Event Begins: Thursday, November 14, 2024 10:00am
Location: Off Campus Location
Organized By: Department of Molecular, Cellular, and Developmental Biology

Mentor: Daniel Klionsky
Check the MCDB Weekly update for the password.

Live stream Sinner vs. Medvedev in the 2024 ATP Finals online for free from anywhere in the world.

Es el tercer y último partido de Carlos Alcaraz en la fase de grupos Leer

Supera a Rublev por 6-3 y 7-6(8) en una demostración de seriedad y dependerá de sí mismo para estar en las semifinales del torneo Leer

Carlos Alcaraz opened his account at the ATP Finals on Wednesday with an entertaining 6-3, 7-6 (10/8) win over Andrey Rublev which boosted his hopes of reaching the semi-finals.

World No. 3 Alcaraz beat Rublev 6-3, 7-6 (10/8) to lift himself off the bottom of the John Newcombe Group.

The violence occurred at Bhatpara, the area adjoining Naihati Assembly where bypolls are being held on November 13, 2024

Spain's Carlos Alcaraz made light of feeling under the weather as he dispatched Russia's Andrey Rublev in impressive fashion to revive his ATP Finals hopes on Wednesday.

FitLine is proud to announce a new multi-year partnership with the world's top-tier men's tennis tour. The athletes will benefit from the FitLine products, with the brand being the new Official Sports Nutrition Partner and Official Energy Bar Partner of the ATP Tour.

“Hello. My name is Gregory Daniels. I’m twelve years old. I live at 3251 Spring Lake Drive, and I’ve been kidnapped!” Not exactly what you’d expect to hear when loading up a lofi beats YouTube channel. Then again, MatPat’s newest alternate reality game LoreFi isn’t only focused on creating a playlist of over eight hours […]

The post Unpacking MatPat’s New LoreFi ARG first appeared on ARGNet: Alternate Reality Gaming Network.

Defending champion Novak Djokovic pulls out of the ATP Finals because of injury, a move which sets the eight-man field for the event.

Britain's Cameron Norrie will contest his first ATP final since February 2023 after a straight-set victory over Corentin Moutet at the Moselle Open.

Jannik Sinner is looking to cap a superb year with a first ATP Finals triumph. Here's everything you need to know about the event - and pick your tip for the title.

Casper Ruud stuns an out-of-sorts Carlos Alcaraz at the ATP Finals, before Alexander Zverev beats Andrey Rublev.

1. Carlos Alcaraz - Andrey Rublev en direct: ATP Finals - Tennis  Eurosport FR
2. Carlos Alcaraz - Andrey Rublev, ATP Finals, Masters (Turin), Groupe John Newcombe, Mercredi 13 novembre 2024  L'Équipe
3. PRONOS PARIS RMC Le pari sûr d’Eric Salliot du 13 novembre – Tennis - Masters  RMC Sport
4. EN DIRECT - Alcaraz-Rublev : Alcaraz prend le premier set  Le Figaro
5. Pronostic Carlos Alcaraz - Andrey Rublev, ATP Finals  SportyTrader

Novak Djokovic won't defend his ATP Finals title after ruling himself out on Tuesday due to an unspecified injury.

U.S. Open finalist Taylor Fritz benefitted from a questionable serving decision by Daniil Medvedev and frustrated his opponent so much that the Russian broke his racket and was docked a point in a 6-4, 6-3 victory for the American in the opening match of the ATP Finals on Sunday.

U.S. Open finalist Taylor Fritz frustrated Daniil Medvedev to the point that the Russian smashed his racket and was docked a point in a 6-4, 6-3 victory for the American in the opening match of the ATP Finals on Sunday.

Daniil Medvedev was able to "block the noise" following a temper tantrum in his previous match and moved back into contention at the ATP Finals with a 6-2, 6-4 victory over Alex de Minaur on Tuesday.

Late in the second set of his victory over Taylor Fritz at the ATP Finals on Tuesday, Jannik Sinner used all the adulation in his home country to his advantage.

Minneapolis — Recently released guidance from the state of Minnesota details steps employers in the meatpacking industry should take to reduce worker exposure to COVID-19.

Davis, CA — U.S. counties that are home to beef-, pork- and poultry-processing plants experienced accelerated COVID-19 infection rates during the pandemic, according to a recent study led by a researcher at the University at California, Davis.

Washington — Legislation recently introduced in the House and Senate is aimed at improving working conditions and whistleblower protections in the meat and poultry processing industry.

