iQOO 13 launched in China with the Snapdragon 8 Elite chipset last month. The Vivo sub-brand recently confirmed that the smartphone will arrive in the Indian market in December first week. The specifications of the Indian variant of iQOO 13 are believed to match with its Chinese counterpart. But compared to the Chinese version, the Indian variant will have a smaller battery.

The new Maruti Suzuki Dzire has made a significant impact with its launch, especially due to its potential 5-star Global NCAP rating. The base model, the LXI Petrol MT, is priced at Rs 6.79 lakh (Ex-showroom). This variant offers a surprising

This seems insane. Why create a more transmissable and lethal version of COVID?

DailyMail.com revealed the team had made a hybrid virus -- combining Omicron and the original Wuhan strain -- that killed 80 per cent of mice in a study.

The revelation exposes how dangerous virus manipulation research continues to go on even in the US, despite fears similar practices may have started the pandemic.

Professor Shmuel Shapira, a leading scientist in the Israeli Government, said: 'This should be totally forbidden, it's playing with fire.'

Gain of function research - when viruses are purposefully manipulated to be more infectious or deadly - is thought to be at the center of Covid's origin.

We may never know the origin of COVID-19 with certainty, but gain-of-function research needs to stop.

In a new paper, researchers argue that a tendency towards self-sacrifice among humans is adaptive in some situations - for instance, a firefighter willingly risking his or her life to save someone from a burning building. But when individuals mistakenly view their own deaths as being worth more than their lives, the results can be needlessly lethal...

Maruti Suzuki recently launched the new fourth-generation Dzire with prices ranging between Rs 6.79 lakh and Rs 10.14 lakh (ex-showroom, Delhi). It continues to be based on the Swift hatchback, shares the same platform and engine but sports a differentiated look. It even goes one up on the equipment front. The new Dzire is available in four trims – LXi, VXi, ZXi and ZXi+ – and we take a close look at all the features you get in each trim.

2024 Maruti Suzuki Dzire trims, variants explained

The Dzire is powered by the same Z12E engine as the Swift: 82hp, 112Nm, 3-cylinder naturally aspirated. It’s available with a 5-speed manual gearbox as standard on all four trims; the AMT is available on all but the base trim. The new Dzire also gets a CNG powertrain right from launch, available on the mid-spec VXi and ZXi trims. Coupled with a 5-speed manual gearbox, the Dzire produces 69.75hp and 101.8Nm in CNG spec.

The new Dzire’s ARAI-rated fuel efficiency figure is 24.79kpl in manual form and 25.71kpl in AMT guise. Meanwhile, in CNG spec, the Dzire returns a claimed efficiency of 33.73km/kg.

New Maruti Dzire variant-wise features

Maruti Dzire LXi: Rs 6.79 lakh

Powertrain: petrol-MT

• Projector halogen headlights
• LED tail-lights
• 14-inch steel wheels without covers
• Shark fin antenna
• Black and beige dual-tone interior
• Fabric seat upholstery
• Adjustable front seat headrests
• Analogue instrument cluster with MID (multi-information display)
• All four power windows
• Auto up/down for the driver-side window
• Keyless entry
• Manual AC
• Tilt-adjustable steering wheel
• Six airbags
• Rear defogger
• 3-point seat belts with reminders for all seats
• Electronic stability program (ESP)
• Hill-hold assist
• ABS with EBD
• Reverse parking sensors

Maruti Dzire VXi: Rs 7.79 lakh–8.74 lakh

Powertrain: petrol-MT, petrol-AMT, CNG-MT

• 14-inch steel wheels with covers
• Chrome finish on the front grille
• Turn indicators on wing mirrors
• Body-coloured door handles and wing mirrors
• Electrically adjustable and foldable wing mirrors
• Silver insert on dashboard
• 7-inch touchscreen
• Wireless Android Auto and Apple CarPlay
• 4 speakers
• Steering-mounted controls
• OTA updates
• Voice assistant
• USB and Bluetooth connectivity
• Height-adjustable driver’s seat
• Adjustable rear headrests
• Day/night inside rearview mirror (IRVM)
• Front roof lamp
• Rear centre armrest with cupholders
• Rear AC vents

