Molecular mechanism of distinct chemokine engagement and functional divergence of the human Duffy antigen receptor.

The Duffy antigen receptor is a seven-transmembrane (7TM) protein expressed primarily at the surface of red blood cells and displays strikingly promiscuous binding to multiple inflammatory and homeostatic chemokines. It serves as the basis of the Duffy blood group system in humans and also acts as the primary attachment site for malarial parasite Plasmodium vivax and pore-forming toxins secreted by Staphylococcus aureus. Here, we comprehensively profile transducer coupling of this receptor, discover potential non-canonical signaling pathways, and determine the cryoelectron microscopy (cryo-EM) structure in complex with the chemokine CCL7. The structure reveals a distinct binding mode of chemokines, as reflected by relatively superficial binding and a partially formed orthosteric binding pocket. We also observe a dramatic shortening of TM5 and 6 on the intracellular side, which precludes the formation of the docking site for canonical signal transducers, thereby providing a possible explanation for the distinct pharmacological and functional phenotype of this receptor.

Comparison of two different positions of an anaesthesiologist for ease of endotracheal intubation in adult patients: A randomised control trial.

BACKGROUND AND AIMS: Maintaining the airway with a cuffed endotracheal tube (ETT) in the trachea remains one of the most essential anaesthesia skills. Many parameters were described to assess the difficulty of intubation in the preoperative period, but none allow the prediction of all difficult intubations. The correct posture of the anaesthesiologist is also an important factor for successful endotracheal intubation. The aim of this study was. This study aimed to compare the impact of two different positions of an anaesthesiologist (sitting vs. standing) at the time of endotracheal intubation. METHODS: One hundred ten American Society of Anaesthesiologists (ASA) Physical Status I/II patients, aged between 17 to 65 years, Mallampati grade I/II, mouth opening 39-70 mm, thyromental distance (TMD) 6-6.5 cm, and sternomental distance (SMD) >13 cm, scheduled for elective laparoscopic cholecystectomy, were recruited. Patients were divided into two groups; Group I consisted of patients who underwent endotracheal intubation by an anaesthesiologist in a sitting posture, while Group II encompassed patients who underwent endotracheal intubation by anaesthesiologists in a standing posture. Assessment parameters include ease of intubation (IDS score), intubation time, intubation success rate, number of attempts, grade of laryngoscopy (Cormack Lehane score, POGO score), and complications like tooth and soft tissue damage. RESULTS: The ease of intubation was higher in group I, 1(0-1), than in group II, 1(1-2) (p = 0.02), and there was a significant difference between the two groups. The Cormack Lehane grade (CL) was I/IIa/IIb/III in 19/23/13/0 in group I and I/IIa/IIb/III in 13/21/18/3 in group II. The first-attempt intubation success rate for groups I and II was 94.54 % and 92.72 % respectively. CONCLUSION: The sitting posture of an anaesthesiologist at the time of laryngoscopy provides a better intubating condition when compared with the standing posture. REGISTRATION: Clinical Trial Registry - India (CTRI) CTRI/2023/03/050371.

The SIRT7-nucleolus connection in cancer: ARF enters the fray.

The nucleolar enzyme sirtuin 7 (SIRT7) promotes cancer progression in certain malignancies, likely in part by controlling ribosome biosynthesis. Recently, we discovered that SIRT7 destabilizes the cyclin dependent kinase inhibitor 2A (CDKN2A, known as ARF) within the nucleolus, aiding cancer progression. We propose that targeting nucleolar SIRT7 offers promise for new anti-cancer therapies.

Hijacking of the methylglyoxal detoxification pathway: a new tactic of Xoo pathogenesis in rice.

