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Biochemistry

Dr. Nina Schor appointed as the NIH Acting Deputy Director for Intramural Research – National Institutes of Health (.gov)

I am pleased to announce the appointment of Nina F. Schor, M.D., Ph.D., as the NIH Acting Deputy Director for Intramural Research (DDIR) in the NIH Office of the Director. Michael M. Gottesman, M.D., who served as NIH DDIR for 29 years, announced his plans last year to step down to return to the Center for Cancer Research, National Cancer Institute, where he is chief of the Laboratory of Cell Biology. Dr. Schor will begin her new role on August 1, 2022.

As Acting DDIR, Dr. Schor will lead the NIH Intramural Research Program (IRP) and facilitate coordination and collaboration among the 24 NIH institutes and centers that are a part of NIHs distinct research community. She will be responsible for the selection and approval of new NIH principal investigators, human subjects research protection, research integrity, technology transfer, and animal care and use for the IRP. Additionally, Dr. Schor will oversee efforts to train the next generation of biomedical and behavioral researchers at NIH, as well as efforts to foster a diverse and inclusive culture across the IRP.

With a career that has touched all realms of the biomedical research enterprise, Dr. Schor brings substantial experience as an educator, scientist, clinician, and administrator. Dr. Schor joined NIH in January 2018 as Deputy Director of the National Institute of Neurological Disorders and Stroke (NINDS), and in May 2021, she also assumed the role of Acting Scientific Director of NINDS. As Deputy Director, she guided the institutes strategic planning activities, career development programs, maternal and child neurologic health collaborations with other NIH institutes, and the creation and implementation of the Ultra-Rare GENe-based Therapies (URGenT) Network. Prior to joining NIH, Dr. Schor worked at the University of Rochester, where for nearly 12 years she held the positions of Chair of the Department of Pediatrics and Pediatrician-in-Chief of the Golisano Childrens Hospital. Prior to that, she spent 20 years building her academic and scientific career at the University of Pittsburgh, culminating with her roles as Associate Dean for Medical Student Research and Chief of the Division of Child Neurology in the Departments of Pediatrics and Neurology.

Dr. Schor earned her Ph.D. in medical biochemistry from Rockefeller University and her M.D. from Cornell University Medical College. Her residency and postdoctoral fellowship training in pediatrics, child neurology, and molecular biochemistry and pharmacology took place at Harvard University Medical School and Boston Childrens Hospital, where she began her three-decades-long, NIH-funded research efforts focused on targeted therapy for neuroblastoma, a type of pediatric cancer, and neuronal cell death caused by oxidative stress, which occurs when harmful forms of oxygen molecules damage cells.

I am profoundly grateful to Dr. Gottesman for his many years of leadership and service at NIH. With his contagious optimism, adept problem-solving attitude, and wise policymaking, Michael leaves a strong legacy to guide the future DDIR. The programs he developed touch every stage of a scientific career from high school and college internship programs, graduate studies, and postdoctoral training, to recruitment, career development, tenure, and emeritus transition of faculty. His leadership will be remembered in many things, including the remarkable improvements seen in research integrity and the recruitment and subsequent achievements of a diverse scientific workforce over the last three decades. We wish him all the best in this next chapter.

Please join me in welcoming Dr. Schor to the NIH leadership team.

Lawrence A. Tabak, D.D.S., Ph.D.Acting Director, National Institutes of Health

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Dr. Nina Schor appointed as the NIH Acting Deputy Director for Intramural Research - National Institutes of Health (.gov)

Biochemistry

U-M researchers track protein binding, build synthetic proteins to study gene expression – University of Michigan News

How does a nose remember that its a nose? Or an eye remember that its an eye?

As scientists probe the question of how cells remember what kind of cells they are supposed to be, or their genetic lineage, its important to understand how cells express different genes without changing the DNA sequence itself.

But studying this subject is difficult: Researchers can purify the proteins that drive genetic expression, put them in a test tube and watch them bind. But doing so inside the nucleus of cells, their native environment, has been so far impossible.

Study: HP1 oligomerization compensates for low-affinity H3K9me recognition and provides a tunable mechanism for heterochromatin-specific localization (DOI: 10.1126/sciadv.abk0793)

Now, a team of researchers at three University of Michigan labs have been able to track how a protein binds to its chromatin substrate within a living cell by establishing a collaboration that combines state-of-the-art ultra high-resolution imaging, synthetic protein design and computational modeling. Their results are published in Science Advances.

The biological question that were asking is, How do cells actually remember past experiences? And how do these experiences also lead to cells establishing distinct identities, as it happens in the case of the human body where you have lineages of cells that form neurons, or blood cells, or brain cells, and all actually maintain their identities for many generations,' said lead author Kaushik Ragunathan, assistant professor of biological chemistry at the U-M Medical School.

An example I like to think about is that if you chop off your nose, you dont get a hand growing there, even though the genome in your nose and the genome in your hand are exactly the same.

Cells control how and which genes are expressed from a copy of the DNA sequence held within each cell, despite that sequence being the same across all cells in the body. One way they control expression is by changing how tightly the DNA is packaged within the nucleus using proteins called histones. Histones can be modified through the addition of small chemical tags that regulate how tightly the DNA is wound around them and thus whether the genes can be expressed.

Proteins that have the ability to read, write and erase these histone tags explore the DNA within the nucleus of the cell very rapidlyon the order of milliseconds, according to Ragunathan. Ultimately, all this epigenetic information needs to be inherited across generations, but the recognition of these tags is a complicated process that involves chromatin binding and proteins meeting and interacting with each other amidst the chaos of all other possible competing interactions within the cell.

Being able to understand each step of the processand therefore enabling control of how the epigenetic information is inheritedintrigued co-author Julie Biteen, professor of chemistry and biophysics.

