Nanoscale imaging of DNA-RNA identifies transcriptional plasticity at heterochromatin.

The three-dimensional structure of DNA is a biophysical determinant of transcription. The density of chromatin condensation is one determinant of transcriptional output. Chromatin condensation is generally viewed as enforcing transcriptional suppression, and therefore, transcriptional output should be inversely proportional to DNA compaction. We coupled stable isotope tracers with multi-isotope imaging mass spectrometry to quantify and image nanovolumetric relationships between DNA density and newly made RNA within individual nuclei. Proliferative cell lines and cycling cells in the murine small intestine unexpectedly demonstrated no consistent relationship between DNA density and newly made RNA, even though localized examples of this phenomenon were detected at nuclear-cytoplasmic transitions. In contrast, non-dividing hepatocytes demonstrated global reduction in newly made RNA and an inverse relationship between DNA density and transcription, driven by DNA condensates at the nuclear periphery devoid of newly made RNA. Collectively, these data support an evolving model of transcriptional plasticity that extends at least to a subset of chromatin at the extreme of condensation as expected of heterochromatin.

Giacomini's vein - a report on the invaluable importance of an anomalous short saphenous vein.

Variations in the drainage (termination) and course of the lower limb veins are not uncommon. When dissecting the left lower limb of the adult male cadaver in the vascular case described herein, a unique kind of unilateral short saphenous vein (SSV) termination was observed. It was found that the SSV had normal origin and course in the dorsum of the foot and the back of the leg, respectively. Most often the SSV terminates in the popliteal vein at the popliteal fossa. In this case, it extended upward into the back of the thigh, passing behind the sciatic nerve and then deep to it and the biceps femoris, and finally ended in the veins of the thigh. The SSV did not penetrate any structures along its course to the end, so this unusual vein appears unlikely to be associated with SSV varicose veins. For general, plastic, cardiothoracic, and vascular surgeons, our case would be of significant value.

Variações na drenagem (terminação) e curso das veias dos membros inferiores não são incomuns. No caso vascular relatado, ao dissecar o membro inferior esquerdo de um cadáver adulto do sexo masculino, foi observado um tipo único de veia safena parva (VSP) unilateral. Verificou-se que a VSP tinha origem e curso normais no dorso do pé e na traseira da perna, respectivamente. É mais comum a VSP terminar na veia poplítea, localizada na fossa poplítea. No caso relatado, ela se estendia para cima até a parte posterior da coxa, passando por trás e profundamente no nervo ciático e no músculo isquiotibial, finalizando nas veias da coxa. A VSP não penetra nenhuma estrutura no seu curso; portanto, não é provável que esta veia incomum esteja associada a veias varicosas da VSP. Para cirurgiões gerais, plásticos, cardiotorácicos e vasculares, nosso caso é de extrema importância.

Empathy development through game-based learning: An investigative study on nursing professionals.

BACKGROUND: Empathy is at the core of patient-centred care. Evidence has continually found that empathy helps foster therapeutic relationships and is essential in the delivery of quality healthcare. In India, many factors are barriers to empathy for nursing professionals. OBJECTIVES: DESIGN AND METHODS: The IDEO design thinking process was followed to design the game. A focus group discussion with 18 nurses helped identify relevant scenarios and barriers to empathy. A scenario of an interaction between a nurse and a cancer patient was identified to create the game. The game mechanics, rubrics, and scenarios were built based on feedback from diverse professionals consisting of doctors, nurses, and UX designers. A learner feedback form assessing usability, contextual specificity, engagement, and perceived learnability was created and its reliability was tested. The game was tested on 60 nurses, followed by administration of the learner feedback form. To assess changes in empathy, an empathy scale was administered before the intervention and seven days after the intervention on 20 nurses. RESULTS: The learner feedback form was found to have Cronbach's Alpha >0.70, and therefore reliable. The responses to the learner feedback form were analysed using the Chi Square test and were found to be positive and statistically significant (p-value<0.001). The differences in pretest and posttest empathy scores were analysed using the Wilcoxon Signed Ranks test and were found to be statistically significant as well (p-value<0.001). CONCLUSIONS: The positive response to the learner feedback form, and the improvement in empathy scores after the intervention, indicates that games have a potential role in teaching empathy to Nursing Professionals.