Xanthomonas oryzae pv. oryzae (Xoo), the causative agent of bacterial blight (BB), has developed a unique strategy to infect rice by hijacking the host's methylglyoxal (MG) detoxification pathway. This results in an over-accumulation of MG, which facilitates tissue colonization and evasion of host's immune responses. While MG role in abiotic stresses is well-documented, its involvement in biotic stresses has not been extensively explored. Recently, Fu et al. (2024) provided the first evidence of MG role in promoting Xoo pathogenesis in rice. This new virulence strategy contributes to the pathogen's remarkable adaptability and survival. In this mechanism of hijacking of MG detoxification pathway, Xoo induces OsWRKY62.1 to inhibit OsGLY II expression, leading to MG overaccumulation in infected rice cells. This excess MG hinders plant cell organelle function, creating a favorable environment for Xoo by compromising the rice defense system. In this article, we have presented our perspectives on how the BB pathogen adapts its virulence mechanisms to infect and cause disease in rice.

Identification of Small Molecule Inhibitors Targeting Phosphoserine Phosphatase: A Novel Target for the Development of Antiamoebic Drugs.

Amoebiasis, a widespread disease caused by the protozoan parasite Entamoeba histolytica, poses challenges due to the adverse effects of existing antiamoebic drugs and rising drug resistance. Novel targeted drugs are in need of the hour to combat the prevalence of this disease. Given the significance of cysteine for Entamoeba survival, the rate-determining step in the serine (the sole substrate of cysteine synthesis) biosynthetic pathway, i.e., the conversion of 3-phosphoserine to l-serine catalyzed by phosphoserine phosphatase (PSP), emerges as a promising drug target. Our previous study unveils the essential role of EhPSP in amoebas' survival, particularly under oxidative stress, by increasing cysteine production. The study also revealed that EhPSP differs significantly from its human counterpart, both structurally and biochemically, highlighting its potential as a viable target for developing new antiamoebic drugs. In the present study, employing in silico screening of vast natural and synthetic small chemical compound libraries, we identified 21 potential EhPSP inhibitor molecules. Out of the 21 compounds examined, only five could inhibit the catalytic activity of EhPSP. The inhibition capability of these five compounds was subsequently validated by in silico binding free energy calculations, SPR-based real-time binding studies, and molecular simulations to assess the stability of the EhPSP-inhibitor complexes. By identifying the five potential inhibitors that can target cysteine synthesis via EhPSP, our findings establish EhPSP as a drug candidate that can serve as a foundation for antiamoebic drug research.

Benzene: A critical review on measurement methodology, certified reference material, exposure limits with its impact on human health and mitigation strategies.

Benzene is a carcinogenic pollutant with significant emission sources present in the atmosphere. The need for accurate and precise measurement of benzene in the atmosphere has become increasingly evident due to its toxicity and the adverse health effects associated with exposure to different concentrations. Certified reference material (CRM) is essential to establish the traceability of measurement results. The present review compiles the available national and international measurement methods, certified reference materials (CRMs) for benzene and the limit of benzene in fuel composition (v/v) worldwide. Overall, the review indicates the benzene level in the atmosphere and the resulting impacts on the environment and human health, which frequently exceed the exposure limits of different environment regulatory agencies. An extensive literature review was conducted to gather information on monitoring and analysis methods for benzene, revealing that the most preferred method, i.e. Gas Chromatography- Flame Ionization Detector and Mass Spectrometry, is neither cost-effective nor suitable for real-time continuous monitoring. By analysing existing literature and studies, this review will shed light on the understanding of the importance of benzene pollution monitoring in ambient air and its implications for public health. Additionally, it will reflect the mitigation strategies applied by regulators & need for future revisions of air quality guidelines.

Preparation and Judd-Ofelt Analysis of Warm Red Luminescent Eu3+ Complexes for Semiconductor Lasing Devices.

