Objective

To describe the clinical and molecular genetic findings in a family segregating a novel mutation in the AIFM1 gene on the X chromosome.

Background

Transient loss of consciousness (TLOC) is a common reason for presentation to primary/emergency care; over 90% are because of epilepsy, syncope, or psychogenic non-epileptic seizures (PNES). Misdiagnoses are common, and there are currently no validated decision rules to aid diagnosis and management. We seek to explore the utility of machine-learning techniques to develop a short diagnostic instrument by extracting features with optimal discriminatory values from responses to detailed questionnaires about TLOC manifestations and comorbidities (86 questions to patients, 31 to TLOC witnesses).

Viruses commonly antagonize innate immune pathways that are primarily driven by nuclear factor kappa B (NF-B), interferon regulatory factor (IRF), and the signal transducer and activator of transcription proteins (STAT) family of transcription factors. Such a strategy allows viruses to evade immune surveillance and maximize their replication. Using an unbiased transcriptome sequencing (RNA-seq)-based approach to measure gene expression induced by transfected viral genomic RNA (vgRNA) and reovirus infection, we discovered that mammalian reovirus inhibits host cell innate immune signaling. We found that, while vgRNA and reovirus infection both induce a similar IRF-dependent gene expression program, gene expression driven by the NF-B family of transcription factors is lower in infected cells. Potent agonists of NF-B such as tumor necrosis factor alpha (TNF-α) and vgRNA failed to induce NF-B-dependent gene expression in infected cells. We demonstrate that NF-B signaling is blocked due to loss of critical members of the inhibitor of kappa B kinase (IKK) complex, NF-B essential modifier (NEMO), and IKKβ. The loss of the IKK complex components prevents nuclear translocation and phosphorylation of NF-B, thereby preventing gene expression. Our study demonstrates that reovirus infection selectively blocks NF-B, likely to counteract its antiviral effects and promote efficient viral replication.

IMPORTANCE Host cells mount a response to curb virus replication in infected cells and prevent spread of virus to neighboring, as yet uninfected, cells. The NF-B family of proteins is important for the cell to mediate this response. In this study, we show that in cells infected with mammalian reovirus, NF-B is inactive. Further, we demonstrate that NF-B is rendered inactive because virus infection results in reduced levels of upstream intermediaries (called IKKs) that are needed for NF-B function. Based on previous evidence that active NF-B limits reovirus infection, we conclude that inactivating NF-B is a viral strategy to produce a cellular environment that is favorable for virus replication.

Chronic pain is a highly prevalent disease with poorly understood pathophysiology. In particular, the brain mechanisms mediating the transition from acute to chronic pain remain largely unknown. Here, we identify a subcortical signature of back pain. Specifically, subacute back pain patients who are at risk for developing chronic pain exhibit...

Synaptic activity in neurons leads to the rapid activation of genes involved in mammalian behavior. ATP-dependent chromatin remodelers such as the BAF complex contribute to these responses and are generally thought to activate transcription. However, the mechanisms keeping such “early activation” genes silent have been a mystery. In the course...

The delicate necklace of threaded petals from the tomb of Rameses II, midnineteenth century glass houses built for the newly discovered Victoria amazonica, and Monet’s giant canvases in the Musée de l'Orangerie all testify to a deep human attraction to water lilies: beguiling plants with showy flowers that seem to...

Fredrik Andreasson, Arne Hegemann, Andreas Nord, and Jan-Ake Nilsson

The capacity to get rid of excess heat produced during hard work is a possible constraint on parental effort during reproduction [heat dissipation limit (HDL) theory]. We released hard-working blue tits (Cyanistes caeruleus) from this constraint by experimentally removing ventral plumage. We then assessed whether this changed their reproductive effort (feeding rate and nestling size) and levels of self-maintenance (change in body mass and innate immune function). Feather-clipped females reduced the number of feeding visits and increased levels of constitutive innate immunity compared with unclipped females but did not fledge smaller nestlings. Thus, they increased self-maintenance without compromising current reproductive output. In contrast, feather clipping did not affect the number of feeding visits or innate immune function in males, despite increased heat loss rate. Our results show that analyses of physiological parameters, such as constitutive innate immune function, can be important when trying to understand sources of variation in investment in self-maintenance versus reproductive effort and that risk of overheating can influence innate immune function during reproduction.

