scholarly journals Structural insights into proteolytic activation of the human Dispatched1 transporter for Hedgehog morphogen release

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Wanqiu Li ◽  
Linlin Wang ◽  
Bradley M. Wierbowski ◽  
Mo Lu ◽  
Feitong Dong ◽  
...  
Keyword(s):  
Small Molecule ◽  
Extracellular Domain ◽  
Proteolytic Cleavage ◽  
Proteolytic Activation ◽  
Atomic Structures ◽  
Cryo Electron Microscopy ◽  
Extracellular Release ◽  
Before And After ◽  
Structural Insights

AbstractThe membrane protein Dispatched (Disp), which belongs to the RND family of small molecule transporters, is essential for Hedgehog (Hh) signaling, by catalyzing the extracellular release of palmitate- and cholesterol-modified Hh ligands from producing cells. Disp function requires Furin-mediated proteolytic cleavage of its extracellular domain, but how this activates Disp remains obscure. Here, we employ cryo-electron microscopy to determine atomic structures of human Disp1 (hDisp1), before and after cleavage, and in complex with lipid-modified Sonic hedgehog (Shh) ligand. These structures, together with biochemical data, reveal that proteolytic cleavage opens the extracellular domain of hDisp1, removing steric hindrance to Shh binding. Structure-guided functional experiments demonstrate the role of hDisp1–Shh interactions in ligand release. Our results clarify the mechanisms of hDisp1 activation and Shh morphogen release, and highlight how a unique proteolytic cleavage event enabled acquisition of a protein substrate by a member of a family of small molecule transporters.

scholarly journals Cryo-EM structures of the TTYH family reveal a novel architecture for lipid interactions

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Anastasiia Sukalskaia ◽  
Monique S. Straub ◽  
Dawid Deneka ◽  
Marta Sawicka ◽  
Raimund Dutzler
Keyword(s):  
Anion Channel ◽  
Extracellular Domain ◽  
Cell Swelling ◽  
Anion Channels ◽  
Lipid Interactions ◽  
Transmembrane Segments ◽  
Cryo Electron Microscopy ◽  
The Brain ◽  
Eukaryotic Membrane Proteins

AbstractThe Tweety homologs (TTYHs) are members of a conserved family of eukaryotic membrane proteins that are abundant in the brain. The three human paralogs were assigned to function as anion channels that are either activated by Ca2+ or cell swelling. To uncover their unknown architecture and its relationship to function, we have determined the structures of human TTYH1–3 by cryo-electron microscopy. All structures display equivalent features of a dimeric membrane protein that contains five transmembrane segments and an extended extracellular domain. As none of the proteins shows attributes reminiscent of an anion channel, we revisited functional experiments and did not find any indication of ion conduction. Instead, we find density in an extended hydrophobic pocket contained in the extracellular domain that emerges from the lipid bilayer, which suggests a role of TTYH proteins in the interaction with lipid-like compounds residing in the membrane.

scholarly journals Structural insights into the mammalian late-stage initiation complexes

2019 ◽  
Author(s):  
Angelita Simonetti ◽  
Ewelina Guca ◽  
Anthony Bochler ◽  
Lauriane Kuhn ◽  
Yaser Hashem
Keyword(s):  
Late Stage ◽  
Ribosomal Proteins ◽  
Start Codon ◽  
Mrna Sequence ◽  
Initiation Factors ◽  
Eukaryotic Initiation Factors ◽  
Cryo Electron Microscopy ◽  
The Impact ◽  
Structural Insights

SUMMARYIn higher eukaryotes, the mRNA sequence in direct vicinity of the start codon, called the Kozak sequence (CRCCaugG, where R is a purine), is known to influence the rate of the initiation process. However, the molecular basis underlying its role remains poorly understood. Here, we present the cryo-electron microscopy (cryo-EM) structures of mammalian late-stage 48S initiation complexes (LS48S IC) in the presence of two different native mRNA sequences, β-globin and histone 4 (H4) at overall resolution of 3Å and 3.5Å, respectively. Our high-resolution structures unravel key interactions from the mRNA to eukaryotic initiation factors (eIF): 1A, 2, 3, 18S rRNA, and several 40S ribosomal proteins. In addition, we were able to study the structural role of ABCE1 in the formation of native 48S ICs. Our results reveal a comprehensive map of the ribosome/eIFs –mRNA and –tRNA interactions and suggest the impact of mRNA sequence on the structure of the LS48S IC.

