Protection of the Telomeric Junction by the Shelterin Complex.

Shelterin serves critical roles in suppressing superfluous DNA damage repair pathways on telomeres. The junction between double-stranded telomeric tracts (dsTEL) and single-stranded telomeric overhang (ssTEL) is the most accessible region of the telomeric DNA. The shelterin complex contains dsTEL and ssTEL binding proteins and can protect this junction by bridging between the ssTEL and dsTEL tracts. To test this possibility, we monitored shelterin binding to telomeric DNA substrates with varying ssTEL and dsTEL lengths and quantified its impact on telomere accessibility using single-molecule fluorescence microscopy methods in vitro. We identified the first dsTEL repeat nearest to the junction as the preferred binding site for creating the shelterin bridge. Shelterin requires at least two ssTEL repeats while the POT1 subunit of shelterin that binds to ssTEL requires longer ssTEL tracts for stable binding to telomeres and effective protection of the junction region. The ability of POT1 to protect the junction is significantly enhanced by the 5'-phosphate at the junction. Collectively, our results show that shelterin enhances the binding stability of POT1 to ssTEL and provides more effective protection compared to POT1 alone by bridging single- and double-stranded telomeric tracts.

The Prognostic Effect of Air Pollution in Patients Presenting to the Emergency Department with Carbon Monoxide Poisoning.

OBJECTIVE: Weather conditions such as low air temperatures, low barometric pressure, and low wind speed have been linked to more cases of carbon monoxide (CO) poisoning. However, limited literature exists regarding the impact of air pollution. This study aims to investigate the relationship between outdoor air pollution and CO poisoning in 2 distinct cities in Turkey. METHODS: A prospective study was conducted at 2 tertiary hospitals, recording demographic data, presenting complaints, vital signs, blood gas and laboratory parameters, carboxyhemoglobin (COHb) levels, meteorological parameters, and pollutant parameters. Complications and outcomes were also documented. RESULTS: The study included 83 patients (Group 1 = 44, Group 2 = 39). The air quality index (AQI) in Group 2 (61.7 ± 27.7) (moderate AQI) was statistically significantly higher (dirtier AQI) than that in Group 1 (47.3 ± 26.4) (good AQI) (P = 0.018). The AQI was identified as an independent predictor for forecasting the need for hospitalization (OR = 1.192, 95% CI: 1.036 - 1.372, P = 0.014) and predicting the risk of developing cardiac complications (OR: 1.060, 95% CI: 1.017 - 1.104, P = 0.005). CONCLUSIONS: The AQI, derived from the calculation of 6 primary air pollutants, can effectively predict the likelihood of hospitalization and cardiac involvement in patients presenting to the emergency department with CO poisoning.

Protection of the Telomeric Junction by the Shelterin Complex.

Shelterin serves critical roles in suppressing superfluous DNA damage repair pathways on telomeres. The junction between double-stranded telomeric tracts (dsTEL) and single-stranded telomeric overhang (ssTEL) is the most accessible region of the telomeric DNA. The shelterin complex contains dsTEL and ssTEL binding proteins and can protect this junction by bridging the ssTEL and dsTEL tracts. To test this possibility, we monitored shelterin binding to telomeric DNA substrates with varying ssTEL and dsTEL lengths and quantified its impact on telomere accessibility using single-molecule fluorescence microscopy methods in vitro. We identified the first dsTEL repeat nearest the junction as the preferred binding site for creating the shelterin bridge. Shelterin requires at least two ssTEL repeats, while the POT1 subunit of shelterin that binds to ssTEL requires longer ssTEL tracts for stable binding to telomeres and effective protection of the junction region. The ability of POT1 to protect the junction is significantly enhanced by the 5'-phosphate at the junction. Collectively, our results show that shelterin enhances the binding stability of POT1 to ssTEL and provides more effective protection compared with POT1 alone by bridging single- and double-stranded telomeric tracts.

Stepping dynamics of dynein characterized by MINFLUX.

Cytoplasmic dynein is a dimeric motor that drives minus-end directed transport on microtubules (MTs). To couple ATP hydrolysis to a mechanical step, a dynein monomer must be released from the MT before undergoing a conformational change that generates a bias towards the minus end. However, the dynamics of dynein stepping have been poorly characterized by tracking flexible regions of the motor with limited resolution. Here, we developed a cysteine-light mutant of yeast dynein and site-specifically labeled its MT-binding domain in vitro. MINFLUX tracking at sub-millisecond resolution revealed that dynein hydrolyzes one ATP per step and takes multitudes of 8 nm steps at physiological ATP. Steps are preceded by the transient movement towards the plus end. We propose that these backward "dips" correspond to MT release and subsequent diffusion of the stepping monomer around its MT-bound partner before taking a minus-end-directed conformational change of its linker. Our results reveal the order of sub-millisecond events that result in a productive step of dynein.

