Modulation of the Endomembrane System by the Anticancer Natural Product Superstolide/ZJ-101.

Marine natural products represent a unique source for clinically relevant drugs due to their vast molecular and mechanistic diversity. ZJ-101 is a structurally simplified analog of the marine natural product superstolide A, isolated from the New Caledonian sea sponge Neosiphonia Superstes. The mechanistic activity of the superstolides has until recently remained a mystery. Here, we have identified potent antiproliferative and antiadhesive effects of ZJ-101 on cancer cell lines. Furthermore, through dose-response transcriptomics, we found unique dysregulation of the endomembrane system by ZJ-101 including a selective inhibition of O-glycosylation via lectin and glycomics analysis. We applied this mechanism to a triple-negative breast cancer spheroid model and identified a potential for the reversal of 3D-induced chemoresistance, suggesting a potential for ZJ-101 as a synergistic therapeutic agent.

HFOV in inhalational injury associated ARDS with broncho-pleural fistula - An old friend to the rescue: Case report.

Introduction: Patients with acute respiratory distress syndrome (ARDS) on mechanical ventilation often require high inspiratory pressure and positive end-expiratory pressure (PEEP). However, effective ventilation becomes difficult in cases where a large air leak develops in patients. The management of such a case requires improvisation and the adoption of special ventilation strategies. Case and outcomes: We present a case study of a burn patient with airway involvement, developing ARDS and who developed a bronchopleural fistula (BPF) leading to failure of conventional ventilation. He was managed successfully with high-frequency oscillatory ventilation (HFOV) and finally discharged. Conclusion: HFOV is a feasible option for ventilating patients with BPF when conventional ventilation fails. At a time when HFOV has largely been relegated to obsolescence, we hope to re-emphasize its relevance under particular circumstances.

Heat shock proteins and the calcineurin-crz1 signaling regulate stress responses in fungi.

The heat shock proteins (Hsps) act as a molecular chaperone to stabilize client proteins involved in various cell functions in fungi. Hsps are classified into different families such as HSP90, HSP70, HSP60, HSP40, and small HSPs (sHsps). Hsp90, a well-studied member of the Hsp family proteins, plays a role in growth, cell survival, and pathogenicity in fungi. Hsp70 and sHsps are involved in the development, tolerance to stress conditions, and drug resistance in fungi. Hsp60 is a mitochondrial chaperone, and Hsp40 regulates fungal ATPase machinery. In this review, we describe the cell functions, regulation, and the molecular link of the Hsps with the calcineurin-crz1 calcium signaling pathway for their role in cell survival, growth, virulence, and drug resistance in fungi and related organisms.

The Impact of High-flow Nasal Cannula vs Other Oxygen Delivery Devices during Bronchoscopy under Sedation: A Systematic Review and Meta-analyses.

Background: The widespread diagnostic and therapeutic application of bronchoscopy is often associated with complications like desaturation. This systematic review and meta-analysis intend to scrutinize whether the high-flow nasal cannula (HFNC) is advantageous for providing respiratory support during bronchoscopic procedures under sedation, in comparison with other conventional modalities for oxygen therapy. Materials and methods: A thorough screening of electronic databases was done till 31st December 2021 after obtaining registration in PROSPERO (CRD42021245420). Randomized controlled trials (RCT), evaluating the impact of HFNC and standard/any other oxygen-delivery devices during bronchoscopy were included in this meta-analysis. Results: We retrieved in nine RCTs, with a total of 1306 patients, the application of HFNC during bronchoscopy led to decreased number of desaturation spells [relative risk (RR) 0.34, 95% confidence interval (CI) 0.27-0.44, I 2 = 23%], higher nadir value of SpO2 [Mean difference (MD) 4.30, 95% CI 2.41-6.19, I 2 = 96%], and improved PaO2 from baseline (MD 21.77, 95% CI 2.8-40.74, I 2 = 99%), along with similar PaCO2 values (MD -0.34, 95% CI -1.82 to 1.13, I 2 = 58%) just after the procedure. However, apart from desaturation spell, the findings are significantly heterogeneous. In subgroup analysis, HFNC had significantly lesser desaturation spells and better oxygenation than low-flow devices, but in comparison to noninvasive ventilation (NIV) had a lower nadir value of SpO2 with no other significant difference. Conclusion: High-flow nasal cannula led to greater oxygenation and prevented desaturation spells more effectively in comparison with low-flow devices like nasal cannula, venturi mask, etc., and may be considered as an alternative to NIV during bronchoscopy in certain high-risk patients. How to cite this article: Roy A, Khanna P, Chowdhury SR, Haritha D, Sarkar S. The Impact of High-flow Nasal Cannula vs Other Oxygen Delivery Devices during Bronchoscopy under Sedation: A Systematic Review and Meta-analyses. Indian J Crit Care Med 2022;26(10):1131-1140.