Child and Adolescent Suicides in Bosnia and Herzegovina Before and After the War (1992–1995)

Crisis ◽  
2010 ◽  
Vol 31 (3) ◽  
pp. 160-164 ◽  
Author(s):  
Almir Fajkic ◽  
Orhan Lepara ◽  
Martin Voracek ◽  
Nestor D. Kapusta ◽  
Thomas Niederkrotenthaler ◽  
...  
Keyword(s):  
Bosnia And Herzegovina ◽  
Age Differences ◽  
Suicide Risk ◽  
Child And Adolescent ◽  
Youth Suicide ◽  
Southeastern Europe ◽  
Suicide Rates ◽  
Before And After ◽  
Sex And Age Differences

Background: Evidence on youth suicides from Southeastern Europe is scarce. We are not aware of previous reports from Bosnia and Herzegovina, which experienced war from 1992 to 1995. Durkheim’s theory of suicide predicts decreased suicide rates in wartime and increased rates afterward. Aims: To compare child and adolescent suicides in Bosnia and Herzegovina before and after the war. Methods: Data on youth suicide for prewar (1986–90) and postwar (2002–06) periods were analyzed with respect to prevalence, sex and age differences, and suicide methods. Suicide data from 1991 through 2001 were not available. Results: Overall youth suicide rates were one-third lower in the postwar than in the prewar period. This effect was most pronounced for girls, whose postwar suicide rates almost halved, and for 15–19-year-old boys, whose rates decreased by about a one-fourth. Suicides increased among boys aged 14 or younger. Firearm suicides almost doubled proportionally and were the predominant postwar method, while the most common prewar method had been hanging. Conclusions: The findings from this study indicate the need for public education in Bosnia and Herzegovina on the role of firearm accessibility in youth suicide and for instructions on safe storage in households. Moreover, raising societal awareness about suicide risk factors and suicide prevention is needed.

Strategic Role of Zakat in Multidimensional Quality of Life in Sijunjung, Indonesia

2018 ◽  
Vol 15 (1) ◽  
pp. 55-72
Author(s):  
Herlin Hamimi ◽  
Abdul Ghafar Ismail ◽  
Muhammad Hasbi Zaenal
Keyword(s):  
Quality Of Life ◽  
Positive Impact ◽  
Wealth Distribution ◽  
Absolute Poverty ◽  
Before And After ◽  
The Status ◽  
Being There ◽  
The Impact

Zakat is one of the five pillars of Islam which has a function of faith, social and economic functions. Muslims who can pay zakat are required to give at least 2.5 per cent of their wealth. The problem of poverty prevalent in disadvantaged regions because of the difficulty of access to information and communication led to a gap that is so high in wealth and resources. The instrument of zakat provides a paradigm in the achievement of equitable wealth distribution and healthy circulation. Zakat potentially offers a better life and improves the quality of human being. There is a human quality improvement not only in economic terms but also in spiritual terms such as improving religiousity. This study aims to examine the role of zakat to alleviate humanitarian issues in disadvantaged regions such as Sijunjung, one of zakat beneficiaries and impoverished areas in Indonesia. The researcher attempted a Cibest method to capture the impact of zakat beneficiaries before and after becoming a member of Zakat Community Development (ZCD) Program in material and spiritual value. The overall analysis shows that zakat has a positive impact on disadvantaged regions development and enhance the quality of life of the community. There is an improvement in the average of mustahik household incomes after becoming a member of ZCD Program. Cibest model demonstrates that material, spiritual, and absolute poverty index decreased by 10, 5, and 6 per cent. Meanwhile, the welfare index is increased by 21 per cent. These findings have significant implications for developing the quality of life in disadvantaged regions in Sijunjung. Therefore, zakat is one of the instruments to change the status of disadvantaged areas to be equivalent to other areas.