Six novel red photoluminescent Eu3+ complexes with 3-formyl chromone as the primary sensitizer (L) were synthesized using the solution precipitation method. These complexes are [Eu(L3).X] where X is 2H2O (C1), phen (C2), neo (C3), bipy (C4), dmph (C5), and biquno (C6). These complexes were characterized by elemental analysis, EDAX analysis, SEM, FT-IR, thermo-gravimetric analysis (TGA/DTA) and photoluminescence spectra. The transition rates, quantum efficiency, and J-O intensity parameters were calculated using emission data and luminescence decay time (τ). Complexes exhibit a strong emission peak (5D0 → 7F2) of the Eu3+ ion in their luminescence emission spectra in solid and solution states, making them an effective emitter of the red color in OLEDs. The branching ratio of these complexes ranges from 80.67-82.92 in solid and 50.53-62.65 in solution state; CIE color coordinate of complexes falls in the red region. The color purity ranges [CP(%)] values for solid 95.26-97.27% and for solution ranges 85.11-93.43%. Correlated color temperature (CCT) of the complexes (C1-C6) ranged from 2710 to 3049 K in the solid state and 1775 to 2450 K in the solution state. These complexes are promising red emitters in OLEDs, semiconductors, and leasing devices.

A phase II, non-comparative randomised trial of two treatments involving liposomal amphotericin B and miltefosine for post-kala-azar dermal leishmaniasis in India and Bangladesh.

BACKGROUND: In Southeast Asia, treatment is recommended for all patients with post-kala-azar dermal leishmaniasis (PKDL). Adherence to the first-line regimen, twelve weeks of miltefosine (MF), is low and ocular toxicity has been observed with this exposure period. We assessed the safety and efficacy of two shorter-course treatments: liposomal amphotericin B (LAmB) alone and combined with MF. METHODOLOGY/PRINCIPAL FINDINGS: An open-label, phase II, randomized, parallel-arm, non-comparative trial was conducted in patients with parasitologically confirmed PKDL, 6 to ≤60 years. Patients were assigned to 20 mg/kg LAmB (total dose, in five injections over 15 days) alone or combined with allometric MF (3 weeks). The primary endpoint was definitive cure at 12 months, defined as complete resolution of papular and nodular lesions and >80% re-pigmentation of macular lesions. Definitive cure at 24 months was a secondary efficacy endpoint. 118/126 patients completed the trial. Definitive cure at 12 months was observed in 29% (18/63) patients receiving LAmB and 30% (19/63) receiving LAmB/MF (mITT), increasing to 58% and 66%, respectively, at 24 months. Most lesions had resolved/improved at 12 and 24 months for patients receiving LAmB (90%, 83%) and LAmB/MF (85%, 88%) by qualitative assessment. One death, unrelated to study drugs, was reported; no study drug-related serious adverse events were observed. The most frequent adverse drug reactions were MF-related vomiting and nausea, and LAmB-related hypokalaemia and infusion reactions. Most adverse events were mild; no ocular adverse events occurred. CONCLUSIONS/SIGNIFICANCE: Both regimens are suitably safe and efficacious alternatives to long-course MF for PKDL in South Asia. TRIAL REGISTRATION: CTRI/2017/04/008421.

SIRT7 promotes lung cancer progression by destabilizing the tumor suppressor ARF.

Sirtuin 7 (SIRT7) is a member of the mammalian family of nicotinamide adenine dinucleotide (NAD+)-dependent histone/protein deacetylases, known as sirtuins. It acts as a potent oncogene in numerous malignancies, but the molecular mechanisms employed by SIRT7 to sustain lung cancer progression remain largely uncharacterized. We demonstrate that SIRT7 exerts oncogenic functions in lung cancer cells by destabilizing the tumor suppressor alternative reading frame (ARF). SIRT7 directly interacts with ARF and prevents binding of ARF to nucleophosmin, thereby promoting proteasomal-dependent degradation of ARF. We show that SIRT7-mediated degradation of ARF increases expression of protumorigenic genes and stimulates proliferation of non-small-cell lung cancer (NSCLC) cells both in vitro and in vivo in a mouse xenograft model. Bioinformatics analysis of transcriptome data from human lung adenocarcinomas revealed a correlation between SIRT7 expression and increased activity of genes normally repressed by ARF. We propose that disruption of SIRT7-ARF signaling stabilizes ARF and thus attenuates cancer cell proliferation, offering a strategy to mitigate NSCLC progression.