Evolution of drug resistance against antiviral agents that target cellular factors.

Antiviral drugs have classically been developed by directly disrupting the functions of viral proteins. However, this strategy has been largely unsuccessful due to the rapid generation of viral escape mutants. It has been well established that as compared to the virus-centric approach, the strategy of developing antiviral drugs by targeting host-dependency factors (HDFs) minimizes drug resistance. However, recent reports have indicated that drug resistance against some of the host-targeting antiviral agents can in fact occur under some circumstances. Long-term selection pressure of a host-targeting antiviral agent may induce the virus to use an alternate cellular factor or alters its affinity towards the target that confers resistance. Alternatively, virus may synchronize its life cycle with the patterns of drug therapy. In addition, virus may subvert host's immune system to perpetuate under the limiting conditions of the targeted cellular factor. This review describes novel potential mechanisms that may account for the acquiring resistance against agents that target HDFs.

Looking Beyond Pneumonia and Asthma in India: An Interesting Case of Churg-Strauss Syndrome.

Churg-Strauss syndrome is a rare multisystem disorder characterized by asthma, eosinophilia, and vasculitis. The patient presented with prolonged fever, cough with blood-stained sputum, weight loss, pain in the abdomen, and a subsequent onset of hoarseness of voice. A history of asthma, left-side vocal cord paralysis, eosinophilia, nodular opacities on radiography, and eosinophilic duodenitis on biopsy led to a diagnosis of Churg-Strauss syndrome. The patient's condition improved on treatment with steroids. This is an interesting case and presents an opportunity to learn about Churg-Strauss syndrome.

I2-Promoted Chemoselective Annulative Coupling of 2-Aminobenzamides with Sulfoxonium Ylides: Easy Access to Quinazolinones.

A flexible and metal-free synthetic approach for synthesizing 2-benzoyl quinazolinones and 2-aryl quinazolinones via molecular iodine-mediated annulative coupling of sulfoxonium ylides with 2-aminobenzamides has been disclosed. The method demonstrates remarkable chemoselectivity and efficiency, leading to high yields of 2-benzoyl quinazolinones and 2-aryl quinazolinones under optimized conditions. The broad substrate scope, scalability, and practical utility were highlighted through diverse applications, including gram-scale reactions and the synthesis of biologically significant compounds such as tryptanthrin and the chemo/biosensor derivative.

Nonoxidovanadium(IV) Complex-Catalyzed Synthesis of 2-Amino-3-cyano-4H-pyrans/4H-chromenes, Biscoumarins, and Xanthenes under Green Conditions.

Reaction of [VIVO(acac)2] (Hacac = acetylacetone) with a Mannich base, N,N,N',N'-tetrakis(2-hydroxy-3,5-di-tert-butyl benzyl)-1,2-diaminoethane (H4L, I) in a 1:1 molar ratio in MeOH, leads to the formation of the nonoxidovanadium(IV) complex [VIVL] (1). Air stable complex 1 has been characterized using various spectroscopic techniques, DFT calculations, and single-crystal X-ray studies. 1 adopts distorted octahedral geometry where ligand coordinates through all coordination functionalities available. This complex has been used as a catalyst in the one-pot, three-component synthesis of 2-amino-3-cyano-4H-pyrans using 1,3-dicarbonyls (1,3-cyclohexanedione, dimedone, barbituric acid, and 4-hydroxycoumarin), malononitrile, and various substituted aromatic aldehydes in equimolar amounts employing ethanol as a green solvent. The catalytic reaction revealed that the multicomponent synthesis of 4H-pyrans and chromenes is greatly influenced by both types of 1,3-dicarbonyl compound employed and the nature of the substituent on the aromatic ring of the aldehyde. Synthesized catalyst has also been used in the synthesis of pharmacologically relevant oxygen-containing heterocycles, specifically, 1,8-dioxo-octahydro-1H-xanthenes and biscoumarins. The possible mechanism for the synthesized one-pot, multicomponent product has been proposed by isolating intermediate(s) generated during synthesis.

Critical insights from recent outbreaks of Mycoplasma pneumoniae: decoding the challenges and effective interventions strategies.