SUBLINGUAL VITAMIN D3 DRUG THERAPY IN VITAMIN D DEFICIENCY PATIENTS AT PRAVARA RURAL HOSPITAL

2019 ◽  
pp. 18-20
Author(s):  
Sanjeeva Kumar Goud T ◽  
Rahul Kunkulol
Keyword(s):  
Vitamin D ◽  
Vitamin D Deficiency ◽  
Vitamin D3 ◽  
Serum Vitamin ◽  
Cross Sectional ◽  
Serum Vitamin D ◽  
Significant Difference ◽  
Before And After

The present study was aimed to study the effect of Sublingual Vitamin D3 on Serum Vitamin D level in Vitamin D deficiency patients. This was a cross-sectional and interventional study. All the Vitamin D deficiency patients of age 18-60years and either gender, willing to participate in the study were included. Patients who had greater than 20 ng/ml were excluded from the study. The total number of participants in our study was 200, out of these 111 males and 89 females, the mean age in our study was 51.07 ± 7.39Yrs. All volunteers were given sublingual vitamin D3 (60,000IU) in six doses every fifteen days of follow up for 3 months. The subject’s serum 25(OH)D levels were estimated before and after the treatment of sublingual vitamin D3. There was a statistically significant difference in serum vitamin D3 level before 16.61±6.71 ng/ml and after 35.80±7.80 ng/ml after treatment with Sublingual Vitamin D3. Six doses of 60,000IU of Vitamin D3 sublingual route having improved the role of serum 25(OH)D levels in the treatment of Vitamin D3 deficiency patients.Keywords: Vitamin D3; Sublingual route

Arthroscopy in Arthrosis: Is It Worth it? A case Presentation

2018 ◽  
Vol 69 (8) ◽  
pp. 2232-2235
Author(s):  
Marius Moga ◽  
Mark Edward Pogarasteanu ◽  
Antoine Edu
Keyword(s):  
Clinical Status ◽  
Loose Body ◽  
Point Of View ◽  
The Other ◽  
Joint Range Of Motion ◽  
Objective Evidence ◽  
Before And After ◽  
Total Knee ◽  
Joint Range

The role of arthroscopy in incipient and mild arthrosis, even combined with proximal tibial ostetomy, is well known and well documented. On the other hand, its role in the treatment of advanced arthrosis of the large joints, especially the knee, is a subject of controversy. The proponents of the use of arthroscopy in advanced arthrosis claim that meniscectomy, synovectomy, ostophytectomy, chondral lesion stabilization, arthroscopic release, plica and loose body removal greatly improve the quality of life for most patients, especially if followed by the use of viscoelastic injection, by diminishing pain and improving joint range of motion. The opponents claim that, even though the advantages are clear in the cases that refuse arthroplasty, in all the other cases the surgical indication should be total knee arthroplasty, as the clinical relief is temporary, but with all the risks of a surgical intervention. We have conducted an overview of the recent literature, in order to find objective evidence to sustain either point of view. We focused on articles published that included an objective measurement of before and after clinical status through clinical scores and objective measurements. We also focused on the follow-up period and on the evolution of the pathology after arthroscopy.

Study of Possible Relation between Fasting Plasma Glucagon, Gestational Diabetes and Development of Type 2 DM

2020 ◽  
Vol 16 (2) ◽  
pp. 148-155 ◽  
Author(s):  
Ashraf Okba ◽  
Salwa Seddik Hosny ◽  
Alyaa Elsherbeny ◽  
Manal Mohsin Kamal
Keyword(s):  
Gestational Diabetes ◽  
Pregnant Women ◽  
Post Partum ◽  
Plasma Glucagon ◽  
Type 2 Dm ◽  
Fasting Plasma ◽  
Before And After ◽  
Two Phases