A force-sensitive mutation reveals a non-canonical role for dynein in anaphase progression.

The diverse roles of the dynein motor in shaping microtubule networks and cargo transport complicate in vivo analysis of its functions significantly. To address this issue, we have generated a series of missense mutations in Drosophila Dynein heavy chain. We show that mutations associated with human neurological disease cause a range of defects, including impaired cargo trafficking in neurons. We also describe a novel microtubule-binding domain mutation that specifically blocks the metaphase-anaphase transition during mitosis in the embryo. This effect is independent from dynein's canonical role in silencing the spindle assembly checkpoint. Optical trapping of purified dynein complexes reveals that this mutation only compromises motor performance under load, a finding rationalized by the results of all-atom molecular dynamics simulations. We propose that dynein has a novel function in anaphase progression that depends on it operating in a specific load regime. More broadly, our work illustrates how in vivo functions of motors can be dissected by manipulating their mechanical properties.

Torques within and outside the human spindle balance twist at anaphase.

At each cell division, nanometer-scale motors and microtubules give rise to the micron-scale spindle. Many mitotic motors step helically around microtubules in vitro, and most are predicted to twist the spindle in a left-handed direction. However, the human spindle exhibits only slight global twist, raising the question of how these molecular torques are balanced. Here, we find that anaphase spindles in the epithelial cell line MCF10A have a high baseline twist, and we identify factors that both increase and decrease this twist. The midzone motors KIF4A and MKLP1 are together required for left-handed twist at anaphase, and we show that KIF4A generates left-handed torque in vitro. The actin cytoskeleton also contributes to left-handed twist, but dynein and its cortical recruitment factor LGN counteract it. Together, our work demonstrates that force generators regulate twist in opposite directions from both within and outside the spindle, preventing strong spindle twist during chromosome segregation.

Molecular interplay between HURP and Kif18A in mitotic spindle regulation.

During mitosis, microtubule dynamics are regulated to ensure proper alignment and segregation of chromosomes. The dynamics of kinetochore-attached microtubules are regulated by hepatoma-upregulated protein (HURP) and the mitotic kinesin-8 Kif18A, but the underlying mechanism remains elusive. Using single-molecule imaging in vitro, we demonstrate that Kif18A motility is regulated by HURP. While sparse decoration of HURP activates the motor, higher concentrations hinder processive motility. To shed light on this behavior, we determined the binding mode of HURP to microtubules using Cryo-EM. The structure reveals that one HURP motif spans laterally across ß-tubulin, while a second motif binds between adjacent protofilaments. HURP partially overlaps with the microtubule-binding site of the Kif18A motor domain, indicating that excess HURP inhibits Kif18A motility by steric exclusion. We also observed that HURP and Kif18A function together to suppress dynamics of the microtubule plus-end, providing a mechanistic basis for how they collectively serve in spindle length control.

Comparison of stress, anxiety and depression levels of health, education and security sector employees: The effect of psychological resilience.

This study compared the stress, anxiety and depression levels in employees working in the health, education and security sectors. The study also investigated the effect of psychological resilience on stress, anxiety, and depression levels and whether the stress, anxiety, depression and psychological resilience levels of employees differ according to occupational and demographic variables. In this cross-sectional study, 1222 employees participated, comprising 50.8% from the health sector, 37.7% from education, and 11.5% from security. Data were collected using the Stress, Anxiety, and Depression Scale-21 and the Brief Resilience Scale. The study revealed varying rates of severe stress (49.1%), anxiety (74.0%), and depression (53.2%) among participants. Health employees experienced higher stress (52.1%), anxiety (77.0%), and depression (58%) rates compared to those in education (46.4%, 72.4%, and 48.4%) and security sectors (44.3%, 66.4%, and 48.5%). Health employees exhibited higher stress, anxiety, and depression levels, signifying a significant difference. Furthermore, the research identified psychological resilience as a crucial predictor of stress, anxiety, and depression. Additionally, these mental health issues were more prevalent among younger individuals with less work experience, females, private sector employees, singles, and those without children. The findings of the study showed that the level of stress, anxiety and depression was high in employees working in all three sectors (health, education and security), but mental problems were more common in health employees. The fact that psychological resilience is a significant predictor of stress, anxiety and depression levels indicates that this factor should be taken into account.