Physiological effect of prone positioning in mechanically ventilated SARS-CoV-2- infected patients with severe ARDS: An observational study.

Background and Aims: Mechanical ventilation in prone position was associated with a reduction in mortality and increase in arterial oxygenation in acute respiratory distress syndrome (ARDS) patients. However, physiological effects of prone position in COVID ARDS patients are unknown. Material and Methods: In this prospective observational study, data of n = 47 consecutive real time RT- PCR confirmed SARS-CoV-2-infected patients with severe ARDS were included. Respiratory mechanics and oxygenation data of recruited patients were collected before and after prone position. Results: Median (Interquartile range, IQR) age of the recruited patients was 60 (50-67) years and median (IQR) PaO2/FiO2 ratio of 61.2 (54-80) mm Hg with application of median (IQR) positive end expiratory pressure (PEEP) of 12 (10-14) cm H2O before initiation of prone position. Out of those patients, 36 (77%) were prone responders at 16 hours after prone session, evident by increase of PaO2 by at least 20 mm Hg or by 20% as compared to baseline, and 73% patients were sustained responders (after returning to supine position). Plateau airway pressure (p < 0.0001), peak airway pressure (p < 0.0001), and driving pressure (p < 0.0001) were significantly reduced in prone position, and static compliance (p = 0.001), PaO2/FiO2 ratio (p < 0.0001), PaO2 (p = 0.0002), and SpO2 (p = 0.0004) were increased at 4 hours and 16 hours since prone position and also after returning to supine position. Conclusion: In SARS-CoV-2-infected patients, mechanical ventilation in prone position is associated with improvement in lung compliance and oxygenation in almost three-fourth of the patients and persisted in supine position in more than 70% of the patients.

The catalytic decarboxylative allylation of enol carbonates: the synthesis of enantioenriched 3-allyl-3'-aryl 2-oxindoles and the core structure of azonazine.

The catalytic asymmetric synthesis of 3-allyl-3'-aryl 2-oxindoles has been shown via the Pd(0)-catalyzed decarboxylative allylation of allylenol carbonates. This methodology provides access to a variety of 2-oxindole substrates (5a-v) with all-carbon quaternary stereocenters (up to 94% ee) at the pseudobenzylic position under additive-free and mild conditions. The synthetic potential of this method was shown by the asymmetric synthesis of the tetracyclic core of the diketopiparazine-based alkaloid azonazine (11).

Dominant mutants of the calcineurin catalytic subunit (CNA-1) showed developmental defects, increased sensitivity to stress conditions, and CNA-1 interacts with CaM and CRZ-1 in Neurospora crassa.

We studied a dominant mutant of the Neurospora crassa calcineurin catalytic (cna-1) subunit generated using the repeat-induced point mutation (RIP). The Cna-1RIP mutants showed defects in morphology, aerial hyphae development, carotenoid accumulation, and fertility. The Cna-1RIP mutants also showed sensitivity to osmotic stress and a reduction in acquisition of thermotolerance on exposure to lethal heat shock temperature. The Cna-1RIP allele was dominant over the wild type cna-1 allele, suggesting that the CNA-1RIP mutant protein acts in a dominant-negative manner. In addition, we studied calcineurin regulatory subunit (cnb-1) mutants, which were previously generated using RIP. The cnb-1RIP mutants showed sensitivity to calcium (Ca2+) and heat-shock stress conditions. Thus, calcineurin plays an essential role for vegetative and sexual developments, and tolerance to stress conditions in N. crassa. Moreover, CNA-1 directly interacts with the calmodulin (CaM) and calcineurin-responsive zinc finger-1 (CRZ-1) proteins under high Ca2+ condition in N. crassa.

