Publisher Health

An impressive number of brain pathologies are closely linked to major cerebrovascular defects, which are currently impossible to treat due to a lack of drugs. The discovery by researchers from the ULB Neuroscience Institute is therefore particularly promising, as not only have they developed a new class of molecules that specifically correct these dysfunctions, they have also demonstrated their effectiveness in mouse models of radically different brain pathologies.
Led by Prof. Benoit Vanhollebeke — WELBIO investigator and professor at the Department of Molecular Biology, Faculty of Sciences, Free University of Brussels — the researchers at the Neurovascular Signalling Laboratory, ULB Neuroscience Institute, specialise in the study of cerebral blood vessels and their dysfunction. By studying the proteins controlling the formation of these vessels during embryonic life, the researchers believe they can identify targets with promising therapeutic potential. The evidence is that by developing molecules targeting the Gpr124/Reck membrane complex, whose role was first revealed in a neurodevelopmental context, Maud Martin and her colleagues have succeeded in slowing down the progression of glioblastoma, the most common primary adult brain cancer, in mice, and reducing the lesions following a stroke.
The same team had previously published on the mechanistic characterisation of the therapeutic target in Science. This new study establishes its therapeutic potential in mice. When the target is activated, dysfunctional cerebral blood vessels made too permeable by the pathology regain their original functionality; they recover a set of cellular and molecular characteristics that strongly limit exchanges between blood and neural tissue and are collectively called the blood-brain barrier. The brain is thus again protected from toxic components circulating in the blood, and the progression of pathologies is slowed.
“One of the most fascinating aspects of this study is the level of specificity with which pathological brain vessels respond to this experimental treatment. Inspired by the natural developmental process, we have designed a new class of molecules that are able to reach their therapeutic target efficiently, while remaining completely inert for healthy vessels and other tissues of the body. On a fundamental basis, this level of specificity seemed a priori out of reach,” explains Benoit Vanhollebeke.
To build on this, the researchers from the Neurovascular Signalling Laboratory now want to explore other experimental models of brain pathologies that could potentially benefit from their approach.
Benoit Vanhollebeke and the ULB have created the spin-off company NeuVasQ Biotechnologies, which, with the support of a consortium of public and private investors, aims to bring this type of neurovascular treatment to the bedside.
The research from the signalling laboratory is supported by the ERC, the WELBIO, the FNRS, the Queen Elisabeth Medical Foundation, and the ULB Foundation.
The work is published in collaboration with the teams of Stefan Liebner (Goethe University Frankfurt, Germany), Richard Daneman (UCSD, USA), Baptiste Lacoste (University of Ottawa, Canada),Timothy Phoenix (University of Cincinnati, USA), Alban de Kerchove d’Exaerde, Eric Bellefroid and David Torres (ULB), as well as the CMMI (ULB and UMONS)
Story Source:
Materials provided by Université libre de Bruxelles. Note: Content may be edited for style and length.

Specialized groups of neurons within the brainstem control movement. Now researchers  have found that activation of such neurons is sufficient to restore full movement function in mice with symptoms of Parkinson’s Disease. The study helps clinicians to focus Deep Brain Stimulation to the right therapeutic spot and hopefully could improve treatment of motor symptoms in Parkinson’s Disease.
Parkinson’s is a neurodegenerative disease where dopaminergic neurons progressively die in the brainstem. Tremor and difficulties to walk are recognizable movement symptoms for many people suffering from Parkinson’s. Over time, nearly a quarter of patients will have so much trouble walking that they often end up freezing on the spot and falling, and many become housebound.
People are primarily treated with medicine, but in some cases doctors use Deep Brain Stimulation (DBS). In DBS, the surgeon places a thin metal wire in the brain, which can be used to send electrical pulses. DBS is effective in treating tremor, but alleviating difficulties in walking and freezing remains a challenge.
Now, a study from the University of Copenhagen conducted in mice demonstrate that DBS treatment of walking problems in Parkinson’s could be optimised by targeting specific eurons in the brainstem — possibly benefitting some of the more than 7 to 10 million people suffering from the disease worldwide.
“Brainstem DBS are the right strategy to facilitate patients to walk properly again”
Based on previous animal studies of motor circuits, which are responsible for the planning, control, and execution of voluntary movements, scientists has hypothesized that freezing of walking in Parkinson’s could be alleviated. That would require DBS to stimulate neurons in the pedunculopontine nucleus (PPN), which is located in the brainstem. The PPN was thought to send signals from the brain to the spinal cord leading to body movements.