Maruti Dzire ZXi: Rs 8.89 lakh–9.84 lakh

Powertrain: petrol-MT, petrol-AMT, CNG-MT

• Auto LED headlights
• LED daytime running lamps
• 15-inch single-tone alloy wheels
• Chrome window garnish
• Silver trim and faux wood insert on dashboard
• Push button start/stop
• Wireless phone charger
• Key-operated boot opening
• Auto AC
• 6 speakers (including 2 tweeters)
• Connected car tech
• Reverse parking camera
• TPMS

Maruti Dzire ZXi+: Rs 9.69 lakh–10.14 lakh

Powertrain: petrol-MT, petrol-AMT

• 15-inch dual-tone alloys
• LED front fog lamps
• Front footwell illumination
• Leatherette-wrapped steering wheel
• 9-inch touchscreen
• Arkamys-tuned sound system
• Single-pane sunroof
• Coloured MID on instrument console
• Cruise control
• Auto-fold wing mirrors on locking the car
• 360-degree camera

Bookings for the new Dzire are ongoing for a token amount of Rs 11,000, and the introductory prices will be applicable till December 31, 2024. The Dzire rivals the Hyundai Aura, the Tata Tigor and the Honda Amaze, with the Amaze also due to receive an all-new generation next month.

Also See:

Maruti Dzire new vs old: price, engine, features comparison

2024 Maruti Suzuki Dzire review: India's favourite sedan massively updated

Maruti Suzuki recently launched the new fourth-generation Dzire with prices ranging between Rs 6.79 lakh and Rs 10.14 lakh (ex-showroom, Delhi). It continues to be based on the Swift hatchback, shares the same platform and engine but sports a differentiated look. It even goes one up on the equipment front. The new Dzire is available in four trims – LXi, VXi, ZXi and ZXi+ – and we take a close look at all the features you get in each trim.

2024 Maruti Suzuki Dzire trims, variants explained

The Dzire is powered by the same Z12E engine as the Swift: 82hp, 112Nm, 3-cylinder naturally aspirated. It’s available with a 5-speed manual gearbox as standard on all four trims; the AMT is available on all but the base trim. The new Dzire also gets a CNG powertrain right from launch, available on the mid-spec VXi and ZXi trims. Coupled with a 5-speed manual gearbox, the Dzire produces 69.75hp and 101.8Nm in CNG spec.

The new Dzire’s ARAI-rated fuel efficiency figure is 24.79kpl in manual form and 25.71kpl in AMT guise. Meanwhile, in CNG spec, the Dzire returns a claimed efficiency of 33.73km/kg.

New Maruti Dzire variant-wise features

Maruti Dzire LXi: Rs 6.79 lakh

Powertrain: petrol-MT

• Projector halogen headlights
• LED tail-lights
• 14-inch steel wheels without covers
• Shark fin antenna
• Black and beige dual-tone interior
• Fabric seat upholstery
• Adjustable front seat headrests
• Analogue instrument cluster with MID (multi-information display)
• All four power windows
• Auto up/down for the driver-side window
• Keyless entry
• Manual AC
• Tilt-adjustable steering wheel
• Six airbags
• Rear defogger
• 3-point seat belts with reminders for all seats
• Electronic stability program (ESP)
• Hill-hold assist
• ABS with EBD
• Reverse parking sensors

Maruti Dzire VXi: Rs 7.79 lakh–8.74 lakh

Powertrain: petrol-MT, petrol-AMT, CNG-MT

• 14-inch steel wheels with covers
• Chrome finish on the front grille
• Turn indicators on wing mirrors
• Body-coloured door handles and wing mirrors
• Electrically adjustable and foldable wing mirrors
• Silver insert on dashboard
• 7-inch touchscreen
• Wireless Android Auto and Apple CarPlay
• 4 speakers
• Steering-mounted controls
• OTA updates
• Voice assistant
• USB and Bluetooth connectivity
• Height-adjustable driver’s seat
• Adjustable rear headrests
• Day/night inside rearview mirror (IRVM)
• Front roof lamp
• Rear centre armrest with cupholders
• Rear AC vents