Production and oxidative stress responses in a cage designed for creep-feeding lambs.

This research aims to assess the production and oxidative stress reactions of lambs fed in a specially designed cage for creep feeding. For this purpose, the Akkaraman lambs (n = 60) were separated into four groups (15 individuals by two sexes and two groups), and all were fed the same ration. On the days that all the data was collected, the lambs were precisely 20, 34, 48, and 62 days old. The study included collecting data on body weights, body measures, and saliva samples from lambs. When the change in body weight was investigated, the results indicated that the differences between caged creep and control feeding groups (P = 0.343) and among the groupings concerning gender (P = 0.735) were insignificant. The importance levels of change differences in body measurements based on feeding methods and gender are withers height: P = 0.003, P = 0.198; body length: P < 0.001, P = 0.394; pectoral chest width: P = 0.030, P = 0.906; chest depth: P < 0.001, P = 0.741; chest circumference: P = 0.093, P = 0.529; back length: P = 0.221, P = 0.935; head length: P = 0.004, P = 0.072 and head width: P = 0.112, P = 0.617 calculated. The study's saliva samples, the effects were examined, and significant differences in Malondialdehyde (P = 0.014), superoxide dismutase (P = 0.029), catalase (P < 0.001), and glutathione s-transferase (P = 0.001) were discovered between control feeding and caged creep feeding methods. In ischemia-modified albumin (P > 0.05), the difference between the groups was insignificant. According to these findings, caged creep feeding systems are preferable for achieving faster growth rates in Akkaraman lambs; however, caged creep feeding techniques in bigger areas with longer periods are considered better for welfare conditions.

Receptor for advanced glycation end products polymorphisms in coronary artery ectasia.

BACKGROUND: Although the implication of receptor of advanced glycation endproducts (RAGE) has been reported in coronary artery disease, its roles in coronary artery ectasia (CAE) have remained undetermined. Furthermore, the effect of RAGE polymorfisms were not well-defined in scope of soluble RAGE (sRAGE) levels. Thus, we aimed to investigate the influence of the functional polymorphisms of RAGE -374T > A (rs1800624) and G82S (rs2070600) in CAE development. METHODS: This prospective observational study was conducted in 2 groups selected of 2452 patients who underwent elective coronary angiography (CAG) for evaluation after positive noninvasive heart tests. Group-I included 98 patients with non-obstructive coronary artery disease and CAE, and Group-II (control) included 100 patients with normal coronary arteries. SNPs were genotyped by real-time PCR using Taqman® genotyping assay. Serum sRAGE and soluble lectin-like oxidized receptor-1 (sOLR1) were assayed by ELISA and serum lipids were measured enzymatically. RESULTS: The frequencies of the RAGE -374A allele and -374AA genotype were significantly higher in CAE patients compared to controls (p < 0.001). sRAGE levels were not different between study groups, while sOLR1 levels were elevated in CAE (p = 0.004). In controls without systemic disease, -374A allele was associated with low sRAGE levels (p < 0.05), but this association was not significant in controls with HT. Similarly, sRAGE levels of CAE patients with both HT and T2DM were higher than those no systemic disease (p = 0.02). The -374A allele was also associated with younger patient age and higher platelet count in the CAE group in both total and subgroup analyses. In the correlation analyses, the -374A allele was also negatively correlated with age and positively correlated with Plt in all of these CAE groups. In the total CAE group, sRAGE levels also showed a positive correlation with age and a negative correlation with HDL-cholesterol levels. On the other hand, a negative correlation was observed between sRAGE and Plt in the total, hypertensive and no systemic disease control subgroups. Multivariate logistic regression analysis confirmed that the -374A allele (p < 0.001), hyperlipidemia (p < 0.05), and high sOLR1 level (p < 0.05) are risk factors for CAE. ROC curve analysis shows that RAGE -374A allele has AUC of 0.713 (sensitivity: 83.7 %, specificity: 59.0 %), which is higher than HLD (sensitivity: 59.2 %, specificity: 69.0 %), HT (sensitivity: 62.4 %, specificity: 61.1 %) and high sOLR1 level (≥0.67 ng/ml)) (sensitivity: 59.8 %, specificity: 58.5 %). CONCLUSION: Beside the demonstration of the relationship between -374A allele and increased risk of CAE for the first time, our results indicate that antihypertensive and antidiabetic treatment in CAE patients causes an increase in sRAGE levels. The lack of an association between the expected -374A allele and low sRAGE levels in total CAE group was attributed to the high proportion of hypertensive patients and hence to antihypertensive treatment. Moreover, the RAGE -374A allele is associated with younger age at CAE and higher Plt, suggesting that -374A may also be associated with platelet activation, which plays a role in the pathogenesis of CAE. However, our data need to be confirmed in a large study for definitive conclusions.

