Influence of Hydroxyproline on Mechanical Behavior of Collagen Mimetic Proteins Under Fraying Deformation-Molecular Dynamics Investigations.

Molecular dynamics modeling is used to simulate, model, and analyze mechanical deformation behavior and predictive properties of three different synthetic collagen proteins obtained from RSC-PDB, 1BKV, 3A08, and 2CUO, with varying concentrations of hydroxyproline (HYP). Hydroxyproline is credited with providing structural support for the collagen protein molecules. Hydroxyproline's influence on these three synthetic collagen proteins' mechanical deformation behavior and predictive properties is investigated in this paper. A detailed study and inference of the protein's mechanical characteristics associated with HYP content are investigated through fraying deformation behavior. A calculated Gibbs free energy value (ΔG) of each polypeptide α chain that corresponds with a complete unfolding of a single polypeptide α-chain from a triple-helical protein is obtained with umbrella sampling. The force needed for complete separation of the polypeptide α-chain from the triple-helical protein is analyzed for proteins to understand the influence of HYP concentration and is discussed in this paper. Along with a difference in ΔG, different unfolding pathways for the molecule and individual chains are observed. The correlation between the fraying deformation mechanical characteristics and the collagen proteins' hydroxyproline content is provided in this study via the three collagen proteins' resulting binding energies.

Exosomal microRNAs: impact on cancer detection, treatment, and monitoring.

Exosomes, measuring between 30 and 150 nm in diameter, are small vesicles enclosed by a lipid bilayer membrane. They are released by various cells in the body and carry a diverse payload of molecules, including proteins, lipids, mRNA, and different RNA species such as long non-coding RNA, circular RNA, and microRNA (miRNA). With lengths of approximately 19-22 nucleotides, miRNAs constitute the predominant cargo in exosomes and serve as crucial regulators of protein biosynthesis. In cancer detection, exosomal miRNAs show promise as non-invasive biomarkers due to their stability and presence in various bodily fluids, aiding in early detection and precise diagnosis with specific miRNA signatures linked to different cancer types. Moreover, exosomal miRNAs influence treatment outcomes by affecting cellular processes like cell growth, cell death, and drug resistance, thereby impacting response to therapy. Additionally, they serve as indicators of disease progression and treatment response, providing insights that can guide treatment decisions and improve patient care. Through longitudinal studies, changes in exosomal miRNA profiles have been observed to correlate with disease progression, metastasis, and response to therapy, highlighting their potential for real-time monitoring of tumor dynamics and treatment efficacy. Understanding the intricate roles of exosomal miRNAs in cancer biology offers opportunities for developing innovative diagnostic tools and therapeutic strategies tailored to individual patients, ultimately advancing precision medicine approaches and improving outcomes for cancer patients. This review aims to provide an understanding of the role of exosomal miRNAs in cancer detection, treatment, and monitoring, shedding light on their potential for revolutionising oncology practices and patient care.

Pseudoaneurysm of profunda femoris artery following dynamic hip screw fixation for intertrochanteric femoral fracture.

Dynamic hip screw fixation is a commonly performed procedure for internal fixation of intertrochanteric femoral fractures. Arterial injury following the operative fixation is a rare but serious event. We present a patient who developed pseudoaneurysm of profunda femoris artery after internal fixation of intertrochanteric fracture with a dynamic hip screw. The diagnosis was confirmed by angiographic study and it was successfully treated by coil embolization.

Organizing and Leading a Multidisciplinary PICU.

Pediatric critical care units (PICUs) have come a long way over the past four decades. They continue to be clinical areas that are resource-intensive. PICUs require a team of highly engaged and well-trained professionals working together to change the trajectory of critical illness. Consequently, it requires strong physician and nursing leadership to lead the team of dedicated individuals to perform at the highest level. A dyad of a PICU Medical Director and a PICU Nursing Director is a good construct for administrative leadership. Several options of models exist-open versus closed or a hybrid model. A 24 × 7 coverage of the PICU with skilled personnel is important to provide timely care but is not always possible due to personnel constraints. Indian PICUs have also evolved and made significant strides in their governance and coverage models. Policies and standard operating procedures (SOPs) govern the care that is delivered and may need to be updated regularly. The NABH reviews these as part of their accreditation process. A multidisciplinary committee structure to review aspects of PICU function and outcomes on a regular basis is vital. Certain guiding principles should determine the philosophy of the PICU, and the leaders in the PICU need to model behavior in keeping with these principles. PICU outcomes should be measured and tracked; a root-cause analysis should be triggered when appropriate; and interventions should be made using the PDSA (plan-do-study-act) cycle of process improvement when outcomes fall short of expectations. Adverse events should ideally be disclosed, but this represents a challenge in the current environment. Indian PICUs continue to evolve rapidly, and establishing a database for comparative analysis of outcomes is a natural next step.