OBJECTIVES: Mycoplasma pneumoniae (M. pneumoniae) continues to pose a significant disease burden on global public health as a respiratory pathogen. The antimicrobial resistance among M. pneumoniae strains has complicated the outbreak control efforts, emphasizing the need for robust surveillance systems and effective antimicrobial stewardship programs. DESIGN: This review comprehensively investigates studies stemming from previous outbreaks to emphasize the multifaceted nature of M. pneumoniae infections, encompassing epidemiological dynamics, diagnostic innovations, antibiotic resistance, and therapeutic challenges. RESULTS: We explored the spectrum of clinical manifestations associated with M. pneumoniae infections, emphasizing the continuum of disease severity and the challenges in gradating it accurately. Artificial intelligence and machine learning have emerged as promising tools in M. pneumoniae diagnostics, offering enhanced accuracy and efficiency in identifying infections. However, their integration into clinical practice presents hurdles that need to be addressed. Further, we elucidate the pivotal role of pharmacological interventions in controlling and treating M. pneumoniae infections as the efficacy of existing therapies is jeopardized by evolving resistance mechanisms. CONCLUSION: Lessons learned from previous outbreaks underscore the importance of adaptive treatment strategies and proactive management approaches. Addressing these complexities demands a holistic approach integrating advanced technologies, genomic surveillance, and adaptive clinical strategies to effectively combat this pathogen.

Meta-analysis of prevalence of paratuberculosis in cattle using published estimates under serum and milk ELISA.

Johne's disease (JD), caused by Mycobacterium avium subspecies paratuberculosis (MAP), poses significant challenges to the global livestock industry, particularly affecting bovine populations. To better understand the prevalence of paratuberculosis and its diagnostic nuances, a comprehensive meta-analysis was conducted. This analysis encompassed 21 studies involving 632,767 cows for milk enzyme-linked immunosorbent assay (ELISA) and 51 studies involving 256,409 cows for serum ELISA. The pooled prevalence estimate for paratuberculosis on a cow-basis was found to be 16% (95% CI: 14%; 18%) for milk ELISA and 8% (95% CI: 7%; 8%) for serum ELISA. Notably, higher confidence intervals (CI) were observed in milk ELISA, the Europe and Asia groups, suggesting variability in prevalence estimates within these regions. Conversely, lower CIs were noted in the USA and Canada groups, indicating greater consistency in prevalence estimates within these countries. However, serum ELISA exhibited high CI values across all regions, underscoring potential variability in diagnostic performance. These findings provide valuable insights for veterinarians, researchers, policymakers, and livestock producers in optimizing paratuberculosis detection and control strategies to mitigate its impact on bovine health and agricultural productivity.

Evaluation of the immune responses in buffaloes vaccinated with a live-attenuated lumpy skin disease vaccine (Lumpi-ProVacInd).

Since 2019, Lumpy skin disease (LSD) has suddenly spread in many Asian countries, including India. LSD primarily occurs in cattle. However, recent LSD outbreaks in India have also revealed significant morbidity and production losses in buffaloes. This has raised concerns about the role of buffaloes in the epidemiology and transmission of LSD and necessitates the inclusion of buffaloes in the mass vaccination program for the prevention and control of the disease in the country. However, there is no significant data on the immune response in buffaloes following vaccination with the LSD vaccine. In this study, we evaluated antibody- and cell-mediated immune responses following vaccination with a newly developed live-attenuated LSD vaccine (Lumpi-ProVacInd). The detectable amount of anti-LSDV antibodies was observed at 1-2 months following vaccination, with a peak antibody titer at 3 months. Upon stimulation of the peripheral blood mononuclear cells (PBMCs) with the UV-inactivated LSDV antigen, there was a significant increase in CD8 + T cell counts in vaccinated animals as compared to the unvaccinated animals. Besides, vaccinated animals also showed a significant increase in IFN-γ levels upon antigenic stimulation of their PBMCs with LSDV antigen. In conclusion, the buffaloes also mount a potent antibody- and cell-mediated immune response following vaccination with Lumpi-ProVacInd.

Origin and evolution of the bread wheat D genome.

