims of thieves here in the market I am powerless to hurt my people, but you could let me make a deal with you Defeat the spearfang slashers who stole the jewelry and the insin-zebo bandits who took the spices And bring the goods to me so I can return them then I'll help you I'll be back in a sec Okay, I am back after doing exactly the same thing basically as we did last quest You retrieved all the goods excellent. I'll get the goods back to their respective merchants at once Great job. I wish you good luck finding your fellow student in younger white stripes is helping you out He scares me a bit. So I'm glad it is you who are dealing with him Tell in younger white stripes that you have earned the right to travel into the savannah Yay, that is fantastic. Um, so you let us hit on in To the savannah actually no, we might do that next episode in younger We'll talk to you first and see what you want us to do Jambo, I can see on your face that you've dealt with all three counsellors. Well done It is time for you to journey into the grasslands of the savannah Be wary of the nomadic tribes, but treat them honorably The savannah hunters are a proud people reduced of late by dire circumstances once through the gates You will first come to the zebra encampment camp mogobo You will want to find mesisi red band a local guide Professor umlilo sanchesa hired her to lead the students into the bush find her and you will find their trail Go now and speak to the gate guard let you blunt tooth He will tell you how best to find mesisi red band. Okay, we are going to talk to the gate guard and Probably end of the episode Back I see The council said you are to be allowed into the savannah. I would never have imagined Go straight through to come mogobo. Do not lead the road. It is quite a hard journey So not telling how long it will take you My people dwell there So of course it is a haven of safety in that wild terrain You are looking for the guide mesisi red band. I do not know her. This is my advice First find tic tic snake top. He's an unusual soul a lion works more like a zebra Tic tic knows everyone and everything if anyone can find your guide he can Okay, so next episode we will head on in and find tic tic snake tongue So yeah, thank you for watching remember to leave a like and subscribe and if you haven't subscribed Press the little bell so you know exactly when I post another video and remember craft outside the box


Well, I think because there is a human consequence to the effects of climate change and one of the consequences is mobility, people movement, whether it's voluntary migration or forced displacement or resettlement, a planned resettlement. And so therefore that has to be well managed and anticipated and people helped along the way in full respect and protection of human rights and dignity. And frankly it's not happening that well and so I think this forum has been very helpful in putting that very real issue that we humanitarians and development doctors have to deal with on a daily basis and so to bring that message here to the negotiators, hoping that it becomes a very important part of the agreement. The climate change is not the immediate trigger of El Nino but it certainly exacerbates the impact of El Nino. We're talking about the worst droughts in 30 years in Ethiopia for example and completely wiping out the potential to wipe out all the development gains of that country that we talk about as being a model case in many of the MDGs but because of the impact of the drought has been so severe, the number of food insecure people, the number of people moving in search of food and bringing communities against each other and with very real potential of the clashes and this is where I saw this happening in Ethiopia but the same thing is happening in many other countries in East Africa and South Africa. I think risk anticipating the risk and we may not pinpoint where exactly the risk is going to materialize but we do know the risks and so we have to work with partners, governments, development actors to identify those risks, to analyze those risks and to mitigate that to the extent we can and prepare for the risks becoming and striking us as a real disaster. Disasters will happen but we need to be better prepared and that has to be based upon better risk analysis and joint planning. I think the climate change agenda certainly has come a long way towards a closer connection with the vulnerable populations. Today we're talking about 125 million people and a big chunk of them are displaced and displaced of course is that just the fact of being displaced leaves people in very vulnerable situations. They're people that lost everything whether they've crossed borders or within their country and so there's a greater need for a particular kind of protection and assistance to displace people and so we feel that the human consequences of not doing something about climate change and climate change not just in terms of natural disaster but also the societal impact it has on scarce resources and that leading to societal tension and perhaps even you know as flaring up into as conflict so we have to look at a holistic picture and in the end look at the human consequences and what this means for the most vulnerable people.