Environmentally friendly organic synthesis using bismuth(III) compounds.

With increasing environmental concerns, the need for environmentally friendly organic synthesis has gained increased importance. In this regard, bismuth(III) compounds are especially attractive as "green" reagents and catalysts for organic synthesis. Bismuth(III) compounds are remarkably nontoxic, relatively air and moisture stable, and easy to handle. The contributions from our laboratory in the last 5 years in the field of applications of bismuth(III) compounds as catalysts are presented.

Applications of bismuth(III) compounds in organic synthesis.

This review article summarizes the applications of bismuth(III) compounds in organic synthesis since 2002. Although there are an increasing number of reports on applications of bismuth(III) salts in polymerization reactions, and their importance is acknowledged, they are not included in this review. This review is largely organized by the reaction type although some reactions can clearly be placed in multiple sections. While every effort has been made to include all relevant reports in this field, any omission is inadvertent and we apologize in advance for the same (358 references).

Disseminated tuberculosis with macrophage activation syndrome in a child with lupus nephritis.

In children with systemic lupus erythematosus on immunosuppressive therapy, infection is a known complication. We present a case of a 12-year-old girl who was previously diagnosed with lupus nephritis but had stopped taking allopathic medications and had been on herbal medicines for a year. She was referred to us with persistent fever and disease activity in spite of restarting immunosuppressive treatment. Results of blood tests and bone marrow aspiration were suggestive of macrophage activation syndrome. Imaging of her chest and abdomen showed features suggestive of miliary tuberculosis (TB) in the lungs and granulomas in the spleen. Mycobacterium tuberculosis was identified in bone marrow cultures, resulting in a diagnosis of disseminated TB. She was successfully treated with intravenous steroids, anti-tuberculous therapy and intravenous immunoglobulin. Mycophenolate mofetil was added after 6 weeks. The patient recovered from TB and her lupus was under control during follow-up.

Functional diversity of Himalayan bat communities declines at high elevation without the loss of phylogenetic diversity.

Species richness exhibits well-known patterns across elevational gradients in various taxa, but represents only one aspect of quantifying biodiversity patterns. Functional and phylogenetic diversity have received much less attention, particularly for vertebrate taxa. There is still a limited understanding of how functional, phylogenetic and taxonomic diversity change in concert across large gradients of elevation. Here, we focused on the Himalaya-representing the largest elevational gradients in the world-to investigate the patterns of taxonomic, functional and phylogenetic diversity in a bat assemblage. Combining field data on species occurrence, relative abundance, and functional traits with measures of phylogenetic diversity, we found that bat species richness and functional diversity declined at high elevation but phylogenetic diversity remained unchanged. At the lowest elevation, we observed low functional dispersion despite high species and functional richness, suggesting a niche packing mechanism. The decline in functional richness, dispersion, and divergence at the highest elevation is consistent with patterns observed due to environmental filtering. These patterns are driven by the absence of rhinolophid bats, four congeners with extreme trait values. Our data, some of the first on mammals from the Himalayan region, suggest that in bat assemblages with relatively high species diversity, phylogenetic diversity may not be a substitute to measure functional diversity.

Immunomodulating Properties of Carrageenan from Tichocarpus crinitus.