Electrochemical Synthesis of Dimeric 2-Oxindole Sharing Vicinal Quaternary Centers Employing Proton-Coupled Electron Transfer.

Dimerization of 3-substituted 2-oxindoles has been developed under a mild electrochemical condition, avoiding toxic chemical oxidants and metal by-products. This methodology forms a C(sp3)-C(sp3) bond at the pseudobenzylic position of two partners of 2-oxindoles with a broad substrate scope. These dimeric structural motifs are important building blocks for the total synthesis of pyrroloindoline alkaloids. Furthermore, this work demonstrates in-depth mechanistic insights employing electrochemistry, which suggests a stepwise one proton transfer (PT) and two electron transfer (ET) processes. Most significantly, reaction rate acceleration has been demonstrated by exploiting the base-assisted proton-coupled electron transfer (PCET) pathway. Hence, this work brings a new dimension in the field of electro-organic synthesis with the help of nature's favorite kinetic route, i.e., PCET, to lower the kinetic barrier.

Oxidative cyanation of 2-oxindoles: formal total synthesis of (±)-gliocladin C.

Efficient oxidative direct cyanations of 3-alkyl/aryl 2-oxindoles using Cyano-1,2-BenziodoXol-3(1H)-one (CBX) (2a) have been reported under 'transition metal-free' conditions to synthesize a wide variety of 3-cyano 3-alkyl/aryl 2-oxindoles sharing an all-carbon quaternary center under additive-free conditions. The application of this process is shown by the formal total synthesis of (±)-gliocladin C (11c) in a few steps.

Transition-Metal Free Oxidative Alkynylation of 2-Oxindoles with Ethynylbenziodoxolone (EBX) Reagents.

We report an efficient direct alkynylations of 3-alkyl/aryl 2-oxindoles employing ethynyl-1,2-benziodoxol-3(1H)-one (EBX) to afford a wide variety of 3-alkynyl-3-alkyl/aryl 2-oxindole under transition-metal free condition. In addition to activated carbonyl compounds viz. 2-oxindole-3-alkylcarboxylates, this direct alkynylations protocol works efficiently on 3-alkyl/aryl 2-oxindols as well thereby widening the scope even further. Eventually, a Pd(0)-catalyzed asymmetric decarboxylative allylation of few products is shown to furnish synthetically viable enantioenriched 2-oxindoles with C-3 quaternary stereocenters.

Synthesis of 2-Oxindoles Sharing Vicinal All-Carbon Quaternary Stereocenters via Organocatalytic Aldol Reaction.

An organocatalytic enantioselective aldol reaction using paraformaldehyde as C1-unit has been developed for the synthesis of 2-oxindoles sharing vicinal all-carbon quaternary stereocenters. The methodology is eventually employed in the formal total synthesis of (+)-folicanthine (1b).

Multifactorial effects of short duration early exposure low intensity magnetic field stimulation in Streptozotocin induced Alzheimer's disease rat model.

Alzheimer's disease (AD) is an approaching, progressive public health crisis which presently lacks an effective treatment. Various non-invasive novel therapies like repetitive transcranial magnetic stimulation have shown potential to improve cognitive performance in AD patients. In the present study, the effect of extremely low intensity magnetic field (MF) stimulation on neurogenesis and cortical electrical activity was explored. Adult Wistar rats were divided into Sham, AD and AD + MF groups. Streptozotocin (STZ) was injected intracerebroventricularly, at a dose of 3 mg/kg body weight for developing AD model. The AD rats were then exposed to MF (17.96 µT) from 8th day of STZ treatment until 15th day, followed by cognitive assessments and electrocortical recording. In brain tissue samples, cresyl violet staining and BrdU immunohistochemistry were done. MF exposure, improved passive avoidance and recognition memory, attenuated neuronal degeneration and enhanced cell proliferation (BrdU positive cells) in comparison to AD rats. It also significantly restores delta wave power from frontal lobe. Our results suggest that early-stage MF exposure could be an asset for AD research and open new avenues in slowing down the progression of Alzheimer's disease.