Molecular interplay between HURP and Kif18A in mitotic spindle regulation.

During mitosis, microtubule dynamics are regulated to ensure proper alignment and segregation of chromosomes. The dynamics of kinetochore-attached microtubules are regulated by hepatoma-upregulated protein (HURP) and the mitotic kinesin-8 Kif18A, but the underlying mechanism remains elusive. Using single-molecule imaging in vitro , we demonstrate that Kif18A motility is regulated by HURP. While sparse decoration of HURP activates the motor, higher concentrations hinder processive motility. To shed light on this behavior, we determined the binding mode of HURP to microtubules using Cryo-EM. The structure reveals that one HURP motif spans laterally across ß-tubulin, while a second motif binds between adjacent protofilaments. HURP partially overlaps with the microtubule-binding site of the Kif18A motor domain, indicating that excess HURP inhibits Kif18A motility by steric exclusion. We also observed that HURP and Kif18A function together to suppress dynamics of the microtubule plus-end, providing a mechanistic basis for how they collectively serve in spindle length control.

Endothelin-converting Enzyme-1b Genetic Variants Increase the Risk of Coronary Artery Ectasia.

Coronary artery ectasia (CAE), defined as a 1.5-fold or greater enlargement of a coronary artery segment compared to the adjacent normal coronary artery, is frequently associated with atherosclerotic coronary artery disease (CAD). Membrane-bound endothelin converting enzyme-1 (ECE-1) is involved in the maturation process of the most potent vasoconstrictor ET-1. Polymorphisms in the endothelin (ET) gene family have been shown associated with the development of atherosclerosis. This study aims to investigate the effects of rs213045 and rs2038089 polymorphisms in the ECE-1 gene which have been previously shown to be associated with atherosclerosis and hypertension (HT), in CAE patients. Ninety-six CAE and 175 patients with normal coronary arteries were included in the study. ECE-1b gene variations rs213045 and rs2038089 were determined by real-time PCR. The frequencies of rs213045 C > A (C338A) CC genotype (60.4% vs. 35.4%, p < 0.001) and rs2038089 T > C T allele (64.58% vs. 35.42%, p = 0.017) were higher in the CAE group compared to the control group. The multivariate regression analysis showed that the ECE-1b rs213045 CC genotype (p = 0.001), rs2038089 T allele (p = 0.017), and hypercholesterolemia (HC) (p = 0.001) are risk factors for CAE. Moreover, in nondiabetic individuals of the CAE and control groups, it was observed that the rs213045 CC genotype (p < 0.001), and rs2038089 T allele (p = 0.003) were a risk factor for CAE, but this relationship was not found in the diabetic subgroups of the study groups (p > 0.05). These results show that ECE-1b polymorphisms may be associated with the risk of CAE and this relationship may change according to the presence of type II diabetes.

The mechanism and energetics of the dynein priming stroke.

Dyneins are an AAA+ motor responsible for motility and force generation toward the minus end of microtubules. Dynein motility is powered by nucleotide-dependent transitions of its linker domain, which transitions between straight (post-powerstroke) and bent (pre-powerstroke) conformations. To understand the dynamics and energetics of the linker, we performed all-atom molecular dynamics simulations of human dynein-2 primed for its power stroke. Simulations revealed that the linker can adopt either a bent conformation or a semi-bent conformation, separated by a 5.7 kT energy barrier. The linker cannot switch back to its straight conformation in the pre-powerstroke state due to a steric clash with the AAA+ ring. Simulations also showed that an isolated linker has a free energy minimum near the semi-bent conformation in the absence of the AAA+ ring, indicating that the linker stores energy as it bends and releases this energy during the powerstroke.

Unusual effects of PCSK9 E670G (rs505151) variation in patients with in-stent restenosis: Variable effects on restenosis risk according to concomitant chronic conditions.

