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This study aimed to investigate the impact of a lubricant derived from trimethylolpropane trioleate on power consumption and surface roughness during high-speed drilling of Al-6061, with the goal of developing an environmentally friendly cutting fluid. The study investigated the impact of additive concentration, spindle speed, and feed rate on energy consumption and surface roughness using a Taguchi L27 orthogonal array. Through analysis of the Taguchi experimental outcomes and single-to-noise ratios, the parameters were ranked accordingly. The results of the ANOVA analysis reveal that spindle speed has the greatest impact on Power (87.89%), followed by followed feed rate (6.96%) and additive concentration (2.98%). However, feed rate (43.51%) has the most significant influence on surface roughness, followed by speed (38.48%) and additive concentration (11.90%). Varying additive concentration affects more on surface quality rather than power consumption. Furthermore, a machine learning algorithm was developed to forecast and compare various key aspects of high-speed drilling machinability, including power and surface roughness. Three different measures of accuracy were used to evaluate the performance of the projected values: coefficient of determination (R2), mean absolute percentage error, and mean square error. The decision tree performed better than other models in accurately predicting power and surface roughness. This research introduces an innovative method for assessing the most effective biodegradable cutting fluid and forecasting power and surface quality by developing an optimal combination., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Kathmore et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

The pioneering German physician and microbiologist Heinrich Hermann Robert Koch (1843-1910) made pivotal contributions to the field of bacteriology, significantly advancing the germ theory of disease. His groundbreaking research in identifying the causative agents of anthrax, tuberculosis, and cholera revolutionized medical science and public health. Koch's development of essential microbiological techniques, such as using agar for bacterial cultures and introducing the Petri dish, transformed laboratory practices. Additionally, his formulation of Koch's postulates established a systematic method for linking specific pathogens to diseases, a framework that remains influential today. Koch's remarkable achievements were recognized with numerous prestigious honors, including the Nobel Prize in Physiology or Medicine in 1905. His legacy lives on through institutions like the Robert Koch Institute and World Tuberculosis Day, commemorating his profound impact on global health and infectious disease research. Koch's work continues to serve as a cornerstone in studying and controlling infectious diseases., Competing Interests: Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Sravanthi et al.)

LM5 alloy is suitable for metal castings for marine and aesthetic uses due to its admirable resistance to corrosion. In order to make intricate shapes in the LM5 alloy, this study intends to assess the impact of Wire Electric Discharge Machining process variables, like Pulse on Time (Ton), Pulse off Time (Toff), Gap Voltage (GV) and Wire Feed (WF) on responses like Material Removal Rate (MRR), Surface Roughness (SR), and Kerf Width (Kw). The LM5 aluminium alloy plate was produced through stir casting process. SEM, EDAX and XRD images confirm the LM5 Al alloy's microstructure and crystal structure. WEDM studies were conducted using design of experiments approach based on L9 orthogonal array and analysed using Taguchi's Signal to Noise Ratio (S/N) analysis. Pulse on Time has the greatest statistical effects on MRR (68.25%), SR (79.46%) and kerf (81.97%). In order to assess the surface integrity of the WEDM machined surfaces, the SEM study on the topography was conducted using the optimum surface roughness process variables: Ton 110 μs, Toff 50 μs, GV 40 V, and WF 9 m/min. SEM images show the recast layer and its thickness. The average absolute error for MRR is 1.69%, SR is 3.89% and kerf is 0.88%, based on mathematical (linear regression) models. The Taguchi's Signal to Noise ratio analysis is the most appropriate for single objective optimization of responses., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Juliyana et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Hungarian physician Ignaz Semmelweis (1818-1865) revolutionized medical practice through his introduction of antiseptic procedures. This breakthrough disrupted the chain of infection among new mothers and their infants, leading to dramatically reduced mortality rates from puerperal fever across continental Europe. Semmelweis faced significant resistance and disbelief when he argued through meticulous, empirically-based evidence that proper hand hygiene may prevent infection. Semmelweis' pioneering work on infection prevention remains highly relevant even today, as evidenced by contemporary practices aimed at controlling the spread of disease and improving patient safety through improved hygiene. In this article, we look into the key moments in Semmelweis's life that led to his revolutionary discoveries as well as oppositions against them and his lasting impact on modern medicine., Competing Interests: Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Paul et al.)

The licensing step of DNA double-strand break repair by homologous recombination entails resection of DNA ends to generate a single-stranded DNA template for assembly of the repair machinery consisting of the RAD51 recombinase and ancillary factors 1 . DNA end resection is mechanistically intricate and reliant on the tumour suppressor complex BRCA1-BARD1 (ref. 2 ). Specifically, three distinct nuclease entities-the 5'-3' exonuclease EXO1 and heterodimeric complexes of the DNA endonuclease DNA2, with either the BLM or WRN helicase-act in synergy to execute the end resection process 3 . A major question concerns whether BRCA1-BARD1 directly regulates end resection. Here, using highly purified protein factors, we provide evidence that BRCA1-BARD1 physically interacts with EXO1, BLM and WRN. Importantly, with reconstituted biochemical systems and a single-molecule analytical tool, we show that BRCA1-BARD1 upregulates the activity of all three resection pathways. We also demonstrate that BRCA1 and BARD1 harbour stand-alone modules that contribute to the overall functionality of BRCA1-BARD1. Moreover, analysis of a BARD1 mutant impaired in DNA binding shows the importance of this BARD1 attribute in end resection, both in vitro and in cells. Thus, BRCA1-BARD1 enhances the efficiency of all three long-range DNA end resection pathways during homologous recombination in human cells., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Background Neurodevelopmental disorders (NDDs) encompass intricate interactions among genetic, brain, cognitive, emotional, and behavioral processes. These disorders, which are influenced by hereditary and environmental factors, impair personal, social, intellectual, or occupational functioning. Typically emerging early in life, NDDs include conditions such as attention deficit hyperactivity disorder (ADHD), intellectual disability, autism spectrum disorders (ASDs), vision and hearing impairments, motor disorders, and specific learning disabilities. Children from impoverished and low-income neighborhoods are particularly vulnerable. The lack of comprehensive health data and public awareness about these conditions results in limited information regarding the prevalence of neurological illnesses in developing countries. India, with its large and ethnically diverse population, exemplifies this gap. Methods It is a prospective study to detect the prevalence and risk factors of neurodevelopmental disorders in children aged six months to nine years at a tertiary care center. Patient details, clinical findings, and relevant history were recorded on a pre-designed pro forma and analyzed statistically. Results Among the 1000 children in the study, 91 (9.1%) tested positive for NDDs. Among the 91 children who tested positive for NDD, the highest frequency is in the three to four years age group (17.6%), males were found to be in a higher ratio with 75.82%, with the male: female ratio being 3:1. Among the 91 children with NDD, intellectual disability was the most common disorder (20.9%), followed by ADHD (17.6%) and vision impairment (14.3%). Autism spectrum disorders, including autism and Asperger syndrome, and communication disorders, including stuttering and speech disorders, accounted for 13.2% each. Hearing loss was seen in 9.9% of children and multiple disorders were seen in 8.8% of the children from among 91 children. Conclusion Neurodevelopmental disorders are common and often coexist with other conditions. Children from low-income backgrounds are more affected. This study provides valuable insights into the prevalence and characteristics of NDDs in a specific population., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Dr. D.Y. Patil Medical College, Hospital and Research Center, Pune issued approval IESC/PGS/2022/37. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Bahal et al.)

