Aberrant activation of AXL may drive progression of squamous cell carcinoma in CLL patients: a mechanistic study with clinical implications.

BACKGROUND: Occurrence of squamous cell carcinoma (SCC) even in early-stage, untreated chronic lymphocytic leukemia (CLL) patients can be a significant morbidity issue with occasional transformation into metastatic skin lesions. METHODS: CLL cells and extracellular vesicles (EVs) from CLL patients' blood/plasma were purified and used. Expression/activation of AXL and its functions in normal keratinocytes (HEKa) were assessed in vitro co-culture system and in SCC tissues. RESULTS: We detected aberrant activation of AXL, AKT and ERK-1/2 in SCC cell lines compared to HEKa. We also detected increased expression of AXL in primary SCC tissues obtained from CLL patients. Increased activation of AXL, AKT, ERK-1/2 and Src was discernible in HEKa upon co-culturing with CLL cells. Further analysis suggests that Gas6, a ligand of AXL, regulates AXL activation in co-cultured HEKa. Interestingly, exposure of HEKa cells to CLL plasma-derived EVs induced expression of AXL, P-AKT, and EMT-associated markers leading to migration of the cells. Finally, pharmacologic inhibition of AXL induced cell death in SCC lines in a dose dependent manner. CONCLUSIONS: Our findings that CLL cells likely are involved in driving SCC progression, at least in part, via activation of the AXL signaling axis, indicating that AXL inhibition may be beneficial for our CLL patients with SCC.

Low-energy electronic structure in the unconventional charge-ordered state of ScV6Sn6.

Kagome vanadates AV3Sb5 display unusual low-temperature electronic properties including charge density waves (CDW), whose microscopic origin remains unsettled. Recently, CDW order has been discovered in a new material ScV6Sn6, providing an opportunity to explore whether the onset of CDW leads to unusual electronic properties. Here, we study this question using angle-resolved photoemission spectroscopy (ARPES) and scanning tunneling microscopy (STM). The ARPES measurements show minimal changes to the electronic structure after the onset of CDW. However, STM quasiparticle interference (QPI) measurements show strong dispersing features related to the CDW ordering vectors. A plausible explanation is the presence of a strong momentum-dependent scattering potential peaked at the CDW wavevector, associated with the existence of competing CDW instabilities. Our STM results further indicate that the bands most affected by the CDW are near vHS, analogous to the case of AV3Sb5 despite very different CDW wavevectors.

1,6-Conjugate addition of in situ generated aryldiazenes to p-quinone methides.

Herein we report a transition-metal free, base-mediated 1,6-conjugate addition of aryldiazenes to para-quinone methides (p-QMs). Arylhydrazines were used for the in situ generation of aryldiazenes using a base-mediated protocol in the presence of air as the oxidant. The 1,6-conjugate addition of aryldiazenes to para-quinone methides via a radical mechanism is followed by an oxidative rearrangement to furnish the desired product, arylhydrazones. Interestingly, our synthetic protocol results in the formation of an aryldiazene radical, which undergoes 1,6-conjugate addition with p-QMs to furnish the arylhydrazones.

Emerging resistome diversity in clinical Vibrio cholerae strains revealing their role as potential reservoirs of antimicrobial resistance.

