The emerging functions of intraflagellar transport 52 in ciliary transport and ciliopathies.

Ciliary transport in eukaryotic cells is an intricate and conserved process involving the coordinated assembly and functioning of a multiprotein intraflagellar transport (IFT) complex. Among the various IFT proteins, intraflagellar transport 52 (IFT52) plays a crucial role in ciliary transport and is implicated in various ciliopathies. IFT52 is a core component of the IFT-B complex that facilitates movement of cargoes along the ciliary axoneme. Stable binding of the IFT-B1 and IFT-B2 subcomplexes by IFT52 in the IFT-B complex regulates recycling of ciliary components and maintenance of ciliary functions such as signal transduction and molecular movement. Mutations in the IFT52 gene can disrupt ciliary trafficking, resulting in dysfunctional cilia and affecting cellular processes in ciliopathies. Such ciliopathies caused by IFT52 mutations exhibit a wide range of clinical features, including skeletal developmental abnormalities, retinal degeneration, respiratory failure and neurological abnormalities in affected individuals. Therefore, IFT52 serves as a promising biomarker for the diagnosis of various ciliopathies, including short-rib thoracic dysplasia 16 with or without polydactyly. Here, we provide an overview of the IFT52-mediated molecular mechanisms underlying ciliary transport and describe the IFT52 mutations that cause different disorders associated with cilia dysfunction.

Assessing type I collagen expression and quality in cellular models of osteogenesis imperfecta.

Osteogenesis imperfecta (OI) is a group of genetic disorders of bone formation characterized by soft and shorter brittle bones in affected individuals. OI is generally considered a collagenopathy resulting from abnormal expression of type I collagen. As assay system to detect the cellular level and quality of type I collagen would help in rapid and correct detection of OI from the diagnostic perspectives. Here, we report an immunofluorescence assay for detection of type I collagen in fibroblast models of OI and represented them into two broad categories based on the expression level and aggregation characteristics of pro-α1(I). Cell phenotypic assays of pro-α1(I) in OI-related gene knocked down fibroblasts revealed aggregates of pro-α1(I) in conditions with knockdown of SERPINF1, CRTAP, P3H1, PPIB, SERPINH1, FKBP10, TMEM38B, MESD, and KDELR2, whereas pro-α1(I) expression was very low in fibroblasts which had knockdown of IFITM5, SP7, BMP1, WNT1, CREB3L1, MBTPS2, and CCDC134. The expression of pro-α1(I) showed abundant and non-aggregated distribution in the fibroblasts with knockdown of non-OI skeletal disorder-related genes (RAB33B and IFT52). The in vitro assay accurately detected abnormally expressed pro-α1(I) levels in cellular models of various types of OI. Thus, this procedure represents a promising point-of-detection assay for potential diagnosis and therapeutic decisions in OI.

Nuclear proteostasis imbalance in laminopathy-associated premature aging diseases.

Laminopathies are a group of rare genetic disorders with heterogeneous clinical phenotypes such as premature aging, cardiomyopathy, lipodystrophy, muscular dystrophy, microcephaly, epilepsy, and so on. The cellular phenomena associated with laminopathy invariably show disruption of nucleoskeleton of lamina due to deregulated expression, localization, function, and interaction of mutant lamin proteins. Impaired spatial and temporal tethering of lamin proteins to the lamina or nucleoplasmic aggregation of lamins are the primary molecular events that can trigger nuclear proteotoxicity by modulating differential protein-protein interactions, sequestering quality control proteins, and initiating a cascade of abnormal post-translational modifications. Clearly, laminopathic cells exhibit moderate to high nuclear proteotoxicity, raising the question of whether an imbalance in nuclear proteostasis is involved in laminopathic diseases, particularly in diseases of early aging such as HGPS and laminopathy-associated premature aging. Here, we review nuclear proteostasis and its deregulation in the context of lamin proteins and laminopathies.

Genome sequencing identifies a large non-coding region deletion of SNX10 causing autosomal recessive osteopetrosis.

