The roles of SDHAF2 and dicarboxylate in covalent flavinylation of SDHA, the human complex II flavoprotein

Mitochondrial complex II, also known as succinate dehydrogenase (SDH), is an integral-membrane heterotetramer (SDHABCD) that links two essential energy-producing processes, the tricarboxylic acid (TCA) cycle and oxidative phosphorylation. A significant amount of information is available on the structure and function of mature complex II from a range of organisms. However, there is a gap in our understanding of how the enzyme assembles into a functional complex, and disease-associated complex II insufficiency may result from incorrect function of the mature enzyme or from assembly defects. Here, we investigate the assembly of human complex II by combining a biochemical reconstructionist approach with structural studies. We report an X-ray structure of human SDHA and its dedicated assembly factor SDHAF2. Importantly, we also identify a small molecule dicarboxylate that acts as an essential cofactor in this process and works in synergy with SDHAF2 to properly orient the flavin and capping domains of SDHA. This reorganizes the active site, which is located at the interface of these domains, and adjusts the pKaof SDHAR451so that covalent attachment of the flavin adenine dinucleotide (FAD) cofactor is supported. We analyze the impact of disease-associated SDHA mutations on assembly and identify four distinct conformational forms of the complex II flavoprotein that we assign to roles in assembly and catalysis.

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Structure and function study of the complex that synthesizesS-adenosylmethionine

IUCrJ ◽

10.1107/s2052252514012585 ◽

2014 ◽

Vol 1 (4) ◽

pp. 240-249 ◽

Cited By ~ 20

Author(s):

Ben Murray ◽

Svetlana V. Antonyuk ◽

Alberto Marina ◽

Sebastiaan M. Van Liempd ◽

Shelly C. Lu ◽

...

Keyword(s):

Complex Formation ◽

Structural Data ◽

Structure Based Drug Design ◽

X Ray ◽

X Ray Crystallography ◽

Methylation Of Dna ◽

Functional Complex ◽

Enzyme Subunits ◽

The Individual ◽

And Function

S-Adenosylmethionine (SAMe) is the principal methyl donor of the cell and is synthesizedviaan ATP-driven process by methionine adenosyltransferase (MAT) enzymes. It is tightly linked with cell proliferation in liver and colon cancer. In humans, there are three genes,mat1A, mat2Aandmat2B, which encode MAT enzymes.mat2Aandmat2Btranscribe MATα2 and MATβ enzyme subunits, respectively, with catalytic and regulatory roles. The MATα2β complex is expressed in nearly all tissues and is thought to be essential in providing the necessary SAMe flux for methylation of DNA and various proteins including histones. In human hepatocellular carcinomamat2Aandmat2Bgenes are upregulated, highlighting the importance of the MATα2β complex in liver disease. The individual subunits have been structurally characterized but the nature of the complex has remained elusive despite its existence having been postulated for more than 20 years and the observation that MATβ is often co-localized with MATα2. Though SAMe can be produced by MAT(α2)4alone, this paper shows that theVmaxof the MATα2β complex is three- to fourfold higher depending on the variants of MATβ that participate in complex formation. Using X-ray crystallography and solution X-ray scattering, the first structures are provided of this 258 kDa functional complex both in crystals and solution with an unexpected stoichiometry of 4α2 and 2βV2 subunits. It is demonstrated that the N-terminal regulates the activity of the complex and it is shown that complex formation takes place surprisinglyviathe C-terminal of MATβV2 that buries itself in a tunnel created at the interface of the MAT(α2)2. The structural data suggest a unique mechanism of regulation and provide a gateway for structure-based drug design in anticancer therapies.

