Doxorubicin-Intercalated Li-Al-Based LDHs as Potential Drug Delivery Nanovehicle with pH-Responsive Therapeutic Cargo for Tumor Treatment.

Clinical oncology is currently experiencing a technology bottleneck due to the expeditious evolution of therapy defiance in tumors. Although drugs used in chemotherapy work for a sort of cell death with potential clinical application, the effectiveness of chemotherapy-inducing drugs is subject to several endogenous conditions when used alone, necessitating the urgent need for controlled mechanisms. A tumor-targeted drug delivery therapy using Li-Al (M+/M3+)-based layered double hydroxide (LDHs) family has been proposed with the general chemical formula [M+1-x M3+x (OH)]2x+[(Am-)2x/m. n(H2O)]2x-, which is fully biodegradable and works in connection with the therapeutic interaction between LDH nanocarriers and anticancerous doxorubicin (DOX). Compositional variation of Li and Al in LDHs has been used as a nanoplatform, which provides a functional balance between circulation lifetime, drug loading capacity, encapsulation efficiency, and tumor-specific uptake to act as self-regulatory therapeutic cargo to be released intracellularly. First-principle analyses based on DFT have been employed to investigate the interaction of bonding and electronic structure of LDH with DOX and assess its capability and potential for a superior drug carrier. Following the internalization into cancer cells, nanoformulations are carried to the nucleus via lysosomes, and the mechanistic pathways have been revealed. Additionally, in vitro along with in vivo therapeutic assessments on melanoma-bearing mice show a dimensional effect of nanoformulation for better biocompatibility and excellent synergetic anticancer activity. Further, the severe toxic consequences associated with traditional chemotherapy have been eradicated by using injectable hydrogel placed just beneath the tumor site, and regulated release of the drug has been confirmed through protein expression applying various markers. However, Li-Al-based LDH nanocarriers open up new design options for multifunctional nanomedicine, which has intriguing potential for use in cancer treatment through sustained drug delivery.

Predictive Value of the Postural Difference in Antero-Posterior Diameter of Renal Pelvis on Ultrasonography of Unilateral Ureteropelvic Junction Obstruction in Determining the Need For Surgery.

BACKGROUND: Ureteropelvic junction obstruction (UPJO) is the most common cause of antenatal hydronephrosis. Although majority of them improve with time, none of the existing diagnostic modalities can accurately predict which hydronephrotic kidney is at the risk of progressive renal damage and will benefit from early surgery. Postural variations in the anteroposterior pelvic diameter (APPD) of the hydronephrotic kidney in children during follow-up postnatal ultrasonography (USG) reflect the intrapelvic tension, which might help in predicting the need of surgery amongst these patients. MATERIALS AND METHODS: We designed this prospective observational study in all unilateral UPJO patients on postural variation in the APPD of renal pelvis on ultrasonography. The mean age of all patients were 2.15 years (0-5 years) and managed at our institute at All India Institute of Medical Sciences, Bhubaneswar. The study duration was from July 2019 to May 2021. The management of these patients was done as per the standard institutional protocol and there was no deviation due to inclusion in this study. We documented the variations in postural APPD both amongst the conservatively managed group and the surgically managed group of patients. Linear correlation between two continuous variables was explored using Pearson's correlation (if the data were normally distributed) and Spearman's correlation (for non-normally distributed data). RESULTS: We found a higher prone APPD than supine APPD in all these patients indicating the obstruction at ureteropelvic junction. However, in the surgical group, there was less variation in the postural APPD compared to the conservative group, and when there was no variation in the postural APPD, the need of surgery was 100%. The limitation of our study was the small sample size (n = 36). A study involving a larger population or involving multiple institutions may further add significance to our findings. CONCLUSION: We found less postural variation in APPD on USG to be more likely associated with severe UPJO requiring early surgery. This may indicate a non-compliant renal pelvis. However, it was statistically not significant.