Autosomal recessive osteopetrosis (ARO) is a rare genetic disorder caused by impaired osteoclast activity. In this study, we describe a 4-year-old boy with increased bone density due to osteopetrosis, autosomal recessive 8. Using genome sequencing, we identified a large deletion in the 5'-untranslated region (UTR) of SNX10 (sorting nexin 10), where the regulatory region of this gene is located. This large deletion resulted in the absence of the SNX10 transcript and led to abnormal osteoclast activity. SNX10 is one of the nine genes known to cause ARO, shown to interact with V-ATPase (vacuolar type H( + )-ATPase), as it plays an important role in bone resorption. Our study highlights the importance of regulatory regions in the 5'-UTR of SNX10 for its expression while also demonstrating the importance of genome sequencing for detecting large deletion of the regulatory region of SNX10.

CuII-Catalyzed cis-Selective Synthesis of Ketoepoxides from Phenacyl Bromides and Water.

A verity of α,ß-ketoepoxides was synthesized using a CuII-catalyzed oxidative C-C/O-C coupled cyclization strategy with high yield and cis-selectivity. Water is used as the source of oxygen and phenacyl bromide as the carbon in the valuable epoxides. The self-coupling method was extended to cross-coupling between phenacyl bromides with benzyl bromides. A high cis-diastereoselectivity was observed in all the synthesized ketoepoxides. Control experiments and density functional theory (DFT) study were performed to understand the CuII-CuI transition mechanism.

Water-based efficient alkyne transformation towards α-acetoxy/imido-ketones via oxidative coupling reactions using an alkylamine catalyst.

A novel approach is unveiled for the expedited synthesis of valuable α-substituted ketones, utilising aliphatic amine catalysis to drive the oxidative C-O/C-N coupling reaction between alkynes and an appropriate nucleophile. This one-pot synthesis employs hypervalent iodine as both the oxidant and coupling agent. A fast, metal-free, and environmentally benign method is developed for synthesising α-acetoxyketones and α-imidoketones in an aqueous medium. To demonstrate the potential for larger-scale production, a gram-scale reaction is conducted. Moreover, the newly developed methodology has successfully enabled the direct synthesis of cathinone, a psychoactive drug. Overall, this work holds significant promise for the efficient and sustainable synthesis of α-substituted ketones and the potential development of novel biologically active compounds.

Post-COVID-19 Cardiovascular Sequelae and Myocarditis.

BACKGROUND AND AIM: Post coronavirus disease 2019 (COVID-19) cardiovascular (CV) pathological changes, myocarditis, and myocardial infarctions (MIs) are major public health issues. This review discusses acute and chronic COVID-19 cardiac manifestations. METHODS: The devastating impact of COVID-19 on global healthcare and economies has likely been one of humanity's deadliest calamities in recent decades, as multiple literature and databases were searched from 2020 to 2022. RESULTS: As of April 2022, we identified 73 articles in various electronic databases that discussed the details of COVID-19 and cardiac manifestations. Cardiometabolic risk factors should now, more than ever, be a top priority for clinicians, as their potent role in exacerbating COVID-19 illness severity has been conclusively demonstrated. CONCLUSION: This review discusses cardiac pathology changes, CV consequences of acute COVID-19, microvascular injury and cardiac complications linked with SARS-CoV2, COVID-19 linked with chronic CV disease, therapeutic drug effects on heart used in COVID-19, and possible investigational approaches and management strategies for post-COVID-19 CV consequences. Highlights Cardiac pathology changes: Effect of COVID-19. Mechanism of development of CV consequences in acute COVID-19: Including autopsy studies. Microvascular injury and cardiac complications: Linked with SARS-CoV2. COVID-19 linked with chronic CV disease. Therapeutic drug effects on heart used in COVID-19. Possible investigational approaches and management strategies for post-COVID-19 CV consequences.

Fundoplication in laparoscopic Heller's cardiomyotomy for achalasia.

