Impact of N-Glycosylation on Protein Structure and Dynamics Linked to Enzymatic C-H Activation in the M. oryzae Lipoxygenase.

Lipoxygenases (LOXs) from pathogenic fungi are potential therapeutic targets for defense against plant and select human diseases. In contrast to the canonical LOXs in plants and animals, fungal LOXs are unique in having appended N-linked glycans. Such important post-translational modifications (PTMs) endow proteins with altered structure, stability, and/or function. In this study, we present the structural and functional outcomes of removing or altering these surface carbohydrates on the LOX from the devastating rice blast fungus, M. oryzae, MoLOX. Alteration of the PTMs did notinfluence the active site enzyme-substrate ground state structures as visualized by electron-nuclear double resonance (ENDOR) spectroscopy. However, removal of the eight N-linked glycans by asparagine-to-glutamine mutagenesis nonetheless led to a change in substrate selectivity and an elevated activation energy for the reaction with substrate linoleic acid, as determined by kinetic measurements. Comparative hydrogen-deuterium exchange mass spectrometry (HDX-MS) analysis of wild-type and Asn-to-Gln MoLOX variants revealed a regionally defined impact on the dynamics of the arched helix that covers the active site. Guided by these HDX results, a single glycan sequon knockout was generated at position 72, and its comparative substrate selectivity from kinetics nearly matched that of the Asn-to-Gln variant. The cumulative data from model glyco-enzyme MoLOX showcase how the presence, alteration, or removal of even a single N-linked glycan can influence the structural integrity and dynamics of the protein that are linked to an enzyme's catalytic proficiency, while indicating that extensive glycosylation protects the enzyme during pathogenesis by protecting it from protease degradation.

CPA-induced Hz to THz broadband absorber with switchable perfect absorption between radio-microwave and THz frequency spectrum.

The coherent perfect absorption (CPA) occurring in the graphene sheet suspended in air can be utilized to develop an ultrathin, ultra-broadband absorber working in the frequency range from a few hertz (Hz) to terahertz (THz) with perfect absorption. A graphene sheet is studied to induce the CPA to cover radio, microwave and lower THz frequency ranges. A graphene resonator able to provide the surface plasmon resonance (SPR) is combined with the graphene sheet to provide CPA at either side of a thin dielectric layer forms metamaterial structure with the cavity and enhances the absorption bandwidth in the THz region by creating a resonance near quasi-CPA frequency. A dielectric silicon resonator is embedded in the structure, which creates dipolar resonances between the resonances obtained by the formed cavity between the graphene sheet and resonator. This enhances the absorption level in the THz region. The absorption bandwidth is further enhanced to 7 THz by including a graphene disc at the top of the silicon resonator. Thus, the multiple multi-order resonances occurring in the silicon dielectric and SPR of graphene resonators are merged with the phenomena of CPA occurring in the graphene sheets to extend the CPA bandwidth in the THz regime. The doping level of graphene or its tunable Fermi energy based on the applied DC electric field provides the tunability in the total obtained absorption bandwidth. The symmetric structure provides polarization-insensitive behavior with an allowed incident angle of more than 45° with more than 90% absorption.

Limitations of U25 CKiD and CKD-EPI eGFR formulae in patients 2-20 years of age with measured GFR > 60 mL/min/1.73 m2-a cross-sectional study.