Background Dengue is one of the most common vector-borne diseases in India, and it is transmitted by Aedes family mosquitoes. Hepatic injury is known to occur from dengue infection. Direct hepatotoxicity and deranged host immune responses to the virus are responsible for this hepatic dysfunction. Hence, the study was undertaken to understand the deranged hepatic enzymes using liver function tests (LFTs) and the severity and outcome of dengue fever in children. Methods This study is an observational-descriptive study conducted between June 2022 and May 2024. The study population includes children between the ages of one month and 16 years who have been diagnosed with dengue fever and admitted to pediatric wards and pediatric intensive care units (PICUs), with a sample size of 151. Informed consent from guardians and institutional ethical clearance were obtained. Results A total of 4.8% (N = 7) mortality was seen in this study with dengue patients. Hepatomegaly was seen in 34% (N = 49) of cases. There is a clear statistical significance that is seen among the non-survived and survived dengue patients with a 10-fold increase in serum glutamic-oxaloacetic transaminase (SGOT) and serum glutamic pyruvic transaminase (SGPT) levels, respectively, along with total bilirubin, activated partial thromboplastin time (APTT), and prothrombin time (PT). Conclusions The current study shows that deranged LFTs are associated with more severe disease with more PICU admissions and mortality of the disease. The evidence clearly indicates the inclusion of LFTs as a routine investigation to understand the severity of the disease and the prognosis of the outcome., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Institutional Ethics Sub-Committee of Dr. D. Y. Patil Medical College, Pune, issued approval IESC/PGS/2022/29. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Avuthu et al.)

This research aims to use energy harvested from conductive materials to power microelectronic components. The proposed method involves using vibration-based energy harvesting to increase the natural vibration frequency, reduce the need for battery replacement, and minimise chemical waste. Piezoelectric transduction, known for its high-power density and ease of application, has garnered significant attention. Additionally, graphene, a non-piezoelectric material, exhibits good piezoelectric properties. The research explores a novel method of printing graphene material using 3D printing, specifically Direct Ink Writing (DIW) and fused deposition modelling (FDM). Both simulation and experimental techniques were used to analyse energy harvesting. The experimental technique involved using the cantilever beam-based vibration energy harvesting method. The results showed that the DIW-derived 3D-printed prototype achieved a peak power output of 12.2 µW, surpassing the 6.4 µW output of the FDM-derived 3D-printed prototype. Furthermore, the simulation using COMSOL Multiphysics yielded a harvested output of 0.69 µV., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Pilomyxoid astrocytoma (PMA) is a subtype of pilocytic astrocytoma (PA). PMA tends to exhibit a more aggressive course compared to PA. We present a case of a two-year-old male with a PMA in the suprasellar region who presented with developmental regression, loss of previously attained milestones such as the ability to hold his neck, walk, and talk, along with hypotonia in all four limbs. Serum cortisol and thyroid-stimulating hormone (TSH) levels were measured to rule out endocrine disturbances and were within normal limits. Magnetic resonance imaging (MRI) of the brain showed a solid lesion in the suprasellar region, extending into the pituitary and interpeduncular fossae, compressing the pituitary gland, and effacing the third ventricle, causing cerebrospinal fluid (CSF) flow obstruction and lateral ventricle dilation. The tumor appears hypointense on T1 and hyperintense on T2, with fluid-attenuated inversion recovery (FLAIR), peripheral contrast enhancement, and no calcification, consistent with PMA. The CSF analysis was negative for malignant cells. Histopathological examination revealed monomorphous bipolar and spindle cells in an angiocentric pattern with a myxoid background, without rosenthal fibers, mitoses, or eosinophilic granular bodies, consistent with PMA but not seen in PA. Immunohistochemistry showed strong positivity for glial fibrillary acidic protein (GFAP) and S100, with a Ki-67 index of 3-4%, indicating a low-grade tumor. The preferred treatment is surgical resection, but due to the tumor's deep location and potential long-term neurological effects, the parents opted against surgery. A ventriculoperitoneal shunt was placed to alleviate CSF flow, following which the child showed mild improvement in symptoms. Treatment of nonresectable astrocytomas was controversial, but gross total surgical resection offers better disease control. Chemotherapy is for patients with recurrence or where total resection of the tumor is not possible, and radiotherapy, though the long-term disease control is good, has a variable visual outcome., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Avuthu et al.)

During the evolution process, a bamboo stem achieves a significant height (up to 20 m) to fulfil its phototropic requirements. While on land, the stem is mostly subjected to bending load which makes it liable to fail by uprooting. However, this failure is prohibited by smart structure of bamboo stem which includes graded arrangement of fibre bundles in the cross-section and a tapered cantilever form of the stem. This paper attempts to understand the optimal design of bamboo stem through the relationship between the stellar arrangement of stiff fibre bundles in the cross-section and the tapered form. In this work, a comparison between two types of stellar arrangement, namely uniform and graded, is presented in view of non-linear bending analysis through elastica theory and fracture-induced delamination, both numerically. It is observed from the results that a bamboo stem prefers to evolve with graded stellar arrangement which provides gradation of stiffness and toughness over the cross-section; the trend in toughness being opposite to that of stiffness. Moreover, interplay of stellar arrangement and gradation of stiffness-toughness thereof is found to be the governing mechanism for ensuring its mechanical integrity and stability in view of an optimal design perspective. The smart structure of bamboo is recommended for bio-mimicking., Competing Interests: On behalf of all authors, the corresponding author states that there is no conflict of interest., (© 2024 The Authors.)

Background The etiological profile of children with bicytopenia and pancytopenia has a very wide spectrum, ranging from transient causes like infections or nutritional deficiencies to bone marrow failure syndromes. Timely diagnosis and treatment impart favorable prognosis to this entity. There is a paucity of data regarding the etiology of cytopenia in hospitalized children at a tertiary center in India. Additionally, only a few studies have discussed the possible association between the severity of cytopenia at presentation and the possible etiology. Methods This is a cross-sectional observational study analyzing bicytopenia and pancytopenia in hospitalized children. Patient details, along with clinical findings and relevant investigations, were recorded on predesigned pro forma and analyzed statistically. Results Out of 202 children, 174 (86.13%) had bicytopenia, and 28 (13.86%) had pancytopenia, with a male predominance resulting in a male-to-female ratio of 1.65:1. The commonest age group affected was pre-adolescent age group (6-12 years). The causes of bicytopenia and pancytopenia in hospitalized children in the decreasing order of frequency were infections (65.84%), benign hematological disorders (18.81%), systemic illness (10.39%), and malignancies (4.95%). The cytopenia was more severe in children with pancytopenia than bicytopenia. Conclusions Infections outweigh the other causes of bicytopenia and pancytopenia. The severity of the cell line affected can help narrow down a diagnosis of cytopenia etiologies. Most of the children with bicytopenia and pancytopenia had treatable etiology and favorable outcomes., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Dr. D. Y. Patil Medical College, Hospital & Research Centre, Pimpri, Pune - 411018 issued approval I.E.S.C./291/2022. This is certify that the synopsis (IESC/PGS/2022/35) titled "Clinical And Etiological Profile of Bicytopenia And Pancytopenia In Pediatric Patients." to be done by Dr. Gaurav Kumar under the guidance of Dr. Sanjay Chavan from Department of Pediatrics is ethically approved. The synopsis was approved by the Institutional Ethics Sub-committee in it's meeting held on 28/09/2022. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Kumar et al.)