BACKGROUND: Laparoscopic Heller's cardiomyotomy (LHC) is the preferred treatment of achalasia. It improves dysphagia by dividing muscles of the lower oesophageal sphincter, but this intervention can result in debilitating gastro-oesophageal reflux symptoms in some patients. To prevent these reflux symptoms, most surgeons add a fundoplication to Heller's cardiomyotomy, but there is no consensus regarding this or the type of fundoplication which is best suited for the purpose. OBJECTIVES: To assess how the addition of a fundoplication affects postoperative reflux and dysphagia in people undergoing LHC and compare the different types of fundoplications used in combination with LHC to determine which is better at controlling reflux without worsening the dysphagia. SEARCH METHODS: We searched three databases (CENTRAL, MEDLINE and Embase) on 31 October 2021 and trial registers to identify all published and unpublished randomised controlled trials (RCTs) in any language, comparing different fundoplications used in combination with LHC to treat achalasia. We also included RCTs where LHC with a fundoplication is compared with LHC without any fundoplication. SELECTION CRITERIA: We only included RCTs which recruited adult participants with achalasia undergoing LHC with minimal hiatal dissection. We excluded non-randomised studies or studies involving paediatric participants. We also excluded studies where the procedure was done by open surgery and where circumferential hiatal dissection of the oesophagus was carried out, unless it was necessary to reduce a hiatus hernia or to facilitate a Toupet or Nissen fundoplication. DATA COLLECTION AND ANALYSIS: Two review authors independently identified studies to be included, assessed risk of bias using the Cochrane RoB 1 tool, and extracted the data. We calculated the risk ratio (RR) with 95% confidence interval (CI) using both fixed-effect and random-effect models with Review Manager (RevMan) software. MAIN RESULTS: We included eight studies in this review, with a total of 571 participants with an average age of 45 years (range 33.5 to 50). LHC without any fundoplication was performed in 65 (11.3%) participants, 298 (52.1%) had Dor fundoplication, 81 (14.1%) had Toupet fundoplication, 72 (12.6%) had Nissen's fundoplication, and 55 (9.6%) participants had angle of His accentuation. Three studies with a total of 143 participants compared LHC + Dor to LHC without fundoplication. We found that the evidence is very uncertain as to whether the addition of a Dor fundoplication made any difference to the outcome of postoperative pathological acid reflux (RR 0.37, 95% CI 0.07 to 1.89; I2 = 56%; 2 studies, 97 participants; very low-certainty evidence) and uncertain for severe postoperative dysphagia (RR 3.00, 95% CI 0.34 to 26.33; I2 = 0%; 3 studies, 142 participants; low-certainty evidence). Three studies with 174 participants compared LHC + Dor to LHC + Toupet. The evidence suggests that there may be little to no difference in the outcomes of postoperative pathological acid reflux (RR 0.75, 95% CI 0.23 to 2.43; I2 = 60%; 3 studies, 105 participants; low-certainty evidence) and severe postoperative dysphagia (RR 0.78, 95% CI 0.19 to 3.15; I2 = 0%; 3 studies, 123 participants; low-certainty evidence) between the two interventions, but the certainty of the evidence is low. One study with 138 participants compared LHC + Dor to LHC + Nissen. Nissen fundoplication caused increased severe postoperative dysphagia (RR 0.19, 95% CI 0.04 to 0.83; 1 study, 138 participants; high-certainty evidence) when compared to Dor fundoplication. This study did not show a difference in postoperative pathological acid reflux (RR 4.72, 95% CI 0.23 to 96.59; 1 study, 138 participants; low-certainty evidence), but the certainty of evidence is low. One study with 110 participants compared LHC + Dor with LCH + angle of His accentuation, and reported that severe postoperative dysphagia was similar between the two interventions (RR 1.56, 95% CI 0.27 to 8.95; 1 study, 110 participants; moderate-certainty evidence), with moderate certainty of evidence. This study did not report on postoperative pathological acid reflux. AUTHORS' CONCLUSIONS: When LHC was performed with minimal hiatal dissection, we were very uncertain whether the addition of a Dor fundoplication made a difference in controlling postoperative reflux, and we were uncertain if it increased the risk of severe postoperative dysphagia. There may be little to no difference in the outcomes of postoperative pathological acid reflux or severe dysphagia between Dor and Toupet fundoplications when used in combination with LHC, but the certainty of the evidence is low. Nissen (total) fundoplication used in combination with LHC for achalasia increased the risk of severe postoperative dysphagia. The angle of His accentuation and Dor fundoplication had a similar effect on severe postoperative dysphagia when combined with LHC, but their effect on postoperative pathological acid reflux was not reported.