Maruti Dzire ZXi: Rs 8.89 lakh–9.84 lakh

Powertrain: petrol-MT, petrol-AMT, CNG-MT

• Auto LED headlights
• LED daytime running lamps
• 15-inch single-tone alloy wheels
• Chrome window garnish
• Silver trim and faux wood insert on dashboard
• Push button start/stop
• Wireless phone charger
• Key-operated boot opening
• Auto AC
• 6 speakers (including 2 tweeters)
• Connected car tech
• Reverse parking camera
• TPMS

Maruti Dzire ZXi+: Rs 9.69 lakh–10.14 lakh

Powertrain: petrol-MT, petrol-AMT

• 15-inch dual-tone alloys
• LED front fog lamps
• Front footwell illumination
• Leatherette-wrapped steering wheel
• 9-inch touchscreen
• Arkamys-tuned sound system
• Single-pane sunroof
• Coloured MID on instrument console
• Cruise control
• Auto-fold wing mirrors on locking the car
• 360-degree camera

Bookings for the new Dzire are ongoing for a token amount of Rs 11,000, and the introductory prices will be applicable till December 31, 2024. The Dzire rivals the Hyundai Aura, the Tata Tigor and the Honda Amaze, with the Amaze also due to receive an all-new generation next month.

Also See:

Maruti Dzire new vs old: price, engine, features comparison

2024 Maruti Suzuki Dzire review: India's favourite sedan massively updated

Tata Motors has finally taken the wraps off the Curvv, a bold looking SUV coupe that is available with petrol, diesel and electric powertrains

The Maruti Suzuki Dzire has long been a top choice in the Indian compact sedan segment, renowned for its balance of practicality, affordability, and reliability

In 2022, Google expanded support for Product structured data, enabling enhanced product experiences in Google Search. Then, in 2023 we added support for shipping and returns structured data. Today, we are adding structured data support for Product variants, allowing merchants to easily show more variations of the products they sell, and show shoppers more relevant, helpful results. Providing variant structured data will also complement and enhance merchant center feeds, including automated feeds.

Test tubes labelled "Monkeypox virus positive and negative" are seen in this illustration taken May 23, 2022. — Reuters

LONDON: An infection with the latest mpox variant, clade 1b, has been detected in the United Kingdom for the first time, the UK Health Security Agency announced...

The World Health Organization said mpox cases in the region of Congo where a new and more infectious variant was first detected appear to be "plateauing," even as the virus continues to increase in other regions of the country, as well as in Burundi and Uganda.

Menomonee Falls, WI — Around 70% of office workers say they’re washing their hands more often because of new strains of the virus that causes COVID-19, while about half avoid shaking hands with others, results of a recent survey show.

Molybdenum- or tungsten-dependent formate dehydrogenases have emerged as significant catalysts for the chemical reduction of CO2 to formate, with biotechnological applications envisaged in climate-change mitigation. The role of Met405 in the active site of Desulfovibrio vulgaris formate dehydrogenase AB (DvFdhAB) has remained elusive. However, its proximity to the metal site and the conformational change that it undergoes between the resting and active forms suggests a functional role. In this work, the M405S variant was engineered, which allowed the active-site geometry in the absence of methionine Sδ interactions with the metal site to be revealed and the role of Met405 in catalysis to be probed. This variant displayed reduced activity in both formate oxidation and CO2 reduction, together with an increased sensitivity to oxygen inactivation.