In two publications in Nature Medicine, a European-Israeli team of researchers show how major disturbances occur in the gut microbiome of patients suffering from heart disease. Given this latest evidence from microbiome research, one of the senior lead researchers, Professor Oluf Pedersen from the University of Copenhagen, calls for stronger and more focused public health initiatives to prevent or delay these common diseases that are a leading cause of premature death worldwide through plant-based and energy-controlled diet, avoidance of smoking and compliance with daily exercise.
The human gut contains trillions of bacteria, collectively called the gut microbiome, which may have positive and negative effects on human health. When in balance they function as an inner chemistry factory producing numerous compounds that promote good health. However, an unhealthy lifestyle — poor diet, smoking, lack of physical activity or disease — can disrupt the balance, leading the microbiome to instead produce compounds that may trigger multiple non-communicable chronic disorders in people at high genetic risk, including myocardial infarction, angina or heart failure.
Scientists have already discovered that the gut microbiome is altered in people with chronic heart disease. They subsequently identified compounds that are produced by the diseased microbiome, for instance a bacterial compound called trimethylamine (TMA) that after modification in the liver of the human host causes arteriosclerosis.
However, these findings of altered gut microbiome are challenged because they were achieved in studies of medicated patients. Patients with heart disease are given several different drugs, each of which are known to modify the gut microbiome. As a result, it was unclear whether drugs or heart disease itself caused the disrupted gut microbiome of people with cardiovascular disorders.
A further complication lies in the fact that heart disease often develops alongside the early stages of overweight and type 2 diabetes, which are also characterized by having disrupted gut microbiomes. As a result, it remained to be shown whether an imbalanced gut microbiome is a feature of heart disease itself.
Heart diseases causes major disturbances in the gut microbiome
To answer these critical questions a European consortium of researchers established the EU-funded MetaCardis research project in 2012 to investigate the role of gut microbes in cardiometabolic disease. Among the principal investigators is Professor Oluf Pedersen from the University of Copenhagen who, together with his colleagues, published the consortium’s findings in in the journal Nature Medicine.

Researchers from the Netherlands Institute for Neuroscience (NIN) shed new light on how myelin loss might underpin aberrant brain activity which have been observed in people with multiple sclerosis. This study, published in eLife, suggests that myelination, however patchy on specific interneurons, is required to reach their full inhibitory potential.
Impact of losing myelin
The brain contains billions of nerves that connect with each other via cable- like structures called axons. Axons transmit electrical impulses and are often wrapped in a fatty substance called myelin. This substance increases the speed of nerve impulses and reduces the energy lost over long distances. Loss or damage of the myelin layer — which is the case for multiple sclerosis- can cause serious disability. Although myelinated axons play pivotal roles in brain function, only little is understood about their role in the electrical architecture of local circuits where experiences are processed, and memories are stored.
However, a fast-firing neuron within the brain, called the PV+ interneuron, has short, sparsely myelinated axons. Even so, PV+ interneurons are powerful inhibitors that regulate important brain rhythms and cognitive processes in gray matter areas of the brain. Recent findings have shown that also axons of PV+ interneurons are insulated by myelin sheaths. Yet it remains unclear how the unusual, patchy myelination affects their function.
Epileptic spikes as indicator
To study the impact on interneurons and slow brain waves, researcher Mohit Dubey, from the NIN, together with colleagues from the Erasmus Medical Centre used genetically engineered mice either lacking or losing myelin. “As mice progressively lost myelin, the speed of inhibitory signals from PV+ interneuron did not change but their signal strength decreased” says Dubey. As a result of being no longer inhibited by PV+ interneurons, the power of slow brain waves dramatically increased. These waves also triggered brief spikes resembling signals seen in epilepsy, only when the mice were inactive and quiet. Restoring the activity of PV+ interneurons helped to reverse the epileptic spikes.
“These results expand our understanding of the importance of myelin in gray matter and its clinical relevance to demyelinating disorders such as multiple sclerosis” says Maarten Kole, group leader at the NIN. More research is needed to determine whether these brief epileptic spikes could be a biomarker of multiple sclerosis and/or a target for developing new therapeutic strategies to limit cognitive impairments.