Bread wheat (Triticum aestivum) is a globally dominant crop and major source of calories and proteins for the human diet. Compared with its wild ancestors, modern bread wheat shows lower genetic diversity, caused by polyploidisation, domestication and breeding bottlenecks1,2. Wild wheat relatives represent genetic reservoirs, and harbour diversity and beneficial alleles that have not been incorporated into bread wheat. Here we establish and analyse extensive genome resources for Tausch's goatgrass (Aegilops tauschii), the donor of the bread wheat D genome. Our analysis of 46 Ae. tauschii genomes enabled us to clone a disease resistance gene and perform haplotype analysis across a complex disease resistance locus, allowing us to discern alleles from paralogous gene copies. We also reveal the complex genetic composition and history of the bread wheat D genome, which involves contributions from genetically and geographically discrete Ae. tauschii subpopulations. Together, our results reveal the complex history of the bread wheat D genome and demonstrate the potential of wild relatives in crop improvement.

Management of Cheilitis Granulomatosa with Pica Disorder: A Rare Case Report.

Aim: To report a rare case of cheilitis granulomatosa (CG) with pica disorder presented as chronic persistent lip swelling with an unusual eating disorder. Background: Cheilitis granulomatosa or Miescher's cheilitis is a rare, persistent, or recurring nontender chronic painless swelling of one or both the lips due to granulomatous inflammation, which was first described by Miescher in 1945. It can present as a monosymptomatic form or as a part of other entities of Melkersson-Rosenthal syndrome (MRS). Case description: A 14-year-old female patient presented with persistent diffuse swelling of the upper lip for 1 year. She also had an unusual habit of eating clay, mud, and potentially harmful items like flakes of paint for 1.5 years. Clinically, chronic persistent lip swelling involving upper lip and gingival enlargements were present along with systemic manifestations. Patient counseling with combination therapy showed excellent response with no signs of relapse at 6 months of follow-up. Conclusion: Cheilitis granulomatosa is a unique rare inflammatory disorder with many possible contributory factors and exact etiology is poorly understood. Clinical significance: This case report draws attention to constant exposure to an allergen that could be one of the possible etiological factors to CG secondary to pica eating disorder. Though it is a rare disease, research on the pathogenesis of CG and clinical trials evaluating the efficacy of the various treatments are needed to enhance our understanding of this disease, to improve the quality of life, as patients are very disturbed by the unsightly and distressing nature of macrocheilitis. How to cite this article: Dayanarayana U, Shastry SP, Kempegowda RT, et al. Management of Cheilitis Granulomatosa with Pica Disorder: A Rare Case Report. Int J Clin Pediatr Dent 2024;17(4):483-489.

Phenylstyrylpyrimidine derivatives as potential multipotent therapeutics for Alzheimer's disease.

Alzheimer's disease (AD) is a multifactorial neurological disorder that affects millions of people worldwide. Despite extensive research efforts, there are currently no effective disease-modifying therapeutics available for the complete cure of AD. In the current study, we have designed and synthesized a series of phenyl-styryl-pyrimidine derivatives as potential multifunctional agents against different targets of AD. The compounds were evaluated for their ability to inhibit acetylcholinesterase (AChE), monoamine oxidase (MAO) and ß amyloid aggregation which are associated with the initiation and progression of the disease. Several compounds in the series exhibited potent inhibitory activity against AChE and MAO-B, with IC50 values in the low micromolar range. In particular, two compounds, BV-12 and BV-14, were found to exhibit a multipotent profile and showed non-competitive inhibition against MAO-B with IC50 values of 4.93 ± 0.38 & 7.265 ± 0.82 µM, respectively and AChE inhibition with IC50 values of 7.265 and 9.291 µM, respectively. BV-12 and BV-14 also displayed ß amyloid self-aggregation inhibition of 32.98% and 23.25%, respectively. Furthermore, molecular modelling studies revealed that BV-14 displayed a docking score of -11.20 kcal mol-1 with MAO-B & -6.767 kcal mol-1 with AChE, forming a stable complex with both proteins. It was concluded that phenyl-styryl-pyrimidine derivatives have the potential to be developed as multitarget directed ligands for the treatment of AD.

Structural regression modelling of peptide based drug delivery vectors for targeted anti-cancer therapy.

