Atypical presentation of unilateral pulmonary artery agenesis diagnosed postpartum.

A 27-year-old woman developed a cough, shortness of breath, and symptoms mimicking pregnancy complications 6 days after childbirth. Unilateral pulmonary artery agenesis (UAPA), a rare congenital condition, was diagnosed through a chest CT scan. This case highlights the variable presentation of UAPA, even in adults, and the challenges of diagnosis during the postpartum period. Early diagnosis and management are critical for improving pregnancy outcomes in women with UAPA.

Rare Vascular Anomalies in an Adult: Absent Left Pulmonary Artery With a Right-Sided Aortic Arch.

Congenital absence of the left pulmonary artery remains a rarely reported anomalous condition and is even less commonly seen in conjunction with a right-sided aortic arch. While most cases are identified during prenatal fetal ultrasonography and require early childhood intervention, some asymptomatic cases can go unrecognized until incidentally detected on chest imaging as an adult. This case details a 31-year-old male with a congenital absence of the left pulmonary artery and right-sided aortic arch with subsequent atretic and fibrotic lung, all found on imaging during admission for acute alcoholic hepatitis.

The interactome of the UapA transporter reveals putative new players in anterograde membrane cargo trafficking.

Neosynthesized plasma membrane (PM) proteins co-translationally translocate to the ER, concentrate at regions called ER-exit sites (ERes) and pack into COPII secretory vesicles which are sorted to the early-Golgi through membrane fusion. Following Golgi maturation, membrane cargoes reach the late-Golgi, from where they exit in clathrin-coated vesicles destined to the PM, directly or through endosomes. Post-Golgi membrane cargo trafficking also involves the cytoskeleton and the exocyst. The Golgi-dependent secretory pathway is thought to be responsible for the trafficking of all major membrane proteins. However, our recent findings in Aspergillus nidulans showed that several plasma membrane cargoes, such as transporters and receptors, follow a sorting route that seems to bypass Golgi functioning. To gain insight on membrane trafficking and specifically Golgi-bypass, here we used proximity dependent biotinylation (PDB) coupled with data-independent acquisition mass spectrometry (DIA-MS) for identifying transient interactors of the UapA transporter. Our assays, which included proteomes of wild-type and mutant strains affecting ER-exit or endocytosis, identified both expected and novel interactions that might be physiologically relevant to UapA trafficking. Among those, we validated, using reverse genetics and fluorescence microscopy, that COPI coatomer is essential for ER-exit and anterograde trafficking of UapA and other membrane cargoes. We also showed that ArfAArf1 GTPase activating protein (GAP) Glo3 contributes to UapA trafficking at increased temperature. This is the first report addressing the identification of transient interactions during membrane cargo biogenesis using PDB and proteomics coupled with fungal genetics. Our work provides a basis for dissecting dynamic membrane cargo trafficking via PDB assays.

Case report: Reconstruction of the long-gap unilateral absence of right pulmonary artery with contralateral pulmonary artery flap and autologous pericardial graft.

Unilateral absence of pulmonary artery (UAPA) is a rare type of congenital abnormality that may coexist with other congenital abnormalities or present as an isolated lesion, the latter form can be asymptomatic. Surgical procedure is usually carried out when UAPA was diagnosed with significant symptoms, and the aim of surgery is to restore the pulmonary flow distribution. The right-side UAPA is a considerable challenge for surgeons to process surgery, however, technical description of this type of UAPA are limited. Here we described a rare case of a two-month girl with absence of right pulmonary artery, we presented a technique that reconstructs this long-gap UAPA with contralateral pulmonary artery flap and autologous pericardial graft.

Surgical repair of unilateral absence of pulmonary artery in children with pulmonary hypertension: a single-center retrospective study.