Glutaric aciduria type 1 (GA1) is an organic aciduria inherited in an autosomal recessive pattern, with an occurrence rate of one in 100,000. It is caused by a deficiency of the enzyme glutaryl-CoA dehydrogenase (GCDH), encoded by the GCDH gene on chromosome 19. It is an important enzyme in the catabolism of amino acids such as tryptophan, lysine, and hydroxylysine. Its deficiency leads to the accumulation of organic acids such as glutaric acid and 3-hydroxyglutaric acid, which interfere with cerebral energy metabolism and cause neurological symptoms. Here, we discuss the case of a six-month-old male child who presented with status epilepticus following an eight-day history of fever. The child was started on anti-epileptics. Initially, the child was on non-invasive ventilation and was later intubated and taken on a mechanical ventilator. A magnetic resonance imaging (MRI) scan of the brain was performed, and the findings suggested GA1. The child was started on carnitine after samples were sent for tandem mass spectrometry (TMS) and urine gas chromatography-mass spectrometry (GC/MS), which came out to be positive for GA1. Despite the timely intervention, the child did not survive. Most cases exhibit movement disorders, with many presenting in acute encephalitic crises. Additionally, a significant portion of patients experience an insidious onset of the disease. An MRI of the brain shows widened Sylvian fissures in the majority of cases. Treatment of GA1 includes dietary modifications, including a low-lysine diet and administering carnitine. Early diagnosis and management result in decreased mortality and morbidity, which underscores the need for newborn screening., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Patil et al.)

Using a cutting-edge net-shape manufacturing technique called Additive Layer Manufacturing (ALM), highly complex components that are not achievable with conventional wrought and cast methods can be produced. As a result, the aerospace sector is paying closer attention to using this technology to fabricate superalloys based on nickel to develop the holistic gas turbine. Because of this, there is an increasing need for the mechanical characterisation of such material. Conventional mechanical testing is hampered by the limited availability of material that has been processed, especially given the large number of process factors that need to be assessed. Thus, the present study focuses on manufacturing CM247LC Ni-based superalloy with exceptional mechanical characteristics by laser powder bed fusion (L-PBF). This study evaluates the effect of input process variables such as laser power, scan speed, hatch distance and volumetric energy density on the mechanical performance of the LPBF CM247LC superalloy. The maximum value of as-built tensile strength obtained in the study is 997.81 MPa. Plotting Pearson's heatmap and the Feature importance (F-test) was used in the data analysis to examine the impact of input parameters on tensile strength. The accuracy of the tensile strength data classification by machine learning algorithms, such as k-nearest neighbours, Naïve Baiyes, Support vector machine, XGBoost, AdaBoost, Decision tree, Random forest, and logistic regression algorithms, was 92.5%, 83.75%, 83%, 85%, 87.5%, 90%, 91.25%, and 77.5%, respectively., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Jatti et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Neonatal supraventricular tachycardia (SVT) poses clinical challenges due to its rarity and potential for serious complications. We present a case of a 2.5 kg female neonate delivered at 37.2 weeks of gestation, diagnosed with SVT shortly after birth. Initial management included adenosine administration, which was initially ineffective until a second dose successfully reduced the heart rate. Subsequent episodes required repeated adenosine and the initiation of propranolol therapy. The neonate showed improvement with cessation of SVT episodes, weaning off respiratory support, and successful breastfeeding initiation. Follow-up at one month revealed no recurrent SVT, affirming effective management and favorable outcomes in neonatal SVT cases., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Garud et al.)

Background Sepsis poses a critical medical challenge due to its profound systemic inflammatory response, which frequently results in organ dysfunction and high mortality rates, especially in pediatric patients. The condition requires prompt recognition and aggressive management to mitigate its severe outcomes. Methods This prospective study enrolled 248 pediatric patients admitted with sepsis to the pediatric intensive care unit (PICU) at our tertiary care center. Patients were randomly assigned to either the C-reactive protein (CRP) or procalcitonin (PCT) groups, with biomarker levels measured upon admission (hour zero) and again at 72 hours post-admission. Clinical parameters such as the need for ionotropic support, use of steroids, incidence of acute kidney injury (AKI), requirement for invasive ventilation, patient outcomes, and changes in antibiotic management were assessed based on these biomarker levels. Results Procalcitonin-positive sepsis cases demonstrated notable clinical severity compared to their C-reactive protein counterparts, showing significantly lower systolic blood pressure (p = 0.012), heightened need for ionotropic support (p < 0.0001), and more pronounced liver and renal dysfunction as indicated by elevated serum bilirubin (p = 0.001) and creatinine levels (p = 0.0058). The incidence of AKI was also higher in procalcitonin-positive cases. Despite these severe clinical parameters, there were no significant differences in the length of the PICU stay or in patient outcomes concerning discharge and mortality rates. Procalcitonin levels effectively guided antibiotic management, resulting in therapy adjustments in a substantial proportion of cases, with 67 (54%) experiencing downgrades and 33 (27%) requiring upgrades based on procalcitonin levels measured 72 hours post-admission. Conclusion Procalcitonin proves to be a valuable biomarker in assessing the severity and management of sepsis in pediatric patients. It correlates significantly with clinical parameters such as blood pressure, the need for ionotropic support, and markers of organ dysfunction., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Dr. D.Y. Patil Medical College, Hospital and Research Centre Institutional Ethics Sub-Committee issued approval I.E.S.C./290/2022. This is to certify that the synopsis (IESC/PGS/2022/34) titled "C-Reactive Protein Versus Procalcitonin As A Biomarkers Of Prognostic Importance In Sepsis In Age Group Of 1 Month 15 Years" to be done by Dr. Neha Tyagi under the guidance of Dr. Manojkumar Gulabrao Patil from Department of MD-Pediatrics is ethically approved. The synopsis was approved by the Institutional Ethics Sub-Committee in its meeting held on 28/09/2022. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Tyagi et al.)