BACKGROUND: When applying Pierce U25 formula for estimating glomerular filtration rate (eGFR), we observed a higher proportion of eGFR < 90 mL/min/1.73 m2 (chronic kidney disease (CKD) stage 2). We compared agreement and accuracy of the Pierce U25 (ages 2-25), Pottel (ages 2-100), and CKD-EPI (ages 18-100) formulae to GFR measurements. METHODS: Post hoc analysis of the three eGFRs compared to 367 99m technetium-diethylene-triamine penta-acetic acid (99Tc DTPA) GFR measurements (240 patients) using 3 sampling points and Brockner/Mørtensen correction (body surface area calculation based on ideal weight) on simultaneous serum creatinine and cystatin C measurements. RESULTS: Overall, the U25 formula performed well with a Spearman r of 0.8102 (95% confidence interval 0.7706 to 0.8435, p < 0.0001) while diagnostic accuracy was low in patients with normal mGFR. The U25 formula reclassified 29.5% of patients with normal mGFR as CKD stage 2; whereas the average of the modified Schwartz formula based on serum creatinine and the Filler formula based on cystatin C, only over-diagnosed CKD stage 2 in 8.5%, 24.5% within 10% and 62.7% within 30%. We therefore combined both. The average Schwartz/Filler eGFR had 36.5% of results within 10%, 84.7% within 30%, and normal mGFR accuracy was 26.8%, 63.9% for 10% and 30%, respectively, outperforming the CKD-EPI and Pottel formulae. CONCLUSIONS: The Pierce U25 formula results correlated well with mGFR < 75 mL/min/1.73 m2. Over the entire GFR range, accuracy was better for patients with a higher mGFR, when averaging the combined Schwartz/Filler formulae. More work is needed to prospectively confirm our findings in other centers.

Treatment of Iron-Induced Cutaneous Hyperpigmentation With Energy-Based Devices.

OBJECTIVES: Iatrogenic cutaneous siderosis is a well-recognized dermatologic complication after parenteral iron infusion. The condition manifests as discrete, hyperpigmented patches near the site of injection. Most cases do not resolve spontaneously, leading to significant aesthetic and psychological distress to patients. A recent case of iatrogenic cutaneous siderosis at our institution prompted a systematic review of the efficacy of energy-based devices previously reported in the treatment of this condition. METHODS: PubMed and Cochrane databases were searched for all peer-reviewed articles published using the following search terms: "iron OR heme OR hemosiderosis OR siderosis" and "hyperpigmentation OR staining OR tattoo." Articles reporting on energy-based devices in the treatment of iron-induced hyperpigmentation were included. RESULTS: A total of seven articles and 54 total patients were included in this review. All patients, including the patient treated at our institution, were female, with an average age of 44 years. Hyperpigmentation was most commonly associated with intravenous iron infusion (48/54, 89%), on the arm or forearm (44/54, 81%), and used for the treatment of underlying iron deficiency anemia (54/54, 100%). The application of six different nanosecond or picosecond quality-switched laser systems was reported in the treatment of cutaneous siderosis, with wavelengths ranging from 532 to 1064 nm. Spot sizes varied between 2 and 7 mm, with energy fluences spanning 0.5-40 J/cm2 depending on both the device and spot size. Outcomes were measured after an average of 5.4 laser treatments and 10.4 months, with over half of all reported patients experiencing complete clearance (27/50, 54%). Our patient received treatment in three test areas with picosecond alexandrite 785 nm, nanosecond Nd:YAG 532 nm, and picosecond Nd:YAG 532 nm devices. The nanosecond Nd:YAG 532 nm treated area demonstrated the greatest improvement, and the entire arm was subsequently treated with this device. CONCLUSIONS: Despite the often intractable nature of iatrogenic cutaneous siderosis, laser surgery is a reasonable and safe treatment modality for patients seeking cosmetic improvement of this dyschromia. Dermatologists should be aware of this entity and the efficacy of the energy-based devices currently in our armamentarium. A combination approach may need to be utilized with different wavelengths and pulsed widths to target iron pigment in both dermal and subcutaneous layers.

Avelumab in the Treatment of Advanced Merkel Cell Carcinoma: A Systematic Review.