Dual amylin and calcitonin receptor agonists (DACRAs) are novel candidates for treatment of type 2 diabetes and obesity because of their beneficial effects on body weight, blood glucose, insulin sensitivity, and food preference, at least short-term. DACRAs activate the receptors for a prolonged time period, resulting in metabolic effects superior to those of amylin. Because of the prolonged receptor activation, different dosing intervals and, hence, less frequent receptor activation might change the efficacy of DACRA treatment in terms of weight loss and food preference. In this study, we compared daily dosing to dosing every other day with the aim of understanding the optimal balance between efficacy and tolerability. Obese and lean male Sprague-Dawley rats were treated with the DACRA KBP-088, applying two different dosing intervals (1.5 nmol/kg once daily and 3 nmol/kg every other day) to assess the effect on body weight, food intake, glucose tolerance, and food preference when given the choice between chow (13% fat) and a high-fat diet (60% fat). Treatment with KBP-088 induced significant weight loss, reduction in adiposity, improvement in glucose control, and altered food preference toward food that is less calorie-dense. KBP-088 dosed every other day (3 nmol/kg) was superior to KBP-088 once daily (1.5 nmol/kg) in terms of weight loss and improvement of food preference. The beneficial effects were evident in both lean and obese rats. Hence, dosing KBP-088 every other day positively affects overall efficacy on metabolic parameters regardless of the lean/obese state, suggesting that less-frequent dosing with KBP-088 could be feasible.

Nayeli G. Reyes-Nava, Hung-Chun Yu, Curtis R. Coughlin II, Tamim H. Shaikh, and Anita M. Quintana

We used whole-exome sequencing (WES) to determine the genetic etiology of a patient with a multi-system disorder characterized by a seizure phenotype. WES identified a heterozygous de novo missense mutation in the GABRA1 gene (c.875C>T). GABRA1 encodes the alpha subunit of the gamma-aminobutyric acid receptor A (GABA_AR). The GABA_AR is a ligand gated ion channel that mediates the fast inhibitory signals of the nervous system, and mutations in the subunits that compose the GABA_AR have been previously associated with human disease. To understand the mechanisms by which GABRA1 regulates brain development, we developed a zebrafish model of gabra1 deficiency. gabra1 expression is restricted to the nervous system and behavioral analysis of morpholino injected larvae suggests that the knockdown of gabra1 results in hypoactivity and defects in the expression of other subunits of the GABA_AR. Expression of the human GABRA1 protein in morphants partially restored the hypomotility phenotype. In contrast, the expression of the c.875C>T variant did not restore these behavioral deficits. Collectively, these results represent a functional approach to understand the mechanisms by which loss-of-function alleles cause disease.

Yu Liu, Shuhua Qi, Fridtjof Thomas, Brittany L. Correia, Angela P. Taylor, Roy V. Sillitoe, and Detlef H. Heck

Respiration is controlled by central pattern generating circuits in the brain stem, whose activity can be modulated by inputs from other brain areas to adapt respiration to autonomic and behavioral demands. The cerebellum is known to be part of the neuronal circuitry activated during respiratory challenges, such as hunger for air, but has not been found to be involved in the control of spontaneous, unobstructed breathing (eupnea). Here we applied a measure of intrinsic rhythmicity, the CV2, which evaluates the similarity of subsequent intervals and is thus sensitive to changes in rhythmicity at the temporal resolution of individual respiratory intervals. The variability of intrinsic respiratory rhythmicity was reduced in a mouse model of cerebellar ataxia compared to their healthy littermates. Irrespective of that difference, the average respiratory rate and the average coefficient of variation (CV) were comparable between healthy and ataxic mice. We argue that these findings are consistent with a proposed role of the cerebellum in modulating the duration of individual respiratory intervals, which could serve the purpose of coordinating respiration with other rhythmic orofacial movements, such as fluid licking and swallowing.