Lipase domain effector AGLIP1 in Rhizoctonia solani triggers necrotic killing in plants.

KEY MESSAGE: We highlight the emerging role of the R. solani novel lipase domain effector AGLIP1 in suppressing pattern-triggered immunity and inducing plant cell death. The dynamic interplay between plants and Rhizoctonia solani constitutes a multifaceted struggle for survival and dominance. Within this complex dynamic, R. solani has evolved virulence mechanisms by secreting effectors that disrupt plants' first line of defense. A newly discovered effector, AGLIP1 in R. solani, plays a pivotal role in inducing plant cell death and subverting immune responses. AGLIP1, a protein containing a signal peptide and a lipase domain, involves complex formation in the intercellular space, followed by translocation to the plant cytoplasm, where it induces cell death (CD) and suppresses defense gene regulation. This study provides valuable insights into the intricate molecular interactions between plants and necrotrophic fungi, underscoring the imperative for further exploration in this field.

Unveiling novel metabolic alterations in postmenopausal osteoporosis and type 2 diabetes mellitus through NMR-based metabolomics: A pioneering approach for identifying early diagnostic markers.

BACKGROUND AND AIMS: Postmenopausal osteoporosis (PMO) and type 2 diabetes mellitus (T2DM) frequently coexist in postmenopausal women. The study aimed to explore metabolic variations linked to these circumstances and their simultaneous presence through proton nuclear magnetic resonance metabolomics (1H NMR). MATERIALS AND METHODS: Serum samples from 80 postmenopausal women, including 20 PMO individuals, 20 T2DM, 20 T2DM + PMO, and 20 healthy postmenopausal women, were analyzed using 1H NMR spectroscopy. RESULTS: Our study revealed significant metabolic profile differences among the four groups. Notably, the T2DM + PMO group showed elevated levels of alanine, pyruvate, glutamate, lactate, and aspartate, indicating their involvement in lipid metabolism, energy, and amino acids. Importantly, our multivariate statistical analysis identified a metabolite set that accurately distinguished the groups, suggesting its potential as an early diagnostic marker. CONCLUSION: The 1H NMR metabolomics approach uncovered metabolic biomarkers intricately linked to postmenopausal osteoporosis (PMO), type 2 diabetes mellitus (T2DM), and their concurrent presence. Among these biomarkers, alanine emerged as a pivotal player, showing its significant role in the metabolic landscape associated with PMO and T2DM. These findings shed light on the pathophysiological mechanisms underlying these conditions and underscore alanine's potential as a diagnostic biomarker.

Pyrazole Paradigms: Unveiling Synthetic Pathways and Unraveling Anti-Cancer Potential.

This review investigates the synthetic methods and anti-cancer activities of pyrazole compounds. Various synthetic approaches, including traditional organic synthesis and microwaveassisted synthesis, have been used to change the pyrazole core structure, resulting in new compounds with improved pharmacological properties. The paper also covers the mechanisms of action that underpin pyrazole derivatives' anti-cancer characteristics, focusing on interactions with major molecular targets implicated in cancer growth and proliferation. SAR insights help to rationally develop novel anti-cancer drugs. In conclusion, the review emphasizes the versatility of pyrazole derivatives as scaffolds for the discovery and development of new anti-cancer medicines. By understanding synthesis routes and unravelling anti-cancer potential, this study hopes to encourage new research endeavours focused on leveraging the therapeutic advantages of pyrazole paradigms in the fight against cancer.

Europium-based ß-hydroxyketone complexes: synthesis, optoelectronic, thermal and computational analyses.