BACKGROUND: Avelumab, a programmed death ligand-1 inhibitor, has shown success in providing durable responses for difficult-to-treat Merkel cell carcinomas (MCCs). OBJECTIVE: Evaluate the efficacy and safety of avelumab in the treatment of advanced MCC. METHODS: Studies reporting the use of avelumab as a monotherapy or in combination with other agents in the treatment of stage III or IV (advanced) MCC were included. The primary outcomes were overall response rate, overall survival (OS), and treatment-related adverse events. RESULTS: A total of 48 studies were included, involving 1,565 patients with advanced MCC. Most patients were male (1,051, 67.3%) with stage IV MCC (517, 97.0%). The overall response rate was 46.1% (partial response-25.4% and complete response-20.7%) after a mean follow-up period of 9.5 months. Kaplan-Meier survival curves for the pooled stage III and IV group demonstrated OS rates of 58% at 1 year, 47% at 2 years, and 28% at 5 years after completion of treatment with avelumab (median OS: 23.1 months). The most common treatment-related adverse events consisted of constitutional (44%), gastrointestinal (19%), and dermatologic (12%) symptoms. CONCLUSION: Avelumab monotherapy and combination therapy have shown success in the overall response rate and survival for patients with advanced MCC.

An ecophysiological explanation for manganese enrichment in rock varnish.

Desert varnish is a dark rock coating that forms in arid environments worldwide. It is highly and selectively enriched in manganese, the mechanism for which has been a long-standing geological mystery. We collected varnish samples from diverse sites across the western United States, examined them in petrographic thin section using microscale chemical imaging techniques, and investigated the associated microbial communities using 16S amplicon and shotgun metagenomic DNA sequencing. Our analyses described a material governed by sunlight, water, and manganese redox cycling that hosts an unusually aerobic microbial ecosystem characterized by a remarkable abundance of photosynthetic Cyanobacteria in the genus Chroococcidiopsis as the major autotrophic constituent. We then showed that diverse Cyanobacteria, including the relevant Chroococcidiopsis taxon, accumulate extraordinary amounts of intracellular manganese-over two orders of magnitude higher manganese content than other cells. The speciation of this manganese determined by advanced paramagnetic resonance techniques suggested that the Cyanobacteria use it as a catalytic antioxidant-a valuable adaptation for coping with the substantial oxidative stress present in this environment. Taken together, these results indicated that the manganese enrichment in varnish is related to its specific uptake and use by likely founding members of varnish microbial communities.

Method validation, residue behaviour and dietary risk assessment of insecticides (cyantraniliprole, acetamiprid, flubendiamide and its metabolite, des-iodo flubendiamide) in or on broccoli using LC-MS/MS.

Residue behaviour and dietary risk assessment of cyantraniliprole, flubendiamide and acetamiprid in broccoli were carried out using the QuEChERS (quick, easy, cheap, effective, rugged and safe) technique coupled with LC-MS/MS. The QuEChERS technique was validated on parameters such as linearity, accuracy, precision, robustness, matrix effects, limit of quantification (LOQ), specificity, retention time and ion ratio as per SANTE (Directorate General for Health and Food Safety) guidelines to attest to the specificity, accuracy and precision of the analytical method in estimating insecticide residues in and on broccoli heads and cropped soil. The LOQ of the method for all three insecticides was 0.01 mg/kg. The initial deposits of cyantraniliprole, flubendiamide and acetamiprid reduced to half of its concentration in 1.873-2.354, 1.975-2.484 and 1.371-1.620 days, respectively. No residues were detected in broccoli-cropped soil at harvest time (30 days after last spray). The proposed maximum residue limits (MRLs) of 1.5, 0.5-0.9 and 2.0-3 mg/kg for cyantraniliprole, flubendiamide and acetamiprid were calculated using the Organisation for Economic Co-operation and Development MRL calculator. The acute and chronic dietary risk assessment of the tested insecticides identified no appreciable dietary risk to the Indian population from the consumption of broccoli heads. The findings of no dietary risk highlight the importance of informed pesticide usage in broccoli and the proposed MRL derived from this study offers crucial guidelines for the regulatory authorities, ensuring the safety of broccoli consumption.

Dissipation kinetics and the evaluation of dietary risks associated with deltamethrin, ethion, fenazaquin, and fenpropathrin on bell pepper (Solanum annuum L.).