Background: The early diagnosis of unilateral absence of pulmonary artery (UAPA) in children offers an opportunity for effective intervention. Due to the lack of clinical evidence, a consensus regarding surgical treatment has yet to be reported. The aim of this study is to evaluate the effectiveness and safety of pulmonary artery (PA) reconstruction with a "two-segment" technique to repair UAPA in patients with pulmonary hypertension. Methods: Intraoperatively, the ligamentum arteriosum connecting the innominate artery and distal PA was dissected and occluded. A conduit created by fresh autologous pericardium formed the first "segment" of the neo-PA. The second "segment" was a Gore vascular graft with integrated rings anastomosed between the proximal end of the pericardial conduit and the main pulmonary artery (MPA). Results: A total of five consecutive patients were included, and the absent PA was successfully reconstructed using the "two-segment" technique in all patients. Following revascularization, the direct measurement of the pressure in MPA during the operation showed that the average mean pulmonary artery pressure (mPAP) decreased from 31.3±16.0 to 16.8±4.2 mmHg (P=0.047). The average mPAP/radial mean arterial pressure (rMAP) ratio decreased from 0.59±0.27 preoperatively to 0.30±0.10 postoperatively (P=0.028). The mean follow-up period was 18.85±4.67 months. The median diameter of the reconstructed PA (pericardial segment) measured by transthoracic echocardiography (TTE) was 6.1 mm. One patient safely underwent a redo operation to repair relative stenosis in the neo-PA. Conclusions: Early PA reconstruction may effectively alleviate pulmonary hypertension in children with UAPA. The "two-segment" technique is safe and can facilitate potential redo pulmonary arterioplasty. Anticoagulation and antiplatelet therapy, as well as frequent follow-up, is required after the operation.

Transporter Specificity: A Tale of Loosened Elevator-Sliding.

Elevator-type transporters are a group of proteins translocating nutrients and metabolites across cell membranes. Despite structural and functional differences, elevator-type transporters use a common mechanism of substrate translocation via reversible movements of a mobile core domain (the elevator), which includes the substrate binding site, along a rigid scaffold domain, stably anchored in the plasma membrane. How substrate specificity is determined in elevator transporters remains elusive. Here, I discuss how a recent report on the sliding elevator mechanism, seen under the context of genetic analysis of a prototype fungal transporter, sheds light on how specificity might be genetically modified. I propose that flexible specificity alterations might occur by 'loosening' of the sliding mechanism from tight coupling to substrate binding.

An adult case with absence of left pulmonary artery and partial anomalous pulmonary venous connection: Case report and literature review.

Unilateral absence of pulmonary artery is a rare congenital disorder that can remain asymptomatic until adulthood. Absence of left pulmonary artery (ALPA) has been reported in one-third of these patients. We are the first to introduce an adult case of ALPA associated with partial anomalous pulmonary venous connection.

Context-dependent Cryptic Roles of Specific Residues in Substrate Selectivity of the UapA Purine Transporter.

Members of the ubiquitous Nucleobase Ascorbate Transporter (NAT) family are H+ or Na+ symporters specific for the cellular uptake of either purines and pyrimidines or L-ascorbic acid. Despite the fact that several bacterial and fungal members have been extensively characterised at a genetic, biochemical or cellular level, and crystal structures of NAT members from Escherichia coli and Aspergillus nidulans have been determined pointing to a mechanism of transport, we have little insight on how substrate selectivity is determined. Here, we present systematic mutational analyses, rational combination of mutations, and novel genetic screens that reveal cryptic context-dependent roles of partially conserved residues in the so-called NAT signature motif in determining the specificity of the UapA transporter of A. nidulans. We show that specific NAT signature motif substitutions, alone and in combinations with each other or with distant mutations in residues known to affect substrate selectivity, lead to novel UapA versions possessing variable transport capacities and specificities for nucleobases. In particular, we show that a UapA version including the quadruple mutation T405S/F406Y/A407S/Q408E in the NAT signature motif (UapA-SYSE) becomes incapable of purine transport, but gains a novel pyrimidine-related profile, which can be further altered to a more promiscuous purine/pyrimidine profile when combined with replacements at distantly located residues, especially at F528. Our results reveal that UapA specificity is genetically highly modifiable and allow us to speculate on how the elevator-type mechanism of transport might account for this flexibility.

Life and Death of Fungal Transporters under the Challenge of Polarity.