Biteen uses single-molecule fluorescence imaging to track individual proteins inside cells. Her lab can see where these proteins are relative to the chromatin, and Ragunathans expertise is in the molecular mechanisms underpinning how histone modifications and histone-binding proteins interact. These two worlds needed to come together so that the biochemistry of what happens in a test tube outside of cells could be tested to figure out what happens inside of them.

The timing of this process is critically important to ensure that the right genes are silenced at the right place and at the right time, Biteen said. What hooked me on this project is that in vitroin a test tubeyou can purify two proteins, watch them bind and see how good that binding is, or what is the affinity for one another. That tells you what can happen in the cells, but not what does happen in the cells.

Biteen and Ragunathan worked with Peter Freddolino, associate professor of biological chemistry, and computational medicine and bioinformatics at the U-M Medical School, to combine computer modeling with their experimental results.

This is really where our collaboration becomes really powerful, Biteen said. On one hand, seeing molecules is very helpful and knowing how fast the molecules move helps a lot in terms of understanding what is possible inside the cell, but here we could take a leap forward by perturbing the system even in unnatural ways in order to understand what these different motions of molecules in the cell actually mean.

While epigenetic marks are tremendously important for maintaining different tissues in complex organisms like humans, they also play an important role in regulating genes of single-celled organisms such as yeast. The team focused on a type of HP1 protein in yeast cells called Swi6. This family of proteins binds to a specific type of histone modifications in the cell to enforce gene silencing. By integrating fluorescent labels with Swi6, Bitees lab watched Swi6 move inside the cells nucleus.

While Swi6 searches for the correct binding site on DNA, it moves quickly, Biteen said. When it finds its target, it slows down significantly. The movement of a protein within the cell is akin to gears in a car and things can move at different speeds based on whom proteins interact with.

From these spaghetti tracks that we get inside the cell, we then figure out how much time they are spending searching and how much of the time they are spending bound, Biteen said. The amount of time they spend not moving tells us about how strongly theyre interacting and their biochemical properties.

While Biteens lab can measure movements in the cell on the scale of tens of milliseconds, much of the biochemistry happening in the cell is happening even faster, she said. Freddolino took this experimental information and developed models to estimate the ability of the Swi6 proteins to jump between the binding states that were identified in experiments.

Freddolinos modeling took into account the experimental measurements and the possible biochemical properties, which includes how the Swi6 molecules interact in the cell. These interactions include molecules that freely float in the solution of the cell, molecules that have bound to DNA, and molecules that are holding hands with each other, he said.

My lab wanted to come up with a more fine-grained model that estimated what was the most likely set of molecular states of the proteins and their ability to jump between those states, that would then give rise to the imaging data that Biteens lab created, Freddolino said.

Having this numerical model allows us to do the computational experiments of what happens if the protein binding is twice as fast as we think. What if its 10 times as fast as we think? Or 10 times slower? Could that still give rise to the data? Very happily, in this case, we were able to show that the relevant processes were really being captured in the fluorescence microscopy.

After identifying the binding properties of natural Swi6, the researchers tested their findings by redesigning Swi6 from its components to see whether they could replicate some of its biochemical properties, Ragunathan said. This allowed the researchers to determine that the imaging and modeling conducted in the first part of the paper reflects how the protein was binding in its native environment.

Can we do what nature did over the course of millions of years and make a protein that in many ways has properties similar to that of Swi6 in cells? Ragunathan said. In vivo biochemistry, which is what weve decided to call this, was not something that was ever thought to be possible inside living cells, but we have shown this is entirely feasible by using imaging as a modality. We are using this project as a foundation in order to understand how these epigenetic states can be established and maintained across generations.

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U-M researchers track protein binding, build synthetic proteins to study gene expression - University of Michigan News

Biochemistry

University of Houston researchers snag $1.8M to develop cancer-fighting virus – InnovationMap

Viruses attack human cells, and that's usually a bad thing some Houston researchers have received fresh funding to develop and use the evil powers of viruses for good.

The developing cancer treatment is called oncolytic virotherapy and has risen in popularity among immunotherapy research. The viruses can kill cancer cells while being ineffective to surrounding cells and tissue. Basically, the virus targets the bad guys by "activating an antitumor immune response made of immune cells such as natural killer (NK) cells," according to a news release from the University of Houston.

However exciting this rising OV treatment seems, the early stage development is far from perfect. Shaun Zhang, director of the Center for Nuclear Receptors and Cell Signaling at the University of Houston, is hoping his work will help improve OV treatment and make it more effective.

We have developed a novel strategy that not only can prevent NK cells from clearing the administered oncolytic virus, but also goes one step further by guiding them to attack tumor cells. We took an entirely different approach to create this oncolytic virotherapy by deleting a region of the gene which has been shown to activate the signaling pathway that enables the virus to replicate in normal cells, Zhang says in the release.

Zhang, who is also a M.D. Anderson professor in the Department of Biology & Biochemistry, has received a $1.8 million grant from the National Institutes of Health to continue his work.

Zhang and his team are specifically creating a new OV called FusOn-H2 and based on the Herpes simplex 2 virus.

Our recent studies showed that arming FusOn-H2 with a chimeric NK engager (C-NK-E) that can engage the infiltrated natural killer cells with tumor cells could significantly enhance the effectiveness of this virotherapy, he says. Most importantly, we observed that tumor destruction by the joint effect of the direct oncolysis and the engaged NK cells led to a measurable elicitation of neoantigen-specific antitumor immunity.