Bell peppers, a globally significant crop, face infestations from various pests. In a study, bell peppers were treated with deltamethrin, ethion, fenazaquin, and fenpropathrin at recommended and double the doses, repeated twice with a 10-day interval. The QuEChERS method underwent validation for linearity, matrix match, accuracy, and precision in bell pepper matrices for residue analysis. The limit of detection for the tested pesticides on bell peppers was 0.01 mg/L, with a quantification limit of 0.05 mg/L. Recovery studies showed a range of 94.80% to 102.80%. Initial deposits of deltamethrin, ethion, fenazaquin, and fenpropathrin on bell peppers at recommended doses were 0.371, 1.237, 0.617, and 0.640 mg/L, respectively, and at double doses were 0.712, 1.945, 1.221, and 1.189 mg/L, respectively. Safe waiting periods of 10, 11, 10, and 8 days were suggested for deltamethrin, ethion, fenazaquin, and fenpropathrin, respectively. The corresponding half-lives for the pesticides were 1.96, 1.79, 2.06, and 1.69 days, all following first-order dissipation kinetics. Dietary risk assessment indicated Hazard Quotients (HQ) below 1 and Theoretical Maximum Daily Intake (TMDI) below Acceptable Daily Intake (ADI) and Maximum Permissible Intake (MPI) levels. Therefore, at their recommended doses, the pesticides were deemed safe for bell pepper cultivation.

Developing, validating, and comparing an analytical method to simultaneously detect z-drugs in urine samples using the QuEChERS approach with both liquid chromatography and gas chromatography-tandem mass spectrometry.

Detecting z-drugs, a sedative-hypnotic medication, is also misused for criminal activities. Therefore, the analysis of urine samples is crucial for clinical and forensic purposes. We conducted a study where we developed, validated, and compared an analytical method for simultaneously detecting z-drugs in urine samples. Our approach uses the QuEChERS method for sample preparation, combined with liquid chromatography (LC) and gas chromatography (GC) coupled with tandem mass spectrometry (MS/MS). We optimized the QuEChERS method to effectively extract z-drugs from urine samples while minimizing matrix effects and achieving high recovery rates. After extraction, we split the samples into two parts for analysis using LC-MS/MS and GC-MS/MS. We validated our methods, and the results showed good linearity over a broad concentration range (1-200 ng/mL) for each z-drug. The limits of detection and quantification were within clinically relevant ranges, ensuring sensitivity for detecting z-drugs in urine samples. We compared the two chromatographic techniques by analyzing a set of urine samples spiked with known concentrations of z-drugs using both LC-MS/MS and GC-MS/MS methods and then applied to the real samples. The results were statistically analyzed to assess any significant differences in accuracy and precision above 95 %, and both methods offered reliable and consistent results with the samples as well. In conclusion, our analytical method coupled with both LC-MS/MS and GC-MS/MS using the QuEChERS approach provides a comprehensive and robust solution for the simultaneous detection of z-drugs in urine samples. The choice between the two chromatographic techniques can be based on the specific z-drugs of interest and the required analytical performance. This method holds promise for applications in clinical toxicology, forensic analysis, and monitoring z-drug usage.

Can gabapentinoids decrease perioperative opioid requirements in orthopaedic trauma patients? A single-centre retrospective analysis.