Eukaryotic plasma membrane (PM) transporters face critical challenges that are not widely present in prokaryotes. The two most important issues are proper subcellular traffic and targeting to the PM, and regulated endocytosis in response to physiological, developmental, or stress signals. Sorting of transporters from their site of synthesis, the endoplasmic reticulum (ER), to the PM has been long thought, but not formally shown, to occur via the conventional Golgi-dependent vesicular secretory pathway. Endocytosis of specific eukaryotic transporters has been studied more systematically and shown to involve ubiquitination, internalization, and sorting to early endosomes, followed by turnover in the multivesicular bodies (MVB)/lysosomes/vacuole system. In specific cases, internalized transporters have been shown to recycle back to the PM. However, the mechanisms of transporter forward trafficking and turnover have been overturned recently through systematic work in the model fungus Aspergillus nidulans. In this review, we present evidence that shows that transporter traffic to the PM takes place through Golgi bypass and transporter endocytosis operates via a mechanism that is distinct from that of recycling membrane cargoes essential for fungal growth. We discuss these findings in relation to adaptation to challenges imposed by cell polarity in fungi as well as in other eukaryotes and provide a rationale of why transporters and possibly other housekeeping membrane proteins 'avoid' routes of polar trafficking.

Unilateral absence of pulmonary artery and azygous continuation of interrupted inferior vena cava.

Unilateral absence of pulmonary artery is a rare developmental anomaly. Infrahepatic inferior vena cava interruption is a well-recognized but uncommon developmental anomaly. Presence of both these anomalies in a single individual is extremely rare. A 58-year-old man with a history of recurrent lower extremity deep vein thrombosis and venous insufficiency presented to our emergency department with bilateral calf pain and swelling. Ultrasound demonstrated extensive deep vein thrombosis throughout bilateral lower extremities. Computed tomography angiography showed smooth tapering of the right pulmonary artery with absent distal most segment. To our knowledge, there is only 1 case report in the literature so far with both the abnormalities present in a single individual.

Specific Residues in a Purine Transporter Are Critical for Dimerization, ER Exit, and Function.

Transporters are transmembrane proteins that mediate the selective translocation of solutes across biological membranes. Recently, we have shown that specific interactions with plasma membrane phospholipids are essential for the formation and/or stability of functional dimers of the purine transporter UapA, a prototypic eukaryotic member of the ubiquitous nucleobase ascorbate transporter (NAT) family. Here, we provide strong evidence that distinct interactions of UapA with membrane lipids are essential for ab initio formation of functional dimers in the ER, or ER exit and further subcellular trafficking. Through genetic screens, we identify mutations that restore defects in dimer formation and/or trafficking. Suppressors of defective dimerization restore ab initio formation of UapA dimers in the ER. Most of these suppressors are located in the movable core domain, but also in the core-dimerization interface and in residues of the dimerization domain exposed to lipids. Molecular dynamics suggest that the majority of suppressors stabilize interhelical interactions in the core domain and thus assist the formation of functional UapA dimers. Among suppressors restoring dimerization, a specific mutation, T401P, was also isolated independently as a suppressor restoring trafficking, suggesting that stabilization of the core domain restores function by sustaining structural defects caused by the abolishment of essential interactions with specific lipids. Importantly, the introduction of mutations topologically equivalent to T401P into a rat homolog of UapA, namely rSNBT1, permitted the functional expression of a mammalian NAT in Aspergillus nidulans Thus, our results provide a potential route for the functional expression and manipulation of mammalian transporters in the model Aspergillus system.

Structural Lipids Enable the Formation of Functional Oligomers of the Eukaryotic Purine Symporter UapA.

The role of membrane lipids in modulating eukaryotic transporter assembly and function remains unclear. We investigated the effect of membrane lipids in the structure and transport activity of the purine transporter UapA from Aspergillus nidulans. We found that UapA exists mainly as a dimer and that two lipid molecules bind per UapA dimer. We identified three phospholipid classes that co-purified with UapA: phosphatidylcholine, phosphatidylethanolamine (PE), and phosphatidylinositol (PI). UapA delipidation caused dissociation of the dimer into monomers. Subsequent addition of PI or PE rescued the UapA dimer and allowed recovery of bound lipids, suggesting a central role of these lipids in stabilizing the dimer. Molecular dynamics simulations predicted a lipid binding site near the UapA dimer interface. Mutational analyses established that lipid binding at this site is essential for formation of functional UapA dimers. We propose that structural lipids have a central role in the formation of functional, dimeric UapA.

