Abnormal interactions between misfolded mutant and wild-type (WT) proinsulin (PI) in the endoplasmic reticulum (ER) drive the molecular pathogenesis of mutant INS gene–induced diabetes of youth (MIDY). How these abnormal interactions are initiated remains unknown. Normally, PI-WT dimerizes in the ER. Here, we suggest that the normal PI-PI contact surface, involving the B-chain, contributes to dominant-negative effects of misfolded MIDY mutants. Specifically, we find that PI B-chain tyrosine-16 (Tyr-B16), which is a key residue in normal PI dimerization, helps confer dominant-negative behavior of MIDY mutant PI-C(A7)Y. Substitutions of Tyr-B16 with either Ala, Asp, or Pro in PI-C(A7)Y decrease the abnormal interactions between the MIDY mutant and PI-WT, rescuing PI-WT export, limiting ER stress, and increasing insulin production in β-cells and human islets. This study reveals the first evidence indicating that noncovalent PI-PI contact initiates dominant-negative behavior of misfolded PI, pointing to a novel therapeutic target to enhance PI-WT export and increase insulin production.

The coordinated electrical activity of β-cells within the pancreatic islet drives oscillatory insulin secretion. A recent hypothesis postulates that specially equipped "hub" or "leader" cells within the β-cell network drive islet oscillations and that electrically silencing or optically ablating these cells suppresses coordinated electrical activity (and thus insulin secretion) in the rest of the islet. In this Perspective, we discuss this hypothesis in relation to established principles of electrophysiological theory. We conclude that whereas electrical coupling between β-cells is sufficient for the propagation of excitation across the islet, there is no obvious electrophysiological mechanism that explains how hyperpolarizing a hub cell results in widespread inhibition of islet electrical activity and disruption of their coordination. Thus, intraislet diffusible factors should perhaps be considered as an alternate mechanism.

BackgroundAutistic people are at increased risk of developing mental health problems. To reduce the negative impact of living with autism in a non-autistic world, efforts to improve take-up and access to care, and support in early years, which will typically start with a GP appointment, must be grounded in the accounts of autistic young adults.AimTo explore how autistic young adults understand and manage mental health problems; and to consider help seeking as a focus.Design and settingA cross-sectional, qualitative study. Autistic participants were purposively selected to represent a range of mental health conditions including anxiety and depression. A subsample were recruited from a population cohort screened for autism in childhood. The study concerns access to primary care.MethodNineteen autistic young adults without learning disabilities, aged 23 or 24 years, were recruited. In-depth, semi-structured interviews explored how they understood and managed mental health problems. Data were analysed thematically.ResultsYoung adults preferred self-management strategies. Multiple factors contributed to a focus on self-management, including: beliefs about the aetiology of mental health difficulties and increased vulnerability with the context of a diagnosis of autism, knowledge of self-management, and a view that formal support was unavailable or inadequate. Families had limited awareness of professional support.ConclusionYoung autistic adults without learning disabilities, and their families, may hold erroneous beliefs about autism and mental health. This may affect help seeking and contribute to an exacerbation of symptoms. GPs need to be alert to the fact that autistic young adults in their care may be experiencing mental health difficulties but may not recognise them as such.

Some years ago, I entered a completely unfamiliar world. This was a landscape that clinicians deal with every day but for the individual suspected of having lung cancer, it can appear hostile and scary, often misrepresented by outdated imagery, information and television portrayal. Lung cancer is not awash with celebrities admitting to having it or grand fundraising campaigns like other conditions. Despite many changes in the treatment landscape, it's still generally much more stigmatised than other cancers.

SUMMARY:

Polymorphous low-grade neuroepithelial tumors of the young (PLNTYs) are recently described CNS tumors. Classically, PLNTYs are epileptogenic and are a subtype of a heterogeneous group of low-grade neuroepithelial tumors that cause refractory epilepsy, such as angiocentric gliomas, oligodendrogliomas, gangliogliomas, and pleomorphic xanthoastrocytomas. Although they are a relatively new entity, a number of imaging and histologic characteristics of PLNTYs are already known. We present the imaging and pathologic findings of such a tumor as well as the surgical approach and clinical management.

Prof. Jason Pomeroy talks about the rise of the digital economy and its impact on the workplace.

In order to find the right accommodation, asking questions and answering them are essential. According to BankBazaar, you definitely need to answer the following 6 important questions before buying a home.