Functionality Modulation Toward Thianthrene-based Metal-Free Electrocatalysts for Water Splitting.

The development of metal-free bifunctional electrocatalysts for hydrogen and oxygen evolution reactions (HER and OER) is significant but rarely demonstrated. Porous organic polymers (POPs) with well-defined electroactive functionalities show superior performance in hydrogen evolution reaction (HER) and oxygen evolution reaction (OER). Precise control of the active sites' local environment requires careful modulation of linkers through the judicious selection of building units. Here, a systematic strategy is introduced for modulating functionality to design and synthesize a series of thianthrene-based bifunctional sp2 C═C bonded POPs with hollow spherical morphologies exhibiting superior electrocatalytic activity. This precise structural tuning allowed to gain insight into the effects of heteroatom incorporation, hydrophilicity, and variations in linker length on electrocatalytic activity. The most efficient bifunctional electrocatalyst THT-PyDAN achieves a current density of 10 mA cm─2 at an overpotential (η10) of ≈65 mV (in 0.5 m H2SO4) and ≈283 mV (in 1 m KOH) for HER and OER, respectively. THT-PyDAN exhibits superior activity to all previously reported metal-free bifunctional electrocatalysts in the literature. Furthermore, these investigations demonstrate that THT-PyDAN maintains its performance even after 36 h of chronoamperometry and 1000 CV cycling. Post-catalytic characterization using FT-IR, XPS, and microscopic imaging techniques underscores the long-term durability of THT-PyDAN.

Oxysterole-binding protein targeted by SARS-CoV-2 viral proteins regulates coronavirus replication.

Introduction: Oxysterol-binding protein (OSBP) is known for its crucial role in lipid transport, facilitating cholesterol exchange between the Golgi apparatus and endoplasmic reticulum membranes. Despite its established function in cellular processes, its involvement in coronavirus replication remains unclear. Methods: In this study, we investigated the role of OSBP in coronavirus replication and explored the potential of a novel OSBP-binding compound, ZJ-1, as an antiviral agent against coronaviruses, including SARS-CoV-2. We utilized a combination of biochemical and cellular assays to elucidate the interactions between OSBP and SARS-CoV-2 non-structural proteins (Nsps) and other viral proteins. Results: Our findings demonstrate that OSBP positively regulates coronavirus replication. Moreover, treatment with ZJ-1 resulted in reduced OSBP levels and exhibited potent antiviral effects against multiple coronaviruses. Through our investigation, we identified specific interactions between OSBP and SARS-CoV-2 Nsps, particularly Nsp3, Nsp4, and Nsp6, which are involved in double-membrane vesicle formation-a crucial step in viral replication. Additionally, we observed that Nsp3 a.a.1-1363, Nsp4, and Nsp6 target vesicle-associated membrane protein (VAMP)-associated protein B (VAP-B), which anchors OSBP to the ER membrane. Interestingly, the interaction between OSBP and VAP-B is disrupted by Nsp3 a.a.1-1363 and partially impaired by Nsp6. Furthermore, we identified SARS-CoV-2 orf7a, orf7b, and orf3a as additional OSBP targets, with OSBP contributing to their stabilization. Conclusion: Our study highlights the significance of OSBP in coronavirus replication and identifies it as a promising target for the development of antiviral therapies against SARS-CoV-2 and other coronaviruses. These findings underscore the potential of OSBP-targeted interventions in combating coronavirus infections.

Utility of high-flow nasal oxygen in comparison to conventional oxygen therapy during upper gastrointestinal endoscopic procedures under sedation: A systematic review and meta-analyses.