A Zn(II)-Coordination Polymer for the Instantaneous Cleavage of Csp3-Csp3 Bond and Simultaneous Reduction of Ketone to Alcohol.

Two coordination polymers of Zn(II) and Cu(II) with n-butylmalonic acid have been achieved in this work. The crystallographic structural descriptions along with the sedimentary rock-type microstructural morphology of these two coordination polymers (CPs) have been explored. The reactivity of ß-hydroxy ketones with these two CPs has also been investigated. The Zn(II)-CP shows a specific reactivity with ß-hydroxy ketone at room temperature and in open air conditions. Through a microcolumn-based filtration technique, the Zn(II)-CP shows the capability to break the Csp3-Csp3 σ bonds of ß-hydroxy ketone and simultaneously reduce the associated ketone to alcohol. Such conversion has been progressed without the use of any additional external reducing agent and any chemical workup or column chromatographic purification protocol. Other similar type CPs of Cu(II) and Mn(II) with n-butylmalonic acid completely failed to show similar reactivity with ß-hydroxy ketone. On the basis of much experimental evidence, the most possible mechanistic pathway of the reactivity between ß-hydroxy ketone and Zn(II)-CP has also been proposed through this work.

An IRES-dependent translation of HYPK mRNA generates a truncated isoform of the protein that lacks the nuclear localization and functional ability.

Different mechanisms of translation initiation process exist to start the protein synthesis from various viral and eukaryotic mRNA. The cap-independent and tertiary structure directed translation initiation of mRNAs forms the basis of internal ribosome entry site (IRES) mediated translation initiation that helps in cellular protein production in different conditions. HYPK protein sequesters different aggregation-prone proteins to help in the cellular proteostasis. HYPK mRNA is differentially translated from an internal start/initiation codon to generate an amino terminal-truncated isoform (HSPC136) of HYPK protein. In this study, we report that an IRES-dependent translation initiation of HYPK mRNA results in the formation of the HSPC136/HYPK-ΔN isoform of HYPK protein. The IRES-driven translation product, HYPK-ΔN, lacks the N-terminal tri-arginine motif that acts as the nuclear localization signal (NLS) in the full-length HYPK protein. While the full-length HYPK protein translocates to the nucleus and prevents the aggregation of the mutant p53 (p53-R248Q) protein, the HYPK-ΔN lacks this activity. The NLS of HYPK is not evolutionarily conserved and its exclusive presence in the HYPK of higher eukaryotic animals imparts additional advantage to the HYPK protein in tackling the cytosolic as well as nuclear protein aggregates. The presence of the NLS in full-length HYPK also allows this protein to modulate the cell cycle. These results provide a mechanistic detail of HYPK mRNA's translation initiation control by an IRES that dictates the formation of HYPC136/HYPK-ΔN which lacks the nuclear localization and functional ability.

Disordered Nanostructure in Huntingtin Interacting Protein K Acts as a Stabilizing Switch To Prevent Protein Aggregation.

Protein misfolding due to mutation(s) and/or generation of unstable intermediate state(s) can be the cause of aberrant aggregations, leading to cellular degeneration. While molecular signatures like amyloidogenic regions cause aggregation, other features in proteins, like disorder and unique complexity regions, regulate and restrict such adhesive accumulation processes. Huntingtin interacting protein K (HYPK) is an aggregation-prone protein. Using various biophysical, microscopy, and computational techniques, we have deciphered how HYPK's N-terminal nanodisordered region plays a significant modulatory role in preventing its own aggregation and that of other proteins. HYPK's C-terminal hydrophobic regions lead to annular oligomerization and intermolecular charge interactions among the residues of low-complexity region (LCR) generate amorphous aggregates. The N-terminal disordered nanostructure loops toward the C-terminus, and a negative charge-rich patch in this region interacts with the LCR to shield LCR's positive charges. This interaction is required to prevent HYPK aggregation. Loss of this interaction causes partial unfolding of the structured C-terminus, resulting in HYPK's molten globule-like state and rapid annular oligomerization. The N-terminus also determines the specificity to mediate the differential bindings with aggregation-prone and wild type Huntingtin-exon1 proteins (Huntingtin97Q-exon1 and Huntingtin25Q-exon1). A sliding interaction of the specific N-terminal segment of HYPK along the extended polyglutamine region of Huntingtin-exon1 is responsible for HYPK's higher affinity for aggregation-prone Huntingtin than for its non-aggregating counterpart. Overall, our study provides evidence of the existence of disordered nanostructure in HYPK protein that mechanistically plays a decisive role in preventing both self and non-self protein aggregation.