INTRODUCTION: Perioperative pain control in patients with orthopaedic trauma/extremity fractures has gained a lot of attraction from the scientific community in the last two decades. In addition to multimodal analgesia, the use of non-opioid drugs like gabapentinoids for pain relief is gradually finding its place in several orthopaedic subspecialties like spinal surgery, arthroplasty, and arthroscopic procedures. We envisage investigating the effectiveness of gabapentin in perioperative pain control in patients with extremity fractures undergoing surgical fixation. METHODOLOGY: This was a retrospective comparative study conducted between January 2020 and January 2022. Patients with isolated fractures of the extremity involving long bones who were treated at our trauma centre, during the study period were divided into two groups based on the analgesics they received. Patients who received gabapentin and paracetamol were placed in group GP and those who received only paracetamol were assigned group NGP. Gabapentin was given in a single dose of 300 mg 4 h before surgery. Postoperatively, they were given 300 mg 12 hourly for 2 days. All patients in our trauma centre are usually managed with parenteral paracetamol administration pre and postoperatively. VAS score was calculated postoperatively at 2, 6, 12, 24 and 48 h. Patients requiring additional analgesics for pain relief were administered intravenous tramadol or a buprenorphine patch was applied. Patients in both groups were compared in terms of pain control, the additional requirement of opioid analgesics, and any adverse event related to medications. RESULTS: One hundred and nineteen patients were enrolled in the study. Out of 65 patients in the NGP group (non-gabapentin group), 74% of patients received additional opioid analgesics apart from paracetamol. Out of the 54 patients in the GP group (gabapentin group), only 41% required additional opioid analgesia for pain control. There was a significant difference in opioid consumption between the two groups (p < 0.01). VAS scores were not significantly different between the two groups at 2, 4, 6, 12, 24 and 48 h. Gender and fracture morphology did not affect opioid intake in the GP group. However, in the non-gabapentin group, there was a significant difference in opioid requirement in patients with intraarticular fractures (p < 0.01). CONCLUSION: Analgesic requirements vary from patient to patient depending on the injury's severity and surgery duration. However, there are no strict guidelines for pain relief in limb trauma surgeries which often leads to overuse and opioid-related complications or underuse and chronic pain. Gabapentinoids can supplement the analgesic effect of paracetamol in trauma patients during the perioperative period, decreasing the need for opioids.

13C Electron Nuclear Double Resonance Spectroscopy-Guided Molecular Dynamics Computations Reveal the Structure of the Enzyme-Substrate Complex of an Active, N-Linked Glycosylated Lipoxygenase.

Lipoxygenase (LOX) enzymes produce important cell-signaling mediators, yet attempts to capture and characterize LOX-substrate complexes by X-ray co-crystallography are commonly unsuccessful, requiring development of alternative structural methods. We previously reported the structure of the complex of soybean lipoxygenase, SLO, with substrate linoleic acid (LA), as visualized through the integration of 13C/1H electron nuclear double resonance (ENDOR) spectroscopy and molecular dynamics (MD) computations. However, this required substitution of the catalytic mononuclear, nonheme iron by the structurally faithful, yet inactive Mn2+ ion as a spin probe. Unlike canonical Fe-LOXs from plants and animals, LOXs from pathogenic fungi contain active mononuclear Mn2+ metallocenters. Here, we report the ground-state active-site structure of the native, fully glycosylated fungal LOX from rice blast pathogen Magnaporthe oryzae, MoLOX complexed with LA, as obtained through the 13C/1H ENDOR-guided MD approach. The catalytically important distance between the hydrogen donor, carbon-11 (C11), and the acceptor, Mn-bound oxygen, (donor-acceptor distance, DAD) for the MoLOX-LA complex derived in this fashion is 3.4 ± 0.1 Å. The difference of the MoLOX-LA DAD from that of the SLO-LA complex, 3.1 ± 0.1 Å, is functionally important, although is only 0.3 Å, despite the MoLOX complex having a Mn-C11 distance of 5.4 Å and a "carboxylate-out" substrate-binding orientation, whereas the SLO complex has a 4.9 Å Mn-C11 distance and a "carboxylate-in" substrate orientation. The results provide structural insights into reactivity differences across the LOX family, give a foundation for guiding development of MoLOX inhibitors, and highlight the robustness of the ENDOR-guided MD approach to describe LOX-substrate structures.

Ascorbate formulation improves healing efficacy in excisional wound mice model through interplay between pro and anti-inflammatory cytokines and angiogenic markers.