Shaun Zhang is the director of the Center for Nuclear Receptors and Cell Signaling at the University of Houston and M.D. Anderson professor in the Department of Biology & Biochemistry. Image via UH.edu

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University of Houston researchers snag $1.8M to develop cancer-fighting virus - InnovationMap

Biochemistry

Far From the Biliary Tree: A Case of Overlapping Autoimmune Liver Disease in a Patient Presenting With Sicca Symptoms – Cureus

Primary biliary cholangitis (PBC) is achronic autoimmune condition with many extrahepatic manifestations that are commonly encountered as a patient's primary presenting complaints. Rarely, PBC co-exists as an overlapping syndrome with other liver-related autoimmune conditions such as autoimmune hepatitis (AIH). Presented is a rare case of PBC with features of AIH diagnosed in a patient who initially presented with hemoptysis and worsened sicca symptoms due to advanced Sjgrens syndrome. The patient had a three-year evolution of abnormal liver biochemistry and was found to be a heterozygous carrier for hereditary hemochromatosis (H63D mutation). Given that patients with PBC-AIH are at an increased risk of complications compared to isolated disease from either disorder, early diagnosis and prompt management can helpspare patients from cirrhosis, liver failure and transplantation, or even death.

Primary biliary cholangitis (PBC) is an autoimmune liver disease characterized by the progressive destruction of intrahepatic bile ducts. Various genetic and environmental interactions trigger an autoimmune response against biliary epithelial cells, which leads to cholestasis and fibrosisand can ultimately result in liver cirrhosis and failure [1]. The global incidence rate of PBC differs widely among geographic areas, ranging from 40 to 400 per million individuals with a peak incidence in the fifth decade of life and a 10:1 predominance in females compared to males [2]. Symptoms of PBC related to cholestasis typically develop within two to four years of diagnosis and include fatigue, pruritus, dyslipidemia, fat-soluble malabsorption, and osteoporosis, though up to 61% of cases are asymptomatic [2-3]. PBC also has many associations with extrahepatic autoimmune disease, most notably Sjgrens (up to 73%), thyroid dysfunction (up to 23.6%), cutaneous scleroderma (up to 12.3%), and rheumatoid arthritis (RA) (5.6%) [4-6]. The diagnosis of PBC is made if two of the following three criteria are met: (1) biochemical evidence of cholestasis through the elevation of alkaline phosphatase (ALP) to two times the upper limit of normal, (2) presence of antimitochondrial antibody (AMA) with a titer greater than 1:40, (3) histologic evidence of nonsuppurative destructive cholangitis and interlobular bile duct destruction [7-8].

Rarely, PBC can co-exist as an overlapping syndrome with other liver-related autoimmune conditions such as autoimmune hepatitis (AIH). This phenomenon is present in 1-3% of patients with PBC and 7% of patients with AIH [8]. A PBC-AIH overlap syndrome can be diagnosed using the Paris criteria with 92% sensitivity and 97% specificity [9].

For PBC alone, early initiation of ursodeoxycholic acid (UDCA) to slow disease progression is associated with a long-term survival benefit and minimal side effects such as headaches, motility issues, and weight gain. Along with interval monitoring of liver biochemical tests, recommendations for immunizations for hepatitis A and B are given to individuals without serologic evidence of immunity, in addition to abstention from heavy alcohol use. In general, evidence is limited to making treatment recommendations for patients with PBC as well as features of AIH, though it includes UDCA with or without a component of immunosuppression [8].

A 52-year-old female with a history of Sjgrens and rheumatoid arthritis presented to the clinic with worsening sicca symptoms and persistent cough with hemoptysis over the past two weeks. She also reported fatigue and arthralgias. She had been seeing a rheumatologist and had been started on azathioprinetwo years prior, in addition to pilocarpine for dry eyes. She was also taking levothyroxine for hypothyroidism. The patients vital signs were all within normal limits. Her physical exam was notable for a non-tender liver edge palpated six centimeters below the mid-clavicular costal margin with negative shifting dullness or fluid wave. Other pertinent negatives included the absence of icteric sclera,skin hyperpigmentation, gland or lymph node prominence or tenderness, focalizing lung findings, active synovitis or contractures, palmar excoriations, or cutaneous vasculitis.

On review of her medical chart, she had an extensive rheumatologic workup notable for positive antinuclear antibody (ANA), positive anti-SS-A with negative anti-SS-B,positive salivary gland biopsy, and positive rheumatoid factor (RF). She also had a history of consistently elevated gamma-glutamyl transferase (GGT) and alanine (ALT) and aspartate (AST) transaminases with normal alkaline phosphatase (ALP) and normal total and direct bilirubin levels. Labs were obtained at her clinic visit and notable for elevated AST 237 IU/L, ALT 223 IU/L, GGT 169 IU/L, and normal ALP 101 IU/L with otherwise normal complete blood count and mildly elevated values on the lipid panel (Table 1).

Based on her autoimmune history and elevated transaminases, an expandedrheumatologic workup was performed, notable for a positive anti-mitochondrial antibody (AMA) 128.6 U (normal < 20.0 U), negative anti-smooth muscle antibody (ASMA) 11.0 U (normal < 19 U), and immunoglobulin A (IgA) 287 mg/dL (normal 87-352 mg/dL). The patient was referred to a gastroenterologist and found to have a normal esophagogastroduodenoscopy. Upon genetic analysis, the patient was noted to be a carrier for hereditary hemochromatosis (heterozygous carrier for H63D mutation). The rest of her workup was negative, including hepatitis panel, alpha-1-antitrypsin, double-stranded DNAand anti-Smith/ribonucleoprotein antibodies, SCL-70 (scleroderma) antibody, and centromere antibody.