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Surgery for Lung Cancer and the Consequences for the Swallow

Perspectives of the ASHA Special Interest Groups ◽

10.1044/persp1.sig13.162 ◽

2016 ◽

Vol 1 (13) ◽

pp. 162-168

Author(s):

Pippa Hales ◽

Corinne Mossey-Gaston

Keyword(s):

Lung Cancer ◽

Treatment Options ◽

Vocal Cord Palsy ◽

Subsequent Treatment ◽

Physiological Reserve ◽

Palliative Phase ◽

And Function ◽

The Impact ◽

Swallow Function

Lung cancer is one of the most commonly diagnosed cancers across Northern America and Europe. Treatment options offered are dependent on the type of cancer, the location of the tumor, the staging, and the overall health of the person. When surgery for lung cancer is offered, difficulty swallowing is a potential complication that can have several influencing factors. Surgical interaction with the recurrent laryngeal nerve (RLN) can lead to unilateral vocal cord palsy, altering swallow function and safety. Understanding whether the RLN has been preserved, damaged, or sacrificed is integral to understanding the effect on the swallow and the subsequent treatment options available. There is also the risk of post-surgical reduction of physiological reserve, which can reduce the strength and function of the swallow in addition to any surgery specific complications. As lung cancer has a limited prognosis, the clinician must also factor in the palliative phase, as this can further increase the burden of an already compromised swallow. By understanding the surgery and the implications this may have for the swallow, there is the potential to reduce the impact of post-surgical complications and so improve quality of life (QOL) for people with lung cancer.

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The Laryngeal Epithelium in Reflux

Perspectives on Voice and Voice Disorders ◽

10.1044/vvd21.3.112 ◽

2011 ◽

Vol 21 (3) ◽

pp. 112-117 ◽

Cited By ~ 2

Author(s):

Elizabeth Erickson-Levendoski ◽

Mahalakshmi Sivasankar

Keyword(s):

Laryngopharyngeal Reflux ◽

Critical Role ◽

Structure And Function ◽

Laryngeal Disease ◽

Health And Disease ◽

And Function ◽

The Impact

The epithelium plays a critical role in the maintenance of laryngeal health. This is evident in that laryngeal disease may result when the integrity of the epithelium is compromised by insults such as laryngopharyngeal reflux. In this article, we will review the structure and function of the laryngeal epithelium and summarize the impact of laryngopharyngeal reflux on the epithelium. Research investigating the ramifications of reflux on the epithelium has improved our understanding of laryngeal disease associated with laryngopharyngeal reflux. It further highlights the need for continued research on the laryngeal epithelium in health and disease.

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Crystal Structures of Fragments D and Double-D from Fibrinogen and Fibrin

Thrombosis and Haemostasis ◽

10.1055/s-0037-1615842 ◽

1999 ◽

Vol 82 (08) ◽

pp. 271-276 ◽

Cited By ~ 8

Author(s):

Glen Spraggon ◽

Stephen Everse ◽

Russell Doolittle

Keyword(s):

Electron Microscopy ◽

High Resolution ◽

Crystal Structures ◽

Structure And Function ◽

X Ray ◽

Long Period ◽

And Function

IntroductionAfter a long period of anticipation,1 the last two years have witnessed the first high-resolution x-ray structures of fragments from fibrinogen and fibrin.2-7 The results confirmed many aspects of fibrinogen structure and function that had previously been inferred from electron microscopy and biochemistry and revealed some unexpected features. Several matters have remained stubbornly unsettled, however, and much more work remains to be done. Here, we review several of the most significant findings that have accompanied the new x-ray structures and discuss some of the problems of the fibrinogen-fibrin conversion that remain unresolved. * Abbreviations: GPR—Gly-Pro-Arg-derivatives; GPRPam—Gly-Pro-Arg-Pro-amide; GHRPam—Gly-His-Arg-Pro-amide

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Investigating Burnt Mounds in Clydesdale during Motorway Construction

Glasgow Archaeological Journal ◽

10.3366/gas.1998.21.21.1 ◽

1998 ◽

Vol 21 (1) ◽

pp. 1-28

Author(s):

John A Atkinson ◽

Camilla Dickson ◽

Jane Downes ◽

Paul Robins ◽

David Sanderson

Keyword(s):

Bronze Age ◽

Research Strategy ◽

Archaeological Evidence ◽

Radiocarbon Dates ◽

Short Account ◽

And Function ◽

The Impact ◽

The Bronze Age

Summary Two small burnt mounds were excavated as part of the programme to mitigate the impact of motorway construction in the Crawford area. The excavations followed a research strategy designed to address questions of date and function. This paper surveys the various competing theories about burnt mounds and how the archaeological evidence was evaluated against those theories. Both sites produced radiocarbon dates from the Bronze Age and evidence to suggest that they were cooking places. In addition, a short account is presented of two further burnt mounds discovered during the construction of the motorway in Annandale.