Recent reports showing that neo-atherosclerosis formation in stented coronary artery is characterized by the accumulation of lipid-laden macrophages within the neointima has strengthened the possibility that elevated low-density lipoprotein (LDL)-cholesterol may be a risk factor for in-stent restenosis (ISR). Protein Convertase Subtilisin/Kexin-9 (PCSK9) protein plays an important role in cholesterol metabolism by degrading of LDL receptors. The gain-of-function E670G (rs505151) mutation of the PCSK9 gene is a well-known genetic risk factor for hypercholesterolemia. This study evaluated for the first time the association of the E670G variation with the serum lipids, PCSK9 levels and concomitant diseases on the ISR risk. The study included 109 ISR, and 82 Non-ISR patients, based on the results of coronary angiography. Genotypes were determined using the real-time PCR and serum PCSK9 levels were measured by ELISA technique. The rare G allele of PCSK9 E670G (p < 0.05), hyperlipidemia (HL) (p < 0.001), and type 2 diabetes (T2DM) (p < 0.01) were associated with increased risk for ISR. In hyperlipidemic conditions, the E670G-G allele was associated with hypercholesterolemia and a higher risk of ISR (p < 0.001), while the E670G-AA genotype has been associated with a high prevalence of T2DM and hypertension. In addition, diabetic ISRs had higher serum PCSK9 levels (p < 0.05) and the E670G-AA genotype was associated with increased levels of diabetes markers. Our results indicated that the unusual effects of both G allele and AA genotype of the PCSK9 E670G variation may be involved in the risk of ISR in association with concomitant metabolic diseases.

This study evaluated the association of the Protein Convertase Subtilisin/Kexin-9 (PCSK9) E670G mutation with the serum lipids, PCSK9 levels and concomitant diseases on the in-stent restenosis (ISR) risk. The E670G-G allele, hyperlipidemia, and type 2 diabetes (T2DM) were found risk factors for ISR. In hyperlipidemic conditions, the E670G-G allele was associated with hypercholesterolemia and a higher risk of ISR, while the E670G-AA genotype has been associated with a high prevalence of T2DM and hypertension. Our results indicated that the unusual effects of both genotypes of the E670G that may be involved in the ISR risk in association with concomitant diseases.

Lis1 slows force-induced detachment of cytoplasmic dynein from microtubules.

Lis1 is a key cofactor for the assembly of active cytoplasmic dynein complexes that transport cargo along microtubules. Lis1 binds to the AAA+ ring and stalk of dynein and slows dynein motility, but the underlying mechanism has remained unclear. Using single-molecule imaging and optical trapping assays, we investigated how Lis1 binding affects the motility and force generation of yeast dynein in vitro. We showed that Lis1 slows motility by binding to the AAA+ ring of dynein, not by serving as a roadblock or tethering dynein to microtubules. Lis1 binding also does not affect force generation, but it induces prolonged stalls and reduces the asymmetry in the force-induced detachment of dynein from microtubules. The mutagenesis of the Lis1-binding sites on the dynein stalk partially recovers this asymmetry but does not restore dynein velocity. These results suggest that Lis1-stalk interaction slows the detachment of dynein from microtubules by interfering with the stalk sliding mechanism.

Dyneins.

Dyneins are a family of motor proteins that carry out motility and force generation functions towards the minus end of microtubule filaments. Cytoplasmic dynein (dynein-1) is responsible for transporting intracellular cargos in the retrograde direction in the cytoplasm, anchoring several organelles to the microtubule network, driving nuclear migration in developing neurons, and orienting the mitotic spindle in dividing cells. All other dyneins are localized to cilia. Similar to dynein-1, dynein-2 walks along microtubules and drives intraflagellar transport in the retrograde direction. Other ciliary dyneins are positioned between adjacent microtubule doublets of the axoneme and power ciliary beating by sliding microtubules relative to each other. In this primer, we first highlight the structure, mechanism, and regulation of dynein-1, which is the best-characterized member of the dynein motor family, and then describe the unique features and cellular roles of other dyneins. We also discuss accessory proteins that regulate the activation and motility of dynein motors in different cellular contexts.

Nde1 promotes Lis1-mediated activation of dynein.