Several in vivo immunotropic effects of κ/ß-carrageenan isolated from the red algae Tichocarpus crinitus were studied, by orally administering it at 100 mg/kg/day to mice for 7 days. Serum levels of IFN-γ, IL-12, IL-1ß, and IL-4 were measured. Carrageenan's ability to influence development of LPS-induced inflammation was also assessed. Oral administration of κ/ß-carrageenan increased serum levels of all the studied cytokines at least twice in comparison to the intact mice, while intraperitoneal LPS injection at 1 mg/kg increased concentration of only the pro-inflammatory cytokines: IFN-γ, IL-12, and IL-1ß. Furthermore, κ/ß-carrageenan demonstrated a higher efficacy at inducing IFN-γ production than LPS. Previous 7-day-long oral carrageenan administration impaired development of LPS-induced inflammation: level of IL-1ß dropped below that found in intact mice, while IFN-γ and IL-12 concentrations were at least 40% lower than in mice with LPS-induced inflammation. Murine peritoneal macrophages were also affected by the oral administration of the κ/ß-carrageenan: their motility was increased, and morphology altered. In sum, we have demonstrated that κ/ß-carrageenan, when administered orally, is not only not immunologically inert, but at the dose of 100 mg/kg possesses pharmacologically exploitable effects.

Ultra performance liquid chromatography coupled with principal component and cluster analysis of Swertia chirayita for adulteration check.

This article describes the study to standardize phytochemically and distinguish Swertia chirayita from that of possible substitution/adulteration using ultra performance liquid chromatography (UPLC) with photodiode array detector (PDA) and chemometric tools viz. principal component analysis (PCA) and hierarchical clustering analysis (HCA). Five ecotypes of Swertia chirayita and five possible substitutions, e.g.,Swertia bimaculata (SB), Swertia chordata (SCH), Swertia ciliata (SCL), Swertia paniculata (SP), and Halenia elliptica (HE) collected from different Indian Himalayan region. Samples evaluated for 04 marker compounds- swertiamarin (SM), mangiferin (MF), gentiopicroside (GP), and sweroside (SW). Reverse phase column (Waters Acquity BEH C18, 50 mm × 2.1 mm , 1.7 µm) provided high resolution for all target analytes with binary gradient elution. The detector response was linear (concentration 2.5-125 µg/mL, R2 > 0.999). The limit of detection (LOD) and quantification (LOQ) of targeted compounds was in the range of 1.40-2.06 and 4.57-6.27 µg/mL respectively. The combined relative standard deviation (%RSD) for intra-day and inter-day precision values were less than 2%. The recoveries study comply the method suitability. Chromatogram similarity analysis based on congruence coefficient was higher than 0.925 for the chirayita ecotypes while much lower than 0.629 for possible substitutes. HCA showed that the samples could be clustered (all 5 clusters in two-level) reasonably into different ecotypes and substitutes. HCA together with loading plots has indicated different chemical properties of all five groups. PCA results showed that the discrimination of chirayita ecotypes is because of the presence of SW while SM may have more influence on the targeted substitutes to discriminate from chirayita ecotypes. Therefore, UPLC fingerprint in association with chemometric tools provides a reliable and accurate quality assessment and detection of possible adulteration.

A Randomized Study Comparing the Incidence of Postoperative Pain After Phrenic Nerve Infiltration Vs Nonphrenic Nerve Infiltration During Thoracotomy.

Thoracotomy is a common surgical procedure performed worldwide for lung disease. Despite major advances in analgesia, patients still experience severe shoulder, central back and surgical incision site pain in the postoperative period. This study aimed to assess whether intraoperative phrenic nerve infiltration reduces the incidence of postoperative pain and improves peak flow volume measurements during incentive spirometry. 90 patients undergoing open lobectomy were randomly assigned to have phrenic nerve infiltration (n = 46) or not (n = 44). The phrenic nerve infiltration group received 10 mL of 0.25% bupivacaine into the periphrenic fat pad. Preoperative assessments of spirometry and pain scores were recorded (at rest and with movement). Postoperative assessments included peak flow and pain measurements at intervals up to 72 hours. Less shoulder pain was experienced with phrenic nerve infiltration up to 6 hours postsurgery at rest (P = 0.005) and up to 12 hours with movement (P < 0.001). Reduced back pain was reported in the phrenic nerve infiltration group up to 6 hours after surgery both at rest (P = 0.001) and with movement (P = 0.00). Phrenic nerve infiltration reduced pain at the incision site for up to 3 hours both at rest (P < 0.001) and with movement (P = 0.001). Spirometry readings dropped in both groups with consistently lower readings at baseline and follow-up in the PNI group (P = 0.007). Lower analgesic usage of patient controlled analgesia morphine (P < 0.0001), epipleural bupivacaine (P = 0.001), and oramorph/zomorph (P = 0.0002) were recorded. Our findings indicate that the use of phrenic nerve infiltration significantly reduced patient pain scores during the early postoperative period, particularly during movement. We believe that each technique has advantages and disadvantages; however, further studies with large sample size are warranted.