Welcome to Toffy TV, it is my three things from Everton One, Liverpool for the Gwderson Park tonight, another awful home defeat for Everton, that's two of the last three home games, we've lost five, two and four one, eight games without a win, it makes awful reading and I don't know what comes next for Everton at this stage in time, but let's begin I want to start with the players because ultimately they wear the shade, they're the people who pull on the kit for us, they go out and they're supposed to give everything for us every week, that's what the manager told us on Sunday, they've given me everything which is quite worrying if it's eight games without a win, one winning 10 or 11 I think it is, so they're giving everything then that's terrifying Tonight ironically though I don't think it was from lack of effort, I think Liverpool is simply better than us for a large portion of that game, I think the issue I've got with these players is they bottle it when they're in possession of the ball, there's absolutely nobody or if there is there's very few of them who are prepared to take over a football and try to do something constructive with it, it's like a hot potato at times they're just flicking things here there and everywhere and it's ridiculous, they get possession, they give it away, they rush it, they turn and pass it back, it's not good enough, they're supposed to be professional footballers that train every day, they're supposed to be elite sportsmen that's off of their game, they don't look like it, when they pull the shade on they don't look like it, everything's, they're uncomfortable on the ball, it takes them three or four touches to kill the ball to get it in under their control, it's not good enough they do it, they've got no bravery either, they're turning and passing the ball back, there's nobody wants to be of, like I said before, very few want to actually do something on the football, they're already great, he got mine on the mat, he's one who's really positive but even him in the first, I've got book for diving when there was a shot on, like trying to do something else, get the shot away, suck his goal really well, he was a constant threat for us, well probably our only real threat, but he is someone who will take the ball, he'll try to take the ball but there's others, everything's rushed and it's just not good enough, it isn't good enough, we know that, they're not the best players in the world we know we were up against a team that has got some of the best players in the world playing in it, but be brave, your football is, be brave on the ball, you do it every day, how can you not get better and better at your job, I mean you do it every single day, how can you not get, be comfortable on the football, either the training is not very good and so you're never challenged enough and I've said this a few times because our squad is poor, when those players are training, they're not up against much because the people who are up against them are very good, quite obviously because they all look like the not Premier League footballers and it doesn't matter, tonight they were up against the top side but other occasions when they're up against very, very average teams and let's be honest, there's a lot of very average teams in this Premier League and evidently one of them, that's for sure, they can't do it then either, so it has to come on the players and the manager is making fundamental mistakes at the moment, he got a team selection wrong tonight in my opinion, the formation that is, we went up against one of the strongest midfields in the league with two players in there and thought we could cope which is just bordering on crazy by the manager but he is starting to make those mistakes now, it's the last few weeks but the players do have to take responsibility as well, these players have got five, four or five managers sacked, they're on the verge of getting another one sacked now and it's simply not good enough and it needs to improve very quickly otherwise evident are going to be in for a relegation fight and that's the way it is and this squad should be good enough to easily avoid all of that but you're not brave on the ball, you don't battle enough, you don't become resilient, you get dragged into it and other teams will have those qualities, they might not have as good a technical footballers as what evident have got if they've got any but they'll have all the other qualities that evident don't possess and that's a worry let's speak about a positive which is Damari Gray, I thought he was good tonight, he obviously scored a goal, he was the one kind of bright spark, the one person you look for who could make something happen so he was the real shining light for me tonight, I thought the Corey did okay as well, just simply outnumbered in that midfield, if only the manager knew what probably most ever told me in the interview which was these have got a good midfield, we have to match it up with three but I thought Gray was a plus, a real positive in the game, constant threat like he said when he got on the ball, it's a pity, we couldn't get the Charles up to the same level, he's just not quite at it at the minute and we've got to have better, Rondon was okay tonight at times, I thought at other times in the first half he was dreadful but he did get better as the game went on, not brilliant, not even good, just okay and that's