Drug resistance in cancer poses a serious challenge in finding an effective remedy for cancer patients, because of the multitude of contributing factors influencing this complex phenomenon. One way to counter this problem is using a more targeted and dose-limiting approach for drug delivery, rather than relying on conventional therapies that exhibit multiple pernicious side-effects. Stability and specificity have traditionally been the core issues of peptide-based delivery vectors. In this study, we employed a structural regression modelling approach in the design, synthesis and characterization of a series of peptides that belong to approximately same topological cluster, yet with different electrostatic signatures encoded as a result of their differential positioning of amino acids in a given sequence. The peptides tagged with the fluorophore 5(6)-carboxyfluorescein, showed higher uptake in cancer cells with some of them colocalizing in the lysosomes. The peptides tagged with the anti-cancer drug methotrexate have displayed enhanced cytotoxicity and inducing apoptosis in triple-negative breast cancer cells. They also showed comparable uptake in side-population cells of lung cancer with stem-cell like properties. The most-optimized peptide showed accumulation in the tumor resulting in significant reduction of tumor size, compared to the untreated mice in in-vivo studies. Our results point to the following directives; (i) peptides can be design engineered for targeted delivery (ii) stereochemical engineering of peptide main chain can resist proteolytic enzymes and (iii) cellular penetration of peptides into cancer cells can be modulated by varying their electrostatic signatures.

Genome structural variants shape adaptive success of an invasive urban malaria vector Anopheles stephensi.

Global changes are associated with the emergence of several invasive species. However, the genomic determinants of the adaptive success of an invasive species in a new environment remain poorly understood. Genomic structural variants (SVs), consisting of copy number variants, play an important role in adaptation. SVs often cause large adaptive shifts in ecologically important traits, which makes SVs compelling candidates for driving rapid adaptations to environmental changes, which is critical to invasive success. To address this problem, we investigated the role SVs play in the adaptive success of Anopheles stephensi , a primary vector of urban malaria in South Asia and an invasive malaria vector in several South Asian islands and Africa. We collected whole genome sequencing data from 115 mosquitoes from invasive island populations and four locations from mainland India, an ancestral range for the species. We identified 2,988 duplication copy number variants and 16,038 deletions in these strains, with ∼50% overlapping genes. SVs are enriched in genomic regions with signatures of selective sweeps in the mainland and invasive island populations, implying a putative adaptive role of SVs. Nearly all high-frequency SVs, including the candidate adaptive variants, in the invasive island populations are present on the mainland, suggesting a major contribution of existing variation to the success of the island populations. Among the candidate adaptive SVs, three duplications involving toxin-resistance genes evolved, likely due to the widespread application of insecticides in India since the 1950s. We also identify two SVs associated with the adaptation of An. stephensi larvae to brackish water in the island and two coastal mainland populations, where the mutations likely originated. Our results suggest that existing SVs play a vital role in the evolutionary success of An. stephensi in new environmental conditions.

Non-canonical NF-κB signaling limits the tolerogenic ß-catenin-Raldh2 axis in gut dendritic cells to exacerbate intestinal pathologies.

Dendritic cell (DC) dysfunction is known to exacerbate intestinal pathologies, but the mechanisms compromising DC-mediated immune regulation in this context remain unclear. Here, we show that intestinal dendritic cells from a mouse model of experimental colitis exhibit significant levels of noncanonical NF-κB signaling, which activates the RelB:p52 heterodimer. Genetic inactivation of this pathway in DCs alleviates intestinal pathologies in mice suffering from colitis. Deficiency of RelB:p52 diminishes transcription of Axin1, a critical component of the ß-catenin destruction complex, reinforcing ß-catenin-dependent expression of Raldh2, which imparts tolerogenic DC attributes by promoting retinoic acid synthesis. DC-specific impairment of noncanonical NF-κB signaling leads to increased colonic numbers of Tregs and IgA+ B cells, which promote luminal IgA production and foster eubiosis. Experimentally introduced ß-catenin haploinsufficiency in DCs with deficient noncanonical NF-κB signaling moderates Raldh2 activity, reinstating colitogenic sensitivity in mice. Finally, inflammatory bowel-disease patients also display a deleterious noncanonical NF-κB signaling signature in intestinal DCs. In sum, we establish how noncanonical NF-κB signaling in dendritic cells can subvert retinoic acid synthesis to fuel intestinal inflammation.