Story Source:
Materials provided by Netherlands Institute for Neuroscience – KNAW. Note: Content may be edited for style and length.

Legionellosis or Legionnaires’ disease affected more than 1,800 people in France in 2019 and caused 160 deaths. This emerging disease is caused by Legionella pneumophila, an environmental bacterium that thrives in hot water systems. Researchers from the Institut Pasteur, the CNRS, the University of Paris have discovered a mechanism that allows Legionella pneumophila to target the immune response of the cells it infects by secreting a small regulatory RNA. This mechanism, not described before, facilitates the survival and proliferation of Legionella pneumophila during infection. The work provides precious information on the strategies used by bacteria to manipulate their host cells. This research has been published online on February 9 on the Nature Communications website.
Intracellular pathogens adopt various strategies to circumvent immune defenses and proliferate inside the cells they infect. Legionella pneumophila has a large repository of effector proteins* that mimic host cell functions and are used by the pathogen to manipulate host signaling pathways to the pathogens advantage.
The teams of Carmen Buchrieser, head of the unit Biology of the Intracellular Bacteria at the Institut Pasteur and associated to CNRS, in collaboration with Gregory Lavieu at the Université de Paris and associated to Inserm and CNRS, have discovered that Legionella pneumophila secretes extracellular vesicles into the host cell during infection in which it packs small, regulatory RNA molecules. These regulatory RNAs mimic eukaryotic regulatory RNAs called micro RNAs that already exist naturally in the host cell.
The researchers have discovered that these two bacterial RNAs, named RsmY and tRNA-Phe, function in the host cell in a microRNA-like manner. They downregulate RIG-I, a protein in the cell that detects foreign RNA molecules in order to initiate an immune response. The down regulation of the expression of RIG-I leads to a diminished host immune response and a better replication of Legionella pneumophila.
This work sheds new light on the diverse, sophisticated strategies employed by intracellular pathogens for survival and development during infection.
* Proteins secreted in the host cell via a dedicated secretion system called type IV secretion system
Story Source:
Materials provided by Institut Pasteur. Note: Content may be edited for style and length.

T-cell responses directed against the receptor-binding domain of the SARS-CoV-2 spike protein were associated with protection from SARS-CoV-2 infection in vaccinated individuals with or without cancer, with lower T-cell responses observed in patients with blood cancers, according to results from a study published in Cancer Discovery, a journal of the American Association for Cancer Research.
The efficacy of COVID-19 vaccines has been typically measured by antibody levels, but this may not be a reliable metric, explained Laurence Zitvogel, MD, PhD, a professor at the Gustave Roussy Institute in Villejuif, France. “Humoral immune responses monitored by antibody titers are only transiently helpful and not well correlated with protection,” she said. “Antibodies do not last more than a couple of weeks in a given individual post-infection or post-vaccination. Data show that antibodies against the SARS-CoV-2 spike protein have failed to predict actual protection against reinfection or breakthrough infection.”
Measuring antibody levels is a way to monitor the presence and the activity of memory B cells, which are immune cells that produce antibodies and represent the first arm of adaptive immunity. T cells, another type of immune cell, represent the second arm of long-term immunity and can be amplified during infection to kill infected cells directly.
In this study, Zitvogel and colleagues examined whether T-cell responses could be a reliable indicator of protection against SARS-CoV-2 infection in healthy individuals and in patients with cancer who had not been exposed to the virus during the first wave of the pandemic. Using blood samples collected prior to infection with SARS-CoV-2, they performed various in vitro experiments to assess how the polarity and repertoire of T-cell responses correlated with susceptibility to infection with SARS-CoV-2 during subsequent waves of the pandemic.
T-cell polarity was assessed by identifying the types of cytokines — which are immune-stimulating proteins — released by the T cells of each individual when exposed to a viral antigen. The release of the IL-2 cytokine was indicative of Th1 T cells, whereas the release of the IL-5 cytokine indicated Th2 T cells. Zitvogel and colleagues examined the makeup of each individual’s T-cell pool to determine the proportion of Th1 and Th2 T cells.