Fluctuation X-ray scattering (FXS) offers a complementary approach for nano- and bioparticle imaging with an X-ray free-electron laser (XFEL), by extracting structural information from correlations in scattered XFEL pulses. Here a workflow is presented for single-particle structure determination using FXS. The workflow includes procedures for extracting the rotational invariants from FXS patterns, performing structure reconstructions via iterative phasing of the invariants, and aligning and averaging multiple reconstructions. The reconstruction pipeline is implemented in the open-source software xFrame and its functionality is demonstrated on several simulated structures.

The dangerous Delta variant of the coronavirus is spreading so quickly in the United States that it's likely the mutant strain will become predominant in the U.S. within weeks, according to a new analysis.

The variant, first identified in India, is the most contagious yet and, among those not yet vaccinated, may trigger serious illness in more people than other variants do, say scientists tracking the spread of infection.

The Delta variant apparently already accounts for at least 14% of all new infections, according to the research analysis posted online Monday of more than 242,000 infections nationwide over the last six months.

Another reason to get vaccinated

"It definitely is of concern," says William Lee, the vice president of science at Helix, which is under contract with the Centers for Disease Control and Prevention to help track the variants.

"Just the fact that it's so transmissible means that it's it's dangerous," Lee says, "and so I think you'll see outbreaks of Delta around the country and more people will get sick from it."

Helix launched the study when researchers spotted a drop in the prevalence of the Alpha variant, a contagious strain first spotted in the U.K. that had quickly become the dominant variant in that country and the U.S.

The researchers discovered the drop in relative frequency of the Alpha variant in their spot checks of strains circulating in the U.S. was due to a rapid increase in two other variants: the Gamma variant, first spotted in Brazil, and the Delta variant. The Gamma variant may be slightly better than the original strain at outmaneuvering the vaccines, researchers say.

"It looks like both of them are going to slowly push out Alpha," says Lee, whose study has not yet been peer-reviewed but has been posted on a pre-print server.

How Delta could prompt another U.S. COVID-19 surge

All the vaccines authorized for use in the U.S. appear, in general, to provide powerful protection against all the variants, including Delta. But the rapid spread of the variants is still raising concern because of the large number of people who remain unvaccinated.

"There still are big portions of the country where the rates of vaccination are quite low," notes Dr. Jeremy Luban, a virologist at the University of Massachusetts Medical School. "And, in fact, the Helix paper shows that this Delta variant is increasing in frequency — the speed at which it's increasing in frequency is greatest in those areas where vaccination rates are lowest."

The Delta variant could trigger yet another moderate surge of infections through many parts of the U.S. because of these pockets of unvaccinated people, according to a recent set of projections from the COVID-19 Scenario Modeling Hub, which is helping the CDC plot the future course of the pandemic.

The projections indicate that infections could start to rise again as soon as some time in July, especially if the vaccination campaign continues to stall.

"For the most part, it's a moderate resurgence," says Justin Lessler, an epidemiologist at Johns Hopkins University who is helping coordinate the hub.

"We're not having massive epidemics at a national level, but we have this kind of continuation of the virus just sticking around and keeping us on our toes," Lessler says. "And in specific places there could be substantial epidemics still."

This content is from Southern California Public Radio. View the original story at SCPR.org.

Moderna says recently completed studies have found its vaccine to have a neutralizing effect against all COVID-19 variants tested, including the delta variant.; Credit: Fred Tanneau/AFP via Getty Images

Studies have found that Moderna's COVID-19 vaccine is effective against several variants of concern, including the delta variant, the biotech company announced.

Moderna said Tuesday that recently completed studies have found the vaccine to have a neutralizing effect against all COVID-19 variants tested, including the beta, delta, eta and kappa variants.

While still highly effective against the delta variant, the study showed the vaccine was less effective against it and certain other variants than against the original strain of the virus.

The antibody response against the delta variant was about two times weaker than against the ancestral strain of the virus.

The news echoes other findings that the Moderna and Pfizer vaccines are highly effective against the delta variant. A study published this month in Nature found that Pfizer's vaccine was able to neutralize variants including delta, though at somewhat reduced strength.