BACKGROUND AND OBJECTIVE: Biomedical research in regenerative medicine prompts researchers to formulate cost-effective therapeutics for wound healing. The present study was conducted to characterize the ascorbate based formulation vis-a-vis investigating the molecular dynamics of the formulation. MATERIALS AND METHODS: To characterize the formulation, particle size, zeta potential, thermal stability, compatibility, anti-oxidant, and permeation prospective were measured using standard protocols. The in-vitro healing potential and safety formulae were evaluated using the L929 cell line. For molecular unravelling of the pharmacodynamics of formulation, an excision wound model was used, and 54 mice were randomly and equally divided into three groups, i.e., untreated, betadine-treated, and formulation-treated, to ascertain the interplay between cytokines and chemokines and their culminative role in the release of growth factors. RESULTS: The ascorbate formulae were found to be amorphous, biocompatible, safe, and long-lasting, with particle sizes and zeta potentials of 389.7 ± 0.69 nm and -38.1 ± 0.65 mV, respectively, and anti-oxidative potential. An in-vitro study revealed that the formulation has a significant (p<0.05) migration potential and is non-toxic. Expression profiling of TGF-ß, FGF-2, VEGF, and collagen III & I showed significant (p<0.05) up-regulation, whereas significant (p<0.05) down-regulation of pro-inflammatory genes like IL-1α, IL-1ß, TNF-α, IL-6, and temporal change in CCR-5 was observed in formulae-treated animals as compared to other groups. CONCLUSION: By up-regulating angiogenic and collagen-promoting growth factor gene expression while down-regulating pro-inflammatory gene expression, ascorbate formulation promotes wound healing via extracellular matrix and granulation tissue deposition with significant improvement in tensile strength.

Multicomponent Reaction of CS2, Amines, and Sulfoxonium Ylides in Water: Straightforward Access to ß-Keto Dithiocarbamates, Thiazolidine-2-thiones, and Thiazole-2-thiones.

Simple, versatile, and catalyst-free synthetic methods for ß-keto dithiocarbamates, thiazolidine-2-thiones, and thiazole-2-thiones via the multicomponent reaction of CS2, amines, and sulfoxonium ylides have been described. The ß-keto sulfoxonium ylides furnished ß-keto dithiocarbamates in the presence of CS2 and secondary amines, whereas primary amines afforded thiazolidine-2-thiones or thiazole-2-thiones after dehydration in an acidic environment. With simple procedures, the reaction has a wide substrate scope and excellent functional group tolerance.

Organocatalyzed epoxidation in the total synthesis of (-)-trans-, (+)-trans- and (+)-cis-disparlures.

A simple, flexible and efficient organocatalyzed synthetic approach for the synthesis of (-)-trans-, (+)-trans- and (+)-cis-disparlures has been described. The pivotal reaction sequence comprises organocatalyzed asymmetric Jørgensen epoxidation, Wittig olefination, migration of epoxide and Mitsunobu inversion reaction. Excellent enantiomeric purity (≥99%) was achieved during the synthesis of disparlure enantiomers by the Jørgensen epoxidation key step.

Proline-catalyzed synthesis of α-substituted (E)-α,ß-unsaturated aldehydes from epoxides.

A novel, simple and metal-free tandem approach for synthesizing α-substituted (E)-α,ß-unsaturated aldehyde derivatives through acid-catalyzed epoxide rearrangement and organocatalyzed aldol condensation processes has been described. This transformation has a broad substrate scope under mild conditions, including epoxides and aldehydes containing diverse functional groups, resulting in moderate to high yields of the desired products. Eventually, large-scale reactions and the synthesis of some bioactive molecules are used to demonstrate the potential applicability of the developed method.

Narsoplimab for severe transplant-associated thrombotic microangiopathy.