BACKGROUND: This is a unique and novel study delineating the genotyping and subsequent prediction of AMR determinants of Vibrio cholerae revealing the potential of contemporary strains to serve as precursors of severe AMR crisis in cholera. METHODS AND RESULTS: Genotyping of representative strains, VC1 and VC2 was undertaken to characterize antimicrobial resistance genes (ARGs) against chloramphenicol, SXT, nalidixic acid and streptomycin against which they were found to be resistant by antibiogram analysis in our previous investigation. strAB, sxt, sul2, qace∆1-sul1 were detected by PCR. Genome annotation and identification of ARGs with WGS helped to detect the presence of almG, varG, strA (APH(3'')-Ib), strB (APH(6)-Id), sul2, catB9, floR, CRP, dfrA1 genes. Signatures of resistance determinants and protein domains involved in antimicrobial resistance, primarily, efflux of antibiotics were identified on the basis of 30-100% homology to reference proteins. These domains were predicted to be involved in other metabolic functions on the basis of 100% identity with 100% coverage with reference protein and nucleotide sequences and were predicted to be of a diverse taxonomic origin accentuating the influence of the microbiota on AMR acquisition. Sequence analysis of QRDR (quinolone resistance-determining region) revealed SNPs. Cytoscape v3.8.2 was employed to analyse protein-protein interaction of MDR proteins, MdtA and EmrD-2, with nodes of vital AMR pathways. Vital nodes involved in efflux of different classes of antibiotics were found to be absent in VC1 and VC2 justifying the sensitivity of these strains to most antibiotics. CONCLUSIONS: The study helped to examine the resistome of VC isolated from recent outbreaks to understand the underlying reason of sensitivity to most antibiotics and also to characterize the ARGs in their genome. It revealed that VC is a reservoir of signatures of resistance determinants and serving as precursors for severe AMR crisis in cholera. This is the first study, to our knowledge, which has scrutinized and presented systematically, information on prospective domains which bear the potential of serving as AMR determinants in VC with the help of bioinformatic tools. This pioneering approach may help in the prediction of AMR landfalls and benefit epidemiological surveillance and early warning systems.

Managing Temporomandibular Joint Ankylosis Concurrent With Extrahepatic Portal Vein Obstruction: A Report of a Rare Case and Literature Review Investigating the Hypercoagulability Link.

This report describes the understudied co-occurrence of temporomandibular joint ankylosis (TMJA) and extrahepatic portal vein obstruction (EHPVO), exploring a shared pathway involving hypercoagulability. TMJA is an acquired pathology where joint surfaces fuse, causing restricted mouth opening and facial asymmetry. Globally, TMJA is prevalent among 1.5 to 5 patients/million, with a higher incidence in developing countries. While trauma and infections often cause TMJA, the pathogenesis remains unclear in many cases. Recent literature notes a link between TMJA and EHPVO, a noncirrhotic vascular disorder causing portal hypertension and upper gastrointestinal bleeding in children. Prothrombotic disorders such as protein C and S deficiency may contribute to EHPVO, mirroring TMJA's association with hypercoagulability. This report focuses on an 11-year-old female diagnosed with TMJA, accompanied by a history of ear infection and concurrent EHPVO. We further presented clinical observations, surgical interventions, and outcomes alongside a literature review to understand the probable connection between EHPVO and TMJA.

Correction: Design and synthesis of eugenol/isoeugenol glycoconjugates and other analogues as antifungal agents against Aspergillus fumigatus.

[This corrects the article DOI: 10.1039/D2MD00138A.].

Micro-distribution of arsenic in toenail clippings using laser ablation inductively coupled plasma mass spectrometry: implications for biomonitoring.

Toenails are a common monitoring tool for arsenic exposure, but the risk of external contamination of toenails has cast doubt on its usefulness. The main objective of this study is to investigate the micro-distribution of arsenic through the dorsoventral plane of nail clippings to understand endogenous vs exogenous sources. We used laser-ablation inductively coupled plasma mass spectrometry to measure arsenic through a dorsoventral cross-section of the nail plate collected from reference (N = 17) and exposed individuals (N = 35). Our main results showed (1) bulk toenail concentrations measured using ICP-MS in this study ranged from 0.54 to 4.35 µg/g; (2) there was a double-hump pattern in arsenic concentrations, i.e., dorsal and ventral layers had higher arsenic than the inner layer; (3) the double-hump was more pronounced in the exposed group (ventral: 6.25 µg/g; inner: 0.75 µg/g; dorsal: 0.95 µg/g) than the reference group (ventral: 0.58 µg/g; inner: 0.15 µg/g; dorsal: 0.29 µg/g) on average; (4) the distribution was, in part, associated with different binding affinity of nail layers (i.e., ventral > dorsal > inner); (5) most individuals in the higher exposure group showed > 25% contamination in ventral and dorsal nail layers; and (6) there were no statistically significant correlations between LA-ICP-MS arsenic with either bulk toenail arsenic or urine arsenic from the same individuals. Our results on micro-distribution and binding affinity provide insight into the impact of external contamination on arsenic concentrations and show how LA-ICP-MS can access the protected inner nail layer to provide a more accurate result.