Dissimilar metal combinations are frequently employed in the power generation and nuclear industries. Where stainless steel piping systems are connected to pressure vessels made of low-alloy steel, the subsystems of liquid rocket engines also have different, dissimilar material combinations. Dissimilar welding plays a vital role in ensuring the integrity, performance, and reliability of components and structures operating in cryogenic environments, in this study, plates of AISI 316L and AISI 321, each 5 mm thick, were successfully joined using the pulsed current gas tungsten arc welding (PCGTAW) technique with optimized process parameters. These weld joints are mostly present in rocket engines subjected to a cryogenic environment. Due to the low temperature environment, the metallurgical properties of these joints change, which affects their mechanical properties. As it is a structural part, PCGTAW welding is most common method for joining this kind of material. In this work, Microstructural analysis of the weldment revealed a combination of vermicular, lacy, and acicular ferrite morphologies in the fusion zone at the root, mid, and crown locations. Furthermore, no solidification cracking was detected in the weldments based on the optical micrograph and SEM results. Intergranular corrosion (IGC) testing indicated the absence of a ditch structure, suggesting that the heat-affected zone (HAZ) on both sides of the weld joint was not being susceptible to sensitization. However, the HAZ of the AISI 316L side exhibited coarser grains compared to AISI 321. Analysis of tensile properties revealed a significant influence of the testing environment on the tensile strength of the dissimilar welded joints. At room temperature, the average ultimate tensile strength (UTS) was measured as 621 MPa. Remarkably, at cryogenic conditions, the average tensile properties significantly increased to 1319 MPa. Microhardness analysis showed the highest hardness associated with the AISI 321 side. The fusion zone exhibited a large deviation in the hardness profile (205 ± 10 HV), with the highest average hardness observed in the middle part of the weld. However, the hot cracking behavior of the weld was investigated by using a suutula diagram at various locations of the weld. The investigation revealed that the Cr eq /Ni eq ratio exceeded the critical threshold value, effectively diminishing the propensity for hot cracking in the fusion zone. Overall, these findings underscore the effectiveness of the PCGTAW technique in joining dissimilar materials, as well as the importance of microstructural and mechanical property evaluations, especially under extreme operating conditions such as cryogenic temperatures. Paraphrase., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Dr. Sachin Salunkhe reports financial support was provided by 10.13039/501100002383King Saud University. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Dr. Kadambini Ganguly was a trailblazing Indian physician and social reformer. As one of the first female graduates and practitioners of Western medicine in India, she broke numerous barriers in a field dominated by men. Her contribution to medicine, particularly in women's healthcare, and her engagement in social reform through the Brahmo Samaj and the Indian National Congress, caused significant progress toward gender equality and social justice. This article looks back on her academic accomplishments, medical career, social activism, and lasting legacy, emphasizing her profound influence on medicine and society in India., Competing Interests: Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Paul et al.)

This paper proposes a convolutional neural network (CNN) model of the signal distribution control algorithm (SDCA) to maximize the dynamic vehicular traffic signal flow for each junction phase. The aim of the proposed algorithm is to determine the reward value and new state. It deconstructs the routing components of the current multi-directional queuing system (MDQS) architecture to identify optimal policies for every traffic scenario. Initially, the state value is divided into a function value and a parameter value. Combining these two scenarios updates the resulting optimized state value. Ultimately, an analogous criterion is developed for the current dataset. Next, the error or loss value for the present scenario is computed. Furthermore, utilizing the Deep Q-learning methodology with a quad agent enhances previous study discoveries. The recommended method outperforms all other traditional approaches in effectively optimizing traffic signal timing.

Surface integrity is one of the key elements used to judge the quality of machined surfaces, and surface roughness is one such quality parameter that determines the pass level of the machined product. In the present study, AISI D2 steel was machined with electric discharge at different process parameters using Jatropha and EDM oil. Titanium dioxide (TiO 2 ) nanopowder was added to the dielectric to improve surface integrity. Experiments were performed using the one variable at a time (OVAT) approach for EDM oil and Jatropha oil as dielectric media. From the experimental results, it was observed that response trends of surface roughness (SR) using Jatropha oil are similar to those of commercially available EDM oil, which proves that Jatropha oil is a technically and operationally feasible dielectric and can be efficiently replaced as dielectric fluid in the EDM process. The lowest value of S.R. (i.e., 4.5 microns) for EDM and Jatropha oil was achieved at current = 9 A, Ton = 30 μs, Toff = 12 μs, and Gap voltage = 50 V. As the values of current and pulse on time increase, the S.R. also increases. Current and pulse-on-time were the most significant parameters affecting S.R. Machine learning methods like linear regression, decision trees, and random forests were used to predict the surface roughness. Random forest modeling is highly accurate, with an R 2 value of 0.89 and an MSE of 1.36% among all methods. Random forest models have better predictive capabilities and may be one of the best options for modeling complex EDM processes., (© 2024. The Author(s).)

Non-exhaust brake dust and pollution arising from metal, semi-metal, and ceramic brake pads have made recent research consider their replacement by potential natural fibers such as hemp, flax, sisal, etc. These natural fibers are lightweight, biodegradable, and cheap. This paper discusses the wear and friction analysis of hemp fiber reinforced polymer brake pad material. Three test specimens viz. HF4P20, HF5P20, and HF6P20 were prepared per ASTM G99 standards for the pin-on disc tribo-test. The test trials and validation were done using the Taguchi design of experiments and ANOVA. The optimum result showed a consistent coefficient of friction and lowered specific wear rate for HF6P20 brake pad material. Worn surface morphology was done using scanning electron microscopy.

Malnutrition in children under 5 years is a major public health problem in developing countries. Malnutrition complex comprises of under-nutrition including multiple conditions like acute, chronic malnutrition, micronutrient deficiencies and nutrition related to obesity. Therefore, it is of interest to report data on the individualized nutritional counselling on nutritional status among mild to moderately malnourished children aged 2 - 5 years at one, three and six month follow up. Their dietary habits will help to determine the aetiology of mild/moderate malnutrition.150 Children attending outpatient department of the Department of Paediatrics of D Y Patil Medical College and admitted with mild/moderate malnutrition were included in the study after taking informed consent from their parents. The children were randomly allocated into 4 groups (group 1 - 4). The groups consisted of children where dedicated nutritional counselling was provided at 1 month, 1 and 3 month follow up and where-in no dedicated counselling was provided. A diet chart was provided with counselling. Group 4 followed up with routine care without any dietary intervention. Detailed dietary, socio economic history, clinical examination with anthropometry was done followed-up at 1, 3, 6 months from date of inclusion. Majority (57.3%) belonged to lower socio-economic class according to Kuppuswamy scale. The mean birth weight was 2.4 kg, age 34.5 months and age of weaning 7.6 months. Data shows that 70% children had mild malnutrition and 30% moderate malnutrition. At 6 month follow up amongst 105 children with mild malnutrition, 82 still had mild malnutrition, 4 normal, 19 had moderate malnutrition. Under-five childhood malnutrition is highly prevalent in poor socioeconomic strata of the society. Nutritional counselling provided by trained healthcare providers in existing settings are effective in improving nutritional status, daily calorie/protein intake, prevention of malnutrition. Prevention/treatment of co-existing illness bears equal importance., Competing Interests: None, (© 2022 Biomedical Informatics.)