Washington — A new Government Accountability Office report recommends OSHA look at “available actions” – including developing a standard on infectious disease – to help protect workers in the meat and poultry processing industries.

Washington — Two days after OSHA and the Centers for Disease Control and Prevention issued voluntary interim guidance aimed at preventing the spread of COVID-19 among workers in the meatpacking and poultry-processing industries, President Donald Trump invoked the Defense Production Act of 1950 and declared the facilities “critical infrastructure” in an Executive Order intended to keep meatpacking facilities open.

Washington — OSHA has expanded and updated its inspection guidance for animal processing and slaughtering.

The post Life and Death of the American Worker: The Immigrants Taking on America’s Largest Meatpacking Company was curated by information for practice.

Type VII secretion (T7S) systems, also referred to as ESAT-6 secretion (ESX) systems, are molecular machines that have gained great attention due to their implications in cell homeostasis and in host–pathogen interactions in mycobacteria. The latter include important human pathogens such as Mycobacterium tuberculosis (Mtb), the etiological cause of human tuberculosis, which constitutes a pandemic accounting for more than one million deaths every year. The ESX-5 system is exclusively found in slow-growing pathogenic mycobacteria, where it mediates the secretion of a large family of virulence factors: the PE and PPE proteins. The secretion driving force is provided by EccC5, a multidomain ATPase that operates using four globular cytosolic domains: an N-terminal domain of unknown function (EccC5DUF) and three FtsK/SpoIIIE ATPase domains. Recent structural and functional studies of ESX-3 and ESX-5 systems have revealed EccCDUF to be an ATPase-like fold domain with potential ATPase activity, the functionality of which is essential for secretion. Here, the crystal structure of the MtbEccC5DUF domain is reported at 2.05 Å resolution, which reveals a nucleotide-free structure with degenerated cis-acting and trans-acting elements involved in ATP binding and hydrolysis. This crystallographic study, together with a biophysical assessment of the interaction of MtbEccC5DUF with ATP/Mg2+, supports the absence of ATPase activity proposed for this domain. It is shown that this degeneration is also present in DUF domains from other ESX and ESX-like systems, which are likely to exhibit poor or null ATPase activity. Moreover, based on an in silico model of the N-terminal region of MtbEccC5DUF, it is hypothesized that MtbEccC5DUF is a degenerated ATPase domain that may have retained the ability to hexamerize. These observations draw attention to DUF domains as structural elements with potential implications in the opening and closure of the membrane pore during the secretion process via their involvement in inter-protomer interactions.

Glanbia Nutritionals, Chicago, introduced OptiATP, a new optimized form of Adenosine 5-Triphosphate that is stable in low pH/high acid and high heat ready-to-drink beverage processing environments.

En la fase de grupos el español se medirá al alemán, reciente ganador del Masters 1000 de París-Bercy, y a dos tenistas que atraviesan una mala racha Leer

Los mejores tenistas del año buscarán alzarse con el último título del año Leer

El tenista murciano afronta el debut en el torneo, con el que se cierra la temporada tenística, con la ilusión de alzarse por primera vez con el triunfo Leer

Cae en sólo dos sets con ciertos problemas respiratorios y para llegar a semifinales deberá ganar a Rublev y Zverev sin opción de fallo Leer

Tenía reservada una pista durante una hora y media, pero peloteó 10 minutos con un sparring y se sintió indispuesto. Este miércoles, a las 14.00 horas, se juega a todo o nada su continuidad ante Rublev Leer

Carlos Alcaraz se enfrenta este miércoles a Andrey Rublev en el que será el segundo partido del español en las ATP Finals 2024 Leer

Location: Electronic Resource- 

In some pictures featuring the award-winning actress as the American civil servant, Sarah is wearing a white top that she pairs with brown fat pantsuit.

The Association of Tennis Professionals [ATP] has approved a slot in their 2025 calendar for an ATP Challenger tour event to take place in Bermuda during the last week of March. A spokesperson said, “The event will be produced and executed by Same-Group Bermuda, LLC. Same-Group organizes sporting and arts events and also manages professional […]

Jannik Sinner hit the accelerator at the end of each set as he cruised past Taylor Fritz 6-4, 6-4 on Tuesday to close in on a semi-final spot at the ATP Finals in Turin.