Foodborne Outbreak by Salmonella enterica Serovar Weltevreden in West Bengal, India.

Foodborne gastroenteritis outbreaks owing to Salmonella enterica serovar Weltevreden (Salmonella Weltevreden) represent a significant global public health problem. In the past two decades, Salmonella Weltevreden has emerged as a dominant foodborne pathogen, especially in South-East Asian countries. This report describes a community foodborne outbreak of gastroenteritis caused by Salmonella Weltevreden in August 2022 following consumption of panipuri from a street vendor in the Polba block in Hooghly district, West Bengal, India. This food item was consumed by 185 people, of whom 129 had acute watery diarrhea with other clinical symptoms and 65 of them were admitted to different District hospitals for treatment. Stool specimens collected from hospitalized cases were positive for S. enterica, and further serotyped as Salmonella Weltevreden. All the Salmonella Weltevreden strains possessed the Salmonella pathogenicity islands associated genes (invA/E, orgA, ttrc, ssaQ, mgtC, misL, spi4D), the enterotoxin (stn), and hyperinvasive locus gene (hilA). Except erythromycin, all the strains were susceptible for commonly used antimicrobials in the treatment of diarrhea. The XbaI-based pulsed-field gel electrophoresis analysis indicated that all the isolates responsible for the recent outbreak were similar, but diverged from other Salmonella Weltevreden that were previously reported in West Bengal. This report indicates that foodborne infection is a major public health concern in India and demands to strengthen capacity-building measures at the local health care levels for linking causative agents of outbreaks.

Unveiling the Cell Wall-Targeting Mechanisms and Multifaceted Virulence Modulation by a Eugenol Glycoconjugate against Aspergillus fumigatus: Insights from in vitro and in ovo Studies.

AIM: The primary objective of this study was to elucidate the putative cell wall-associated targets of compound 6i, a glycoconjugate of eugenol, in Aspergillus fumigatus, while also evaluating its toxicity and assessing histopathologic alterations in the liver, heart, and kidney of compound 6i-treated embryos using an in ovo model. METHOD: To achieve this aim, compound 6i was synthesized, and a series of biochemical assays were performed to determine its impact on the fungal cell wall. Additionally, qRT-PCR and LC-MS/MS analyses were conducted to investigate changes in gene and protein expression profiles associated with melanin biosynthesis, conidiation, siderophore production, transcriptional regulation of ß-glucan biosynthesis, and calcineurin activity in A. fumigatus. RESULTS: The experimental findings revealed that compound 6i exhibited notable antifungal activity against A. fumigatus by perturbing cell wall integrity, hindering ergosterol, glucan, and chitin biosynthesis, and inhibiting catalase production. Moreover, relative gene expression and proteomic analyses demonstrated that compound 6i exerted both down-regulatory and up-regulatory effects on several crucial genes and proteins involved in the aforementioned fungal processes. Furthermore, increased expression of oxidative stress-related proteins was observed in the presence of compound 6i. Notably, the glycoconjugate of eugenol did not elicit cytotoxicity in the liver, heart, and kidney of chick embryos. CONCLUSION: The current investigation elucidated the multifaceted mechanisms by which compound 6i exerts its antifungal effects against A. fumigatus, primarily through targeting cell wall components and signaling pathways. These findings underscore the potential of the eugenol glycoconjugate as a promising antifungal candidate, warranting further exploration and development for combating A. fumigatus infections.

Two-dimensional heavy fermions in the van der Waals metal CeSiI.

Heavy-fermion metals are prototype systems for observing emergent quantum phases driven by electronic interactions1-6. A long-standing aspiration is the dimensional reduction of these materials to exert control over their quantum phases7-11, which remains a significant challenge because traditional intermetallic heavy-fermion compounds have three-dimensional atomic and electronic structures. Here we report comprehensive thermodynamic and spectroscopic evidence of an antiferromagnetically ordered heavy-fermion ground state in CeSiI, an intermetallic comprising two-dimensional (2D) metallic sheets held together by weak interlayer van der Waals (vdW) interactions. Owing to its vdW nature, CeSiI has a quasi-2D electronic structure, and we can control its physical dimension through exfoliation. The emergence of coherent hybridization of f and conduction electrons at low temperature is supported by the temperature evolution of angle-resolved photoemission and scanning tunnelling spectra near the Fermi level and by heat capacity measurements. Electrical transport measurements on few-layer flakes reveal heavy-fermion behaviour and magnetic order down to the ultra-thin regime. Our work establishes CeSiI and related materials as a unique platform for studying dimensionally confined heavy fermions in bulk crystals and employing 2D device fabrication techniques and vdW heterostructures12 to manipulate the interplay between Kondo screening, magnetic order and proximity effects.