Senescence is the arrest of cell proliferation and is a tumor suppressor phenomenon. In a previous study, we have shown that therapy-induced senescence of glioblastoma multiforme (GBM) cells can prevent relapse of GBM tumors. Here, we demonstrate that ciprofloxacin-induced senescence in glioma-derived cell lines and primary glioma cultures is defined by SA-β-gal positivity, a senescence-associated secretory phenotype (SASP), a giant cell (GC) phenotype, increased levels of reactive oxygen species (ROS), γ-H2AX and a senescence-associated gene expression signature, and has three stages of senescence -initiation, pseudo-senescence and permanent senescence. Ciprofloxacin withdrawal during initiation and pseudo-senescence reinitiated proliferation in vitro and tumor formation in vivo Importantly, prolonged treatment with ciprofloxacin induced permanent senescence that failed to reverse following ciprofloxacin withdrawal. RNA-seq revealed downregulation of the p65 (RELA) transcription network, as well as incremental expression of SMAD pathway genes from initiation to permanent senescence. Ciprofloxacin withdrawal during initiation and pseudo-senescence, but not permanent senescence, increased the nuclear localization of p65 and escape from ciprofloxacin-induced senescence. By contrast, permanently senescent cells showed loss of nuclear p65 and increased apoptosis. Pharmacological inhibition or genetic knockdown of p65 upheld senescence in vitro and inhibited tumor formation in vivo Our study demonstrates that levels of nuclear p65 define the window of reversibility of therapy-induced senescence and that permanent senescence can be induced in GBM cells when the use of senotherapeutics is coupled with p65 inhibitors., Competing Interests: Competing interestsThe authors declare no competing or financial interests., (© 2021. Published by The Company of Biologists Ltd.)

Background and Aims: Assessment of pain using pain scales is essential. In the Numeric Rating Scale (NRS), patients are asked to score their pain intensity on a scale from 0 to 10 (10- worst pain). This requires some abstract thinking by the patient, also the pain scores (PS) may not essentially communicate the patients' need for more analgesia. We planned a study to evaluate the change in patients' self-assessed PS after understanding clinical interpretation of the NRS., Methods: This prospective study was registered after approval from our hospital ethics board. Sample size estimated for the trial was 360 patients. All postoperative patients were recruited after informed consent. Patients having prolonged stay in Intensive Care Unit (more than 48 h), or those who underwent emergency surgeries were excluded. During Acute Pain Service (APS) rounds, patients were asked to rate their PS on the NRS. This was followed by a briefing about the clinical interpretation of the scale, and the patients were asked to re score their pain using the same scale. The change in pain severity was compared using Chi-square test., Results: Following explanation, a change in severity was seen for PS at rest [ X 2 (9, N- 360) = 441, P < 0.001] and at movement [X 2 (9, N- 360) = 508, P < 0.001]. Overall, a change in PS severity was seen in 162 patients (45%). A decrease and an increase in the severity of pain was seen in 119 and 41 patients respectively., Conclusion: Explaining the clinical interpretation of PS on a NRS does lead to a change in patients' self-assessed PS., Competing Interests: There are no conflicts of interest., (Copyright: © 2021 Indian Journal of Anaesthesia.)