Imaging with ultrasound demonstrated hepatomegaly with fatty infiltration of the liver (Figure 1). The patient was evaluated by a pulmonologist forher cough and hemoptysis and a CT chest was performed. CT imaging demonstrated prominent mucus and debris along the trachea with subpleural reticulations possibly due to respiratory involvement of her Sjgrens syndrome (images were unable to be obtained for inclusion in this article). It also noted questionable hepatic surface lobulation that could represent early cirrhosis morphology. With a positive AMA and biochemical pattern of cholestasis and hepatocellular injury, the patient was referred forliver biopsy, which revealed extensive inflammatory infiltrate consisting of lymphocytes and plasma cells surrounding portal tract structures, with the presence of interface hepatitis into lobular parenchyma (Figure 2). No evidence of malignancy was noted.

The patient met the criteria for diagnosis (Table 2) and was started on UDCA at 15 mg/kg. She was alsocontinued on azathioprine at a therapeutic dose of 2 mg/kg for AIH. At the three-month follow-up, the patient had down-trending transaminases and was reporting subjective improvement in symptoms of fatigue and arthralgias.

Primary biliary cholangitis (PBC) is a rare but potentially life-threatening autoimmune cholestatic disease of the liver that, when left undiagnosed and untreated, can culminate in end-stage liver cirrhosis. Similar to the patient presented in this case report, PBC has a peak prevalence for those between their fourth and sixth decades of life with a predominance for women [2-3]. Diagnostic criteria for primary hepatic autoimmune diseases rely on biochemical evidence of either cholestasis or hepatocellular damage, presence of auto-antibodies, and histopathological features on liver biopsy [7-9]. While present in fewer than 10% of patients with either PBC or AIH, the overlapping syndrome (PBC-AIH) is well-represented in the current case [8]. There are several subtypes and classifications of this condition, though, like other autoimmune disorders, it can be thought to exist on a spectrum of primary tissue involvement. It is hypothesized that patients with underlying bile duct destruction (characteristic of PBC) also possess a genetic predisposition to develop a hepatitic pattern of liver injury (more consistent with AIH), and thus can also be referred to as PBC, hepatitic form [10].

The patient presented in this case report met the Paris criteria for PBC-AIH both on histology as well as an elevated ALT and presence of anti-AMA antibody. Though not meeting diagnostic criteria (5 times upper limit of normal (ULN)), she also had an elevated GGT at 3.1 times ULN. Her past medical history of several extrahepatic autoimmune diseases is consistent with other cases of PBC-AIH. PBC is known to have associations with Sjgrens syndrome in more than half of individualsand to a lesser extent, with thyroid dysfunction, RA, and cutaneous scleroderma[4-6]. Though a majority of patients eventually diagnosed with PBC are asymptomatic, this patient had multiple symptoms on presentation. She presented with cough and hemoptysis along with xerostomia and dry eyes, all potentially attributed to her Sjgrens diagnosis. She was found to have hepatomegaly both on clinical exam and ultrasound imaging, as well as three years of worsening liver transaminases that prompted an expanded autoimmune work-up.

This case highlights the importance of primary care physicians to not only be familiar with the criteria for autoimmune liver diseases but also to not devalue minor changes in liver biochemistry. Though she had been previously followed by a rheumatologist, the patient had been lost to follow-up and her medical record revealed several inconsistencies regarding the interpretation of her autoimmune laboratory findings between specialists and generalists that she had seen in the past. She had also been noted to have an extensive history of alcohol consumption throughout her medical record. While her AST and ALT abnormalities have been attributed to this, her AST:ALT ratio was inconsistent with this assertion.

Interestingly, this patient was also found to be a heterozygous carrier for hereditary hemochromatosis (HH). On discussion with her gastroenterologist, it is difficult to discern the patients elevated ferritin as related to excess collection versus an acute phase reactant given her history of autoimmune disease. In general, HFE H63D heterozygous carriers rarely develop clinically significant iron overload syndromes [11] though may be at increased riskfor breast and colorectal cancers [12-13]. As of the time of this publication, there are no reports in the literature regarding increased rates of PBC or AIH in those with the H63D mutation.

Compared to patients with PBC alone, individuals with PBC-AIH have higher rates of portal hypertension, esophageal varices, gastrointestinal bleeding, ascites, and liver failure [14-15]. Studies have demonstrated death or liver transplantation in PBC-AIH at rates twice as high compared to PBC alone at six-year mean follow-up [14] and nearly four times as high compared to AIH alone at the two-year follow-up [16]. At 10 years following diagnosis, 44-48% of patients with PBC-AIH progress to cirrhosis [8,15], and transplant-free survival ranges from 52-92% [8-9,14].

Goals of management for autoimmune liver disease include suppression of the underlying pathogenic process as well as treatment of acute symptoms that result from chronic cholestasis, including pruritus, fatigue, and xerostomia. Evidence is limited regarding specific treatment recommendations for diseases with overlapping characteristics. The 2018 practice guidelines from the American Association for the Study of Liver Diseases (AASLD) guidelines concede that the clinical benefit and harm of adding immunosuppressive medications require further study, and recommend tailoring pharmacotherapy to the predominant histologic pattern (PBC or AIH) [17-18]. The 2017 practice guidelines from the European Association for the Study of Liver Diseases (EASL) recommend that in addition to UDCA, immunosuppression be given, or considered, in patients with severe to moderate interface hepatitis, respectively [19]. A meta-analysis for the comparative treatment of various overlap syndromes demonstrated that combination therapy with UDCA and immunosuppression may be superior to both UDCA alone and to steroids with or without azathioprine with respect to biochemical improvement and transplant-free survival [8]. The authors concede, however, that these studies are limited by the inclusion ofpatients with a wide range of histologic severity. Additionally, it has been reported that the degree of baseline interface activity on biopsy (pathognomonic of AIH) is a more accurate predictor of failure with UDCA monotherapy compared to the addition of immunosuppressive therapies [19].