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Analyzing the Impact of X-Ray Tomography on the Reliability of Integrated Circuits

ISTFA 2015: Conference Proceedings from the 41st International Symposium for Testing and Failure Analysis ◽

10.31399/asm.cp.istfa2015p0154 ◽

2015 ◽

Author(s):

Halit Dogan ◽

Md Mahbub Alam ◽

Navid Asadizanjani ◽

Sina Shahbazmohamadi ◽

Domenic Forte ◽

...

Keyword(s):

Integrated Circuits ◽

Integrated Circuit ◽

3D Imaging ◽

Three Dimensional ◽

Serial Sectioning ◽

Promising Technique ◽

Flash Memories ◽

X Ray ◽

3D Information ◽

The Impact

Abstract X-ray tomography is a promising technique that can provide micron level, internal structure, and three dimensional (3D) information of an integrated circuit (IC) component without the need for serial sectioning or decapsulation. This is especially useful for counterfeit IC detection as demonstrated by recent work. Although the components remain physically intact during tomography, the effect of radiation on the electrical functionality is not yet fully investigated. In this paper we analyze the impact of X-ray tomography on the reliability of ICs with different fabrication technologies. We perform a 3D imaging using an advanced X-ray machine on Intel flash memories, Macronix flash memories, Xilinx Spartan 3 and Spartan 6 FPGAs. Electrical functionalities are then tested in a systematic procedure after each round of tomography to estimate the impact of X-ray on Flash erase time, read margin, and program operation, and the frequencies of ring oscillators in the FPGAs. A major finding is that erase times for flash memories of older technology are significantly degraded when exposed to tomography, eventually resulting in failure. However, the flash and Xilinx FPGAs of newer technologies seem less sensitive to tomography, as only minor degradations are observed. Further, we did not identify permanent failures for any chips in the time needed to perform tomography for counterfeit detection (approximately 2 hours).

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Understanding Motivating Operations and the Impact on the Function of Behavior

Intervention in School and Clinic ◽

10.1177/1053451220914901 ◽

2020 ◽

Vol 56 (2) ◽

pp. 119-122

Author(s):

Doris Adams Hill ◽

Theoni Mantzoros ◽

Jonté C. Taylor

Keyword(s):

Behavioral Interventions ◽

Special Educators ◽

Motivating Operations ◽

Behavior Intervention Plans ◽

Education Professionals ◽

Functional Behavior ◽

Special Education Professionals ◽

And Function ◽

And Behavior ◽

The Impact

Special educators are often considered the experts in their school when it comes to developing functional behavior assessments (FBA) and behavior intervention plans (BIP), yet rarely are they trained much beyond basic antecedents, behaviors, and consequences (ABC). This column discusses concepts that will expand special education professionals’ knowledge to make better decisions regarding interventions for the students they serve. Specifically, the focus is on motivating operations (MO) and function-based interventions and the implications of these on behavior. Knowledge of the concept of MOs can enhance a teacher’s ability to provide evidence-based interventions and more fully developed behavioral interventions for students in their purview.

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Spring Freeze Damage of Pecan Bloom: A Review

Horticulturae ◽

10.3390/horticulturae6040082 ◽

2020 ◽

Vol 6 (4) ◽

pp. 82

Author(s):

Amandeep Kaur ◽

Louise Ferguson ◽

Niels Maness ◽

Becky Carroll ◽

William Reid ◽

...