Enhanced biodegradation of 2, 4-dichlorophenol in packed bed biofilm reactor by impregnation of polyurethane foam with Fe3O4 nanoparticles: Bio-kinetics, process optimization, performance evaluation and toxicity assessment.

In this work, an effort has been made to enhance the efficacy of biological process for the effective degradation of 2, 4-dichlorophenol (2, 4-DCP) from wastewater. The polyurethane foam was modified with Fe3O4 nanoparticles and combined with polyvinyl alcohol, sodium alginate, and bacterial consortium for biodegradation of 2, 4-DCP in a packed bed biofilm reactor. The maximum removal efficiency of 2, 4-DCP chemical oxygen demand, and total organic carbon were found to be 92.51 ± 0.83 %, 86.85 ± 1.32, and 91.78 ± 1.24 %, respectively, in 4 days and 100 mg L-1 of 2, 4-DCP concentration at an influent loading rate of 2 mg L-1h-1 and hydraulic retention time of 50 h. Packed bed biofilm reactor was effective for up to four cycles to remove 2, 4-DCP. Growth inhibition kinetics were evaluated using the Edward model, yielding maximum growth rate of 0.45 day-1, inhibition constant of 110.6 mg L-1, and saturation constant of 62.3 mg L-1.

Effects of Molecular Hydrogen in the Pathophysiology and Management of Cardiovascular and Metabolic Diseases.

Diet and lifestyle choices, notably the Western-type diet, are implicated in oxidative stress and inflammation, factors that elevate the risk of cardiovascular diseases (CVDs) and type 2 diabetes mellitus (T2DM). In contrast, the Mediterranean of diet, rich in antioxidants, appears to have protective effects against these risks. This article highlights the dual role of diet in generating molecular hydrogen ( H 2 ) in the gut, and H 2 's subsequent influence on the pathophysiology and prevention of CVD and T2DM. Dietary fiber, flavonoids, and probiotics contribute to the production of liters of H 2 in the gut, functioning as antioxidants to neutralize free radicals and dampen inflammation. In the last two decades, mounting evidence has demonstrated that both endogenously produced and exogenously administered H 2 , whether via inhalation or H 2 -rich water (HRW), have potent anti-inflammatory effects across a wide range of biochemical and pathophysiological processes. Recent studies indicate that H 2 can neutralize hydroxyl and nitrosyl radicals, acting as a cellular antioxidant, thereby reducing oxidative stress and inflammation-leading to a significant decline in CVDs and metabolic diseases. Clinical and experimental research support the therapeutic potential of H 2 interventions such as HRW in managing CVDs and metabolic diseases. However, larger studies are necessary to verify the role of H 2 therapy in the management of these chronic diseases.

Exploring isoindolin-1-ones as potential CDK7 inhibitors using cheminformatic tools.

In women who die from cancer, breast cancer is the most common cause of death. The development of small molecular scaffolds as specific Cyclin-dependent kinase (CDK) inhibitors is a promising strategy in the discovery of anti-breast cancer drugs. Isoindolin-1-ones are heterocyclic compounds with useful therapeutic properties. In this study, a library of 48 isoindolinones has been virtually screened by molecular docking that showed high binding affinity up to - 10.1 kcal/mol and conventional hydrogen bonding interactions with active amino acid residues of CDK7. The molecular dynamics simulation (MDS), fragment molecular orbital (FMO), density functional theory (DFT), and pharmacokinetics studies of the best two docked scored ligands 7 and 14 have been studied. Examining the ligand root mean square deviation and hydrogen bonding occupancy of the 100 ns MDS trajectory, both ligands 7 and 14 showed docked pose stability. FMO calculations displayed that LYS139 and LYS41 are majorly contributing to the binding interactions with ligands 7 and 14 in the docked poses. DFT studies of ligands 7 and 14 showed high values of global softness and low values of global hardness and chemical potential thus displaying chemically reactive soft molecules and this influences their anti-cancer activity. Our hits exhibited superior qualities to known CDK7 inhibitors, according to the comprehensive pharmacokinetic parameters that were predicted. The results indicate that isoindolin-1-one moieties are good candidates for anti-cancer action and could serve as effective CDK7 inhibitors. Supplementary Information: The online version contains supplementary material available at 10.1007/s40203-024-00225-0.