To make the dream of settling down in a prosperous city come true, young couples, especially ones with limited budgets, need to prepare the right steps to get your home sweet home.

Buying a new house is a very big deal, and you want to make sure that your dream home doesn’t turn into a nightmare. It’s wise to check things out before you put in an offer.

Most of us will stop renting and become a homeowner one day. But how do you know when it’s a good time to buy your own home? These are four signs that you’re ready to stop renting and become a home owner.

In a home buying process, it can be easy to make missteps or to get caught up in small details that really don’t make much difference. These are four of the most common mistakes you should avoid to hunt your dream home.

According to American financial expert Dani Pascarella, if any of the three scenarios below apply to you, it’s very likely that home ownership will make your life a lot more stressful than happy.

If you’re excited and in good shape to buy a home, self-made millionaire Barbara Corcoran says these are the five steps for you to take.

Many people have headaches considering landed house or condominium (condo) for their accommodation choice. By analyzing the pros and cons of each of these types, the infographic below will help you make the right choice.

If you do not want to pay appraisal fee to the third party nor incur losses, here are 4 ways to determine value of a property yourself before entering a transaction.

Buying a home always need time and effort. Many home buyers can not manage a series of buying steps themselves, so hiring real estate agents to finish the deal quickly and more effectively is a smart decision. If you are still considering whether you should hire an agent or not, the following infographic will show you the benefits of buying a home with an agent:

To save money, time, or both, many buyers choose pre-existing homes. However, before signing a sales and purchase contract, you must be careful with the following signs of the wrong home to buy.

Condo projects are now mushrooming across the country, becoming the favorite choice of most urban residents. However, to choose the right one which will make you satisfy, you need to find answers to the following 20 questions.

To ensure that you can afford for your living expenditures, you should not spend more than 30-40% of income on housing.

Home moving is surely a hassle. Luckily, a little preparation work can mean the difference between a minor headache and an all-out life takeover.

The decision to list your home for resale is a big one. No doubt it came about after much thought, weighing pros and cons, and series of long discussions. However, once you decide to put your home on the market, get ready for the next big discussion: interior design.

One of the most dramatic changes you can make to effectively boost value of your home is giving your kitchen some renovations.

Normally, you have to sell the current property if you need the money to buy a new one. But there are occasions when it makes practical or financial sense to keep the old home.

Normally, you put your property on the market but the estate agent is the one who actually sells it to buyers. It is a critical decision to choose the right agent and protect you from any future trouble. The questions below may help you.

Paint your home blue before selling it, as the color brings a sense of peace, softness. Many people love blue and it may help you sell home more quickly.

London’s leading real estate agents Daniel Cobb have revealed top 10 simple tricks to add values to your home and sell it faster, The Sun reported.

Lots of people sell their current home at the same time as buying a new one, forming a property chain. Selling before you buy has risks, but it can also have great advantages.

What’s keeping your house from finding its next owner? In order to speed up the selling process, consider every little thing like clutter in the house.

Every home seller wants to sell it fast and reach as many buyers as possible. Here are some tips to make your listing stand out to potential buyers from the crowd.

As a home seller, everyone wants to sell their home quickly at the highest price. Five simple tips below can help you.

Your home’s value will not be added when you try to take care of your garden, gilded handles in bathroom or swimming pool. In fact, home buyers pay attention to more useful items.

For many people, home is the biggest investment. However, not many of them know about value of a home and things that can ruin it such as bad decorations, noisy neighbors or an unfortunately-placed sinkhole.

When you are confident that your home does not need any major repairs that will stop a buyer’s home inspection, you can focus on easy updates to make your home more attractive to buyers.

If you make a mistake during the listing process, you might end up getting less than your home is worth or find that it takes significantly longer to sell your home than it should.

You are preparing your home for sale? Don’t forget to make some small repairs since they can make a big difference both in terms of interest levels and offer prices for the home.

Business Insider asked real-estate agents across the U.S., and they point out 11 reason that prevent your home from being sold.

Finding a home that satisfies all your requirement has been a difficult task, but for many people, selling home is even more difficult. Lots of sellers have to sell their homes at a cheaper price than they expected before and accept a loss. To avoid being troubled with the sale and make it faster, follow guides in the Infographic below for the best preparation before selling your home.