Our patient had already been started on azathioprine for her other rheumatological conditions two years prior to her initial presentation to our clinic. Therefore, given her extrahepatic autoimmune diseases that prompted early immunosuppression, she had theoretically been spared from several years of additional damage due to her PBC-AIH. Relapse rates of AIH up to 90% have been demonstrated when discontinuing immunosuppression. Despite this, a withdrawal trial of immunosuppressives can be consideredonce remissionhas been established (normalization of aminotransferases) and maintained for 24 months[19-20]. She was also started on UDCA after confirming the diagnosis with a biopsy and therefore is now on combination UDCA with immunosuppressive therapy. Long-term monitoring for patients with PBC includes liver biochemical and function tests every three to six months in addition to annual screening for thyroid dysfunction and bone mineral densitometry. Of note, our patient did have a degree of long-bone osteopenia on a dual-energy X-ray absorptiometry scan. We also recommended screening for colorectal and breast cancer given her increased risk with HH carrier status.

Primary liver autoimmune conditions are often associated with extrahepatic manifestations, either as a result of chronic cholestatic symptoms or as distinct, laboratory-identifiable syndromes.Therefore, in patients with a significant rheumatological disease history or when a primary autoimmune workup is being performed in the context of abnormal liver biochemistry, PBC and AIH must both be considered. The Paris diagnostic criteria can be used with a high degree of both sensitivity and specificity to either distinguish or correlate these conditions.Based on the current evidence, early initiation of UDCA with immunosuppressive therapies has been shown to help delay cirrhosis, liver failure and transplantation, and even death.

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Far From the Biliary Tree: A Case of Overlapping Autoimmune Liver Disease in a Patient Presenting With Sicca Symptoms - Cureus

Embryology

Handful of Tories declare themselves as candidates to replace Johnson – Morning Star Online

THEresignation of Boris Johnson as prime minister has seenattention turntowho will replace him.

Only a handful of Tories have so far declared themselves candidates, although a number of others are thought to be set to do so.

Attorney GeneralSuella Braverman and Commons foreign affairs committee chairman Tom Tugendhat have confirmed their intention to stand while Steve Baker has said he is seriously considering standing.

Ms Bravermantook the unusual step this week of calling on Mr Johnson to resign, saying that she would not be stepping down but at the same time throwing her hat into the ring as his potential successor.

Mr Tugendhatlaunched his leadership bid with an article in the Daily Telegraph today, promising tax cuts and new energy and ideas for government.

"I have served before in the military and now in Parliament. Now I hope to answer the call once again as prime minister, said the former soldier, who has been a prominent critic of Mr Johnson and an advocate of a more aggressive foreign policy.

Former chancellorRishi Sunak also unveiled his candidacy today, the most high-profile figure so far to do so.

Foreign Secretary Liz Truss, former health secretarySajid Javid, ChancellorNadhim Zahawi, health and social care select committee chairmanJeremy Hunt and Transport SecretaryGrant Shapps are all expected to enter an increasingly crowded field.

More declarations are expected in the coming days, but some senior Tories have already said that they will not be standing, including former levelling up secretary Michael Gove, Deputy Prime Minister Dominic Raab and disgraced former health secretary Matt Hancock.

Another candidate yet to confirm, but already installed as the bookies favourites, is Defence Secretary Ben Wallace.

Polling of Tory Party members by YouGov also puts Mr Wallace in pole position, where he beats all of the main presumed contenders.

Mr Wallace, who served in the Scots Guards, has had a prominent role in Britains response to the Russian invasion of Ukraine.

However, he has one of the worst voting records on LGBT rights in Parliament.

He has opposed every piece of LGBT legislation put in front of him, including same-sex marriage and the Equality Act.

Mr Wallace also voted in favour of the Human Fertilisation and Embryology Bill, which, had it passed, would have made it harder for lesbian couples to conceive children through IVF.

Hehas also repeatedly opposed raising welfare benefits and has always backed more hard-line immigration and asylum laws.

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Handful of Tories declare themselves as candidates to replace Johnson - Morning Star Online

Embryology

Y Combinator-Backed Lilia Launches A More Convenient And Affordable Egg Freezing Offering Built For The Millennial Women – Forbes

While a womans age at thaw has relatively little impact on a womans chances of success, the age at ... [+] freeze does, according to the U.K.'s Human Fertilisation and Embryology Authority

Lilia, a full-service egg freezing concierge, today announced they are now offering egg freezing directly for their clients at nearly half the price of an average IVF procedure and in half the time, and coordinated to make the experience less isolating. With this new breakthrough offering, women have access to the leading, most progressive doctors in the country dedicated to Lilias mission of giving every woman the freedom to make her own decisions on her own timeline.

According to the Human Fertilisation and Embryology Authority, the U.K.'s independent fertility regulator, the data shows that while a womans age at thaw has relatively little impact on a womans chances of success, the age at freeze does, with evidence showing that if eggs are frozen below the age of 35, the chances of success will be higher than the natural conception rate as the woman gets older.

Alyssa Atkins, founder and CEO of Lilia

As a Y Combinator graduate, and having raised roughly $1.5 million to date, Lilia is revolutionizing how women plan their futures. Founded in 2019 by Alyssa Atkins, who froze her eggs at the age of 29, the idea for Lilia was conceived when she founder realized the whole experience was built for an IVF couple, not young women focused on their futures. The company is currently operating with doctors in New York City, Chicago, and San Francisco, with plans to go national by the end of 2023. As explained by Atkins, Lilia is now a single point of contact for women - no more waiting on hold for doctors offices or fielding a million emails from the clinics different departments.