BACKGROUND: Sedation and analgesia are the integral components of modern-day upper gastrointestinal (GI) endoscopic procedures. Irrespective of the sedative agent, hypoxia is the most commonly encountered unwarranted event with sedation. The current study intends to scrutinize whether high-flow nasal oxygen (HFNO) is advantageous for providing respiratory support during upper GI endoscopic procedures over other conventional low-flow oxygen delivery modalities, e.g. nasal cannula, facemask, etc. METHODS: An extensive screening of electronic databases was done till July 31, 2022, after enlisting in International prospective register of systematic reviews (PROSPERO) (CRD42021245409). Randomized controlled trials (RCT), comparative cohort studies, case series, cross-sectional studies and case-control studies evaluating the utility of HFNO during upper GI endoscopy under sedation were included in this meta-analysis. RESULTS: We retrieved eight randomized control studies and one longitudinal study with 3294 patients. The application of HFNO during endoscopy led to lesser incidence of desaturation spells (odds ratio [OR] = 0.23; 95% CI 0.11-0.48; I2 = 71%), reduced procedural interruption (OR = 0.11; 95% CI 0.02-0.60; I2 = 88%), better nadir SpO2 level during procedure (mean difference [MD] = 3.16; 95% CI 0.54-5.78; I2 = 73%), overall lesser incidence of sedation-related adverse events (OR = 0.63; 95% CI 0.42-0.93; I2 = 25%), with no significant impact on the duration of endoscopy (MD = 0.15; 95% CI - 0.02 to 0.31, I2 = 0%). CONCLUSION: HFNO is a novel option for upper GI endoscopy under sedation. CLINICAL TRIAL NUMBER AND REGISTRY URL: CRD42021245409 ( https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021245409 ).

Quadratus lumborum block vs. transversus abdominis plane block in laparoscopic trans-abdominal pre-peritoneal repair of inguinal hernia in adults: A randomised controlled trial.

Background and Aims: Laparoscopic trans abdominal preperitoneal (TAPP) repair of hernia is one of the most commonly performed surgeries and may cause significant postoperative pain. Among different truncal block techniques, quadratus lumborum (QL) and transversus abdominis plane blocks (TAP) are used during this abdominal surgery. We aimed to investigate whether, bilateral QL block by trans-muscular approach provided better analgesia as compared to posterior TAP block in these patients. Methods: Forty adult patients with American Society of Anesthesiologists physical status I and II, undergoing inguinal hernia repair were randomized to receive either QL or TAP block, with 20 mL of 0.25% ropivacaine bilaterally. The primary objective of the study was to compare the total fentanyl consumption (in µg) within 24 hours postoperatively. The secondary objectives studied were dermatomal spread, quality of recovery at discharge and at 3 months postoperatively. Results: There was a significant reduction in total 24-hour fentanyl consumption (552 ± 229.56 vs 735.5 ± 264 µg, P =0.01) in the QL group, with longer duration of analgesia [282.5 ± 89.9 min group TAP vs. 354.8 ± 107 min QL, (mean difference -72.34,95% confidence interval -135.516 to -9.024), P =0.03], as compared to TAP group. At T8 and T9 dermatomes, greater proportion of patients in the QL group attained analgesia. Quality of Recovery at 24 hours and at 3 months of follow-up were comparable. Conclusion: QL block provided better perioperative analgesia than TAP block, in patients undergoing laparoscopic hernia repair. It also leads to greater dermatomal spread but without any decrease in the incidence of chronic pain at 3 months postoperatively.

Acute sleep deprivation induces synaptic remodeling at the soleus muscle neuromuscular junction in rats.