They found pre-existing SARS-CoV-2-specific T cell responses in about 20-25 percent of the population, both in healthy individuals and in cancer patients. In addition, they observed that the types of cytokines released by memory T cells were associated with protection against SARS-CoV-2 infection. An imbalance between the IL-2 and IL-5 cytokines was associated with a higher susceptibility to SARS-CoV-2 infection, with an IL-2/IL-5 ratio less than 1 predicting infection, regardless of cancer status. This suggests that the relative levels of cytokines released by T cells may provide insight into susceptibility to SARS-CoV-2 infection, explained Zitvogel.

Treating babies with antibiotics in the first week of life is linked with a decrease in healthy bacteria necessary amongst others to digest milk and an increase in antimicrobial resistance, research suggests.
Experts say that clinicians should consider using antibiotics in a way that causes least harm to the newborns microbiome — the community of microbes that live in our body.
Under current guidelines, antibiotics directed at a wide range of bacteria — known as broad-spectrum — are currently prescribed to four to 10 per cent of all newborns for suspected infections.
However, experts say that in most cases the antibiotics are prescribed unnecessarily as only a small proportion of those who receive the drugs are eventually diagnosed with an infection.
This overprescription is to ensure early treatment for those who are ultimately found to have an infection as any delay may quickly become life-threatening.
Researchers from the Universities of Edinburgh and Birmingham, and the Spaarne Hospital and University Medical Centre Utrecht, The Netherlands, conducted a clinical trial involving 227 babies to analyse how antibiotics affect a newborn’s microbiome.

MIT chemists have discovered the structure of a protein that can pump toxic molecules out of bacterial cells. Proteins similar to this one, which is found in E. coli, are believed to help bacteria become resistant to multiple antibiotics.
Using nuclear magnetic resonance (NMR) spectroscopy, the researchers were able to determine how the structure of this protein changes as a drug-like molecule moves through it. Knowledge of this detailed structure may make it possible to design drugs that could block these transport proteins and help resensitize drug-resistant bacteria to existing antibiotics, says Mei Hong, an MIT professor of chemistry.
“Knowing the structure of the drug-binding pocket of this protein, one might try to design competitors to these substrates, so that you could block the binding site and prevent the protein from removing antibiotics from the cell,” says Hong, who is the senior author of the paper.
MIT graduate student Alexander Shcherbakov is the lead author of the study, which appears today in Nature Communications. The research team also includes MIT graduate student Aurelio Dregni and two researchers from the University of Wisconsin at Madison: graduate student Peyton Spreacker and professor of biochemistry Katherine Henzler-Wildman.
Drug-resistance transporters
Pumping drugs out through their cell membranes is one of many strategies that bacteria can use to evade antibiotics. For several years, Henzler-Wildman’s group at the University of Wisconsin has been studying a membrane-bound protein called EmrE, which can transport many different toxic molecules, including herbicides and antimicrobial compounds.

SharecloseShare pageCopy linkAbout sharingImage source, AFPMalawi has declared a wild polio outbreak after a case was identified in a three-year-old girl – the first of its kind in Africa for more than five years.The continent was declared free of all forms of wild polio in 2020.The Malawian authorities are now working to contain any possible spread including by boosting immunisation.Wild polio remains endemic in only two countries in the world – Afghanistan and Pakistan.BBC AFRICA LIVE: Updates from the continentThe strain that was identified in Malawi was linked to one found in Pakistan, but it is not clear how or when it arrived in the southern African country.The case was confirmed after tests were carried out on samples from the infected child who was suffering from paralysis, according to the Global Polio Eradication Initiative.Polio usually affects children under five, sometimes leading to irreversible paralysis. Death can occur when breathing muscles are affected.Twenty-five years ago thousands of children in Africa were paralysed by the virus. But following a mass vaccination campaign across the continent 95% of the population has been immunised.There is no cure but the polio vaccine protects children for life.As the case came from Pakistan, it does not affect the continent’s wild poliovirus-free status, the World Health Organization (WHO) says.Wild polio is caught from the environment, but there is another type of polio linked to the oral vaccine (which contains live, weakened virus) that is equally worrying. It can linger in the gut, mutate and spread in areas where few people are vaccinated. There have been outbreaks of this form of polio in more than 20 African countries in recent years.But an injectable form of the vaccine is now used, containing dead virus, which does not lead to polio cases.Setback for the continentThe first case in Africa for five years is devastating for this young girl who faces a lifetime of paralysis. It is also a setback for a continent that thought it had seen the back of wild polio. The size of the outbreak is unclear. Only one case has been reported, but paralysis occurs in less than one in 200 polio infections. The immediate goal will be to ensure Malawi does not suffer a large outbreak. Polio has been one of the most feared diseases for much of human history. But every case is preventable through vaccination. A remarkable global immunisation campaign had pushed the virus back to just Pakistan and Afghanistan. We are so close to eliminating polio from the world and seeing an end to the tragedy this virus can cause, but the final step has proven the hardest to take. More on the fight against polio:Africa declared free of polioHistory of polio’I opposed vaccinations until my son caught polio’Africa Today podcastsGlobal Polio Eradication InitiativeThe BBC is not responsible for the content of external sites.