Aluminium stress tolerance by Citrus plants: a consolidated review.

Aluminium, a metallic element abundant in soils as aluminosilicates minerals, poses a toxic threat to plants, particularly in acidic soil conditions, thereby affecting their growth and development. Given their adaptability to diverse soil and climate conditions, Citrus plants have gained significant attention regarding their tolerance to Aluminium toxicity. In the North-eastern region of India, where soils are often slightly acidic with elevated aluminium levels, Citrus species are predominantly found. Understanding the tolerance mechanisms of these Citrus fruits and screening wild Citrus species for their adaptability to abiotic stresses is crucial for enhancing fruit production. Numerous investigations have demonstrated that Citrus species exhibit remarkable tolerance to aluminium contamination, surpassing the typical threshold of 30% incidence. When cultivated in acidic soils, Citrus plants encounter restricted root growth and reduced nutrient and moisture uptake, leading to various nutrient deficiency symptoms. However, promisingly, certain Citrus species such as Citrus jambhiri (Rough lemon), Poncirus trifoliata, Citrus sinensis, and Citrus grandis have shown considerable aluminium tolerance. This comprehensive review delves into the subject of aluminium toxicity and its implications, while also shedding light on the mechanisms through which Citrus plants develop tolerance to this element.

Mitogenomic Insights into the Evolution, Divergence Time, and Ancestral Ranges of Coturnix Quails.

The Old-World quails, Coturnix coturnix (common quail) and Coturnix japonica (Japanese quail), are morphologically similar yet occupy distinct geographic ranges. This study aimed to elucidate their evolutionary trajectory and ancestral distribution patterns through a thorough analysis of their mitochondrial genomes. Mitogenomic analysis revealed high structural conservation, identical translational mechanisms, and similar evolutionary pressures in both species. Selection analysis revealed significant evidence of positive selection across the Coturnix lineage for the nad4 gene tree owing to environmental changes and acclimatization requirements during its evolutionary history. Divergence time estimations imply that diversification among Coturnix species occurred in the mid-Miocene (13.89 Ma), and their current distributions were primarily shaped by dispersal rather than global vicariance events. Phylogenetic analysis indicates a close relationship between C. coturnix and C. japonica, with divergence estimated at 2.25 Ma during the Pleistocene epoch. Ancestral range reconstructions indicate that the ancestors of the Coturnix clade were distributed over the Oriental region. C. coturnix subsequently dispersed to Eurasia and Africa, and C. japonica to eastern Asia. We hypothesize that the current geographic distributions of C. coturnix and C. japonica result from their unique dispersal strategies, developed to evade interspecific territoriality and influenced by the Tibetan Plateau's geographic constraints. This study advances our understanding of the biogeographic and evolutionary processes leading to the diversification of C. coturnix and C. japonica, laying important groundwork for further research on this genus.

Potable water production through a low-cost single chamber solar still in north India.

The main aim of this study is to evaluate the performance of a single slope solar still and to assess the effect of nanofluid on its performance. A single basin single slope solar still was designed and fabricated at the Department of Chemical Engineering, IET Lucknow. Its performance was assessed in terms of the yield of potable water. The effect of various climatic parameters was also studied. Al2O3 nanofluid was used to enhance the yield of the solar still. In the presence of nanofluid, the total yield of the solar still improved by 16.6%. Its economic feasibility was analyzed and reported. The portability of the small size of solar stills, its better economics, easy fabrication, and good performance make them very useful for industrial as well as household purposes.

Marching Ahead through the Pandemic: Continuing Anesthesia Services in COVID Era-Our Experience from a Tertiary Care Cancer Centre.