Keyword(s):

Tree Height ◽

The United States ◽

Reproductive Organs ◽

Tree Age ◽

The Us ◽

Nut Production ◽

Freeze Damage ◽

Terminal Buds ◽

And Function ◽

The Impact

Pecan is native to the United States. The US is the world’s largest pecan producer with an average yearly production of 250 to 300 million pounds; 80 percent of the world’s supply. Georgia, New Mexico, Texas, Arizona, Oklahoma, California, Louisiana, and Florida are the major US pecan producing states. Pecan trees frequently suffer from spring freeze at bud break and bloom as the buds are quite sensitive to freeze damage. This leads to poor flower and nut production. This review focuses on the impact of spring freeze during bud differentiation and flower development. Spring freeze kills the primary terminal buds, the pecan tree has a second chance for growth and flowering through secondary buds. Unfortunately, secondary buds have less bloom potential than primary buds and nut yield is reduced. Spring freeze damage depends on severity of the freeze, bud growth stage, cultivar type and tree age, tree height and tree vigor. This review discusses the impact of temperature on structure and function of male and female reproductive organs. It also summarizes carbohydrate relations as another factor that may play an important role in spring growth and transition of primary and secondary buds to flowers.

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The role of point-of-care ultrasound in the diagnosis of pericardial effusion: a single academic center retrospective study

The Ultrasound Journal ◽

10.1186/s13089-021-00205-x ◽

2021 ◽

Vol 13 (1) ◽

Author(s):

Matthew G. Hanson ◽

Barry Chan

Keyword(s):

Pericardial Effusion ◽

Point Of Care ◽

Physical Exam ◽

Right Atrial ◽

Point Of Care Ultrasound ◽

X Ray ◽

Average Systolic Blood Pressure ◽

Time To Diagnosis ◽

Clinically Significant ◽

The Impact

Abstract Background Symptomatic pericardial effusion (PCE) presents with non-specific features and are often missed on the initial physical exam, chest X-ray (CXR), and electrocardiogram (ECG). In extreme cases, misdiagnosis can evolve into decompensated cardiac tamponade, a life-threatening obstructive shock. The purpose of this study is to evaluate the impact of point-of-care ultrasound (POCUS) on the diagnosis and therapeutic intervention of clinically significant PCE. Methods In a retrospective chart review, we looked at all patients between 2002 and 2018 at a major Canadian academic hospital who had a pericardiocentesis for clinically significant PCE. We extracted the rate of presenting complaints, physical exam findings, X-ray findings, ECG findings, time-to-diagnosis, and time-to-pericardiocentesis and how these were impacted by POCUS. Results The most common presenting symptom was dyspnea (64%) and the average systolic blood pressure (SBP) was 120 mmHg. 86% of people presenting had an effusion > 1 cm, and 89% were circumferential on departmental echocardiogram (ECHO) with 64% having evidence of right atrial systolic collapse and 58% with early diastolic right ventricular collapse. The average time-to-diagnosis with POCUS was 5.9 h compared to > 12 h with other imaging including departmental ECHO. Those who had the PCE identified by POCUS had an average time-to-pericardiocentesis of 28.1 h compared to > 48 h with other diagnostic modalities. Conclusion POCUS expedites the diagnosis of symptomatic PCE given its non-specific clinical findings which, in turn, may accelerate the time-to-intervention.

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The lung–gut axis during viral respiratory infections: the impact of gut dysbiosis on secondary disease outcomes

Mucosal Immunology ◽

10.1038/s41385-020-00361-8 ◽

2021 ◽

Author(s):

Valentin Sencio ◽

Marina Gomes Machado ◽

François Trottein

Keyword(s):

Gut Microbiota ◽

Bacterial Infections ◽

Respiratory Infections ◽

Critical Role ◽

Good Health ◽

Disease Outcomes ◽

And Function ◽

Viral Respiratory Infections ◽

The Impact ◽

Viral Respiratory

AbstractBacteria that colonize the human gastrointestinal tract are essential for good health. The gut microbiota has a critical role in pulmonary immunity and host’s defense against viral respiratory infections. The gut microbiota’s composition and function can be profoundly affected in many disease settings, including acute infections, and these changes can aggravate the severity of the disease. Here, we discuss mechanisms by which the gut microbiota arms the lung to control viral respiratory infections. We summarize the impact of viral respiratory infections on the gut microbiota and discuss the potential mechanisms leading to alterations of gut microbiota’s composition and functions. We also discuss the effects of gut microbial imbalance on disease outcomes, including gastrointestinal disorders and secondary bacterial infections. Lastly, we discuss the potential role of the lung–gut axis in coronavirus disease 2019.

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