The symptoms of attention deficit hyperactivity disorder can push couples to their breaking point, but there is hope for those willing to seek help.When Chris Lawson began dating Alexandra Salamis, the woman who would eventually become his partner, he was “Mr. Super Attentive Dude,” he said, the type of guy who enjoyed buying cards and flowers for no reason other than to show how much he loved her.But after they moved in together in 2015, things changed.He became more distracted and forgetful. Whether it was chores, planning social events or anything deadline-driven — like renewing a driver’s license — Ms. Salamis, 60, had to continually prod Mr. Lawson to get things done. Invariably, she just ended up doing them herself.“I was responsible for nothing,” Mr. Lawson, 55, admitted.Ms. Salamis, who is not one to mince words, described that period of their relationship as “like living with a child,” later adding, “I hated him, frankly.”But when she brought up her frustrations, Mr. Lawson would become defensive. And as she continued to nag, she started to feel more like a parent than a partner, something they both resented.Then in 2019, at a friend’s suggestion, the pair read an article about how attention deficit hyperactivity disorder, or A.D.H.D., can affect romantic relationships.“We both kind of looked at each other and our jaws dropped,” Ms. Salamis said.The couple, who live in Ottawa, had discovered something millions of others have realized, often after years of conflict: One of them — in this case, Mr. Lawson — most likely had A.D.H.D., a neurodevelopmental disorder often characterized by inattention, disorganization, hyperactivity and impulsivity.When one or both members of a couple have A.D.H.D., the relationship typically has unique challenges, which are usually exacerbated when the disorder goes undiagnosed, experts say. Studies suggest that people with A.D.H.D. have higher levels of interpersonal problems than their peers do, and marriages that include adults with A.D.H.D. are more likely to be unsatisfying.Forums like the one found on the popular website A.D.H.D. and Marriage are often filled with stories of frazzled, emotionally spent spouses stuck in unhealthy, yearslong patterns. But if a couple makes a strong effort to learn more about the disorder, manage its symptoms and find more effective ways to communicate, they can revitalize their relationship.Understand the symptomsPeople with A.D.H.D. may lack self-awareness, which can make it difficult to recognize how they are coming across to other people or how their behavior contributes to the problems they’re experiencing in their relationships, according to Russell A. Barkley, a psychologist and the author of “Taking Charge of Adult A.D.H.D.”Those who struggle with impulsivity might take unnecessary risks, or they might opt for immediate rewards, such as the pleasure of playing a video game, instead of focusing on mundane tasks that need to get done. People with A.D.H.D. are also often forgetful about what they’re supposed to be doing and tend to have big, emotional reactions that are stronger than what a situation might warrant — which can lead to explosive conflict.Contrary to the assumption that people with A.D.H.D. are always unfocused, many can focus intently on the things that interest them. But if they are especially attentive to a loved one during a relationship’s honeymoon phase and that intense interest eventually fades, a pattern can emerge where the non-A.D.H.D. partner feels unloved.“If your partner is chronically distracted, that means they are also distracted from you,” said Melissa Orlov, a marriage consultant who leads seminars for couples who are struggling with relationship difficulties, in part because of A.D.H.D. “That becomes very confusing and then it angers the partner because they feel like they’re not really being paid attention to. You’re like, ‘What, don’t you love me anymore? This isn’t the way it used to be.’”While this can be incredibly frustrating to the partner who does not have A.D.H.D., understanding these symptoms is a step toward embracing feelings of compassion and empathy over continual resentment.