Swati BhanIntroduction This paper aims to provide an overview of the administrative and clinical preparations done in a tertiary care cancer hospital in continuing operation theatre (OT) services through the COVID pandemic. Methods Retrospective data collection, data for the past 1.5 years (COVID period) March 2020 to August 2021 were compared to surgical output for a similar duration of time before the COVID era (September 2018-February 2020). Results A total of 1,022 surgeries were done under anesthesia in the COVID period as against 1,710 surgeries done in a similar time frame in the pre-COVID era. Overall, we saw a 40%drop in the total number of cases. Thorax, abdominal, and miscellaneous surgeries (soft tissue sarcomas, urology, and gyneconcology) saw a maximum fall in numbers; however, head and neck cases saw an increase in numbers during the pandemic. Surgical morbidity and mortality were similar in the COVID and pre-COVID era. No cases of severe COVID infection were reported among the healthcare staff working in OT. Discussion We could successfully continue our anesthesia services with minimal risk to healthcare staff throughout the pandemic by adopting major guidelines in a pragmatic and practical approach with minor changes to suit our setup.

Genome-Wide Computational Prediction and Analysis of Noncoding RNAs in Oleidesulfovibrio alaskensis G20.

Noncoding RNAs (ncRNAs) play key roles in the regulation of important pathways, including cellular growth, stress management, signaling, and biofilm formation. Sulfate-reducing bacteria (SRB) contribute to huge economic losses causing microbial-induced corrosion through biofilms on metal surfaces. To effectively combat the challenges posed by SRB, it is essential to understand their molecular mechanisms of biofilm formation. This study aimed to identify ncRNAs in the genome of a model SRB, Oleidesulfovibrio alaskensis G20 (OA G20). Three in silico approaches revealed genome-wide distribution of 37 ncRNAs excluding tRNAs in the OA G20. These ncRNAs belonged to 18 different Rfam families. This study identified riboswitches, sRNAs, RNP, and SRP. The analysis revealed that these ncRNAs could play key roles in the regulation of several pathways of biosynthesis and transport involved in biofilm formation by OA G20. Three sRNAs, Pseudomonas P10, Hammerhead type II, and sX4, which were found in OA G20, are rare and their roles have not been determined in SRB. These results suggest that applying various computational methods could enrich the results and lead to the discovery of additional novel ncRNAs, which could lead to understanding the "rules of life of OA G20" during biofilm formation.

Genome-based approach to evaluate the metabolic potentials and exopolysaccharides production of Bacillus paralicheniformis CamBx3 isolated from a Chilean hot spring.

In the present study, a thermophilic strain designated CamBx3 was isolated from the Campanario hot spring, Chile. Based on 16S rRNA gene sequence, phylogenomic, and average nucleotide identity analysis the strain CamBx3 was identified as Bacillus paralicheniformis. Genome analysis of B. paralicheniformis CamBx3 revealed the presence of genes related to heat tolerance, exopolysaccharides (EPS), dissimilatory nitrate reduction, and assimilatory sulfate reduction. The pangenome analysis of strain CamBx3 with eight Bacillus spp. resulted in 26,562 gene clusters, 7,002 shell genes, and 19,484 cloud genes. The EPS produced by B. paralicheniformis CamBx3 was extracted, partially purified, and evaluated for its functional activities. B. paralicheniformis CamBx3 EPS with concentration 5 mg mL-1 showed an optimum 92 mM ferrous equivalent FRAP activity, while the same concentration showed a maximum 91% of Fe2+ chelating activity. B. paralicheniformis CamBx3 EPS (0.2 mg mL-1) demonstrated ß-glucosidase inhibition. The EPS formed a viscoelastic gel at 45°C with a maximum instantaneous viscosity of 315 Pa.s at acidic pH 5. The present study suggests that B. paralicheniformis CamBx3 could be a valuable resource for biopolymers and bioactive molecules for industrial applications.

A Role for GABAA Receptor ß3 Subunits in Mediating Harmaline Tremor Suppression by Alcohol: Implications for Essential Tremor Therapy.