Six red-light-emitting Eu(III) complexes having a ß-hydroxyketone as ligand and heterocyclic ring containing compounds as ancillary ligands were synthesized to explore their use in displays and optoelectronics. The coordinating behavior of complexes was determined by various techniques such as FTIR (Fourier transform infrared), 1H-NMR (Nuclear magnetic resonance), and 13C-NMR that establishes a bonding of ligand and ancillary ligand with the Eu(III) ion. Morphology and purity were investigated through XRD (X-ray diffraction), SEM (scanning electron microscopy) and EDS (energy-dispersive X-ray spectroscopy) analyses that suggest semicrystalline and pure complex formation. Thermal analysis of complexes by TGA/DTG (thermogravimetric/derivative thermogravimetric) indicates that complexes are stable upto 200 ºC temperature making them suitable for use in display devices. Analysis of the photophysical properties was carried out in both solid and solution states using PL (photoluminescence) studies, color parameters, J-O (Judd-Ofelt) analysis and bandgap. Most emissive transition (5D0 → 7F2) is responsible for the red emission in the complexes. The CIE (Commission International de I'Eclairage) coordinates of complexes also indicate the red emission on UV excitation. The bandgap which was obtained in the range of 2.54-3.02 eV reveals the semiconducting behavior of complexes. Values of J-O parameters and Ω2 in the complexes reflect asymmetric chemical environment around Eu (III) and less covalence and the Ω4 indicates that complexes are less rigid. Bandgap calculated through DFT (density function theory) for complexes is in range of 2.37-2.77 eV, and intensity parameters (J-O), energy transfer rates, and spherical coordinates were determined by LUMPAC software. The computational data are in good harmony with the experimental data. Further biological aspects of complexes were studied using antioxidant and antimicrobial studies.

Effect of different doses of dexmedetomidine as an adjuvant to lignocaine nebulization: A comparative study during awake flexible fiberoptic bronchoscopy.

Background and Aims: Mild to moderate sedation during bronchoscopy is essential for patient safety, comfort during and after the procedure, and to facilitate the performance of the bronchoscopist. Dexmedetomidine is a highly selective, centrally acting α-2 agonist used to provide conscious sedation during various procedures. The aim of this study was to compare the efficacy of three different doses of dexmedetomidine nebulization as an adjuvant to lignocaine during bronchoscopy. Material and Methods: Ninety American Society of Anesthesiologists physical status I/II patients, aged from 18 to 60 years, scheduled for an elective bronchoscopy, were recruited. They were divided into three groups: 30 patients in each group. Group I: The patient was nebulized with a mixture of 4 ml of 4% lignocaine and dexmedetomidine 0.5 µg/kg. Group II: The patient was nebulized with a mixture of 4% lignocaine, 4 ml, and dexmedetomidine, 1 µg/kg. Group III: The patient was nebulized with 4% lignocaine 4 ml and dexmedetomidine 1.5 µg/kg. Results: The mean cough score was (1.17 ± 0.37), (1.40 ± 0.49), and (1.70 ± 0.75) in group III, group II, and group I, respectively. A significant difference was found between the groups. Patients were more comfortable with a statistically significant difference in the comfort score in group III as compared to group II and group I. Conclusion: Dexmedetomidine nebulization in a dose of 1.5 µg/kg (compared to 1 µg/kg or 0.5 µg/kg) as an adjuvant to lignocaine, provides better bronchoscopy conditions and patient satisfaction.

Factors Associated with Nursing Professionalism: Insights from Tertiary Care Center in India.