Background and Aims: Women who develop GDM (gestational diabetes mellitus) have a relative insulin secretion deficiency, the severity of which may be predictive for later development of diabetes. This study aimed to investigate the role of fasting plasma glucagon in the prediction of later development of diabetes in pregnant women with GDM. Materials and Methods: The study was conducted on 150 pregnant women with GDM after giving informed oral and written consents and being approved by the research ethical committee according to the declaration of Helsinki. The study was conducted in two phases, first phase during pregnancy and the second one was 6 months post-partum, as we measured fasting plasma glucagon before and after delivery together with fasting and 2 hour post-prandial plasma sugar. Results: Our findings suggested that glucagon levels significantly increased after delivery in the majority 14/25 (56%) of GDM women who developed type 2 DM within 6 months after delivery compared to 6/20 (30%) patients with impaired fasting plasma glucose (IFG) and only 22/105 (20%) non DM women, as the median glucagon levels were 80,76, 55, respectively. Also, there was a high statistical difference between fasting plasma glucagon post-delivery among diabetic and non-diabetic women (p ≤ 0.001). These results indicated the useful role of assessing fasting plasma glucagon before and after delivery in patients with GDM to predict the possibility of type 2 DM. Conclusion: There is a relatively high glucagon level in GDM patients, which is a significant pathogenic factor in the incidence of subsequent diabetes in women with a history of GDM. This could be important in the design of follow-up programs for women with previous GDM.

A Comparative Study of 1D Descriptors Supported CoMFA and CoMSIA QSAR Models to Gain Novel Insights into 1,2,4-Triazoles Acting As Antitubercular Agents

2020 ◽  
Vol 16 ◽  
Author(s):  
Rajdeep Ray ◽  
Gautham Shenoy ◽  
N V Ganesh Kumar Tummalapalli
Keyword(s):  
External Validation ◽  
Antitubercular Activity ◽  
New Drugs ◽  
Rational Approach ◽  
Antitubercular Drugs ◽  
Comfa Model ◽  
Qsar Models ◽  
Structural Insights ◽  
The Way

: Tuberculosis is one of the leading cause for deaths due to infectious disease worldwide. There is an urgent need for developing new drugs due to the rising incidents of drug resistance. Triazoles have previously been reported to show antitubercular activity. Various computational tools pave the way for a rational approach in understanding the structural importance of these compounds in inhibiting Mycobacterium tuberculosis growth. The aim of this study is to develop and compare two different QSAR models based on a set of previously reported molecules and use the best one for gaining structural insights in to the Triazole molecules. In the current study, two separate models were generated with CoMFA and CoMSIA descriptors respectively based on a dataset of triazole molecules showing antitubercular activity. Several one dimensional (1D) descriptors were added to each of the models and the validation results and the contour data generated from them were compared. The best model was studied to give a detailed understanding of the triazole molecules and their role in the antitubercular activity.The r2, q2, predicted r2 and SEP (Standard error of prediction) for the CoMFA model were 0.866, 0.573, 0.119 and 0.736 respectively and for the CoMSIA model the r2, q2, predicted r2 and SEP were calculated to be 0.998, 0.634, 0.013 and 0.869 respectively. Although both the QSAR models produced acceptable internal and external validation scores but the CoMSIA results were significantly better. The CoMSIA contours also provided a better match than CoMFA with most of the features of the active compound 30b. Hence, the CoMSIA model was chosen and its contours were explored for gaining structural insights on the triazole molecules. The CoMSIA contours helped us to understand the role of several atoms and groups of the triazole molecules in their biological activity. The possibilities for substitution in the triazole compounds that would enhance the activity were also analysed. Thus, this study paves the way for designing new antitubercular drugs in future.

Sleep Problems During the Preschool Years and Beyond as a Marker of Risk and Resilience in Substance Use

2018 ◽  
Author(s):  
Maria M. Wong
Keyword(s):  
Substance Use ◽  
Alcohol Use ◽  
Sleep Problems ◽  
Problem Drinking ◽  
Alcohol Problems ◽  
Risk And Resilience ◽  
Regulatory Processes ◽  
Sleep Physiology ◽  
Before And After

Individuals with alcohol problems have well-described disturbances of sleep, but the development of these disturbances both before and after the onset of problem drinking is poorly understood. This chapter first discusses sleep physiology and its measurement in humans. It then examines the functions of sleep and its role in development. Next, it reviews recent research on the relationship between sleep and alcohol use and related problems. Whereas sleep problems (e.g., difficulties falling or staying asleep) increase the risk of early onset of alcohol use and related problems, sleep rhythmicity promotes resilience to the development of alcohol use disorder and problem substance use. Based on existing research, this chapter proposes a theoretical model of sleep and alcohol use, highlighting the role of self-regulatory processes as mediators of this relationship.

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