Background: Essential tremor patients may find that low alcohol amounts suppress tremor. A candidate mechanism is modulation of α6ß3δ extra-synaptic GABAA receptors, that in vitro respond to non-intoxicating alcohol levels. We previously found that low-dose alcohol reduces harmaline tremor in wild-type mice, but not in littermates lacking δ or α6 subunits. Here we addressed whether low-dose alcohol requires the ß3 subunit for tremor suppression. Methods: We tested whether low-dose alcohol suppresses tremor in cre-negative mice with intact ß3 exon 3 flanked by loxP, and in littermates in which this region was excised by cre expressed under the α6 subunit promotor. Tremor in the harmaline model was measured as a percentage of motion power in the tremor bandwidth divided by overall motion power. Results: Alcohol, 0.500 and 0.575 g/kg, reduced harmaline tremor compared to vehicle-treated controls in floxed ß3 cre- mice, but had no effect on tremor in floxed ß3 cre+ littermates that have ß3 knocked out. This was not due to potential interference of α6 expression by the insertion of the cre gene into the α6 gene since non-floxed ß3 cre+ and cre- littermates exhibited similar tremor suppression by alcohol. Discussion: As α6ß3δ GABAA receptors are sensitive to low-dose alcohol, and cerebellar granule cells express ß3 and are the predominant brain site for α6 and δ expression together, our overall findings suggest alcohol acts to suppress tremor by modulating α6ß3δ GABAA receptors on these cells. Novel drugs that target this receptor may potentially be effective and well-tolerated for essential tremor. Highlights: We previously found with the harmaline essential tremor model that GABAA receptors containing α6 and δ subunits mediate tremor suppression by alcohol. We now show that ß3 subunits in α6-expressing cells, likely cerebellar granule cells, are also required, indicating that alcohol suppresses tremor by modulating α6ß3δ extra-synaptic GABAA receptors.

Arabidopsis BECLIN1-induced autophagy mediates reprogramming in tapetal programmed cell death by altering the gross cellular homeostasis.

In flowering plants, the tapetum degeneration in post-meiotic anther occurs through developmental programmed cell death (dPCD), which is one of the most critical and sensitive steps for the proper development of male gametophytes and fertility. Yet the pathways of dPCD, its regulation, and its interaction with autophagy remain elusive. Here, we report that high-level expression of Arabidopsis autophagy-related gene BECLIN1 (BECN1 or AtATG6) in the tobacco tapetum prior to their dPCD resulted in developmental defects. BECN1 induces severe autophagy and multiple cytoplasm-to-vacuole pathways, which alters tapetal cell reactive oxygen species (ROS)-homeostasis that represses the tapetal dPCD. The transcriptome analysis reveals that BECN1- expression caused major changes in the pathway, resulting in altered cellular homeostasis in the tapetal cell. Moreover, BECN1-mediated autophagy reprograms the execution of tapetal PCD by altering the expression of the key developmental PCD marker genes: SCPL48, CEP1, DMP4, BFN1, MC9, EXI1, and Bcl-2 member BAG5, and BAG6. This study demonstrates that BECN1-mediated autophagy is inhibitory to the dPCD of the tapetum, but the severity of autophagy leads to autophagic death in the later stages. The delayed and altered mode of tapetal degeneration resulted in male sterility.

Tellurium Containing Long Lived Emissive Fluorophore for Selective and Visual Detection of Picric Acid through Photo-Induced Electron Transfer.