BACKGROUND: Professionalism among nurses plays a critical role in ensuring patient safety and quality care and involves delivering competent, safe, and ethical care while also working with clients, families, communities, and healthcare teams. AIMS AND OBJECTIVES: To assess the level of nursing professionalism and the factors affecting professionalism among nurses working at a tertiary care center in India. METHODS: A descriptive cross-sectional study was conducted from October 2022 to March 2023 using a total enumeration sampling technique. Following institutional ethics committee approval, standardized tools were administered consisting of Nursing Professionalism Scale and socio-demographic, personal, and organizational characteristics. RESULTS: A total of 270 nurses participated, with a response rate of 93.7%. The mean age of the participants was 27.33 ± 2.75 years, with the majority being female (82.6%) and belonged to the age group of 23-27 years (59.6%). More than half of the nurses exhibited high professionalism (53%), with the highest and lowest median scores for professional responsibility (29.0) and valuing human beings (13.0) respectively. Multivariate regression analysis demonstrated that, compared with their counterparts, nurses with a graduate nursing qualification (AOR = 4.77, 95% CI = 1.16-19.68), up-to-date training (AOR = 4.13, 95% CI = 1.88-9.06), and adequate career opportunity (AOR = 33.91, 95% CI = 14.48-79.39) had significant associations with high nursing professionalism. CONCLUSION/IMPLICATIONS FOR PRACTICE: The majority of the nurses had high professionalism, particularly in the domains of professional responsibility and management. Hospitals and healthcare institutions can use these findings to develop policies and prioritize opportunities for nurses to attend conferences and workshops to enhance their professional values, ultimately leading to improved patient care outcomes. PATIENT AND PUBLIC CONTRIBUTION: No patient or public contribution.

Comparative evaluation of nebulised dexmedetomidine vs fentanyl for the treatment of post-dural puncture headache (PDPH) in parturients after caesarean section under spinal anaesthesia: A randomised controlled study.

Background and Aims: The incidence of post-dural puncture headache (PDPH) following spinal anaesthesia in the obstetric population is around 0.5%-2%. Hydration, bed rest, caffeine, paracetamol, non-steroid anti-inflammatory drugs, epidural blood patches, etc., are the various modalities used for its management. This study aims to compare nebulised dexmedetomidine versus fentanyl for the treatment of PDPH in parturients after caesarean section under spinal anaesthesia. Methods: Ninety obstetric patients aged 18-35 years with American Society of Anesthesiologists (ASA) physical status II/III and suffering from PDPH as per the criteria of the International Headache Society after caesarean section under spinal anaesthesia were recruited in this double-blinded randomised study. Patients were randomised to Group D (dexmedetomidine 1 µg/kg nebulisation), Group F (fentanyl 1 µg/kg nebulisation), and Group S (saline nebulisation 4mL). The nebulisation was done 12 hourly for 72 hours. Assessment parameters included pain score and the requirement of additional treatment such as paracetamol, caffeine, and epidural blood patch. Analysis of variance test was used for continuous quantitative variables, and the Kruskal-Wallis test was used for quantitative discrete data. Results: The pain scores at 1, 6, 12, 24, 48, and 72 hours following nebulisation were significantly lower in Group D in comparison to groups F and S (P < 0.001). The number of patients requiring additional analgesic therapy was lower in Group D in comparison to patients in other groups (P < 0.001). Conclusion: Dexmedetomidine nebulisation resulted in effective reduction in PDPH symptoms and pain scores. Nebulisation with fentanyl did not alleviate PDPH symptoms when compared to the control group.

SIRT7: a novel molecular target for personalized cancer treatment?

The Sirtuin family of NAD+-dependent enzymes assumes a pivotal role in orchestrating adaptive responses to environmental fluctuations and stress stimuli, operating at both genomic and metabolic levels. Within this family, SIRT7 emerges as a versatile player in tumorigenesis, displaying both pro-tumorigenic and tumor-suppressive functions in a context-dependent manner. While other sirtuins, such as SIRT1 and SIRT6, exhibit a similar dual role in cancer, SIRT7 stands out due to distinctive attributes that sharply distinguish it from other family members. Among these are a unique key role in regulation of nucleolar functions, a close functional relationship with RNA metabolism and processing -exceptional among sirtuins- and a complex multienzymatic nature, which provides a diverse range of molecular targets. This review offers a comprehensive overview of the current understanding of the role of SIRT7 in various malignancies, placing particular emphasis on the intricate molecular mechanisms employed by SIRT7 to either stimulate or counteract tumorigenesis. Additionally, it delves into the unique features of SIRT7, discussing their potential and specific implications in tumor initiation and progression, underscoring the promising avenue of targeting SIRT7 for the development of innovative anti-cancer therapies.