"These new data are encouraging and reinforce our belief that the Moderna COVID-19 Vaccine should remain protective against newly detected variants," Stéphane Bancel, Moderna's chief executive officer, said in a statement. "These findings highlight the importance of continuing to vaccinate populations with an effective primary series vaccine."

The company also said it is developing a booster candidate: a 50-50 mix of its currently authorized COVID-19 vaccine and another messenger RNA vaccine it has developed.

The delta variant is spreading fast

The delta variant is the fast-moving form of the coronavirus that is now found in 96 countries, including the United States.

Last week, Dr. Anthony Fauci of the National Institutes of Health said the delta variant is "currently the greatest threat in the U.S. to our attempt to eliminate COVID-19," noting that the proportion of infections being caused by the variant is doubling every two weeks.

The delta variant is now infecting at least 1 out of every 5 people who get the virus in the United States. In some sections of the country, the variant is already far more common, particularly in parts of the Midwest and West. At its current pace, the delta variant is expected to be the dominant virus in the U.S. within weeks.

Dr. Maria Van Kerkhove, an infectious disease expert at the World Health Organization, called the delta variant "incredibly transmissible."

"These viruses are becoming more fit. The virus is evolving, and this is natural," she told NPR's Morning Edition. "It's more transmissible than the alpha variant, so we need to just do all we can to prevent as many infections as we can and do what we can do to reduce the spread."

This content is from Southern California Public Radio. View the original story at SCPR.org.

Detail of boxes with the U.S. donated Johnson & Johnson vaccine against Covid-19 at Universidad de Baja California on June 17, 2021 in Tijuana, Baja California. ; Credit: Francisco Vega/Getty Images

In our continuing series looking at the latest medical research and news on COVID-19, Larry Mantle speaks with Dr. Annabelle De St. Maurice from University of California Los Angeles/Mattel Children’s hospital.

Topics today include:

• J&J says its vaccine is effective against Delta variant

  • J&J vaccine lasts at least 8 months

• WHO says all vaccines it authorized should be recognized by reopening countries

• White House says it will miss July 4 vaccination goal

• Postpartum depression on the rise during the pandemic

• Experts believe Novavax may play a role in combating vaccine hesitancy

• Delta variant is not driving a surge in hospitalization rates in England

Guest: 

Annabelle De St. Maurice, M.D., assistant professor of pediatrics in the division of infectious diseases and the co-chief infection prevention officer at University of California Los Angeles/Mattel Children’s hospital; she tweets @destmauricemd

This content is from Southern California Public Radio. View the original story at SCPR.org.

A passenger wearing a protective face covering to combat the spread of the coronavirus, checks her phone while travelling on a bus along Oxford Street in central London on July 5, 2021.; Credit: DANIEL LEAL-OLIVAS/AFP via Getty Images

In our continuing series looking at the latest medical research and news on COVID-19, Larry Mantle speaks with Professor Kristen Choi of UCLA. 

Topics today include:

• Biden to announce new efforts on vaccination campaign as Delta variant spreads

• Hospitalization rates getting worse for black residents of L.A. County 

• Which parts of the U.S. could be breeding grounds for variants?

• New Israeli data about effectiveness of Pfizer against Delta variant

• England to lift mask restrictions

• Cases on rise in immigration detention centers in the U.S. 

• Bay area zoo is vaccinating big cats and some other animals 

Guest:

Kristen R. Choi, professor of nursing and public health at UCLA; registered nurse practicing at Gateways Hospital, based in Echo Park

This content is from Southern California Public Radio. View the original story at SCPR.org.

As vaccination campaigns begin ramping up around the world, experts discuss how variants, misinformation, and “brain drain” are affecting pandemic-control efforts.

As the omicron variant of the coronavirus sweeps through the U.S. and other parts of the world — and with the possibility of emerging new variants looming — building confidence in vaccines has become even more important. How can knowledge from the social sciences inform effective communication around vaccines?