BackgroundA brief intervention whereby GPs opportunistically facilitate an NHS-funded referral to a weight loss programme is clinically and cost-effective.AimTo test the acceptability of a brief intervention and attendance at a weight loss programme when GPs facilitate a referral that requires patients to pay for the service.Design and settingAn observational study of the effect of a GP encouraging attendance at a weight loss programme requiring self-payment in the West Midlands from 16 October 2018 to 30 November 2018, to compare with a previous trial in England in which the service was NHS-funded.MethodSixty patients with obesity who consecutively attended primary care appointments received an opportunistic brief intervention by a GP to endorse and offer a referral to a weight loss programme at the patient’s own expense. Participants were randomised to GPs who either stated the weekly monetary cost of the programme (basic cost) or who compared the weekly cost to an everyday discretionary item (cost comparison). Participants were subsequently asked to report whether they had attended a weight loss programme.ResultsOverall, 47% of participants (n = 28) accepted the referral; 50% (n = 15) in the basic cost group and 43% (n = 13) in the cost comparison group. This was significantly less than in a previous study when the programme was NHS-funded (77%, n = 722/940; P<0.0001). Most participants reported the intervention to be helpful/very helpful and appropriate/very appropriate (78%, n = 46/59 and 85%, n = 50/59, respectively) but scores were significantly lower than when the programme was NHS-funded (92% n = 851/922 and 88% n = 813/922, respectively; P = 0.004). One person (2%) attended the weight loss programme, which is significantly lower than the 40% of participants who attended when the programme was NHS-funded (P<0.0001).ConclusionGP referral to a weight loss programme that requires patients to pay rather than offering an NHS-funded programme is acceptable; however, it results in almost no attendance.

Adele posted a message to her social media channels this week thanking those on the front lines fighting COVID-19. In the process, the celebrated singer unveiled a thinner frame—and the internet had a lot of thoughts about it, almost all trash.

Enter Bill Maher, noted #MeToo skeptic, with perhaps the most garbage take of them all.

On Friday night, during the interview portion of his HBO show Real Time, the comedian began by placing the bulk of the blame for the high amount of COVID-19 deaths in the U.S. compared to other countries on America’s obesity problem—not, say, the fact that the Trump administration didn’t do a single thing during the month of February to contain the spread of the virus.

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We know that there is at least one planet orbiting Proxima Centauri, the nearest star to our solar system, and now astronomers may have taken the first picture of a second world

Gamescom has wrapped up but we’re just getting started! Final Fantasy XII remaster rumors and eczema outbreaaks were leading the headlines, but Blizzard, not one...

You know who you are. You know what you did. And to the driver who killed Nathan Beaulieu’s dog in a cowardly hit-and-run, the Winnipeg Jets defenceman wants you to ...

Astronomers using NASA’s Neil Gehrels Swift Observatory have tracked water loss from 2I/Borisov, the first known interstellar comet to visit our Solar System, as it approached and rounded the Sun. Their findings were published in the Astrophysical Journal Letters. 2I/Borisov was detected on August 30, 2019 by Gennady Borisov, an astronomer at the Crimean Astrophysical [...]

The U.S. Postal Service on Friday said its losses more than doubled to $4.5 billion in the quarter ending in March and warned the economic slowdown spurred by the spread of COVID-19 could severely hurt its finances over the next 18 months.

The U.S. government reported more catastrophic economic fallout from the coronavirus crisis on Friday as the pandemic pierced the very walls of the White House and California gave the green light for its factories to restart after a seven-week lockdown.

The report by Crisil also added that the losses will climb if travel restrictions last longer in hubs such as Mumbai, Delhi, Chennai and Kolkata.

The 'Hello' singer turned 32 on Tuesday (05.05.20) and when she took to Instagram to thank fans for their well-wishes on her special day

Provisions for credit losses were $30.2 million, an increase of 397.9 per cent from a year earlier

TD also said it will have about $600 million of set-asides tied to U.S. credit cards

The U.S. Postal Service on Friday said its losses more than doubled to $4.5 billion in the quarter ending in March and warned the economic slowdown spurred by the spread of COVID-19 could severely hurt its finances over the next 18 months.

The U.S. economy likely lost a staggering 22 million jobs in April, in what would be the steepest plunge in payrolls since the Great Depression and the starkest sign yet of how the novel coronavirus pandemic is battering the world's biggest economy.