Molecular modeling and SPRi investigations of interleukin 6 (IL6) protein and DNA aptamers.

Interleukin 6 (IL6), an inflammatory response protein has major implications in immune-related inflammatory diseases. Identification of aptamers for the IL6 protein aids in diagnostic, therapeutic, and theranostic applications. Three different DNA aptamers and their interactions with IL6 protein were extensively investigated in a phosphate buffed saline (PBS) solution. Molecular-level modeling through molecular dynamics provided insights of structural, conformational changes and specific binding domains of these protein-aptamer complexes. Multiple simulations reveal consistent binding region for all protein-aptamer complexes. Conformational changes coupled with quantitative analysis of center of mass (COM) distance, radius of gyration (Rg), and number of intermolecular hydrogen bonds in each IL6 protein-aptamer complex was used to determine their binding performance strength and obtain molecular configurations with strong binding. A similarity comparison of the molecular configurations with strong binding from molecular-level modeling concurred with Surface Plasmon Resonance imaging (SPRi) for these three aptamer complexes, thus corroborating molecular modeling analysis findings. Insights from the natural progression of IL6 protein-aptamer binding modeled in this work has identified key features such as the orientation and location of the aptamer in the binding event. These key features are not readily feasible from wet lab experiments and impact the efficacy of the aptamers in diagnostic and theranostic applications.

Modified two flap palatoplasty in asymptomatic transsphenoidal encephalocele: a case report.

About one-third of patients with transsphenoidal basal encephaloceles have associated congenital anomalies, including cleft palate. Moreover, they are often plagued by symptomatic exacerbations in the form of upper respiratory obstructions, cerebrospinal fluid leaks, meningitis, etc., with few patients being asymptomatic. We herein present a rare asymptomatic case of transsphenoidal basal encephalocele in an 18-month-old child with cleft palate and highlight a modified version of two-flap palatoplasty.

Deformation strain is the main physical driver for skeletal precursors to undergo osteogenesis in earlier stages of osteogenic cell maturation.

Mesenchymal stem cells play a major role during bone remodelling and are thus of high interest for tissue engineering and regenerative medicine applications. Mechanical stimuli, that is, deformation strain and interstitial fluid-flow-induced shear stress, promote osteogenic lineage commitment. However, the predominant physical stimulus that drives early osteogenic cell maturation is not clearly identified. The evaluation of each stimulus is challenging, as deformation and fluid-flow-induced shear stress interdepend. In this study, we developed a bioreactor that was used to culture mesenchymal stem cells harbouring a strain-responsive AP-1 luciferase reporter construct, on porous scaffolds. In addition to the reporter, mineralization and vitality of the cells was investigated by alizarin red staining and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide. Quantification of the expression of genes associated to bone regeneration and bone remodelling was used to confirm alizarin red measurements. Controlled perfusion and deformation of the 3-dimensional scaffold facilitated the alteration of the expression of osteogenic markers, luciferase activity, and calcification. To isolate the specific impact of scaffold deformation, a computational model was developed to derive a perfusion flow profile that results in dynamic shear stress conditions present in periodically loaded scaffolds. In comparison to actually deformed scaffolds, a lower expression of all measured readout parameters indicated that deformation strain is the predominant stimulus for skeletal precursors to undergo osteogenesis in earlier stages of osteogenic cell maturation.

Verteporfin therapy for neovascular age-related macular degeneration in Indian eyes.