Use of Atrial Fibrillation Electrograms and T1/T2 Magnetic Resonance Imaging to Define the Progressive Nature of Molecular and Structural Remodeling: A New Paradigm Underlying the Emergence of Persistent Atrial Fibrillation.

BACKGROUND: The temporal progression states of the molecular and structural substrate in atrial fibrillation (AF) are not well understood. We hypothesized that these can be detected by AF electrograms and magnetic resonance imaging parametric mapping. METHODS AND RESULTS: AF was induced in 43 dogs (25-35 kg, ≥1 year) by rapid atrial pacing (RAP) (3-33 weeks, 600 beats/min), and 4 controls were used. We performed high-resolution epicardial mapping (UnEmap, 6 atrial regions, both atria, 130 electrodes, distance 2.5 mm) and analyzed electrogram cycle length, dominant frequency, organization index, and peak-to-peak bipolar voltage. Implantable telemetry recordings were used to quantify parasympathetic nerve activity over RAP time. Magnetic resonance imaging native T1, postcontrast T1, T2 mapping, and extracellular volume fraction were assessed (1.5T, Siemens) at baseline and AF. In explanted atrial tissue, DNA oxidative damage (8-hydroxy-2'-deoxyguanosine staining) and percentage of fibrofatty tissue were quantified. Cycle length and organization index decreased (R=0.5, P<0.05; and R=0.5, P<0.05; respectively), and dominant frequency increased (R=0.3, P n.s.) until 80 days of RAP but not thereafter. In contrast, voltage continued to decrease throughout the duration of RAP (R=0.6, P<0.05). Parasympathetic nerve activity increased following RAP and plateaued at 80 days. Magnetic resonance imaging native T1 and T2 times increased with RAP days (R=0.5, P<0.05; R=0.6, P<0.05) in the posterior left atrium throughout RAP. Increased RAP days correlated with increasing 8-hydroxy-2'-deoxyguanosine levels and with fibrosis percentage (R=0.5, P<0.05 for both). CONCLUSIONS: A combination of AF electrogram characteristics and T1/T2 magnetic resonance imaging can detect early-stage AF remodeling (autonomic remodeling, oxidative stress) and advanced AF remodeling due to oxidative stress and fibrosis.

Interplay between Local Moment and Itinerant Magnetism in the Layered Metallic Antiferromagnet TaFe1.14Te3.

Two-dimensional antiferromagnets have garnered considerable interest for the next generation of functional spintronics. However, many bulk materials from which two-dimensional antiferromagnets are isolated are limited by their air sensitivity, low ordering temperatures, and insulating transport properties. TaFe1+yTe3 aims to address these challenges with increased air stability, metallic transport, and robust antiferromagnetism. Here, we synthesize TaFe1+yTe3 (y = 0.14), identify its structural, magnetic, and electronic properties, and elucidate the relationships between them. Axial-dependent high-field magnetization measurements on TaFe1.14Te3 reveal saturation magnetic fields ranging between 27 and 30 T with saturation magnetic moments of 2.05-2.12 µB. Magnetotransport measurements confirm that TaFe1.14Te3 is metallic with strong coupling between magnetic order and electronic transport. Angle-resolved photoemission spectroscopy measurements across the magnetic transition uncover a complex interplay between itinerant electrons and local magnetic moments that drives the magnetic transition. We demonstrate the ability to isolate few-layer sheets of TaFe1.14Te3, establishing TaFe1.14Te3 as a potential platform for two-dimensional spintronics.

Mechanistic Insight into the Defect-Engineered White Light Emission from the Single-Phase Orthovanadate Phosphor Synthesized by a Facile Rapid Microwave-Assisted Synthesis.