Scientists have used whole genome sequencing data from Norwegian infants to identify a genetic variant that almost totally prevents jaundice in 1 in 8 ...

SARS-CoV-2, the pandemic virus that causes COVID-19, has mutated endlessly since it burst on the scene in late 2019. An new antibody could help stop it

Scientists have used whole genome sequencing data from Norwegian infants to identify a genetic variant that almost totally prevents jaundice in 1 in 8 ...

Scientists have used whole genome sequencing data from Norwegian infants to identify a genetic variant that almost totally prevents jaundice in 1 in 8 ...

SARS-CoV-2, the pandemic virus that causes COVID-19, has mutated endlessly since it burst on the scene in late 2019. An new antibody could help stop it

"Batman: White Knight Presents: Harley Quinn takes place two years after Batman: Curse of the White Knight. Azrael has wiped out criminals in Gotham, Jack Napier (formerly The Joker) is dead, Bruce Wayne (Batman) is in prison, and Harley Quinn is adjusting to life as a single mother, raising the twins she had with Jack. But as new villains arise, Harley is forced to dance with madness once again and confront her own past with The Joker and Batman while helping the Gotham City police and an eager young FBI agent uncover the truth behind a series of gruesome murders. This collection also features a chapter from Harley Quinn's newest digital first series, Harley Quinn Black + White + Red, told in a traditional black-and-white format with the color red uniquely shaping Harley Quinn's story." -- Provided by publisher.

Nanoparticle enrichment mass-spectrometry proteomics identifies protein-altering variants for precise pQTL mapping  Nature.com

Sanofi/GSK launch Phase III trial of COVID-19 vaccine, will test efficacy against variants

Expertos creen que no se puede determinar si estamos en la mitad, el inicio o el fin de la pandemia. Plantean que mayor reto es la inequidad de las vacunas.

Leonardo Donoso habló con 6AM, expuso las medidas que tomó el municipio frente a los bloqueos de los trasportadores.

A new COVID-19 subvariant has now been confirmed in multiple provinces in Canada. The Omicron offshoot is also rising rapidly south of the border, and scientists say it could soon be a dominant strain in the U.S. and other countries.

Cybersecurity researchers have discovered a new version of a well-known Android malware family dubbed FakeCall that employs voice phishing (aka vishing) techniques to trick users into parting with their personal information. "FakeCall is an extremely sophisticated Vishing attack that leverages malware to take almost complete control of the mobile device, including the interception of incoming

HIV Type 1 (HIV-1) and simian immunodeficiency virus (SIV) display differential replication kinetics in macrophages. This is because high expression levels of the active host deoxynucleotide triphosphohydrolase sterile α motif domain and histidine-aspartate domain–containing protein 1 (SAMHD1) deplete intracellular dNTPs, which restrict HIV-1 reverse transcription, and result in a restrictive infection in this myeloid cell type. Some SIVs overcome SAMHD1 restriction using viral protein X (Vpx), a viral accessory protein that induces proteasomal degradation of SAMHD1, increasing cellular dNTP concentrations and enabling efficient proviral DNA synthesis. We previously reported that SAMHD1-noncounteracting lentiviruses may have evolved to harbor RT proteins that efficiently polymerize DNA, even at low dNTP concentrations, to circumvent SAMHD1 restriction. Here we investigated whether RTs from SIVmac239 virus lacking a Vpx protein evolve during in vivo infection to more efficiently synthesize DNA at the low dNTP concentrations found in macrophages. Sequence analysis of RTs cloned from Vpx (+) and Vpx (−) SIVmac239–infected animals revealed that Vpx (−) RTs contained more extensive mutations than Vpx (+) RTs. Although the amino acid substitutions were dispersed indiscriminately across the protein, steady-state and pre-steady-state analysis demonstrated that selected SIVmac239 Vpx (−) RTs are characterized by higher catalytic efficiency and incorporation efficiency values than RTs cloned from SIVmac239 Vpx (+) infections. Overall, this study supports the possibility that the loss of Vpx may generate in vivo SIVmac239 RT variants that can counteract the limited availability of dNTP substrate in macrophages.