Unilateral absent pulmonary artery in an adult - A diagnostic and therapeutic challenge.

Unilateral absent pulmonary artery (UAPA) is a congenital abnormality rarely diagnosed in adults. UAPA has a myriad of clinical presentations and pulmonary hypertension is present in a quarter of all cases. Isolated UAPA commonly affects the right pulmonary artery and occurs as a result of abnormal development of the sixth aortic arch segment. Due to its rarity, it remains a diagnostic and therapeutic challenge. We describe a case of UAPA in an adult presenting with severe pulmonary hypertension. We describe the appropriate diagnostic approach to a patient with pulmonary hypertension and illustrate the importance of a detailed evaluation to determine the underlying aetiology, particularly in rare causes. Furthermore, we review the clinical presentation, diagnosis and management challenges of UAPA in adults.

Isolated unilateral absence of pulmonary artery in adulthood: a clinical analysis of 65 cases from a case series and systematic review.

BACKGROUND: Isolated unilateral absence of pulmonary artery (UAPA) in adulthood is a rare congenital anomaly. Although some case reports exist, the clinical symptomatology, lung parenchymal features, collateral circulation and therapeutic approaches in adult patients with isolated UAPA remain unknown. The objectives of this study are to investigate the clinical characteristics, elucidate the correlation between clinical symptomatology and radiology, and summarize treatment of adult patients with isolated UAPA. METHODS: Cases of adult patients with isolated UAPA who had been diagnosed at our hospital and identified from PubMed, EMBASE and Web of Science from 1990 to 2016 were analyzed. RESULTS: Hemoptysis was present in 41.5% of patients, exertional dyspnea in 41.5%, and recurrent respiratory infection in 35.4%. Lung parenchymal abnormalities were found on chest computed tomography (CT) scan, including bronchiectasis, which occurred in 30.2% of the patients, interstitial changes in 14.0%, and multiple bullae in 14.0% of the patients. Exertional dyspnea was more frequent in patients with pulmonary hypertension than in those without pulmonary hypertension (P<0.001). Recurrent respiratory infection were more frequent in patients with bronchiectasis than in those without bronchiectasis (P<0.001). Hypertrophic bronchial, phrenic, internal thoracic and intercostal arteries were found in 71.9%, 46.9%, 43.8%, and 43.8% of the patients, respectively. Pneumonectomy reduced hemoptysis in seven cases. Oral phosphodiesterase inhibitors or endothelin receptor antagonist improved exertional dyspnea in three cases with pulmonary hypertension. CONCLUSIONS: Clinicians should be aware of undiagnosed cases of isolated UAPA in adults with unexplained hemoptysis or exertional dyspnea. Early recognition and management of isolated UAPA in adult patients are crucial to avoid the devastating effect of massive hemoptysis or severe pulmonary hypertension (PHT) in the long term.

Dissection of Transporter Function: From Genetics to Structure.

Transporters are transmembrane proteins mediating the selective uptake or efflux of solutes, metabolites, drugs, or ions across cellular membranes. Despite their immense biological importance in cell nutrition, communication, signaling, and homeostasis, their study remains technically difficult mostly due to their lipid-embedded nature. The study of eukaryotic transporters presents additional complexity due to multiple subcellular control mechanisms that operate to ensure proper membrane traffic, membrane localization, and turnover. Model fungi present unique genetic tools to study eukaryotic transporter function. This review highlights how fungal transporter genetics combined with new methodologies for assaying their cellular expression and function as well as recent structural approaches have led to the functional dissection of selected transporter paradigms in Aspergillus nidulans.

Unilateral Absence of the Left Pulmonary Artery With an Associated Vascular Anomaly in Adulthood.