The convenience of Lilias offerings is reflected in the fact that they coordinate everything for the patient from contracts, to appointments, meds, and virtual consulting and prep work. The whole process, Atkins highlights, takes less than a month. And lets be honest until now, no one has focused specifically on serving the millions of women aged 24 35 for whom egg freezing works best.

Most women have considered freezing their eggs at some point and many have been thinking about it for years. But when they turn to Google, they are bounced out by the complexity of how to start, where to go, or what to do. Egg freezing, when done early, is the best way to relieve reproductive pressure and give women more optionality. Optionality is freedom and freedom is everything for women who dont want to be pressured into having a child before they are ready.

Lilia is changing a stale narrative about what a womans life ought to look like. Society is pretty prescriptive about its expectations of women college, career, marriage, baby in that order and ideally by 30, which leaves most women feeling behind no matter what theyve accomplished or what their personal goals are, explains Atkins.

Its 2022 (in case you havent noticed) and its time we usher in a new normal. One where egg freezing isnt perceived as something you do in your late 30s as a last resort, but something you can do early, in your 20s, because you have the right to reproductive freedom, autonomy, and choice. Its not just something to be done for your future self; it has real and direct impacts on the present you by taking the pressure off, especially in dating. With eggs secured early, women dont have to rush; every first date isnt an evaluation of whether the person in front of you is the future father of your children.

Atkins admits she sees so many women in their late 30s saying they wish someone had told them to freeze their eggs earlier. So, she and her team are working on showing women how common and normal this process is and educating them along the way. People think egg freezing is about the future you, but really its about taking the pressure off of you today because it lets you date differently, make different career moves, and live with more freedom, she adds.

It is more important now than ever that women have the power of choice and freedom. Choice over whether they take certain jobs, and when or whether to have kids at all. They deserve the freedom not to settle, to stop doing the dating math, and not to be rushed in making important decisions about their careers or matters of the heart. Every woman deserves the feeling of freedom and inner peace that comes from knowing all doors to her future are open, continues Atkins.

So who are Lilia's users and target audience? Obviously, someone for whom being a biological mom is incredibly important, and they want to ensure this happens at some point in their lives. Perhaps its a woman who knows she wants to use a surrogate at some point and so egg freezing is a path to this; startup founders, who are super busy and want kids but know they need time to build their companies first; women who arent sure they want kids at all, but want the option later; basically, any woman who wants to take the pressure off and keep their options open.

We believe that in time, egg freezing will be as common as birth control, and it should not only be a luxury for a small group of society. While egg freezing might not have been part of our fairy tale stories growing up, it has become extremely common and is one of the most radical acts of self-care a woman can make. We don't want women to wait until egg freezing becomes an absolute emergency, at which point its either often too late to retrieve enough healthy eggs, or to do so would require many cycles and the corresponding costs that come with it, adds Atkins.

Lilia is under the medical leadership of Dr. Roohi Jeelani, who does the highest volume of ... [+] egg-freezing retrievals in the country

The time and cost savings are created to let the company deliver an outstanding experience to women for a predictable $9,000 all-in, instead of the nebulous $15,000+ women are usually faced with. Under the medical leadership of Dr. Roohi Jeelani, who does the highest volume of egg-freezing retrievals in the country, Lilia is able to deliver this breakthrough offering while maintaining the highest standards in medicine.

We have carefully selected clinic partners who are equally committed to making egg freezing affordable and accessible to all, and dedicated to together creating a better experience for women.

Atkins and her team spent a lot of time getting the offering right, ensuring they could drive down costs and improve the experience while maintaining a superlative standard of care. Now that theyve done this, theyre working on changing the entire narrative around egg freezing and normalizing this process as a regular part of womanhood.

Were especially interested in how dating and egg freezing relate, because we know when women freeze eggs early theyre able to date differently and that it gives them more power in their love lives. Were working on telling more womens stories about whove frozen their eggs so women see just how common this is. Something I realized when I froze my eggs is I had all these friends whod done it but werent talking about it, concludes Atkins.

Originally posted here:
Y Combinator-Backed Lilia Launches A More Convenient And Affordable Egg Freezing Offering Built For The Millennial Women - Forbes

Anatomy

The anatomy of a rumor: Fact checking abortion claims – The Dickinson Press

DICKINSON Dr. Thomas Arnold is a practicing gynecologist and obstetrician at CHI St. Alexius Health in Dickinson who also volunteers at Connect Medical Clinic. Arnold earned his degree from the Uiversity of North Dakota, School of Medicine, in 1984 and has been a practicing OBGYN for decades.

Arnold explained how an ectopic pregnancy occurs, noting that it is defined as those rare instances when a fertilized egg grows outside the uterus usually in the fallopian tubes. He said that both legally and medically, this is completely different from an abortion.

Ectopic pregnancies most commonly occur in the fallopian tubes, and they can be life threatening to the mother because of rupture and bleeding that can occur. They're not pregnancies that can be sustained in the woman's body. The fallopian tubes cannot accommodate a pregnancy like that, Arnold said. If you have a patient that has an ectopic pregnancy, that can be managed within the environment of the Catholic Health System.

Public commons photo

He explained the distinction between an elective abortion and the termination of a non-viable pregnancy and how the two are widely recognized throughout the medical community.

Colleagues of mine, physicians and medical personnel in general, consider an abortion to be the termination of a live pregnancy. I just read an article about someone who had a fetal demise about seven months into the pregnancy and she was told that if if they intervene that it was an abortion. Well, I don't think most medical professionals will look at management of a fetal demise, where you have a baby that's non-viable, as an abortion, he said.

Among those who have spread misinformation on this topic, one of the most seemingly credible sources was Daily Beast Columnist Wajahat Ali. He incorrectly conflated abortion with ectopic pregnancies and further spread a commonly misunderstood legal liability concern to his nearly 300,000 followers on social media both assertions being incorrect.