BACKGROUND: Transplantation-associated thrombotic microangiopathy (TA-TMA) is an endothelial injury syndrome linked to the overactivation of complement pathways. It manifests with microangiopathic hemolytic anemia, consumptive thrombocytopenia, and microvascular thrombosis leading to ischemic tissue injury. Mannose residues on fungi and viruses activate the mannose-binding lectin complement pathway, and hence activation of the lectin pathway could be one of the reasons for triggering TA-TMA. Narsoplimab, a human monoclonal antibody targeting MASP-2 is a potent inhibitor of the lectin pathway. We describe the transplant course of a pediatric patient who developed TA-TMA following Candida-triggered macrophage activation syndrome and was treated with Narsoplimab. The data collection was performed prospectively. CASE PRESENTATION: The six-year-old girl underwent a human leucocyte antigen (HLA) haploidentical hematopoietic stem cell transplant using post-transplant Cyclophosphamide for severe aplastic anemia. In the second week of the transplant, the patient developed macrophage activation syndrome necessitating treatment with steroids and intravenous immunoglobulin. Subsequently, USG abdomen and blood fungal PCR revealed the diagnosis of hepatosplenic candidiasis. Candida-triggered macrophage activation syndrome responded to antifungals, steroids, intravenous immunoglobulin, and alemtuzumab. However, the subsequent clinical course was complicated by thrombotic microangiopathy. The patient developed hypertension in the 2nd week, followed by high lactate dehydrogenase (1010 U/L), schistocytes (5 per hpf), low haptoglobin (< 5 mg/dl), thrombocytopenia, and anemia in the 3rd week. Ciclosporin was stopped, and the patient was treated with 10 days of defibrotide without response. The course was further complicated by the involvement of the gastrointestinal tract and kidneys. She had per rectal bleeding with frequent but low-volume stools, severe abdominal pain, and hypoalbuminemia with a rising urine protein:creatinine ratio. Narsoplimab was started in the 5th week of the transplant. A fall in lactate dehydrogenase was observed after starting Narsoplimab. This was followed by the resolution of gastrointestinal symptoms, proteinuria, and recovery of cytopenia. The second episode of TA-TMA occurred with parvoviraemia and was also successfully treated with Narsoplimab. CONCLUSION: Lectin pathway inhibition could be useful in treating the fatal complication of transplant-associated thrombotic microangiopathy.

Cardiovascular Adaptations of Space Travel: A Systematic Review.

INTRODUCTION: Space travel imposes significant gravitational and radiation stress on both cellular and systemic physiology, resulting in myriad cardiovascular changes that have not been fully characterized. METHODS: We conducted a systematic review of the cellular and clinical adaptations of the cardiovascular system after exposure to real or simulated space travel in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The PubMed and Cochrane databases were searched in June 2021 for all peer-reviewed articles published since 1950 related to the following search terms entered in separate pairs: "cardiology and space" and "cardiology and astronaut." Only cellular and clinical studies in English concerning the investigation of cardiology and space were included. RESULTS: Eighteen studies were identified, comprising 14 clinical and 4 cellular investigations. On the genetic level, pluripotent stem cells in humans and cardiomyocytes in mice displayed increased beat irregularity, with clinical studies revealing a persistent increase in heart rate after space travel. Further cardiovascular adaptations included a higher frequency of orthostatic tachycardia but no evidence of orthostatic hypotension, after return to sea level. Hemoglobin concentration was also consistently decreased after return to Earth. No consistent change in systolic or diastolic blood pressure or any clinically significant arrhythmias were observed during or after space travel. CONCLUSION: Changes in oxygen carrying capacity, blood pressure, and post-flight orthostatic tachycardia may serve as reasons to further screen for pre-existing anemic and hypotensive conditions among astronauts.

Impact of the 2022 American Heart Association pediatric ambulatory blood pressure monitoring statement on the diagnosis of hypertension.

BACKGROUND: The diagnosis of hypertension and hypertension-induced target organ injury by the 2022 American Heart Association (AHA) ambulatory blood pressure threshold as compared with 2014 AHA and 2016 European Society of Hypertension (ESH) thresholds has not been evaluated. METHODS: In a cross-sectional study (n = 291, aged 5-18 years, at a tertiary care outpatient clinic), we compared 2022 AHA with 2014 AHA and ESH thresholds (revised with 2018 adult ESH thresholds where applicable) to diagnose ambulatory hypertension (AH), and detect ambulatory arterial stiffness index (AASI) and left ventricular target organ injury (LVTOI). RESULTS: The 2022 AHA threshold diagnosed significantly more AH (53%) than the 2014 AHA (42%, p < 0.01) and ESH (36%, p < 0.001) thresholds. The 2022 AHA threshold demonstrated only a moderate agreement with the 2014 AHA (kappa (k) = 0.77) and ESH (k = 0.66) thresholds to diagnose AH. Adjusted logistic regression analysis found that only the 2022 AHA threshold predicted elevated AASI significantly (odds ratio 2.40, 95% CI 1.09, 5.25, p = 0.02; AUC 0.61, p < 0.01). In those with elevated AASI, more participants had AH by the 2022 AHA threshold (72%) than the 2014 AHA (46%, p = 0.02) and ESH (48%, p = 0.03) thresholds. AH defined by the 2022 AHA threshold continued to maintain higher odds, larger AUC, and higher sensitivity to identify LVTOI than the 2014 AHA and ESH thresholds; however, the difference did not reach a statistically significant level. CONCLUSIONS: AH defined by the 2022 AHA threshold diagnoses more children with hypertension and identifies more children with hypertension-induced target organ injury than the 2014 AHA and ESH thresholds. A higher resolution version of the Graphical abstract is available as Supplementary information.