Background: Residual disease of glioblastoma (GBM) causes recurrence. However, targeting residual cells has failed, due to their inaccessibility and our lack of understanding of their survival mechanisms to radiation therapy. Here we deciphered a residual cell-specific survival mechanism essential for GBM relapse., Methods: Therapy resistant residual (RR) cells were captured from primary patient samples and cell line models mimicking clinical scenario of radiation resistance. Molecular signaling of resistance in RR cells was identified using RNA sequencing, genetic and pharmacological perturbations, overexpression systems, and molecular and biochemical assays. Findings were validated in patient samples and an orthotopic mouse model., Results: RR cells form more aggressive tumors than the parental cells in an orthotopic mouse model. Upon radiation-induced damage, RR cells preferentially activated a nonhomologous end joining (NHEJ) repair pathway, upregulating Ku80 and Artemis while downregulating meiotic recombination 11 (Mre11) at protein but not RNA levels. Mechanistically, RR cells upregulate the Su(var)3-9/enhancer-of-zeste/trithorax (SET) domain and mariner transposase fusion gene (SETMAR), mediating high levels of H3K36me2 and global euchromatization. High H3K36me2 leads to efficiently recruiting NHEJ proteins. Conditional knockdown of SETMAR in RR cells induced irreversible senescence partly mediated by reduced H3K36me2. RR cells expressing mutant H3K36A could not retain Ku80 at double-strand breaks, thus compromising NHEJ repair, leading to apoptosis and abrogation of tumorigenicity in vitro and in vivo. Pharmacological inhibition of the NHEJ pathway phenocopied H3K36 mutation effect, confirming dependency of RR cells on the NHEJ pathway for their survival., Conclusions: We demonstrate that the SETMAR-NHEJ regulatory axis is essential for the survival of clinically relevant radiation RR cells, abrogation of which prevents recurrence in GBM., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Alteration in metabolic repertoire is associated with resistance phenotype. Although a common phenotype, not much efforts have been undertaken to design effective strategies to target the metabolic drift in cancerous cells with drug resistant properties. Here, we identified that drug resistant AML cell line HL-60/MX2 did not follow classical Warburg effect, instead these cells exhibited drastically low levels of aerobic glycolysis. Biochemical analysis confirmed reduced glucose consumption and lactic acid production by resistant population with no differences in glutamine consumption. Raman spectroscopy revealed increased lipid and cytochrome content in resistant cells which were also visualized as lipid droplets by Raman mapping, electron microscopy and lipid specific staining. Gene set enrichment analysis data from sensitive and resistant cell lines revealed significant enrichment of lipid metabolic pathways in HL-60/MX2 cells. Further, HL-60/MX2 possessed higher mitochondrial activity and increased OXPHOS suggesting the role of fatty acid metabolism as energy source which was confirmed by increased rate of fatty acid oxidation. Accordingly, OXPHOS inhibitor increased sensitivity of resistant cells to chemotherapeutic drug and fatty acid oxidation inhibitor Etomoxir reduced colony formation ability of resistant cells demonstrating the requirement of fatty acid metabolism and dependency on OXPHOS by resistant leukemic cells for survival and tumorigenicity., Competing Interests: Declaration of competing interest Authors declare no conflict of interests., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Exosomes are natural nanovesicles excreted by many cells for intercellular communication and for transfer of materials including proteins, nucleic acids and even synthetic therapeutic agents. Surface modification of exosomes imparts additional functionality to the exosomes to enable site specific drug delivery and in vivo imaging and tracking and is an emerging area in drug delivery research. The present review focuses upon these modifications on the exosomal surface, the chemistry involved and their impact on targeted drug delivery for the treatment of brain, breast, lung, liver, colon tumors and, heart diseases and for understanding their in vivo fate including their uptake mechanisms, pharmacokinetics and biodistribution. The specific exosomal membrane proteins such as tetraspanins (CD63, CD81, CD9), lactadherin (LA), lysosome associated membrane protein-2b (Lamp-2b) and, glycosyl-phosphatidyl-inositol (GPI) involved in functionalization of exosome surface have also been discussed along with different strategies of surface modification like genetic engineering, covalent modification (click chemistry and metabolic engineering of parent cells of exosomes) and non-covalent modification (multivalent electrostatic interactions, ligand-receptor interaction, hydrophobic interaction, aptamer based modification and modification by anchoring CP05 peptide) along with optical (fluorescent and bioluminescent) and radioactive isotope labelling techniques of exosomes for imaging purpose., Competing Interests: Declaration of Competing Interest Authors declare no potential conflict of interests., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Immunological memory is a critical characteristic of a successful long-term adaptive immune response. During the initial phases of antigen:B lymphocyte interactions, B cells participate in the germinal center reaction, in which T-B cell interactions take place. CD154 on T cells acts as a ligand that binds to the CD40 receptor on B cells and facilitates the differentiation of B cells to memory B cells. However, cell fate determinants controlled by CD40 signal for cellular differentiation are unclear. In this study, we explored miRNA and miRNA-targets as cell fate determinants in CD40 signaled B cells. We selected candidate miRNAs based on their involvement in the regulation of B cell development, activation, and differentiation. We found that CD40 signal reduced transcript levels of miR150-5p, 17-5p, 146a-5p, 26a-5p and increased levels of miR292a-5p. Gene set enrichment analyses of previously submitted microarray data revealed accordant changes in levels of gene targets of these miRNA. Gene ontology analysis of miRNA-targets showed enrichment of genes participating in pathways such as DNA damage response, RNA/protein metabolism, and cell cycle regulation. Subsequently, studies on candidate miRNA-targets showed a CD40 signal driven differential regulation of Ccnd2, Pten, Traf6, c-Myb, and Btla. Further, 'gain of function' studies using mimics of the downregulated miRNAs, confirmed a predicted reduction in miRNA responsive targets; such as reduction of Ccnd2 levels in mimic treated groups of miR146a-5p, 26a-5p, and 17-5p. In conclusion, our study reveals that CD40 signal modulates levels of selected miRNAs as well as their cognate targets, whose enriched participation in diverse processes may help delineate downstream cell fate decisions., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Corrosion at modular junctions of total hip replacement (THR) remains a major concern today. Multiple types of damage modes have been identified at modular junctions, correlated with different corrosion characteristics that may eventually lead to implant failure. Recently, within the head-taper region of the CoCrMo retrieval implants, cell-like features and trails of etching patterns were observed that could potentially be linked to the involvement of cells of the periprosthetic region. However, there is no experimental evidence to corroborate this phenomenon. Therefore, we aimed to study the potential role of periprosthetic cell types on corrosion of CoCrMo alloy under different culture conditions, including the presence of CoCrMo wear debris. Cells were incubated with and without CoCrMo wear debris (obtained from a hip simulator) with an average particle size of 119 ± 138 nm. Electrochemical impedance spectroscopy (EIS) was used to evaluate the corrosion tendency, corrosion rate, and corrosion kinetics using the media after 24 h of cell culture as the electrolyte. Results of the study showed that there was lower corrosion resistance (p < 0.02) and higher capacitance (p < 0.05) within cell media from macrophages challenged with particles when compared with the other media conditions studied. The potentiodynamic results were also in agreement with the EIS values, showing significantly higher corrosion tendency (low E corr ) (p < 0.0001) and high I corr (p < 0.05) in media from challenged macrophages compared with media with H 2 O 2 solution. Overall, the study provides in vitro experimental evidence for the possible role of macrophages in altering the chemical environment within the crevice and thereby accelerating corrosion of CoCrMo alloy. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 38:393-404, 2020., (© 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.)

Cytogenetic-based subjective prognostication of acute myeloid leukemia (AML) patients is a cumbersome process. Top scoring pair (TSP)-based decision tree using a robust analytical algorithm with statistical rigor offers a promising alternative. We describe CytoPred as a 7-gene pair signature based on the analysis of 2547 AML patient sample gene expression data using a modified TSP algorithm to estimate cytogenetic risk. The essential modification in TSP that helped computational encumbrance includes the filtration of gene pairs above random weighted guessers as well as sampling the gene pairs from the original gene pair pool to reduce overfitting issue. The CytoPred classifies AML cohort into clinically relevant `good' and `Int&#95;poor' prognosis groups with distinct survival differences. The 7-gene pair was derived using 1248 AML patient samples in training set and 675 samples used for internal testing of the algorithm. The finest classifier 7-gene pair was picked from an initial pool size of 6.1 × 107 gene pairs that generated 57 687 decision trees. Further, for unbiased evaluation of CytoPred performance, we did an independent validation in 624 AML patient cohort. The CytoPred well qualifies the cutoffs for diagnostic application with 98.27% sensitivity and 99.27% specificity to predictive value in Int&#95;poor class while 97.09% sensitivity and 91.74% specificity to predictive value for good class. Furthermore, CytoPred predicts almost identical survival probabilities like cytogenetics and its performance is not much influenced by various recurrent mutations as well as individual French-American-British (FAB) subtypes. In summary, we present a robust 7-gene pair-based metric to clinically prognosticate AML patients., (© The Author(s) 2018. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Evidence that macrophages can play a role in accelerating corrosion in CoCrMo alloy in total hip replacement (THR) interfaces leads to questions regarding the underlying cellular mechanisms and immunological responses. Hence, we evaluated the role of macrophages in corrosion processes using the cell culture supernatant from different conditions and the effect of wear particles on macrophage dynamics. Monocytes were exposed to CoCrMo wear particles and their effect on macrophage differentiation was investigated by comparisons with M1 and M2 macrophage differentiation. Corrosion associated macrophages (M CA macrophages) exhibited upregulation of TNF-α, iNOS, STAT-6, and PPARG and down-regulation of CD86 and ARG, when compared to M1 and M2 macrophages. M CA cells also secreted higher levels of IL-8, IL-1β, IL-6, IL-10, TNF-α, and IL-12p70 than M1 macrophages and/or M2 macrophages. Our findings revealed variation in macrophage phenotype (M CA ) induced by CoCrMo wear particles in generating a chemical environment that induces cell-accelerated corrosion of CoCrMo alloy at THR modular interfaces. STATEMENT OF SIGNIFICANCE: Fretting wear and corrosion within the implant's modular taper junction are prominent causes of implant failure, as they promote the release of corrosion products and subsequent development of adverse local tissue reactions. Being a multifactorial process, several in vitro models have been developed to recreate the in vivo corrosion process, often summarized as mechanically-assisted crevice corrosion. Considering the excellent corrosion properties of CoCrMo alloy, the severity of chemically-generated damage observed at the modular interface has been surprising and poorly understood. The aim of the current study is to provide a better understanding of macrophages and their plasticity at the THR taper interface when they encounter wear debris from CoCrMo alloy. This is a preliminary study along the path towards determining the mechanism(s) of CAC., (Copyright © 2019 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Dendrimers are emerging class of nanoparticles used in targeted drug delivery systems. These are radially symmetric molecules with well-defined, homogeneous, and monodisperse structures. Due to the nano size, they can easily cross the biological membrane and increase bioavailability. The surface functionalization facilitates targeting of the particular site of action, assists the high drug loading and improves the therapeutic efficiency of the drug. These properties make dendrimers advantageous over conventional drug delivery systems. This article explains the features of dendrimers along with their method of synthesis, such as divergent growth method, convergent growth method, double exponential and mixed method, hyper-core and branched method. Dendrimers are effectively used in anticancer delivery and can be targeted at the site of tumor either by active or passive targeting. There are three mechanisms by which drugs interact with dendrimers, and they are physical encapsulation, electrostatic interaction, chemical conjugation of drug molecules. Drug releases from dendrimer either by in vivo cleavage of the covalent bond between drugdendrimer complexes or by physical changes or stimulus like pH, temperature, etc., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