because he set the bar so low for himself but I felt if we would have had another midfielder in there we would have allowed the Corey to break on and I think that would have favoured Gray a little bit more Rondon, doesn't really move much and so the Charles was almost lost as well but I thought Gray, he's the one positive in this video for me and he got mine out of the match so there you go and finally after talking about the hierarchy, I'm sorry I do, it's a nonsense what's gone on at that football club, we've spent a lot of money, everybody knows we've spent a lot of money to be in a position where in is just down to shocking decisions from the owner, from Bill Kenwright, from the board, all of them making shocking decisions I've said that about Bran, some of his recruitment has been atrocious, some of others have been fine, if he's not being allowed to do his job properly then he needs to go and have a real heart and heart a heart he needs to go and put some stuff on the board's toes or whoever's making the decision to allow other things to happen at the football club and it's probably the owner he needs to go and have a proper conversation with the owner and grow a pair of balls and say you either let me run the football club the way you want to direct at a football to do it or I go and that's really now for me the only two choices he's got because there's a video going round of him tonight, he's been given a bit of abuse, let's say he's been questioned quite straight forward he's not happy and rightly so and he stops and he mentions something about the players on the pitch and then he walks off if he's been blamed for the recruitment and it isn't him then if that was me then I would walk, if I'm not allowed to do my job I would go if he's been allowed to do his job and he's doing it the way he wants then he needs to be sacked because he's not doing it very well and they're the two things I think it's time that we had someone in the football club who knows about running a football club and so if Denise Barrett Axandale is very good at a job then we need to replace the chairman with a football man who has got experience at running Premier League football clubs and business maybe because something needs to happen with this football club that actually begins to push it in a way that it needs to go because at the moment the way it's gone it's just going round and say it's going backwards but it's going round in circles as well we're not getting any better there's no direction there's no clear plan we've got a manager most of us don't want or didn't want at the start of the season we've got players that most of us don't like because they just don't give everything for the bads it's passionless in a sport that relies on passion you see them you see the gainer giving it all out with their fans they love it and the team response they work so hard and they're very talented and you look at us and we're just all fractured everywhere the fans the team the players the board there's fractures everywhere it's no good it's not conducive to moving this football club forward that's just my opinion but I'm looking at it and thinking something has to change very quickly you can sack the manager you know it wouldn't surprise me one little bit results would suggest he needs to be sacked no wins in eight one in eleven I think it is results Premier League managers tend not to get eight games without winning one of them they just don't they don't get it there's loads of mitigating circumstances he's had injuries different things have happened wasn't giving a lot of money it isn't all his fault absolutely isn't all his fault I'm just saying in other clubs they just wouldn't accept this this run of results but something has to happen even if it isn't sacking the manager something has to happen within this football club that shows us the fans that there is change and that might be a new chairman it might be someone coming on to the board to direct the club a consultant whatever you want to call it who runs the football club because right now there isn't enough of those people driving this thing forward and it's if apathy sets in then that's terrifying if people start going oh well what can you do and then lose an interest and the ground emptied with 15 minutes left there was a lot of people went that's a terrible sign it really is I've come out the game I'm gutted we've lost but I'm not devastated because I don't know I think I just expected it and that's a terrible thing for me to feel it's horrible and I don't like it and there'll be a lot of blues who are just like we expected it for what we've had the money we've had it's not acceptable not acceptable to lose a doubt before one home and on top of everything else that's gone on and so something needs to happen and it needs to happen very quickly at this football club otherwise we are in for a long and horrible season again so there you go there my thoughts let me know what you think give the video a thumbs up subscribe if you haven't checked out Peds aftermatch stuff yeah that's it see you later