The synthesis of single-phase barium orthovanadate phosphors by a one-pot microwave-assisted hydrothermal approach has been reported, wherein the homogeneous thermal zone generated at the molecular level by microwave radiation gives rise to tunable distortion in the tetrahedral VO4-3 and oxygen vacancies, eventually enabling intrinsic white light emission with CIE of 0.31,0.38, high photoluminescence internal quantum efficiency of 35%, and external quantum efficiency of 28% whereas phosphor synthesized by the hydrothermal route exhibits only bluish-green emission (PLQE: 0.5%). The Rietveld refinement confirms the formation of a single trigonal phase having dissimilar V-O bond lengths and bond angles, implying the formation of a distorted phosphor under optimized conditions, and corroborates with Raman and Fourier transform infrared analyses. The X-ray photoelectron spectroscopy and electron paramagnetic resonance analysis reveal that the origin of white light emission is due to short- and long-range defects, in particular the oxygen vacancies, which eventually form an intermediate energy level in the forbidden region between the valence and conduction bands. Lifetime spectra show triexponential fitting, corresponding to two charge transfer blue and green emission bands (3T2, 3T1 to 1A1) and one oxygen vacancy-related red emission at RT. Furthermore, these phosphors are thermally stable, as no change in the structure or emission characteristics are observed. A prototype fabricated using a 365 nm chip exhibits white-light-emission CIE of 0.353,0.392, correlated color temperature of 4867 K, color rendering index of 85, and high luminous efficacy of 102 lm/W at 140 mA operating current, portentous for practical applications.

A Comparative Study of Pain in Patients Planned for Tooth Extraction and Dental Implant Insertion.

Introduction: A variation in dental pain following tooth extraction and implant placement has been observed. The present study aimed to compare pain in patients undergoing tooth extraction and implant placement. Materials and Methods: Eighty-four patients underwent tooth extraction and implant placement in maxillary central incisor. Pain (VAS) was recorded at 24 h, 24 h, and 48 h. Results: The mean pain value (VAS) at 24 h post-operatively after tooth extraction was 6.1 and after implant insertion was 2.9. At 48 h after tooth extraction was 4.3 and after implant insertion was 1.1 and after 72 h after tooth extraction was 2.4 and after implant insertion was 0.27. A significant difference was observed between both procedures at different intervals of time (P < 0.05). Conclusion: The pain experienced by patients during dental implant insertion was comparatively less as compared to dental tooth extraction.

Giant and Tunable Out-of-Plane Spin Polarization of Topological Antimonene.

Topological insulators are bulk insulators with metallic and fully spin-polarized surface states displaying Dirac-like band dispersion. Due to spin-momentum locking, these topological surface states (TSSs) have a predominant in-plane spin polarization in the bulk fundamental gap. Here, we show by spin-resolved photoemission spectroscopy that the TSS of a topological insulator interfaced with an antimonene bilayer exhibits nearly full out-of-plane spin polarization within the substrate gap. We connect this phenomenon to a symmetry-protected band crossing of the spin-polarized surface states. The nearly full out-of-plane spin polarization of the TSS occurs along a continuous path in the energy-momentum space, and the spin polarization within the gap can be reversibly tuned from nearly full out-of-plane to nearly full in-plane by electron doping. These findings pave the way to advanced spintronics applications that exploit the giant out-of-plane spin polarization of TSSs.

An accelerated Rauhut-Currier dimerization enabled the synthesis of (±)-incarvilleatone and anticancer studies.

The total synthesis of racemic incarvilleatone has been achieved by utilizing unexplored accelerated Rauhut-Currier (RC) dimerization. The other key steps of the synthesis are oxa-Michael and aldol reactions in a tandem sequence. Racemic incarvilleatone was separated by chiral HPLC and the configuration of each enantiomer was determined by single-crystal X-ray analysis. In addition, a one-pot synthesis of (±)-incarviditone has been achieved from rac-rengyolone by using KHMDS as a base. We have also assessed the anticancer activity of all the synthesized compounds in breast cancer cells nonetheless, they exhibited very limited growth suppression activity.

Late-Stage C(sp2 )-H Arylation of Artemisinic Acid and Arteannuin B: Effect of Olefin Migration Towards Synthesis of C-13 Arylated Artemisinin Derivatives.