Do I abort this ectopic pregnancy to literally save my life or do I go to jail? Question women in America now have to ask, Ali stated in a viral tweet. Also, doctors who have taken an Oath to save lives now have to risk jail as well. It's a mess.

Reuters reports that only abortionists, those who perform clandestine abortions, or pharmacists who illegally distribute abortion inducing pills to end life in the womb can suffer prosecution under these state laws. Thirteen states, including North Dakota, have trigger laws that subsequently banned abortion after Roe v. Wade was overturned. The states trigger law took effect on June 28, as the 2007 statute behind it included a 30-day waiting period after Roe being struck down.

Five other states had statutory abortion bans prior to 1973 that now go back into effect.

Of all 18 states, each has an exception to allow procedures to terminate pregnancies in the event the mothers life is in danger. No state penalizes women who seek abortions, and anti-abortion activist groups overwhelmingly oppose prosecuting said women.

Prominent New York Congresswoman Alexandria Ocasio-Cortez also made misleading claims about reproductive health care in a viral Instagram video to her millions of followers.

A bunch of men who are very ignorant about medicine, biology, rape culture and the misogyny that they were raised in, including legal liability and how it factors in with the medical field people who are ignorant to all of that are the ones that are writing these laws, Ocasio-Cortez argued in an Instagram video. "Some of them were even written in the 1800s So dont tell me that people in the 1800s knew what an ectopic pregnancy was."

Despite the seemingly primitive medical technology of the era, not only were medical professionals impressively able to identify ectopic pregnancies, but by the final decades of that century they were even treating them.

In 1883 British surgeon Robert Lawson Tait performed the first successful procedure terminating an ectopic pregnancy, a condition which then had a 60% mortality rate. Tait lost only two of the 42 women he performed this surgery on.

Miscarriages have also been a hot topic of misinformation in light of some states moving to bans on abortion in the wake of the Supreme Court ruling. In a June 24 Facebook post , Lillian Jones, a Democratic NPL nominated candidate for state house in District 41, shared her opposition to the Dobbs v. Jackson decision.

I lost an unexpected child to miscarriage and endured a procedure that saved my life. A womans Constitutional right to choose just got struck down, along with a familys right to make decisions regarding health and household composition, Jones said in the post, implying that such procedures may no longer be available to women who need them.

CHI St. Alexius, an ardently "pro-life institution of the Catholic church," has been providing surgery and medication to treat miscarriages nearly since its inception, and Arnold said they will continue to do so. As previously explained by Arnold, no abortion ban in any state hinders doctors from treating miscarriages.

Arnold categorized a miscarriage as a medical condition that is more common than most people realize, and most often occurs before the woman realizes shes pregnant.

Miscarriages are most often due to a genetic abnormality, where the pregnancy progresses inside the uterus to a certain gestational stage. Then for reasons we don't always find out, the pregnancy becomes non-viable, he said. The body perceives this at some point. It will usually respond by trying to eliminate the pregnancy by contracting, bleeding and passing over the tissue naturally. That's not a perfect system however, and in some cases, the bleeding and cramping can be severe enough where women will come into the clinic or the emergency room for a surgical evacuation of the uterus.

He reiterated that his and most definitions of abortion only include viable pregnancies.

Most people will say the difference between a miscarriage and a termination or an abortion would be that one is a non-viable pregnancy and the other is a viable pregnancy, Arnold said.

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The anatomy of a rumor: Fact checking abortion claims - The Dickinson Press

Anatomy

Grey’s Anatomy season 19: When could we hear about season 20? – CarterMatt

Greys Anatomyseason 19 is coming to ABC a little this year but for the sake of this article, were looking ahead far ahead. To be specific, were talking about season 20 and when some of the first news could officially come out about that.

Just like youre having to be patient to get news on season 19 production, youre also going to need patience to get news on season 20 a LOT of patience, in fact. The earliest that we can see discussions even happening on the future is this fall, and thats because the top priority is getting the new season off the ground. The important thing to remember along the way here is that the writers are typically several scripts ahead of where the cast and crew are in filming. That means that by the end of the fall, it would be useful for them to have a rough idea.

We would assume that by the first couple of months in the new year, folks behind the scenes will start to understand more of which way things are leaning. For us as viewers, ABC could easily drag this out further. Dont be shocked if there is a situation where we dont find out anything definite until the spring. We do think they will tell us prior to the final episodes if this is the final season or not, largely because that is the thing that makes the most overall sense.

Do we think the show is going to be winding down at some point sooner rather than later? Most likely, yes however, season 20 is such a nice number to end things on, and we can think of no other appropriate way to tie everything together. (Of course, if ABC gives the show a season 20 we wouldnt be mad about that, either.)

Related Be sure to get some more news when it comes to Greys Anatomy right now

Share right now in the comments! Once you do just that, come back there are other updates on the way and of course, we dont want you missing any of them. (Photo: ABC.)

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Grey's Anatomy season 19: When could we hear about season 20? - CarterMatt

Anatomy

Anatomy of a modern data stack and 4 key benefits it creates – Construction Dive

Construction firms that know how to harness their data are increasingly at a competitive advantage in today's complex world and the latest research emphasizes just how much of an advantage.

In fact, faulty construction data may have caused $1.8 trillion in losses worldwide and been responsible for 14% of avoidable rework, or $88 billion, according to Autodesk and FMI.

That same report found that 75% of contractors said there's an increased need for rapid decision-making in the field exactly where good data is crucial. But only 55% of contractors had implemented a formal data strategy for project data, and only 12% always incorporated project data into their decision-making.

The solution to these problems is the modern data stack. But just what is it, and why should contractors care?