Welcome back to the channel. This is my favorite code editor, which is a VS code, Visual Studio code for short. And one of the things that I love about it is that you're able to extend whatever functionality you want in here. For example, if I wanted to do short codes that I all use over and over from different computers, and I find that sometimes it's useful. So I don't keep those snippets to myself. So I write actual extensions for them. So you're able to go to your extension spanner here, and you can quickly install a particular extension and then use it for your daily work. For example, these are some of the extensions that I use every day. Now today, we're going to write an extension for Elementor, which is one of the biggest page builders in WordPress land. And that's a project I've been working on and then Nintendo and growing and making it bigger and adding more short codes. But I want to show you how you can write your own extension using this as a start point. So the first thing that you need is you will go to the docs of a Visual Studio code and we see that we're not doing Visual Studio, we're doing Visual Studio code. So you go to the docs of a Visual Studio code and you will go to the API. Under the API, you're able to see requirements that you need to start writing your extensions. So the first line of code that we need is actually we're going to use Node.js. That's why we have the npm here. And then we're going to use your, which is packaged for npm node. And then we are going to use the generator code, which is for the VS code extension generator. So everything is automated in a way to make this really easy for you. So we'll need Node.js, we'll need your man, and then we'll need to have a VS code extension generator. So the first thing that I need to do is test for Node. So I go for Node, dash V, and I have Node installed here, but if you don't have it, you just need to go to Node.js.org, download the version that's suitable for your operating system, and then install it like any other program to have it installed. So after installing Node, we're going to install your man and the VS code generator on our computer. So the first thing that I need to do here is just type npm install dash G to have it global. And then I'll add the extension of your that I want to install. Then we need the generator dash code. We need generator dash code to install it. And then we'll run this. So this will take a little bit of time. I'm just going to move to the end of the progress. This should be automated. So you don't have to worry about getting any errors. Unless you do, then you run them by Node.js to see why you're having those issues. So I'll wait for the end of this. So you can develop a number of extensions, and we have some code samples here for us to see. Some will be in a JavaScript or TypeScript, and others will just be short snippets of what we are going to actually build. So in this particular case, I want to build an extension that has snippets so that when people type them in their PHP files or JavaScript, I about to just get a code block that they will edit and reuse over and over and over again, sort of make templates of code. So after everything, our npm packages are installed and we are ready to actually go. So the next thing that we're going to do is go into our folder here. So for example, I just want to store my files in this file called VS extensions because I want to keep them centered. So I'll change directory inside those. So while I'm inside there, I'm now going to begin working on my extension. So the first thing that I need to do is type your code, which will give me the bootstrap of writing an extension. So I'm going to answer just a couple of questions to help me get through this whole process. So I don't want to share any anonymous reports. That's why I chose no. Now we're going to do a code snippet. You could do a color theme or language support, but we're going to go for a code snippet. So that's what I'll use down here. And since it's new, we'll not add anything. We leave it blank. And then the name of our extension is going to be Elementor snippets. And that will be the identifier. Adds code snippets. Go building Elementor widgets. And then the language I'll add PHP and that will allow us to create everything that we need. So we just need to go into Elementor dash snippets, which is our folder. And then we can open it in VS code. So we type code dot. So in here, we're presented with a number of files that we don't really need to edit. Some will do edit later. But for this, we don't need to edit now. We have a file open for us to add our snippets. The change log, where we can write all our changes, our package of JSON. For now, I'm going to change this to 1.18 as the engine that I want to run. We'll add a couple of other things as we get to publish the whole package. But for now, let's just head into Elementor. And we'll just see what let's say something that we need to add as a widget. So I'll go to Elementor. And I'm going to look at widgets. And I'll go to the controls. So in the developer panel, the one thing that we probably wanted to add is how to add controls. So I'll just copy this. And then when I come here to my Elementor, I'm going to go into the snippets codes here. And I'm going to add the first thing that I need is a name for this. And I'm going to call this add text widget, add an EL to it for Elementor for short. So we add the ID for our snippet. And then we're going to add these calling brackets here after. We shall need a prefix. So we need to add a prefix to this. And the prefix in most cases, I'll just duplicate this because it's about the same thing like the ID. Then the next thing that I'm going to