Lys234 is one of the residues present in class A β-lactamases that is under selective pressure due to antibiotic use. Located adjacent to proton shuttle residue Ser130, it is suggested to play a role in proton transfer during catalysis of the antibiotics. The mechanism underpinning how substitutions in this position modulate inhibitor efficiency and substrate specificity leading to drug resistance is unclear. The K234R substitution identified in several inhibitor-resistant β-lactamase variants is associated with decreased potency of the inhibitor clavulanic acid, which is used in combination with amoxicillin to overcome β-lactamase–mediated antibiotic resistance. Here we show that for CTX-M-14 β-lactamase, whereas Lys234 is required for hydrolysis of cephalosporins such as cefotaxime, either lysine or arginine is sufficient for hydrolysis of ampicillin. Further, by determining the acylation and deacylation rates for cefotaxime hydrolysis, we show that both rates are fast, and neither is rate-limiting. The K234R substitution causes a 1500-fold decrease in the cefotaxime acylation rate but a 5-fold increase in kcat for ampicillin, suggesting that the K234R enzyme is a good penicillinase but a poor cephalosporinase due to slow acylation. Structural results suggest that the slow acylation by the K234R enzyme is due to a conformational change in Ser130, and this change also leads to decreased inhibition potency of clavulanic acid. Because other inhibitor resistance mutations also act through changes at Ser130 and such changes drastically reduce cephalosporin but not penicillin hydrolysis, we suggest that clavulanic acid paired with an oxyimino-cephalosporin rather than penicillin would impede the evolution of resistance.

Tsz-Kiu Aaron Chow and Yangyang Li
Trans. Amer. Math. Soc. 377 (), 5993-6020.
Abstract, references and article information

Ahmed Elshafei, Ana Cristina Ferreira, Miguel Sánchez and Abdelghani Zeghib
Trans. Amer. Math. Soc. 377 (), 5837-5862.
Abstract, references and article information

Daniel López Neumann
Trans. Amer. Math. Soc. 377 (), 5361-5387.
Abstract, references and article information

Sudip Ranjan Bhuia
Proc. Amer. Math. Soc. 152 (), 5249-5263.
Abstract, references and article information

Systemic antibody light chains (AL) amyloidosis is characterized by deposition of amyloid fibrils derived from a particular antibody light chain. Cardiac involvement is a major risk factor for mortality. Using MAS solid-state NMR, we studied the fibril structure of a recombinant light chain fragment corresponding to the fibril protein from patient FOR005, together with fibrils formed by protein sequence variants that are derived from the closest germline (GL) sequence. Both analyzed fibril structures were seeded with ex-vivo amyloid fibrils purified from the explanted heart of this patient. We find that residues 11-42 and 69-102 adopt β-sheet conformation in patient protein fibrils. We identify arginine-49 as a key residue that forms a salt bridge to aspartate-25 in the patient protein fibril structure. In the germline sequence, this residue is replaced by a glycine. Fibrils from the GL protein and from the patient protein harboring the single point mutation R49G can be both heterologously seeded using patient ex-vivo fibrils. Seeded R49G fibrils show an increased heterogeneity in the C-terminal residues 80-102, which is reflected by the disappearance of all resonances of these residues. By contrast, residues 11-42 and 69-77, which are visible in the MAS solid-state NMR spectra, show 13Cα chemical shifts that are highly like patient fibrils. The mutation R49G thus induces a conformational heterogeneity at the C terminus in the fibril state, whereas the overall fibril topology is retained. These findings imply that patient mutations in FOR005 can stabilize the fibril structure.