"The modern data stack is a scalable, low barrier to entry, group of technologies that firms can adopt to drive value from their data," said Matt Monihan, CEO of ResponseVault, a data-engineering firm specializing in the construction industry. "That's important because, with the modern data stack, you can surface data without every single app having a direct integration with another one."

Monihan said the goal is true data integration, which many construction firms mistakenly believe they have achieved because of questionable claims from software-makers about integration. But, while integrations may technically be available, they don't always provide true data insights firms need to make smarter decisions and predict outcomes. "The granularity of the integration is key and varies between vendors," Monihan said.

In this article, we'll explore the anatomy of the modern data stack and answer questions about four key benefits it creates.

Point solutions are where your data originates. Whether it's coming from the field, the office or the owner, your data is being collected in a structured form, like Procore change events, or from free-form data sources like Spreadsheets. The data generated from these point solutions run your business, and the solutions are made to collect the data properly.

Once you've collected your jobsite data in point solutions, the next step is to securely and reliably export that data into a storage container, often referred to as a data warehouse, data lake or even a data lakehouse. As technology evolves, the differences between those industry terms have blurred, but what's important is that a piece of middleware is required to move the data between the point solution and its staging area in the warehouse.

The data we're extracting from our point solutions needs to live somewhere, and that is where our storage method is chosen. The cost of entry to this component has reduced, both with the introduction of Amazon Redshift as a lower-cost analytical database and with the rise of accessible, open-source databases introducing features that enable many use cases that weren't previously possible in years past. So, once you've selected and set up your storage and data is flowing, next is doing something with the data: Analysis.

Now is the time to model the data across your data sources, identify fields that combine disparate data sets, and clean the data into unified models. This step requires a dedicated data analyst who can communicate with people in the field who are generating the source data and reconcile any discrepancies with stakeholders looking for reports and dashboards. Your analyst will need to work with many Business Intelligence (BI) tools available in the market today. No one BI tool covers everything you may need. What's important is that you pick one and stick with it.

This step is where you'll need a layer that continually tests and lets you know that the entire stack is functioning correctly. It's where you'll receive alerts about outages, expired authentication tokens, broken models and more.

The goal is to have a robust and comprehensive set of tools to not only proactively monitor the stack's health but also provide a straightforward process for investigating problems that may arise.

Now that you understand the anatomy of a modern tech stack, it's essential to understand its benefits.

1. How does the stack reduce manual data entry and inconsistent data? Manual data entry and conflicting data are collectively costing contractors billions. These twin problems often cause multiple apps and tech tools companies use to gather data. Although processes are digitized, the apps and tools don't integrate; thus, data becomes siloed in the various solutions. To get a report, someone must manually go into the different tools or apps and export the data. 42% of companies use four to six apps for their construction jobs, and 27% report that none of those apps integrate. As a result, data is transferred manually nearly 50% of the time, according to JBKnowledge. Because it integrates data across apps and systems, modern data stacks provide digital access across the enterprise and a single source of truth.

2. How do disparate data sources get connected? Although many construction IT professionals know about major database suppliers, such as Oracle, they may not be aware of the many better off-the-shelf data tools available to integrate data. These connectors save considerable IT time and cost and ensure the data is secure and reliable with a trusted single source of truth. In that scenario, BIM changes can be made in a 3D render using real-time job site data. Then, if an architect or owner wants to make a change, a cost analysis can be done in real-time based on how the project is going.

3. Where does the data go? The modern data stack relies on a data warehouse that's typically cloud-based. This cloud data warehouse can store and quickly access large quantities of data without breaking the bank. It ensures that all company data flows appropriately to this data warehouse so that firms can gain actionable insight into real-time data. That's key because poor project data and miscommunication cause 52% of rework. This means $31.3 billion in rework was caused by bad project data and miscommunication in the U.S. alone in 2018, according to FMI/Autodesk report.

4. How do we ensure that the various integrations are working properly and that data is correct? Unlike black-boxed integrations, the modern data stack provides a clear picture of data, so it's easy to see, manage and manipulate. For example, the stack includes orchestration tooling, data management frameworks and data-quality monitoring tooling for high observability other tools, such as data governance, surface organizational problems.

The result is the ability to create meaningful data dashboards that get insights that matter, such as subs' quality of work, safety scores and schedules. "With the modern data stack, you have a window into exactly what's happening," Monihan said. "It's not a black box. It's a transparent system for diagnosing, understanding and customizing how integration works."

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Anatomy of a modern data stack and 4 key benefits it creates - Construction Dive

Anatomy

Grey’s Anatomy star Kevin McKidd to continue filming The Elect in Glasgow tomorrow – here’s where – Glasgow Times

A Glasgow pub will be taken over by camera crews as filming continues for a new ITV drama starring Greys Anatomy heartthrob Kevin McKidd.

The Elect, a four-part Western adaptation of Japanese crime novel Six/Four, has been filming in and around the city.

As well as in the St Vincent Street area back in May, Trainspotting star McKidd was also spotted filming in the citys Drury Laneon Monday evening.

READ MORE:Grey's Anatomy star Kevin McKidd spotted by excited fan in Glasgow city centre

Now, on short notice, the crew will be shooting at The State Bar on Holland Street, which is mere seconds away from several popular Sauchiehall Street destinations.

Nearby residents received a letter through their door on Tuesday apologising for any inconvenience caused with interior filming expected to take place on Wednesday at some point between 8am and 4pm.

English actor Richard Coyle, who appeared in the Netflix series Chilling Adventures of Sabrina, is also starring in the drama alongside Saskia Ashdown and Brian McCardie.

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Grey's Anatomy star Kevin McKidd to continue filming The Elect in Glasgow tomorrow - here's where - Glasgow Times