In recent years, C-H bond functionalization has emerged as a pivotal tool for late-stage functionalization of complex natural products for the synthesis of potent biologically active derivatives. Artemisinin and its C-12 functionalized semi-synthetic derivatives are well-known clinically used anti-malarial drugs due to the presence of the essential 1,2,4-trioxane pharmacophore. However, in the wake of parasite developing resistance against artemisinin-based drugs, we conceptualized the synthesis of C-13 functionalized artemisinin derivatives as new antimalarials. In this regard, we envisaged that artemisinic acid could be a suitable precursor for the synthesis of C-13 functionalized artemisinin derivatives. Herein, we report C-13 arylation of artemisinic acid, a sesquiterpene acid and our attempts towards synthesis of C-13 arylated artemisinin derivatives. However, all our efforts resulted in the formation of a novel ring-contracted rearranged product. Additionally, we have extended our developed protocol for C-13 arylation of arteannuin B, a sesquiterpene lactone epoxide considered to be the biogenetic precursor of artemisinic acid. Indeed, the synthesis of C-13 arylated arteannuin B renders our developed protocol to be effective in sesquiterpene lactone as well.

Genomic insights into extensively drug-resistant Pseudomonas aeruginosa isolated from a diarrhea case in Kolkata, India.

Aim: To characterize extensively drug-resistant Pseudomonas aeruginosa from a patient with diarrhea. Materials & methods: Antimicrobial susceptibility was tested by the disk diffusion method. The P. aeruginosa genome was sequenced to identify virulence, antibiotic resistance and prophages encoding genes. Results: P. aeruginosa had a wide spectrum of resistance to antibiotics. Genomic analysis of P. aeruginosa revealed 76 genes associated with antimicrobial resistance, xenobiotic degradation and the type three secretion system. Conclusion: This is the first report on diarrhea associated with P. aeruginosa. Since no other organism was identified, the authors assume that the patient had dysbiosis due to antibiotic exposure, leading to antibiotic-associated diarrhea. The in vivo toxicity expressed by the pathogen may be associated with T3SS.

Recent trends in chronic pain medicine.

Chronic pain presents as an unequalled challenge for physicians, owing to the complexity of biochemical and biological pathways involved in pain transmission and high variability of pain perception among individuals. Often, there is an inadequate response to conservative treatment, and opioid treatment has its own drawbacks, such as side effects and opioid dependence. Hence, novel strategies have evolved for the effective and safe management of chronic pain. Radiofrequency technique, regenerative biomaterial, platelet-rich plasma, mesenchymal stem cells, reactive oxygen species scavenger nanomaterial, ultrasound-guided interventional pain management procedures, endoscopic spinal procedures, vertebral augmentation therapy, and neuromodulation are some of the promising and upcoming modalities in the armamentarium of pain physicians.

Design and Synthesis of 1,3-Diynes as Potent Antifungal Agents against Aspergillus fumigatus.

Eugenol and isoeugenol, secondary metabolites isolated from the plant Myristica fragrans have displayed antifungal activities against Aspergillus fumigatus (IC50 1900 µM). Compounds having conjugated unsaturation have been of great use as antifungals i. e. amphotericin B, nystatin and terbinafine etc. Hence, in the present study, we have designed and synthesised 1,3-diynes by utilizing Glaser-Hay and Cadiot-Chodkiewicz coupling reactions to furnish possible antifungal agents. Synthesis of 1,6-diphenoxyhexa-2,4-diyne derivatives was achieved by Cu(I) catalysed coupling of propargylated eugenol, isoeugenol, guaiacol, vanillin and dihydrogenated eugenol or eugenol in good to excellent yields. All the synthesized compounds were evaluated against pathogenic fungus A. fumigatus. Among all the synthesized compounds, one of the compounds was found to be exhibiting promising antifungal activity with IC50 value of 7.75 µM thereby suggesting that this type of scaffold could pave the way for developing new antifungal agents. The most active compound was found to be low cytotoxic when assayed against L-132 cancer cell line. Effect of the most active compound on ergosterol biosynthesis has also been studied. Also, the most active compound exhibited significant anti-biofilm activity although the concentration was found to be higher than its anti-fungal activity. Morphological changes in the biofilm were remarkable under confocal laser scanning microscopy.