The U.S. economy lost a staggering 20.5 million jobs in April, the steepest plunge in payrolls since the Great Depression, laying bare both the economic and human tragedy wrought by the novel coronavirus pandemic.

Major U.S. stock indexes jumped on Friday and logged solid gains for the week after data on historic job losses due to the coronavirus crisis showed they were slightly fewer than feared.

As many parts of the world's biggest economy begin to reopen after weeks of stay-at-home orders that slowed the spread of the coronavirus but gutted jobs, Americans should not expect a quick return to growth, U.S. Federal Reserve officials said on Friday.

'By expanding our thinking of how oceans behaved in the past, we could gain some insights into oceans today,' says scientist at Stanford University

Actor Kevin Spacey has broken his silence over sex assault allegations, comparing being shunned by the film industry to those who are out of work as a result of the coronavirus crisis. The 60-year-old American Beauty star has not appeared in a professional movie or series since accusations of abuse were made by several men. "I don't think it will come as a surprise for anyone to say that my world completely changed in the fall of 2017,” he said in comments made during an interview for the German business conference Bits & Pretzels podcast. “My job, many of my relationships, my standing in my own industry were all gone in just a matter of hours.” The former House of Cards lead, who was dropped by the show after allegations surfaced, has largely kept a low profile since the allegations were made. He was also removed from the film All the Money in the World, which had to be reshot with actor Christopher Plummer. Spacey has always denied the claims, several of which date back several decades. “While we may have found ourselves in similar situations, albeit for very different reasons and circumstances, I still believe that some of the emotional struggles are very much the same," he said. “And so I do have empathy for what it feels like to suddenly be told that you can't go back to work or that you might lose your job and that it's a situation that you have absolutely no control over.” At the end of the podcast interview, Spacey added: “I was so busy defining myself by what I did or what I was trying to do, that when it all stopped I had no idea what to do next. All I knew how to do was act, I was born to do it. “I don’t want to sugarcoat this devastating time that we’re in, I am hoping that I can encourage you to see an opportunity in all of this and turn this into a positive.”

The full regular-season schedule is out. The Chiefs open defense of their Super Bowl title vs. Houston.

Jonathan Tapper says he "couldn't move at one point" and was "really struggling for breath"

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Causes, prevention and treatment... we speak to an award-winning hair doctor to get some advice on preserving your precious locks

The retired footballer had been a business partner at the label since 2015

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The once-acclaimed actor then admitted he felt lost when the #MeToo movement turned his life upside down.

Company expects to be cash flow positive in the next two quarters.

Arsenal's squad are ready to knock back the club's wage-cute proposals which would cost players up to 12.5 per cent of their annual salary.

According to those who know him best, Tottenham's head of coaching and development, John McDermott, is one of English football's more recent pioneers.

The Ligue de Football Professionnel (LFP) have confirmed they will help support Ligue 1 and Ligue 2 clubs financially following the cancellation of the season with a state-guaranteed loan to cover lost television rights money.

Compared to the Great Recession, fewer male and blue-collar workers have lost jobs, while women, Latinos, African Americans and young workers have been hit hardest.

HAIR loss treatment: The quest for magic cure to help halt the process of hair loss produces numerous searches and theories. Taking this essential mineral helps strengthen hair follicles which stimulate hair growth.

The owners of Sydney's troubled Mascot Towers claim new test have revealed a "loss of soil" under the apartment complex's north east corner the same area cracks first appeared before the building was evacuated in June.

She credits her fitness to one lifestyle change.

Coronavirus unemployment hits a broad swath of industries across California.

Australia's troubled second airline, which saw its cash flow collapse because of tough coronavirus travel restrictions, appoints accounting firm Deloitte to act as administrator after the Federal Government rejected calls to bail it out.

The COVID-19 pandemic resulted in a 5.5 per cent slump in jobs in the first week after extensive business shutdowns and social-distancing limits were introduced to contain the virus, new ABS figures show.

Australian shares recoup earlier losses as retailers and banks rise, after initial falls were spurred by oil prices falling to their lowest value in 18 years.