Sleep is important for cognitive and physical performance. Sleep deprivation not only affects neural functions but also results in muscular fatigue. A good night's sleep reverses these functional derangements caused by sleep deprivation. The role of sleep in brain function has been extensively studied. However, its role in neuromuscular junction (NMJ) or skeletal muscle morphology is sparsely addressed although skeletal muscle atonia and suspended thermoregulation during rapid eye movement sleep possibly provide a conducive environment for the muscle to rest and repair; somewhat similar to slow-wave sleep for synaptic downscaling. In the present study, we have investigated the effect of 24 h sleep deprivation on the NMJ morphology and neurochemistry using electron microscopy and immunohistochemistry in the rat soleus muscle. Acute sleep deprivation altered synaptic ultra-structure viz. mitochondria, synaptic vesicle, synaptic proteins, basal lamina, and junctional folds needed for neuromuscular transmission. Further acute sleep deprivation showed the depletion of the neurotransmitter acetylcholine and the overactivity of its degrading enzyme acetylcholine esterase at the NMJ. The impact of sleep deprivation on synaptic homeostasis in the brain has been extensively reported recently. The present evidence from our studies shows new information on the role of sleep on the NMJ homeostasis and its functioning.

The use of preoperative inferior vena cava ultrasound to predict anaesthesia-induced hypotension: a systematic review.

Preoperative ultrasound assessment of inferior vena cava (IVC) diameter and the collapsi-bility index might identify patients with intravascular volume depletion. The purpose of this review was to gather the existing evidence to find out whether preoperative IVC ultrasound (IVCUS) derived parameters can reliably predict hypotension after spinal or general anaesthesia. PubMed was searched to identify research articles that addressed the role of IVC ultrasound in predicting hypotension after spinal and general anaesthesia in adult patients. We included 4 randomized control trials and 17 observational studies in our final review. Among these, 15 studies involved spinal anaesthesia and 6 studies involved general anaesthesia. Heterogeneity with respect to the patient populations under evaluation, definitions used for hypotension after anaesthesia, IVCUS assessment methods, and cut-off values for IVCUS-derived parameters to predict hypotension precluded pooled meta-analysis. The maximum and minimum reported sensitivity of the IVC collapsibility index (IVCCI) for predicting post-spinal hypotension was 84.6% and 58.8% respectively, while the maximum and minimum specificities were 93.1% and 23.5% respectively. For the prediction of hypotension after general anaesthesia induction, the reported ranges of sensitivity and specificity of IVCCI were 86.67% to 45.5% and 94.29% to 77.27%, respectively. Current literature on the predictive role of IVCUS for hypotension after anaesthesia is heterogeneous both in methodology and in results. Standardization of the definition of hypotension under anaesthesia, method of IVCUS assessment, and the cut-offs for IVC diameter and the collapsibility index for prediction of hypotension after anaesthesia are necessary for drawing clinically relevant conclusions.

Dendritic reorganization in the hippocampus, anterior temporal lobe, and frontal neocortex of lithium-pilocarpine induced Status Epilepticus (SE).

Status Epilepticus (SE) is a distributed network disorder, which involves the hippocampus and extra-hippocampal structures. Epileptogenesis in SE is tightly associated with neurogenesis, plastic changes and neural network reorganization facilitating hyper-excitability. On the other hand, dendritic spines are known to be the excitatory synapse in the brain. Therefore, dendritic spine dynamics could play an intricate role in these network alterations. However, the exact reason behind these structural changes in SE are elusive. In the present study, we have investigated the aforementioned hypothesis in the lithium-pilocarpine treated rat model of SE. We have examined cytoarchitectural and morphological changes using hematoxylin-eosin and Golgi-Cox staining in three different brain regions viz. CA1 pyramidal layer of the dorsal hippocampus, layer V pyramidal neurons of anterior temporal lobe (ATL), and frontal neocortex of the same animals. We observed macrostructural and layer-wise alteration of the pyramidal layer mainly in the hippocampus and ATL of SE rats, which is associated with sclerosis in the hippocampus. Sholl analysis exhibited partial dendritic plasticity in apical and basal dendrites of pyramidal cells as compared to the saline-treated weight-/age-matched control group. These findings indicate that region-specific alterations in dendritogenesis may contribute to the development of independent epileptogenic networks in the hippocampus, ATL, and frontal neocortex of SE rats.