Transvesical blockade of the obturator nerve to prevent adductor contraction in transurethral resection of urinary bladder tumor.

INTRODUCTION: Urinary bladder tumors are one of the most common urological malignancies. Traditionally, it has been managed with trans-urethral resection of urinary bladder tumor (TURBT) for both diagnostic and therapeutic purposes. During TURBT of lateral wall tumors, there is risk of obturator nerve reflex (ONR), which can lead to serious complications such as inadvertent bleeding and urinary bladder perforation. To prevent this, obturator nerve block is given after spinal anesthesia. In this study, we have used the transvesical approach to block the obturator nerve. MATERIALS AND METHODS: In total, 60 patients were included in the study. In 30 of them, TURBT was performed under only SA and transvesical obturator nerve block (ONB). In the other 30 patients, TURBT was performed under SA and peripheral nerve stimulator (PNS) guided obturator nerve block (performed by anesthetists) was given. The patients underwent TURBT using conventional monopolar cautery. The procedure time and peri-operative complications were studied. In all patients, informed consent was taken. RESULTS: In this study, 30 ONBs (all bilateral) were performed transvesically. After confirming the location of the obturator nerve, transvesical ONB was given using local anesthetic. Two patients (6.67%) experienced adductor jerk during the operation. In the 30 patients who underwent peripheral nerve stimulator (PNS) guided ONB, 6 of the patients (20%) experienced adductor jerk during the operation and 1 of those (3.33%) suffered from urinary bladder perforation which was managed conservatively. CONCLUSION: Transvesical ONB is an easy method to prevent adductor jerk during TURBT of lateral wall tumors. The learning curve is less and it has a high success rate.

Identification and characterization of nuclear localization signals in the circumsporozoite protein of Plasmodium falciparum.

Secretory proteins of Plasmodium exhibit differential spatial and functional activity within the host cell nucleus. However, the nuclear localization signals (NLSs) for these proteins remain largely uncharacterized. In this study, we have identified and characterized two NLSs in the circumsporozoite protein of Plasmodium falciparum (Pf-CSP). Both NLSs in the Pf-CSP contain clusters of lysine and arginine residues essential for specific interactions with the conserved tryptophan and asparagine residues of importin-α, facilitating nuclear translocation of Pf-CSP. While the two NLSs of Pf-CSP function independently and are both crucial for nuclear localization, a single NLS of Pf-CSP leads to weak nuclear localization. These findings shed light on the mechanism of nuclear penetrability of secretory proteins of Plasmodium proteins.

Endoscopic Endonasal Trans-Sphenoidal Minimally Invasive Pituitary Surgery with Image Guided Navigation System (Igns): Learning Experience of Ent Surgeon: First Author.