The motive behind present work was to discover a solution for overcoming the problems allied with a deprived oral bioavailability of salbutamol sulfate (SS) due to its first pass hepatic metabolism, shorter half-life, and systemic toxicity at high doses. Pulmonary delivery provides an alternative route of administration to avoid hepatic metabolism of SS, moreover facilitated diffusion and prolonged retention can be achieved by incorporation into liposomes. Liposomes were prepared by thin film hydration technique using 3 2 full factorial design and formulation was optimized based on the vesicle size and percent drug entrapment (PDE) of liposomes. Optimized liposomal formulation exhibited an average size of about 167.2 ± 0.170 nm, with 80.68 ± 0.74% drug entrapment, and 9.74 ± 1.10 mV zeta potential. The liposomal dispersion was then spray dried and further characterized for in-vitro aerosol performance using Andersen Cascade Impactor. Optimized liposomal formulation revealed prolonged in-vitro drug release of more than 90% up to 14 h following Higuchi's controlled release model. Thus, the proposed new-fangled liposomal formulation would be a propitious alternative to conventional therapy for efficient and methodical treatment of asthma and alike respiratory ailments.

Background: The study aimed at assessing the prevalence and clinical profile of minimal hepatic encephalopathy (MHE) in patients with cirrhosis using neuropsychological assessment and at understanding the management practices of MHE in the Indian clinical setting., Methods: This cross-sectional, clinicoepidemiological study conducted at 20 sites enrolled liver cirrhosis patients with Grade 0 hepatic encephalopathy according to West-Haven Criteria. Patients were subjected to mini-mental state examination and those with a score of ≥24 were assessed using psychometric hepatic encephalopathy score. Short Form-36 questionnaire was administered to assess the impact on health-related quality of life., Results: Of the 1260 enrolled patients, 1114 were included in the analysis. The mean age was 49.5 years and majority were males (901 [81%]). The prevalence of MHE was found to be 59.7% (665/1114) based on the psychometric hepatic encephalopathy score of ≤-5. Alcohol-related liver disease was the most common etiology (482 [43.27%]) followed by viral infection (239 [21.45%]). Past smokers as well as those currently smoking were more likely to have MHE than nonsmokers. A significant association was found between tobacco chewing, smoking, alcohol consumption, diabetes, and the presence of MHE. Multivariable analysis revealed smoking as the only parameter associated with MHE. A total of 300 (26.9%) patients were on prophylaxis with lactulose/lactitol or rifaximin. These patients were less likely to have MHE as compared to those not on prophylaxis (odds ratio, 0.67; 95% confidence interval, 0.50-0.88; P  = 0.005)., Conclusion: The disease burden of MHE is quite substantial in patients with cirrhosis with no apparent cognitive defect. Smoking, whether past or current, has significant association with the presence of MHE. Although MHE has been shown to adversely affect quality of life, prophylaxis for MHE is not routinely practiced in the Indian setting.The study has been registered under clinical trials registry of India (CTRI/2014/01/004306).

The uncommonness of gallbladder cancer in the developed world has contributed to the generally poor understanding of the disease. Our integrated analysis of whole exome sequencing, copy number alterations, immunohistochemical, and phospho-proteome array profiling indicates ERBB2 alterations in 40% early-stage rare gallbladder tumors, among an ethnically distinct population not studied before, that occurs through overexpression in 24% (n = 25) and recurrent mutations in 14% tumors (n = 44); along with co-occurring KRAS mutation in 7% tumors (n = 44). We demonstrate that ERBB2 heterodimerizes with EGFR to constitutively activate the ErbB signaling pathway in gallbladder cells. Consistent with this, treatment with ERBB2-specific, EGFR-specific shRNA or with a covalent EGFR family inhibitor Afatinib inhibits tumor-associated characteristics of the gallbladder cancer cells. Furthermore, we observe an in vivo reduction in tumor size of gallbladder xenografts in response to Afatinib is paralleled by a reduction in the amounts of phospho-ERK, in tumors harboring KRAS (G13D) mutation but not in KRAS (G12V) mutation, supporting an essential role of the ErbB pathway. In overall, besides implicating ERBB2 as an important therapeutic target under neo-adjuvant or adjuvant settings, we present the first evidence that the presence of KRAS mutations may preclude gallbladder cancer patients to respond to anti-EGFR treatment, similar to a clinical algorithm commonly practiced to opt for anti-EGFR treatment in colorectal cancer., (© 2018 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Purpose: Previously we have shown, using a primary glioblastoma (GBM) cell model, that a subpopulation of innately radiation resistant (RR) GBM cells survive radiotherapy and form multinucleated and giant cells (MNGCs) by homotypic fusions. We also showed that MNGCs may cause relapse. Here, we set out to explore whether molecular characteristics of RR cells captured from patient-derived primary GBM cultures bear clinical relevance., Methods: Primary cultures were derived from 19 naive GBM tumor samples. RR cells generated from these cultures were characterized using various cell biological assays. We also collected clinicopathological data of the 19 patients and assessed associations with RR variables using Spearman's correlation test and with patient survival using Kaplan-Meier analysis. Significance was determined using a log-rank test., Results: We found that SF2 (surviving fraction 2) values (p = 0.029), days of RR cell formation (p = 0.019) and percentage of giant cells (p = 0.034) in the RR population independently correlated with a poor patient survival. We also found that low ATM (Ataxia-telangiectasia mutated) expression levels in RR cells showed a significant (p = 0.002) negative correlation with SF2 values. A low ATM expression level in RR cells along with a high tumor volume was also found to negatively correlate with patient survival (p = 0.011). Finally, we found that the ATM expression levels in RR cells independently correlated with a poor patient survival (p = 0.014)., Conclusions: Our data indicate that molecular features of innately radiation resistant GBM cells independently correlate with clinical outcome. Our study also highlights the relevance of using patient-derived primary GBM cultures for the characterization of RR cells that are otherwise inaccessible for analysis.