Michael Dean
Jul 1, 2001; 42:1007-1017
Thematic Reviews

The bacterial enhancer-binding protein (bEBP) FlrC, controls motility and colonization of Vibrio cholerae by regulating the transcription of class-III flagellar genes in σ54-dependent manner. However, the mechanism by which FlrC regulates transcription is not fully elucidated. Although, most bEBPs require nucleotides to stimulate the oligomerization necessary for function, our previous study showed that the central domain of FlrC (FlrCC) forms heptamer in a nucleotide-independent manner. Furthermore, heptameric FlrCC binds ATP in “cis-mediated” style without any contribution from sensor I motif 285REDXXYR291 of the trans protomer. This atypical ATP binding raises the question of whether heptamerization of FlrC is solely required for transcription regulation, or if it is also critical for ATPase activity. ATPase assays and size exclusion chromatography of the trans-variants FlrCC-Y290A and FlrCC-R291A showed destabilization of heptameric assembly with concomitant abrogation of ATPase activity. Crystal structures showed that in the cis-variant FlrCC-R349A drastic shift of Walker A encroached ATP-binding site, whereas the site remained occupied by ADP in FlrCC-Y290A. We postulated that FlrCC heptamerizes through concentration-dependent cooperativity for maximal ATPase activity and upon heptamerization, packing of trans-acting Tyr290 against cis-acting Arg349 compels Arg349 to maintain proper conformation of Walker A. Finally, a Trp quenching study revealed binding of cyclic-di-GMP with FlrCC. Excess cyclic-di-GMP repressed ATPase activity of FlrCC through destabilization of heptameric assembly, especially at low concentration of protein. Systematic phylogenetic analysis allowed us to propose similar regulatory mechanisms for FlrCs of several Vibrio species and a set of monotrichous Gram-negative bacteria.

Yadong Yu
Dec 1, 2020; 19:1997-2014
Research

Martin Prescher
Dec 1, 2020; 61:1605-1616
Research Articles

ABCB4/MDR3 is located in the canalicular membrane of hepatocytes and translocates PC-lipids from the cytoplasmic to the extracellular leaflet. ABCB4 is an ATP-dependent transporter that reduces the harsh detergent effect of the bile salts by counteracting self-digestion. To do so, ABCB4 provides PC lipids for extraction into bile. PC lipids account for 40% of the entire pool of lipids in the canalicular membrane with an unknown distribution over both leaflets. Extracted PC lipids end up in so-called mixed micelles. Mixed micelles are composed of phospholipids, bile salts, and cholesterol. Ninety to ninety-five percent of the phospholipids are members of the PC family, but only a subset of mainly 16.0-18:1 PC and 16:0-18:2 PC variants are present. To elucidate whether ABCB4 is the key discriminator in this enrichment of specific PC lipids, we used in vitro studies to identify crucial determinants in substrate selection. We demonstrate that PC-lipid moieties alone are insufficient for stimulating ABCB4 ATPase activity, and that at least two acyl chains and the backbone itself are required for a productive interaction. The nature of the fatty acids, like length or saturation has a quantitative impact on the ATPase activity. Our data demonstrate a two-step enrichment and protective function of ABCB4 to mitigate the harsh detergent effect of the bile salts, because ABCB4 can translocate more than just the PC-lipid variants found in bile.

The plasma membrane of a cell is characterized by an asymmetric distribution of lipid species across the exofacial and cytofacial aspects of the bilayer. Regulation of membrane asymmetry is a fundamental characteristic of membrane biology and is crucial for signal transduction, vesicle transport, and cell division. The type IV family of P-ATPases, or P4-ATPases, establishes membrane asymmetry by selection and transfer of a subset of membrane lipids from the lumenal or exofacial leaflet to the cytofacial aspect of the bilayer. It is unclear how P4-ATPases sort through the spectrum of membrane lipids to identify their desired substrate(s) and how the membrane environment modulates this activity. Therefore, we tested how the yeast plasma membrane P4-ATPase, Dnf2, responds to changes in membrane composition induced by perturbation of endogenous lipid biosynthetic pathways or exogenous application of lipid. The primary substrates of Dnf2 are glucosylceramide (GlcCer) and phosphatidylcholine (PC, or their lyso-lipid derivatives), and we find that these substrates compete with each other for transport. Acutely inhibiting sphingolipid synthesis using myriocin attenuates transport of exogenously applied GlcCer without perturbing PC transport. Deletion of genes controlling later steps of glycosphingolipid production also perturb GlcCer transport to a greater extent than PC transport. In contrast, perturbation of ergosterol biosynthesis reduces PC and GlcCer transport equivalently. Surprisingly, application of lipids that are poor transport substrates differentially affects PC and GlcCer transport by Dnf2, thus altering substrate preference. Our data indicate that Dnf2 exhibits exquisite sensitivity to the membrane composition, thus providing feedback onto the function of the P4-ATPases.