Oktawia Nilsson
Nov 17, 2020; 0:jlr.RA120000920v1-jlr.RA120000920
Research Articles

Apolipoprotein A-I (ApoA-I) of high-density lipoprotein (HDL) is essential for the transportation of cholesterol between peripheral tissues and the liver. However, specific mutations in Apolipoprotein A-I (ApoA-I) of high-density lipoprotein (HDL) are responsible for a late-onset systemic amyloidosis, the pathological accumulation of protein fibrils in tissues and organs. Carriers of these mutations do not exhibit increased cardiovascular disease risk despite displaying reduced levels of ApoA-I/ HDL-cholesterol. To explain this paradox, we show that the HDL particle profile of patients carrying either L75P or L174S ApoA-I amyloidogenic variants a higher relative abundance of the 8.4 nm vs 9.6 nm particles, and that serum from patients, as well as reconstituted 8.4 and 9.6 nm HDL particles (rHDL), possess increased capacity to catalyze cholesterol efflux from macrophages. Synchrotron radiation circular dichroism and hydrogen-deuterium exchange revealed that the variants in 8.4 nm rHDL have altered secondary structure composition and display a more flexible binding to lipids compared to their native counterpart. The reduced HDL-cholesterol levels of patients carrying ApoA-I amyloidogenic variants are thus balanced by higher proportion of small, dense HDL particles and better cholesterol efflux due to altered, region-specific protein structure dynamics.

S-Acylation, the reversible post-translational lipid modification of proteins, is an important mechanism to control the properties and function of ion channels and other polytopic transmembrane proteins. However, although increasing evidence reveals the role of diverse acyl protein transferases (zDHHC) in controlling ion channel S-acylation, the acyl protein thioesterases that control ion channel deacylation are very poorly defined. Here we show that ABHD17a (α/β-hydrolase domain-containing protein 17a) deacylates the stress-regulated exon domain of large conductance voltage- and calcium-activated potassium (BK) channels inhibiting channel activity independently of effects on channel surface expression. Importantly, ABHD17a deacylates BK channels in a site-specific manner because it has no effect on the S-acylated S0–S1 domain conserved in all BK channels that controls membrane trafficking and is deacylated by the acyl protein thioesterase Lypla1. Thus, distinct S-acylated domains in the same polytopic transmembrane protein can be regulated by different acyl protein thioesterases revealing mechanisms for generating both specificity and diversity for these important enzymes to control the properties and functions of ion channels.

Influenza A virus (IAV) mutates rapidly, resulting in antigenic drift and poor year-to-year vaccine effectiveness. One challenge in designing effective vaccines is that genetic mutations frequently cause amino acid variations in IAV envelope protein hemagglutinin (HA) that create new N-glycosylation sequons; resulting N-glycans cause antigenic shielding, allowing viral escape from adaptive immune responses. Vaccine candidate strain selection currently involves correlating antigenicity with HA protein sequence among circulating strains, but quantitative comparison of site-specific glycosylation information may likely improve the ability to design vaccines with broader effectiveness against evolving strains. However, there is poor understanding of the influence of glycosylation on immunodominance, antigenicity, and immunogenicity of HA, and there are no well-tested methods for comparing glycosylation similarity among virus samples. Here, we present a method for statistically rigorous quantification of similarity between two related virus strains that considers the presence and abundance of glycopeptide glycoforms. We demonstrate the strength of our approach by determining that there was a quantifiable difference in glycosylation at the protein level between WT IAV HA from A/Switzerland/9715293/2013 (SWZ13) and a mutant strain of SWZ13, even though no N-glycosylation sequons were changed. We determined site-specifically that WT and mutant HA have varying similarity at the glycosylation sites of the head domain, reflecting competing pressures to evade host immune response while retaining viral fitness. To our knowledge, our results are the first to quantify changes in glycosylation state that occur in related proteins of considerable glycan heterogeneity. Our results provide a method for understanding how changes in glycosylation state are correlated with variations in protein sequence, which is necessary for improving IAV vaccine strain selection. Understanding glycosylation will be especially important as we find new expression vectors for vaccine production, as glycosylation state depends greatly on the host species.