A novel tellurium (Te) containing fluorophore, 1 and its nickel (2) and copper (3) containing metal organic complex (MOC) have been synthesized to exploit their structural and optical properties and to deploy these molecules as fluorescent probes for the selective and sensitive detection of picric acid (PA) over other commonly available nitro-explosives. Furthermore, density functional theory (DFT) and single crystal X-ray diffraction (SCXRD) techniques revealed the inclusion of "soft" Tellurium (Te) and "hard" Nitrogen (N), Oxygen (O) atoms in the molecular frameworks. Owing to the presence of electron rich "N" and "O" atoms along with "Te" in the molecular framework, 1 could efficiently and selectively sense PA with more than 80 % fluorescence quenching efficiency in organic medium and having detection limit of 4.60 µM. The selective detection of PA compared to other nitro-explosives follows a multi-mechanism based "turn-off" sensing which includes photo-induced electron transfer (PET), electrostatic (π-π stacking and π-anion/cation) interaction, intermolecular hydrogen bonding and inner filter effect (IFE). The test strip study also establishes the sensitivity of 1 for detection of PA.

Gastric Teratoma in Children: A Report of Two Cases and Review of Literature.

ABSTRACT: Gastric teratomas are very rare tumours. They present with upper abdomen distension which can easily be confused with other common conditions with mass per abdomen in the paediatric age group. Surgical excision is curative for gastric teratomas. The diagnosis is confirmed by radiological evaluation followed by histopathological analysis of excised specimen. We are reporting two such cases of gastric teratomas who presented with complaints of upper abdomen distension. They were evaluated with radiological imaging and successfully managed by surgical excision.

Congenital Urethrocutaneous Fistula.

ABSTRACT: Male congenital urethrocutaneous fistula is an extremely rare anomaly that is commonly associated with chordee or anorectal malformations. It is characterised by an abnormal urethral opening on the ventral aspect of the penis with well-formed distal urethra and meatus at the tip of the glans. The treatment is individualised according to the site of the fistula, associated anomalies and condition of the distal urethra. The principles of hypospadias surgery should be strictly followed.

Novel Anti-B-cell Maturation Antigen Alpha-Amanitin Antibody-drug Conjugate HDP-101 Shows Superior Activity to Belantamab Mafodotin and Enhanced Efficacy in Deletion 17p Myeloma Models.

B-cell maturation antigen (BCMA) plays a pathobiologic role in myeloma and is a validated target with five BCMA-specific therapeutics having been approved for relapsed/refractory disease. However, these drugs are not curative, and responses are inferior in patients with molecularly-defined high-risk disease, including those with deletion 17p (del17p) involving the tumor suppressor TP53, supporting the need for further drug development. Del17p has been associated with reduced copy number and gene expression of RNA polymerase II subunit alpha (POLR2A) in other tumor types. We therefore studied the possibility that HDP-101, an anti-BCMA antibody drug conjugate (ADC) with the POLR2A poison α-amanitin could be an attractive agent in myeloma, especially with del17p. HDP-101 reduced viability in myeloma cell lines representing different molecular disease subtypes, and overcame adhesion-mediated and both conventional and novel drug resistance. After confirming that del17p is associated with reduced POLR2A levels in publicly available myeloma patient databases, we engineered TP53 wild-type cells with a TP53 knockout (KO), POLR2A knockdown (KD), or both, the latter to mimic del17p. HDP-101 showed potent anti-myeloma activity against all tested cell lines, and exerted enhanced efficacy against POLR2A KD and dual TP53 KO/POLR2A KD cells. Mechanistic studies showed HDP-101 up-regulated the unfolded protein response, activated apoptosis, and induced immunogenic cell death. Notably, HDP-101 impacted CD138-positive but not-negative primary cells, showed potent efficacy against aldehyde dehydrogenase-positive clonogenic cells, and eradicated myeloma in an in vivo cell line-derived xenograft (CDX). Interestingly, in the CDX model, prior treatment with HDP-101 precluded subsequent engraftment on tumor cell line rechallenge in a manner that appeared to be dependent in part on natural killer cells and macrophages. Finally, HDP-101 was superior to the BCMA-targeted ADC belantamab mafodotin against cell lines and primary myeloma cells in vitro, and in an in vivo CDX. Together, the data support the rationale for translation of HDP-101 to the clinic, where it is now undergoing Phase I trials, and suggest that it could emerge as a more potent ADC for myeloma with especially interesting activity against the high-risk del17p myeloma subtype.