add is we need a body. And in here, you can see it's already telling us what it's expecting. But we saw a number of things here. We saw something like a description which we can add. So we can say add a control for our text widget item. I can just call that there. And then the next thing that we need if we can add a scope, if we want to and say this will only be in PHP. But we can also add the scope directly inside our package to JSON where we add language PHP. We can have others for JavaScript and so on, depending on the particular snippet that we're bringing in. So I'll not add the scope at this place, but rather I'm going to add the body. Go back to Elementor. We're going to copy our text field here. And then I'm just going to come and paste it inside the body at this point. So I'm just going to use my VS code to help me fix this really quickly. So I'll select this, use control shift L to go to the end, add the first bracket with a comma. And then I'll go to the beginning and add the opening bracket. And this works out well. The only issue we have is these brackets that are not well closed. This is a namespace for Elementor that's needed. So we need to escape this slash that we actually see here. We need to also add a slash at the end for this to make sure it is well escaped. So we have our body, we have our description, we have our prefix, and everything is going on well. So let me test this. Now for us to test this, we just need to press F5. And this will open for us another instance of VS code. And we are going to first save this file as PHP. So I'll call it index PHP to allow us to test this because our new extension will only work in a PHP environment. So in here, if I type EL, you will see that we have EL underscore. And as we add text widget, we see the description we gave this, and we have our code. So when I just type that, we're able to get all our code showing up here. So we'll edit this and just make the changes that we need to make. So this is working out beautifully for now. Let me just go back here and I'm going to add a few things that will help us to change. Let's say if we need to change the name here for the plugin and the text widget. So what we do in this case is we add a dollar sign and we add two curly brackets. And then what I'm going to do here is add a one for it to be the first item we'll edit. We're going to call it a control name. And we're going to just copy this again here, change it here in the plugin name. I'm going to give it a position of two. And this is what is usually our text domain. So I'm going to change this and call this text domain. So we have this set up going to just press F5 again. So when we open that and let's say we are working in our PHP and we need to add our add text widget when we add it. You'll see that this is already highlighted for control name. And I'll just say text control. And then the text domain is going to be taking place. So that's how we save all our instances of snippets. So if I want to add another snippet, I'll just duplicate this, add a comma at the end here, then I'll come back to what we have here as our base.  We can add all these classes inside our snippet so that we can always have them whenever we need to. So I'll just add this control here, which is for a slider. So come back, go into the body, check this out to make sure it's clean. And then we'll just change a few of these pieces and say this is slider underscore. And then I'll come back, check my code, go to the end and our closing bracket with a comma at the beginning, add our opening quotations. We didn't add this to this point. So I'll add our quotations here to the comma, go home, and then add the opening quotations. And for this last piece, I'll remove that dash, I'll remove this dash here as well. Come back and escape this as well as this and save. So we have a couple of problems that we need to flick. That is because in our body here, we opened and then closed this wrongfully. So I'll save this after making those changes, press my F5 to test. We can test again and then say we'll add slider and then we'll get the full code edited here. So we can this dynamic and this dynamic. And you'll see at the part where we escaped our strings, we still have our slash coming in. So we don't affect the namespace of Elementor. Now, this is just a sample to show you what's happening. I have the full code of working on this on my GitHub, which is here. So we got Bahira Elementor snippets, and you can make a PR suggesting any new snippets that you want to have in that Elementor snippets. The reason why I would ask for PR is because I'm just starting this project and I just have few hooks and controls and categories that I've added and main classes. So those would be helpful. The next thing we are actually going to do is actually publish our snippets. So we'll close this off, open our snippets. We're going to package our extension for publishing on the Microsoft website. So we'll come back into our snippets folder here. I'm going to overwrite all of this by testing. Then I'll explain what everything does. So we have our name here. We have a display name that usually shows in the extensions part. So if I go to this, this is the display name that we're talking about. We have the description which shows up or is here at the bottom. Then we have a version number that will show all that helps VS Code to track whether they