Introduction- Endoscopic minimally invasive pituitary surgery (MIPS) is advantageous over microscopic technique, as it provides superior close up, wide angle view of surgical target area. Image guided navigation system (IGNS) guides the surgeon to localize the lesion. In the present study we analyzed the Image Guided Surgical procedure and outcome of Endoscopic minimally invasive pituitary surgery and shared our experiences regarding disease clearance. MATERIALS AND METHODS: During the period of April 2015 to August 2022 a total 104 patients, diagnosed with pituitary adenoma underwent surgery and further followed up in a multidisciplinary team approach in a tertiary care hospital of Kolkata, India. The data obtained were reviewed statistically to satisfy the study objectives. RESULTS: Total 104 operations were done on 98 patients and total cases taken for calculation and analysis was 98, which consist of 11 microadenomas, 81 macroadenomas. Among 35 patients with normal preoperative hormonal assay, one patient developed postoperative hypopituitarism. Among 6 patients with preoperative hypopituitarism 4 patients (66.6%) recovered after surgery. Overall, 85 cases had total disease clearance as detected on post-operative MRI. In functioning pituitary adenoma (FPA) clinical and endocrinological improvement occurred after primary surgery in 85.36% (n = 35) and after revision surgery it was 84.44% (n = 38). Macroadenomas, giant adenomas were found to have statistically significant higher risk of incomplete disease clearance but large adenomas do not have statistically higher risk of incomplete clearance. CONCLUSION: IGNS requires extra time for setup, but with proper registration of tracker instruments it adds precision to the surgery. IGNS supplements endoscopic visualization with localization of target lesion by real time stereotactic feedback using preset preoperative imaging data, thus increasing accuracy, safety and effectiveness of minimally invasive surgery.

Phenolic composition and bioactivity of Ribes magellanicum fruits from southern Patagonia.

Eight Ribes magellanicum collections from three different places in southern Patagonia were compared for content of different groups of phenolics, antioxidant capacity and inhibition of enzymes related to metabolic syndrome (α-amylase, α-glucosidase and pancreatic lipase). The sample with the highest antioxidant capacity was assessed for glutathione (GSH) synthesis stimulation in human gastric adenocarcinoma (AGS) cells. The chemical profile was determined by high performance liquid chromatography with tandem mass spectrometry detection (HPLC-MS/MS) and the main phenolics were quantified. The samples from Navarino Island and Reserva Nacional Magallanes showed higher content of anthocyanins and caffeoylquinic acid, with better activity towards α-glucosidase and antioxidant capacity. A sample from Omora (Navarino Island), significantly increased intracellular GSH content in AGS cells. Some 70 compounds were identified in the fruit extracts by HPLC-MS/MS. The glucoside and rutinoside from delphinidin and cyanidin and 3-caffeoylquinic acid were the main compounds. Different chemical profiles were found according to the collection places.

Autophagy is a cell death mechanism in Toxoplasma gondii.

Nutrient sensing and the capacity to respond to starvation is tightly regulated as a means of cell survival. Among the features of the starvation response are induction of both translational repression and autophagy. Despite the fact that intracellular parasite like Toxoplasma gondii within a host cell predicted to be nutrient rich, they encode genes involved in both translational repression and autophagy. We therefore examined the consequence of starvation, a classic trigger of autophagy, on intracellular parasites. As expected, starvation results in the activation of the translational repression system as evidenced by elevation of phosphorylated TgIF2α (TgIF2α-P). Surprisingly, we also observe a rapid and selective fragmentation of the single parasite mitochondrion that leads irreversibly to parasite death. This profound effect was dependent primarily on the limitation of amino acids and involved signalling by the parasite TOR homologue. Notably, the effective blockade of mitochondrial fragmentation by the autophagy inhibitor 3-methyl adenine (3-MA) suggests an autophagic mechanism. In the absence of a documented apoptotic cascade in T. gondii, the data suggest that autophagy is the primary mechanism of programmed cell death in T. gondii and potentially other related parasites.

Acyl-CoA binding protein regulates nutrient-dependent autophagy.

BACKGROUND: Homeostasis of autophagy under normal conditions and nutrient stress is maintained by adaptive activation of regulatory proteins. However, the protein-lipid crosstalk that modulates the switch from suppression to activation of autophagy initiation is largely unknown. RESULTS: Here, we show that human diazepam-binding inhibitor (DBI), also known as acyl-CoA binding protein (ACBP), binds to phosphatidylethanolamine of the phagophore membrane under nutrient-rich growth conditions, leading to inhibition of LC3 lipidation and suppression of autophagy initiation. Specific residues, including the conserved tyrosine residues of DBI, interact with phosphatidylethanolamine to stabilize the later molecule in the acyl-CoA binding cavity of the protein. Under starvation, phosphorylation of serine-21 of DBI mediated by the AMP-activated protein kinase results in a drastic reduction in the affinity of the protein for phosphatidylethanolamine. The release of serine-21 phosphorylated DBI from the phagophore upon nutrient starvation restores the high LC3 lipidation flux and maturation of the phagophore to autophagosome. CONCLUSION: DBI acts as a strategic barrier against overactivation of phagophore maturation under nutrient-rich conditions, while triggering autophagy under nutrient-deficient conditions.