Left-sided pulmonary artery agenesis is a rare malformation that commonly requires childhood intervention secondary to associated congenital cardiovascular anomalies. We present an uncommon case of left-sided agenesis with an associated right-sided aortic arch and significant hypoplasia of the ipsilateral lung. Additionally, there is radiographic evidence of emphysema and pulmonary artery hypertension. Pulmonary artery agenesis is not a common entity, but should be considered in adult patients presenting with recurrent pneumonias and radiographic evidence suggestive of pulmonary hypoplasia. A prompt diagnosis is beneficial for affected individuals who may be candidates for a revascularization procedure or embolization of collaterals. Earlier diagnosis also allows for proper management and follow-up care, considering pulmonary artery hypertension is a severe complication of pulmonary artery agenesis.

Ausencia unilateral de una arteria pulmonar en el adulto / Unilateral Absence of the Pulmonary Artery in an Adult

La agenesia de la arteria pulmonar unilateral (UAPA) generalmente está asociada a otros defectos cardiovasculares congénitos cuando se diagnostica en la niñez. La ausencia asilada es una entidad rara y usualmente detectada en el adulto, con síntomas inespecíficos e incluso asintomáticos que dan lugar a un retraso en el diagnóstico y tratamiento. Nosotros reportamos el caso de una mujer de 40 años de edad con agenesia de la arteria pulmonar izquierda diagnosticada en el puerperio inmediato al debutar con hemoptisis. La radiografía de tórax muestra signos de congestión e hipertensión pulmonar. La angiotomografía de tórax revela la ausencia de la arteria pulmonar izquierda. Los médicos deberíamos considerar la posibilidad de UAPA no diagnosticada en adultos a través de una radiografía que sugiera el diagnóstico y confirmarlo con una angiotomografía de tórax.

Unilateral absence of the pulmonary artery (UAPA) is usually associated with other congenital cardiovascular defects when it is diagnosed in childhood. Its isolated absence is a rare entity that is usually detected in the adult; the clinical picture may be nonspecific and even asymptomatic leading to delays in diagnosis and treatment. We report the case of a 40 year old female with absence of the left pulmonary artery diagnosed in the immediate postpartum period because she had hemoptysis. The chest radiography showed signs of congestion and pulmonary hypertension. The angiography of the chest revealed the absence of the left pulmonary artery. Physicians should consider the possibility of undiagnosed UAPA in adults through a chest radiography that suggests the diagnosis. Confirmation can be established by CT angiography.

Case report of isolated congenital absence of right pulmonary artery with collaterals from coronary circulation.

Isolated unilateral absence of a proximal pulmonary main artery is a rare congenital lesion which is often associated with other cardiovascular abnormalities and a diverse clinical presentation. It is usually diagnosed in childhood. Patients who survive into adulthood is uncommon. We report a case of 46 year old hypertensive and obese female who presented with progressive dyspnea. She had features of pulmonary hypertension. The diagnosis was confirmed by CT pulmonary angiography which showed absence of right pulmonary artery and conventional pulmonary angiography which showed ipsilateral lung receiving collaterals from Right coronary artery and its branches. The purpose of this report is to highlight the fact that UAPA, although a rare entity, should be kept in mind in patients with unexplained PAH and prolonged respiratory symptoms unresponsive to routine treatment modalities.

Unilateral absence of pulmonary artery: pathophysiology, symptoms, diagnosis and current treatment.

Unilateral absence of pulmonary artery (UAPA) is a rare malformation that can present as an isolated lesion or may be associated with other congenital heart defects. UAPA is often associated with other congenital cardiovascular anomalies, such as tetralogy of Fallot, atrial septal defect, coarctation of aorta, right aortic arch, truncus arteriosus and pulmonary atresia. Diagnosis of UAPA is very difficult and is based on taking a complete medical history, physical examination and imaging examinations. Clinical symptoms include exercise intolerance, haemoptysis and recurrent respiratory infections. Adult patients with UAPA are often asymptomatic. There is no consensus regarding the treatment for UAPA. The therapeutic approach should be based on symptoms of the patient, pulmonary artery anatomy and associated aortopulmonary collaterals. Treatment options for these patients include partial or total pneumonectomy, closure of selected collateral arteries not solely responsible for pulmonary blood flow or a primary versus staged pulmonary artery anastomosis. This review summarizes pathophysiology, symptomatology and current diagnosis and treatment of this disease.