Layered double hydroxides and their tailored hybrids/composites: Progressive trends for delivery of natural/synthetic-drug/cosmetic biomolecules.

Layered double hydroxides (LDHs) are well-known and important class of hydrotalcite-type anionic clays (HTs) materials that are cost-effective with additional advantages of facile synthesis, composition, tenability, and reusability. These convincing characteristics are liable for their applications in various fields related to energy, environment, catalysis, biomedical, and biotechnology. HTs/LDHs are generally synthesized from low cost abundantly available chemical precursors through the aqueous synthetic pathways under mild reaction conditions. These materials can be termed green materials based on their non-toxic nature, availability of precursors, facile and low-cost production using aqueous medium conditions with less hazardous effluents. Diverse and fascinating characteristics have been attributed to HTs/LDHs like anion exchange ability, surface basicity, biocompatibility, controlled release of the anion specific area, porosity, easy surface modification, and pH dependent biodegradability. Hence, HTs/LDHs and their modified and/or functionalized nanohybrids/nanocomposites are reported as the potential drug delivery carriers with a capability to stabilize the susceptible bioactive molecules, may enhance the solubility of poorly soluble drugs along with controlled drug/bioactive molecule release and delivery. These clay and bioactive hybrid materials have good biocompatibility, less cytotoxicity, and better site-targeting with improved cellular uptake than that of free parent biomolecules. These lamellar solids of micro/nanostructure are compatible, host-guest materials and able to fabricate with drugs/cosmeceutical/bio- or synthetic polymers without any change in their molecular structure and reactivity along with improvement in their stabilities. Other important features are facile synthesis, basicity, high stability with easy storage, and efficient administration with low bio-toxicity. This study enlightens the applications of HTs/LDHs along with their hybrids/composites in the field of drug/cosmeceutical/gene delivery systems of natural/synthetic biomolecules.

Antibacterial and antioxidant assay of novel heteroaryl-substituted methane derivatives synthesized via ceric ammonium nitrate (CAN) catalyzed one-pot green approach.

Individually, hydroxycoumarin and amino pyrimidine derivatives are of significant biological interest owing to their importance in drugs and pharmaceuticals. To access their combined biological impact into one molecule, we designed a novel, one-pot green approach for synthesizing trisubstituted methanes. A series of new heteroaryl-substituted methanes have been synthesized and subjected to in vitro antibacterial and antioxidant evaluation. Tests against clinical isolates of Escherichia coli (gram-negative) and Staphylococcus aureus showed potent activity of the derivatives 4a, 4b, 4d, 4e, 4f, 4l, and 5 against the former, and 4a, 4e, 4j, and 4l against the later one. Further, antioxidant assay for these TRSMs was also studied where 4a, 4b, 4f, 4j, and 4l exhibited the most promising results. These preliminary bioassay evaluations strongly suggest the promise and scope of these molecules in medical science. A one pot methodology for the synthesis of coumarin and uracil tethered trisubstituted methanes has been reported. The synthesized derivatives were further analyzed for their antibacterial and antioxidant properties to explore their medicinal applications. The salient features of this methodology are operational simplicity, short reaction time, good to moderate yields of the products, easy purification method. Biochemical assay of the synthesized TRSMs a reveals their utility in medicinal & pharma industry.