PURPOSE: To determine visual outcome after a 12-month follow-up period of verteporfin therapy for subfoveal choroidal neovascularization (CNV) secondary to age-related macular degeneration (AMD) in Indian patients. METHODS: Twenty-five patients (26 eyes) who completed a 12-month follow-up after photodynamic therapy for subfoveal CNV secondary to AMD were included in the study. The follow-up schedule was every month for 2 months and then every 3 months thereafter until 12 months. Improvement in visual acuity was defined as a >or=10-letter gain, and deterioration as a >or=10-letter loss in the Early Treatment Diabetic Retinopathy Study chart at 4 m. RESULTS: The mean age of the 25 patients was 62.3 +/- 9 years. There were 17 male patients (68%). The mean initial letter acuity was 28. 4 +/- 14.1, and the final letter acuity was 25.5 +/- 18.4 at 12 months. Initial visual acuity was >or=20/40 in seven eyes, 20/50-20/80 in nine eyes, and 20/100-20/200 in ten eyes; seven eyes had a >or=10-letter gain, and three eyes had a >or=10-letter loss. At the end of 12 months, six eyes had a >or=10-letter gain and ten eyes had a >or=10-letter loss. CONCLUSION: Photodynamic therapy appears to preserve the vision in subfoveal CNV secondary to AMD in the eyes of Indian patients.

Combination therapy of intravitreal triamcinolone and photodynamic therapy with verteporfin for subfoveal choroidal neovascularization.

AIM: To evaluate the six months follow-up outcome of combined intravitreal triamcinolone acetonide (IVTA) and photodynamic therapy (PDT) for subfoveal choroidal neovascularization compared to PDT alone. STUDY DESIGN: Prospective interventional pilot study. MATERIALS AND METHODS: Patients with six months follow-up of IVTA following PDT (Group I, eight eyes) and PDT alone (Group II, eight eyes) were included. Four mg/ 0.1 ml of IVTA was injected 7-10 days following PDT. The patients were reevaluated every month for the first two months and every three months thereafter in both the groups. RESULTS: Group I: The mean age was 65.8+/-11.8 years (range: 47-79 years). Five patients were male. The total treatment sessions in six months were 11 (mean: 1.36). At six months, one eye had >or= 10 letters gain and three eyes had > 10 letters loss. Four eyes had stable vision. Two eyes (25%) developed increased intraocular pressure (>40 mmHg) during follow-up. Group II: The mean age was 58.7+/-11.7 years (range: 46-76 years). Five patients were male. The total treatment sessions in six months were 17 (mean: 2.13). At six months, six eyes had >or= 10 letters gain and none had > 10 letters loss. Two eyes had stable vision. CONCLUSION: The mean number of treatment sessions following combination therapy of IVTA (4 mg) and PDT appears relatively less (1.36 at six months) compared to PDT alone (mean: 2.13). (P =0.02).

Vitamin D insufficiency among children with cancer in India.

BACKGROUND: Vitamin D plays an important role in regulating various homeostatic mechanisms and has yet untapped potential in cancer prevention and prognosis. Only a few studies have been done worldwide in relating the Vitamin D levels in pediatric cancer patients to the general population but none so far in an Indian setting to the best of our knowledge. OBJECTIVE: To compare the Vitamin D levels in a group of children with cancer to that of the general pediatric population and to note differences in the prevalence of Vitamin D insufficiency and make inferences arising from demographic and therapeutic variations. MATERIALS AND METHODS: Vitamin D levels were found by immuno-chemilumino-metric assay in 102 children (51 cases and 51 controls) over a 6 months period. RESULTS: In comparing the Vitamin D levels of children with cancer and controls from a healthy population we found an increased incidence of Vitamin D insufficiency in cancer children (80.39%) when compared to controls (50.98%) and a much lower mean Vitamin D value in cancer children (22.8 ng/ml) when compared to controls (33 ng/dl). It was also found that cancer children above 6 years had a greater chance for developing Vitamin D insufficiency (P = 0.038) as did children suffering from hematological malignancies (P = 0.025). CONCLUSION: Our study showed an increased prevalence of Vitamin D insufficiency in children with cancer and hence we suggest routine measurement of Vitamin D levels in children with cancer and subsequent supplementation.

Computational modeling of peptide-aptamer binding.