“Our loved ones with A.D.H.D. cannot help behaving the way they do,” Dr. Barkley said. It is a biological disorder, he added, “not a lifestyle choice. It is not simply something they could change in their mind over time if they wanted to.”Find coping strategiesDr. Alicia Hart, 34, a primary care doctor, met her husband when she was 18. They both said “I love you” within three days and “were in a committed serious relationship from then on,” she said. “People thought we were nuts. I mean, we met at a frat party.”The couple, who live in Portland, Ore., with their three kids, both have A.D.H.D.Most of their conflict has revolved around scheduling mishaps, “threatening to record conversations to prove that they happened or me starting another overambitious project without thinking it through or thinking of the impact on him,” Dr. Hart said in an email. “I also hate being late and have developed one million strategies to avoid this, where he has literally no concept of time and cannot be on time to save his life.”By playing to their individual strengths, they’re able to keep the household running. He pays the bills and manages all the finances. She keeps track of the daily routine, setting alarms on their smart speaker to help him remember things like lunchtime. They use a shared online calendar and a wall calendar, too.Robyn Aaron, a 36-year-old mother of two who was diagnosed with A.D.H.D. last year, said she and her husband now have a weekly meeting to stay organized, but they try to make it as fun as possible.“We treat it like a date night — pour a glass of wine, maybe even light a candle,” said Ms. Aaron, who lives in Lisbon, Iowa. “He gives the check-in on finances; I give the skinny on the calendar.”They also discuss their ongoing do-it-yourself projects, upcoming trips and any needs or wants.“It’s become even more important to us since the pandemic began to connect in this way, and it’s super helpful for my coping strategies with A.D.H.D., too,” she added.Show your partner you’re tryingIn the book “A.D.H.D. After Dark: Better Sex Life, Better Relationship,” Ari Tuckman, the author, psychologist and sex therapist, surveyed more than 3,000 adults in couples where one partner had A.D.H.D. He found that the people who felt that their partners put in the most effort at either managing their own A.D.H.D. or supporting a partner with A.D.H.D. had almost twice as much sex as those who said their partners put in the least effort.For some partners with A.D.H.D., it can be hard to accept the need for change and can also be difficult to be optimistic that new strategies will make a difference, especially if medications or past strategies haven’t worked.But it’s worth continuing to educate yourself about the different options available to people with A.D.H.D., or perhaps even seeking out a different clinician from the one you’ve been seeing, he added.Dr. Tuckman also advised both partners to choose their battles.“A.D.H.D. doesn’t invent new problems, it just exacerbates the universal ones,” he said. “It’s the stuff that every other couple argues about, just more often.”It is within your right to insist that your partner get the kids to school on time, for example, and ideally you will find a way to make that happen. But, Dr. Tuckman cautioned, “you only get a small number of deal breakers.”Consider a blend of treatmentsExperts agree that medication alone is not the best way to manage A.D.H.D., but it can complement other strategies like cognitive behavioral therapy, coaching, mindfulness and exercise.It wasn’t until he had been married for 16 years that Taylor Weeks, 36, finally realized that A.D.H.D. had been at the root of so much of the discord between him and his wife.As far back as he can remember, he struggled with time blindness and forgetfulness, continually dropping the ball and then chastising himself for it.“It has always been kind of a huge stressor for my wife,” said Mr. Weeks, who lives in Rio Rancho, N.M. “She’s constantly been frustrated with me.”He is now seeing a psychologist, taking medication for the A.D.H.D. symptoms and practicing mindfulness to help ease his anxiety.He still struggles with forgetfulness, but his mind feels more clear.“Before, I felt like I always had a bunch of thoughts going through my mind all the time,” he said. “But when it came down to try to articulate what I’m thinking, it was really difficult for me to get that out of my head and get my point across.”His wife is noticing, he added, and told him he’s easier to communicate with and seems more engaged with their four children.Mr. Lawson’s relationship also improved after he was eventually diagnosed with A.D.H.D. and prescribed a medication that improved his memory and ability to focus.“It’s literally like a blanket has been removed from my head,” he said.Just as important, they also attended couples therapy and learned how to better relate to each other and develop strategies to get things done at home.Ms. Salamis, for her part, worked to break old patterns of behavior where she would continually check up on her partner or try to manage every aspect of their household. There was no need to do so anymore, because he was actually doing the things that needed to get done.It has been a long road to get to this point, Mr. Lawson continued, but now, he said, “I can be the guy she fell in love with.”