should update the package or they should ignore it because you have the current one. The engine I've chosen for VS Code to be 1.8, which is a good version. Then you add the publisher name. Now this publisher name, you get it as you register one account with Microsoft. So you're going to go to the extensions. You're going to go to markettests.visualstudio.com slash VS Code. And then you're going to actually sign up. But in my case, I'll be signing in two into my account. So you can sign in even with your GitHub. I can now always open this with my GitHub easily. So in here, we shall publish our extension. But let's first go and finish up. So we add our author name, which is my full names, but the publisher name, we actually get it when we set up our account. So we add a license for which we are releasing this. We add a home page for our site so that people can always click and go to see where they can file issues. That's why this bugs is here. We see also the repository. So I just set up everything on GitHub to make it easy and manage. Then we add an icon. This could be a PNG or whatever it is. And you will see that inside here, I need to create a new folder called images and add this particular logo in here. Then for the keywords, this help for the person searching for the extension to find it. So you put things that are as close as possible to your particular extension. So you add the keywords here and separate them with comas. The category is that it's a snippet. So you leave that fine. And then you can always add extra files of snippets by just duplicating this and then adding a comma, rename this, and then add those other files inside your snippets here with a different name, of course, at the end here. Or you could group them depending on how you want to do your file structure. So undo that and save. So this is what you need all in all. Now the next thing that you need to do is come back to the docs here and say, I am now ready. My snippets are working well. I've tested them with pressing F5. Now I am ready to release that extension. So you come to publishing your extension. The first thing that you need to do is again to install using NPM, you install VSE, which is going to help you to register your Excel. Come back NPM install dash G, VSE. This takes a while. So I'll fast forward to the end. And then that is done. When we come back here, we are already logged into the directory of our snippet. The next thing that we are going to do is we're going to type VSE package to generate a file for. So I'll do the VSE package. So you always do this whenever you're making a release of your package. So just change the version. If you update something, either it's a minor change, a major change, just a simple versioning. So you make the changes here and then you come and do VSE package. Once you hit enter, you'll see that they ask you to make an edit of your readme because by default, they have scanned and see it's the same. So my readme is still the same. It's default. I'm just going to paste some things here that I had worked with, save this, then come back and do the same thing, VSE package, click package. And we'll see they're telling us, of course, this is not there. The extension dash images is not there. So for now, I'm going to need that to be working. So come back here, copy this, come back and create a new file, press 13, press enter. And let's assume that is working fine. You can put a PNG file in there. So I'll hit enter. And you will see that we have a release of our file here. So I'll open this in my folder. I'll win it in the Explorer. And then come back to our Microsoft and we'll click publish extension. And when we come in here, we have an option to add our new extension or to actually update. So we'll click new extension, click Visual Studio Code. Then we're going to grab this drag and drop our file in here. And once we are done, we click upload. So when that is uploaded, we'll see that our extension is actually showing up here. And then the public is ready to consume this particular extension that we do have. So when we go to the marketplace and research for Elementor, just searching like that, we'll actually see this showing up and it will show us the number of people who are using it. When click on it, we'll see what we saved in our readme file. We're able to see what reporter issues, where the repository is found. We can download this direct. Everything is set up for us and it's that easy to install. The other way you could find this like extension is by going to the extensions panel inside your VS Code, search for Elementor. If it is the one that you want, and then you'll just click and install the plugin right there. And then this will be ready for use. And you can use it to develop your Elementor widgets. So thank you for watching this video. I hope to see people make more widgets that are helpful to others. And check this out, download the Elementor snippets.  I've loved a classic press snippet that allows you to just have WordPress snippets there for you so you can have the auto completions. Like for example, if you want to start up a new plugin, this gives you the small starter that you need to go right ahead. So let me know if you're using these extensions, if you're developing your own and share with your friends the video. Give a thumbs up if you found the video very helpful and leave a comment if you have any questions.