Foreign Body Aspiration in Children and Emergency Rigid Bronchoscopy: A Retrospective Observational Study.

Foreign body aspiration is potentially life-threatening in paediatric age group. Early recognition and emergency intervention by Rigid bronchoscopy is life-saving. To highlight various difficulties in emergency paediatric bronchoscopy and discuss our experience in 138 patients. < 12 years children with suspected foreign body aspiration were included. Data of 138 patients < 12 years of age were studied. The most common foreign body found was peanut and organic foreign bodies constituted of total foreign bodies removed. Choking, Cough and sudden onset breathlessness were common symptoms. Tachypnoea, asymmetric breath sound, rhonchi, stridor, reduced chest movements were common signs. Obstructive emphysema was commonest radiological findings. Majority of the patients were discharged within 72 h & only two patients expired. History, clinical and radiological findings are highly indicative of foreign body in the airway. Inspite of being a high risk procedure, Rigid bronchoscopy when performed with necessary expertise,trained anaesthesia team and a paediatric ICU, saves majority of lives of children with tracheobronchial foreign bodies.

Cu(I)-catalysed cross-coupling reaction of in situ generated azomethine ylides towards easy construction of fused N-heterocycles.

In this study, we have devised a new method for synthesizing highly valuable 5,6,7,8a-tetrahydropyrrolo[2,1-b]thiazoles using a decarboxylative C-N coupling reaction between phenyl glyoxal and proline or its analogue, which is catalyzed by CuI in the presence of K2CO3. This reaction is followed by a regiospecific C-C and C-S coupling cyclization with dialkyl trithiocarbonate. Furthermore, we have demonstrated that this cross-coupling method can also be extended to imines, leading to the formation of fused symmetrical and unsymmetrical 6,7-dihydro-5H-pyrrolo[1,2-a]imidazoles. This finding greatly expands the scope and versatility of the synthetic approach. Therefore, this work represents a significant contribution to the field of organic synthesis, providing a novel and efficient method for the preparation of fused N-heterocyclic compounds that could have useful applications in areas such as material science and pharmaceuticals.

Mutant MESD links cellular stress to type I collagen aggregation in osteogenesis imperfecta type XX.

Aberrant forms of endoplasmic reticulum (ER)-resident chaperones are implicated in loss of protein quality control in rare diseases. Here we report a novel mutation (p.Asp233Asn) in the ER retention signal of MESD by whole exome sequencing of an individual diagnosed with osteogenesis imperfecta (OI) type XX. While MESDD233N has similar stability and chaperone activity as wild-type MESD, its mislocalization to cytoplasm leads to imbalance of ER proteostasis, resulting in improper folding and aggregation of proteins, including LRP5 and type I collagen. Aggregated LRP5 loses its plasma membrane localization to disrupt the expression of WNT-responsive genes, such as BMP2, BMP4, in proband fibroblasts. We show that MESD is a direct chaperone of pro-α1(I) [COL1A1], and absence of MESDD233N in ER results in cytosolic type I collagen aggregates that remain mostly not secreted. While cytosolic type I collagen aggregates block the intercellular nanotubes, decreased extracellular type I collagen also results in loss of interaction of ITGB1 with type I collagen and weaker attachment of fibroblasts to matrix. Although proband fibroblasts show increased autophagy to degrade the aggregated type I collagen, an overall cellular stress overwhelms the proband fibroblasts. In summary, we present an essential chaperone function of MESD for LRP5 and type I collagen and demonstrating how the D233N mutation in MESD correlates with impaired WNT signaling and proteostasis in OI.