Cytoplasmic dynein drives the motility and force generation functions towards the microtubule minus end. The assembly of dynein with dynactin and a cargo adaptor in an active transport complex is facilitated by Lis1 and Nde1/Ndel1. Recent studies proposed that Lis1 relieves dynein from its autoinhibited conformation, but the physiological function of Nde1/Ndel1 remains elusive. Here, we investigate how human Nde1 and Lis1 regulate the assembly and subsequent motility of mammalian dynein using in vitro reconstitution and single molecule imaging. We find that Nde1 recruits Lis1 to autoinhibited dynein and promotes Lis1-mediated assembly of dynein-dynactin adaptor complexes. Nde1 can compete with the α2 subunit of platelet activator factor acetylhydrolase 1B (PAF-AH1B) for the binding of Lis1, which suggests that Nde1 may disrupt PAF-AH1B recruitment of Lis1 as a noncatalytic subunit, thus promoting Lis1 binding to dynein. Before the initiation of motility, the association of dynactin with dynein triggers the dissociation of Nde1 from dynein by competing against Nde1 binding to the dynein intermediate chain. Our results provide a mechanistic explanation for how Nde1 and Lis1 synergistically activate the dynein transport machinery.

A force-sensitive mutation reveals a spindle assembly checkpoint-independent role for dynein in anaphase progression.

The cytoplasmic dynein-1 (dynein) motor organizes cells by shaping microtubule networks and moving a large variety of cargoes along them. However, dynein's diverse roles complicate in vivo studies of its functions significantly. To address this issue, we have used gene editing to generate a series of missense mutations in Drosophila Dynein heavy chain (Dhc). We find that mutations associated with human neurological disease cause a range of defects in larval and adult flies, including impaired cargo trafficking in neurons. We also describe a novel mutation in the microtubule-binding domain (MTBD) of Dhc that, remarkably, causes metaphase arrest of mitotic spindles in the embryo but does not impair other dynein-dependent processes. We demonstrate that the mitotic arrest is independent of dynein's well-established roles in silencing the spindle assembly checkpoint. In vitro reconstitution and optical trapping assays reveal that the mutation only impairs the performance of dynein under load. In silico all-atom molecular dynamics simulations show that this effect correlates with increased flexibility of the MTBD, as well as an altered orientation of the stalk domain, with respect to the microtubule. Collectively, our data point to a novel role of dynein in anaphase progression that depends on the motor operating in a specific load regime. More broadly, our work illustrates how cytoskeletal transport processes can be dissected in vivo by manipulating mechanical properties of motors.

Nde1 Promotes Lis1-Mediated Activation of Dynein.

Cytoplasmic dynein is the primary motor that drives the motility and force generation functions towards the microtubule minus end. The activation of dynein motility requires its assembly with dynactin and a cargo adaptor. This process is facilitated by two dynein-associated factors, Lis1 and Nde1/Ndel1. Recent studies proposed that Lis1 rescues dynein from its autoinhibited conformation, but the physiological function of Nde1/Ndel1 remains elusive. Here, we investigated how human Nde1 and Lis1 regulate the assembly and subsequent motility of the mammalian dynein/dynactin complex using in vitro reconstitution and single molecule imaging. We found that Nde1 promotes the assembly of active dynein complexes in two distinct ways. Nde1 competes with the α2 subunit of platelet activator factor acetylhydrolase (PAF-AH) 1B, which recruits Lis1 as a noncatalytic subunit and prevents its binding to dynein. Second, Nde1 recruits Lis1 to autoinhibited dynein and promotes Lis1-mediated assembly of dynein-dynactin-adaptor complexes. However, excess Nde1 inhibits dynein, presumably by competing against dynactin to bind the dynein intermediate chain. The association of dynactin with dynein triggers Nde1 dissociation before the initiation of dynein motility. Our results provide a mechanistic explanation for how Nde1 and Lis1 synergistically activate the dynein transport machinery.

Percutaneous Treatment of Left Main Coronary Artery Compression in a Pulmonary Artery Hypertension Patient Associated with Atrial Septal Defect.

Pulmonary arterial hypertension is still a fatal disease persisting with poor prognosis, despite all the advances in treatment (new agents and new combination strategies) in recent years. Patients present with different symptoms which are not specific to the disease (dyspnea, angina, palpitation, and syncope). Angina may occur secondary to myocardial ischemia due to increased right ventricular after load (oxygen supply and demand mismatch) or external compression on the left main coronary artery. Left main coronary artery compression is associated with post-exercise sudden cardiac death in pulmonary arterial hypertension patients. It should be kept in mind in the differential diagnosis of angina in patients with pulmonary arterial hypertension and should be treated immediately. Here, we report a pulmonary arterial hypertension patient associated with secundum-type atrial septal defect presented with ostial left main coronary artery compression caused by an enlarged pulmonary artery and treated with intravascular ultrasound-guided percutaneous coronary intervention.