Backstepping based intelligent control of tractor-trailer mobile manipulators with wheel slip consideration.

In this research, a new hybrid backstepping control strategy based on a neural network is proposed for tractor-trailer mobile manipulators in the presence of unknown wheel slippage and disturbances. To minimize the negative impacts of wheel slippage, the desired velocities of the tractor's wheels are computed with a proposed kinematic control model with an adaptive term. As the system's dynamical model contains unavoidable uncertainties, model-based backstepping control technique is unable to effectively manage these systems. Hence, the proposed controller blends a radial basis function neural network with the merits of a dynamical model-based backstepping approach. The neural networks are employed to approximate the non-linear unknown smooth function. To minimize the impact of external disturbances, and network reconstruction error an adaptive term is added to the control law. The Lyapunov theorem and Barbalat's lemma are employed to guarantee the stability of the control method. The tracking error is shown to be bounded and to rapidly converge to zero with the proposed method. To demonstrate the efficacy and validity of the control mechanism, comparison simulation results are presented.

Optimizing forage harvest and the nutritive value of Italian ryegrass-based mixed forage cropping under northwestern Himalayan conditions.

The scarcity of high-quality forage has a significant influence on the productivity and profitability of livestock. Addressing this concern, an investigation was undertaken to assess the effects of distinct Italian ryegrass genotypes, namely, Punjab ryegrass-1, Kashmir collection, and Makhan grass, in conjunction with varying seeding ratios of Italian ryegrass to Egyptian clover. The seeding ratios considered were 100:0 (Italian ryegrass to Egyptian clover), 75:25, 50:50, and 25:75. All possible combinations of Italian ryegrass and Egyptian clover with seeding ratios were set up in a randomized complete block design and replicated thrice. Co-cultivating Italian ryegrass and Egyptian clover at a 75:25 seeding ratio yields the best yield benefit, as determined by the land equivalent ratio. It is noteworthy that in this configuration, real yield loss is higher for Egyptian clover and for Italian ryegrass when the seeding ratio is 25:75. The higher competitiveness of Italian ryegrass in comparison to Egyptian clover is highlighted by the competitive ratio. Notably, the nutritive parameter, crude protein yield, was significantly higher in the Makhan grass-based 50:50 and 75:25 seeding ratio. Results of the study ascertained the compatibility of grass-legume co-cultivation with significantly higher quantity and quality forage harvested under mixed cropping systems whereas Makhan grass as the superior and dominant genotype in comparison to Kashmir collection. The outcomes of this study revealed that the 100:0 seeding ratio, coupled with the Makhan grass genotype, exhibited superior performance in terms of cumulative forage harvest, dry matter accumulation, net returns, and benefit-cost ratio.

Microplastics - A Growing Concern as Carcinogens in Cancer Etiology: Emphasis on Biochemical and Molecular Mechanisms.

In today's world, the widespread presence of microplastics is undeniable, with concentrations found in various environments, including up to 1000 particles per liter in seawater and up to 10 particles per cubic meter in the atmosphere. Originating from diverse sources, both intentional and unintentional, these minuscule fragments, measuring less than 5 mm, pose significant threats to environmental and human health. Recent research has uncovered a concerning link between microplastics and cancer, prompting urgent investigation. Studies demonstrate microplastics can infiltrate cells, disrupt biological processes, and potentially foster carcinogenic environments. From inducing DNA damage and oxidative stress to triggering inflammatory responses and dysregulating cellular pathways, microplastics exhibit a multifaceted capability in contributing to cancer development. Furthermore, microplastics act as carriers for a range of contaminants, compounding their impact on human health. Their accumulation within tissues and organs raises concerns for short and long-term health consequences, including chronic diseases, reproductive issues, and developmental abnormalities. This review explores the biochemical and molecular mechanisms underlying the interaction between microplastics and cellular systems, providing insights into routes of exposure and health effects, with a focus on lung, skin, and digestive system cancers. As we confront this pressing environmental and public health challenge, a deeper understanding of the microplastic-cancer relationship is crucial to safeguarding the well-being of present and future generations.