The EGFR tyrosine kinase inhibitor gefitinib is commonly used for lung cancer patients. However, some patients eventually become resistant to gefitinib and develop progressive disease. Here, we indicate that ecto-ATP synthase, which ectopically translocated from mitochondrial inner membrane to plasma membrane, is considered as a potential therapeutic target for drug-resistant cells. Quantitative multi-omics profiling reveals that ecto-ATP synthase inhibitor mediates CK2-dependent phosphorylation of DNA topoisomerase IIα (topo IIα) at serine 1106 and subsequently increases the expression of long noncoding RNA, GAS5. Additionally, we also determine that downstream of GAS5, p53 pathway, is activated by ecto-ATP synthase inhibitor for regulation of programed cell death. Interestingly, GAS5-proteins interactomic profiling elucidates that GAS5 associates with topo IIα and subsequently enhancing the phosphorylation level of topo IIα. Taken together, our findings suggest that ecto-ATP synthase blockade is an effective therapeutic strategy via regulation of CK2/phospho-topo IIα/GAS5 network in gefitinib-resistant lung cancer cells.

AAA+ ATPases constitute a large family of proteins that are involved in a plethora of cellular processes including DNA disassembly, protein degradation and protein complex disassembly. They typically form a hexametric ring-shaped structure with six subunits in a (pseudo) 6-fold symmetry. In a subset of AAA+ ATPases that facilitate protein unfolding and degradation, six subunits cooperate to translocate protein substrates through a central pore in the ring. The number and type of nucleotides in an AAA+ ATPase hexamer is inherently linked to the mechanism that underlies cooperation among subunits and couples ATP hydrolysis with substrate translocation. We conducted a native MS study of a monodispersed form of PAN, an archaeal proteasome AAA+ ATPase, to determine the number of nucleotides bound to each hexamer of the WT protein. We utilized ADP and its analogs (TNP-ADP and mant-ADP), and a nonhydrolyzable ATP analog (AMP-PNP) to study nucleotide site occupancy within the PAN hexamer in ADP- and ATP-binding states, respectively. Throughout all experiments we used a Walker A mutant (PAN^K217A) that is impaired in nucleotide binding as an internal standard to mitigate the effects of residual solvation on mass measurement accuracy and to serve as a reference protein to control for nonspecific nucleotide binding. This approach led to the unambiguous finding that a WT PAN hexamer carried – from expression host – six tightly bound ADP molecules that could be exchanged for ADP and ATP analogs. Although the Walker A mutant did not bind ADP analogs, it did bind AMP-PNP, albeit at multiple stoichiometries. We observed variable levels of hexamer dissociation and an appearance of multimeric species with the over-charged molecular ion distributions across repeated experiments. We posit that these phenomena originated during ESI process at the final stages of ESI droplet evolution.

Xinying Guo
Oct 23, 2024; 44:e0727242024-e0727242024
Cellular

Perivascular mural cells including vascular smooth cells (VSMCs) and pericytes are integral components of the vascular system. In the central nervous system (CNS), pericytes are also indispensable for the blood–brain barrier (BBB), blood–spinal cord barrier, and blood–retinal barrier and play key roles in maintaining cerebrovascular and neuronal functions. However, the functional specifications of pericytes between CNS and peripheral organs have not been resolved at the genetic and molecular levels. Hence, the generation of reliable CNS pericyte-specific models and genetic tools remains very challenging. Here, we report a new CNS pericyte marker in mice. This putative cation-transporting ATPase 13A5 (Atp13a5) marker was identified through single-cell transcriptomics, based on its specificity to brain pericytes. We further generated a knock-in model with both tdTomato reporter and Cre recombinase. Using this model to trace the distribution of Atp13a5-positive pericytes in mice, we found that the tdTomato reporter reliably labels the CNS pericytes, including the ones in spinal cord and retina but not peripheral organs. Interestingly, brain pericytes are likely shaped by the developing neural environment, as Atp13a5-positive pericytes start to appear around murine embryonic day 15 (E15) and expand along the cerebrovasculature. Thus, Atp13a5 is a specific marker of CNS pericyte lineage, and this Atp13a5-based model is a reliable tool to explore the heterogeneity of pericytes and BBB functions in health and diseases.