Evolution is the progressive process that holds each living creature in its grasp. From strands of DNA evolution shapes life with response to our ever-changing environment and time. It is the continued study of this most primitive process that has led to the advancement of modern biology. The success and failure in the reading, processing, replication, and expression of genetic code and its resulting biomolecules keep the delicate balance of life. Investigations into these fundamental processes continue to make headlines as science continues to explore smaller scale interactions with increasing complexity. New applications and advanced understanding of DNA, RNA, peptides, and proteins are pushing technology and science forward and together. Today the addition of computers and advances in science has led to the fields of computational biology and chemistry. Through these computational advances it is now possible not only to quantify the end results but also visualize, analyze, and fully understand mechanisms by gaining deeper insights. The biomolecular motion that exists governing the physical and chemical phenomena can now be analyzed with the advent of computational modeling. Ever-increasing computational power combined with efficient algorithms and components are further expanding the fidelity and scope of such modeling and simulations. This chapter discusses computational methods that apply biological processes, in particular computational modeling of peptide-aptamer binding.

Molecular Dynamics Simulation Analysis of Anti-MUC1 Aptamer and Mucin 1 Peptide Binding.

Aptasensors utilize aptamers as bioreceptors. Aptamers are highly efficient, have a high specificity and are reusable. Within the biosensor the aptamers are immobilized to maximize their access to target molecules. Knowledge of the orientation and location of the aptamer and peptide during binding could be gained through computational modeling. Experimentally, the aptamer (anti-MUC1 S2.2) has been identified as a bioreceptor for breast cancer biomarker mucin 1 (MUC1) protein. However, within this protein lie several peptide variants with the common sequence APDTRPAP that are targeted by the aptamer. Understanding orientation and location of the binding region for a peptide-aptamer complex is critical in their biosensor applicability. In this study, we investigate through computational modeling how this peptide sequence and its minor variants affect the peptide-aptamer complex binding. We use molecular dynamics simulations to study multiple peptide-aptamer systems consisting of MUC1 (APDTRPAP) and MUC1-G (APDTRPAPG) peptides with the anti-MUC1 aptamer under similar physiological conditions reported experimentally. Multiple simulations of the MUC1 peptide and aptamer reveal that the peptide interacts between 3' and 5' ends of the aptamer but does not fully bind. Multiple simulations of the MUC1-G peptide indicate consistent binding with the thymine loop of the aptamer, initiated by the arginine residue of the peptide. We find that the binding event induces structural changes in the aptamer by altering the number of hydrogen bonds within the aptamer and establishes a stable peptide-aptamer complex. In all MUC1-G cases the occurrence of binding was confirmed by systematically studying the distance distributions between peptide and aptamers. These results are found to corroborate well with experimental study reported in the literature that indicated a strong binding in the case of MUC1-G peptide and anti-MUC1 aptamer. Present MD simulations highlight the role of the arginine residue of MUC1-G peptide in initiating the binding. The addition of the glycine residue to the peptide, as in the case of MUC1-G, is shown to yield a stable binding. Our study clearly demonstrates the ability of MD simulations to obtain molecular insights for peptide-aptamer binding, and to provide details on the orientation and location of binding between the peptide-aptamer that can be instrumental in biosensor development.

Hedgehog signaling inhibitors as anti-cancer agents in osteosarcoma.

Osteosarcoma is a rare type of cancer associated with a poor clinical outcome. Even though the pathologic characteristics of OS are well established, much remains to be understood, particularly at the molecular signaling level. The molecular mechanisms of osteosarcoma progression and metastases have not yet been fully elucidated and several evolutionary signaling pathways have been found to be linked with osteosarcoma pathogenesis, especially the hedgehog signaling (Hh) pathway. The present review will outline the importance and targeting the hedgehog signaling (Hh) pathway in osteosarcoma tumor biology. Available data also suggest that aberrant Hh signaling has pro-migratory effects and leads to the development of osteoblastic osteosarcoma. Activation of Hh signaling has been observed in osteosarcoma cell lines and also in primary human osteosarcoma specimens. Emerging data suggests that interference with Hh signal transduction by inhibitors may reduce osteosarcoma cell proliferation and tumor growth thereby preventing osteosarcomagenesis. From this perspective, we outline the current state of Hh pathway inhibitors in osteosarcoma. In summary, targeting Hh signaling by inhibitors promise to increase the efficacy of osteosarcoma treatment and improve patient outcome.