Preoperative progesterone intervention has been shown to confer a survival benefit to breast cancer patients independently of their progesterone receptor (PR) status. This observation raises the question how progesterone affects the outcome of PR-negative cancer. Here, using microarray and RNA-Seq-based gene expression profiling and ChIP-Seq analyses of breast cancer cells, we observed that the serum- and glucocorticoid-regulated kinase gene ( SGK1 ) and the tumor metastasis-suppressor gene N-Myc downstream regulated gene 1 ( NDRG1 ) are up-regulated and that the microRNAs miR-29a and miR-101-1 targeting the 3'-UTR of SGK1 are down-regulated in response to progesterone. We further demonstrate a dual-phase transcriptional and post-transcriptional regulation of SGK1 in response to progesterone, leading to an up-regulation of NDRG1 that is mediated by a set of genes regulated by the transcription factor AP-1. We found that NDRG1 , in turn, inactivates a set of kinases, impeding the invasion and migration of breast cancer cells. In summary, we propose a model for the mode of action of progesterone in breast cancer. This model helps decipher the molecular basis of observations in a randomized clinical trial of the effect of progesterone on breast cancer and has therefore the potential to improve the prognosis of breast cancer patients receiving preoperative progesterone treatment., (© 2018 Godbole et al.)

Therapy resistance and recurrence in Glioblastoma is due to the presence of residual radiation resistant cells. However, because of their inaccessibility from patient biopsies, the molecular mechanisms driving their survival remain unexplored. Residual Radiation Resistant (RR) and Relapse (R) cells were captured using cellular radiation resistant model generated from patient derived primary cultures and cell lines. iTRAQ based quantitative proteomics was performed to identify pathways unique to RR cells followed by in vitro and in vivo experiments showing their role in radio-resistance. 2720 proteins were identified across Parent (P), RR and R population with 824 and 874 differential proteins in RR and R cells. Unsupervised clustering showed proteasome pathway as the most significantly deregulated pathway in RR cells. Concordantly, the RR cells displayed enhanced expression and activity of proteasome subunits, which triggered NFkB signalling. Pharmacological inhibition of proteasome activity led to impeded NFkB transcriptional activity, radio-sensitization of RR cells in vitro , and significantly reduced capacity to form orthotopic tumours in vivo . We demonstrate that combination of proteasome inhibitor with radio-therapy abolish the inaccessible residual resistant cells thereby preventing GBM recurrence. Furthermore, we identified first proteomic signature of RR cells that can be exploited for GBM therapeutics., Competing Interests: CONFLICTS OF INTEREST Authors declare no conflicts of interest.

Leukemia is majorly treated by topoisomerase inhibitors that induce DNA double strand breaks (DSB) resulting in cell death. Consequently, modulation of DSB repair pathway renders leukemic cells resistant to therapy. As we do not fully understand the regulation of DSB repair acquired by resistant cells, targeting these cells has been a challenge. Here we investigated the regulation of DSB repair pathway in early drug resistant population (EDRP) and late drug resistant population (LDRP). We found that doxorubicin induced equal DSBs in parent and EDRP cells; however, cell death is induced only in the parent cells. Further analysis revealed that EDRP cells acquire relaxed chromatin via upregulation of lysine acetyl transferase KAT2A (GCN5). Drug treatment induces GCN5 interaction with ATM facilitating its recruitment to DSB sites. Hyperactivated ATM maximize H2AX, NBS1, BRCA1, Chk2, and Mcl-1 activation, accelerating DNA repair and survival of EDRP cells. Consequently, inhibition of GCN5 significantly reduces ATM activation and survival of EDRP cells. Contrary to EDRP, doxorubicin failed to induce DSBs in LDRP because of reduced drug uptake and downregulation of TOP2β. Accordingly, ATM inhibition prior to doxorubicin treatment completely eliminated EDRP but not LDRP. Furthermore, baseline AML samples (n = 44) showed significantly higher GCN5 at mRNA and protein levels in MRD positive compared to MRD negative samples. Additionally, meta-analysis (n = 221) showed high GCN5 expression correlates with poor overall survival. Together, these results provide important insights into the molecular mechanism specific to EDRP and will have implications for the development of novel therapeutics for AML., (© 2018 UICC.)

Bystander cells of the tumor microenvironment show evidence of DNA damage and inflammation that can lead to their oncogenic transformation. Mediator(s) of cell-cell communication that brings about these pro-oncogenic pathologies has not been identified. We show here that cell-free chromatin (cfCh) released from dying cancer cells are the key mediators that trigger both DNA damage and inflammation in the surrounding healthy cells. When dying human cancer cells were cultured along with NIH3T3 mouse fibroblast cells, numerous cfCh emerged from them and rapidly entered into nuclei of bystander NIH3T3 cells to integrate into their genomes. This led to activation of H2AX and inflammatory cytokines NF κ B, IL-6, TNF α and IFN γ . Genomic integration of cfCh triggered global deregulation of transcription and upregulation of pathways related to phagocytosis, DNA damage and inflammation. None of these activities were observed when living cancer cells were co-cultivated with NIH3T3 cells. However, upon intravenous injection into mice, both dead and live cells were found to be active. Living cancer cells are known to undergo extensive cell death when injected intravenously, and we observed that cfCh emerging from both types of cells integrated into genomes of cells of distant organs and induced DNA damage and inflammation. γ H2AX and NF κ B were frequently co-expressed in the same cells suggesting that DNA damage and inflammation are closely linked pathologies. As concurrent DNA damage and inflammation is a potent stimulus for oncogenic transformation, our results suggest that cfCh from dying cancer cells can transform cells of the microenvironment both locally and in distant organs providing a novel mechanism of tumor invasion and metastasis. The afore-described pro-oncogenic pathologies could be abrogated by concurrent treatment with chromatin neutralizing/degrading agents suggesting therapeutic possibilities., Competing Interests: The authors declare no conflict of interest.

Background & Aims: The present study examines the associations of folic acid, vitamin B₁₂ and omega-3 fatty acids and increased homocysteine which are implicated in the pathology of pre-eclampsia., Methods: 49 Pre-eclamptic and 57 normotensive women were recruited at Bharati hospital, Pune, India. Plasma folate, vitamin B₁₂, homocysteine and erythrocyte omega-3 and omega-6 fatty acids were analyzed., Results: Homocysteine concentrations were higher in pre-eclamptic than in normotensive women (14.28±7.31 vs. 11.03±4.38 μmol/l, p<0.01) despite similar levels of folic acid and vitamin B₁₂. In the pre-eclamptic group, plasma folate levels were positively associated with erythrocyte omega-6 fatty acids (p<0.05) while erythrocyte docosahexaenoic acid levels were negatively associated with plasma homocysteine levels (p<0.01)., Conclusions: Our study provides evidence for the associations of altered omega-3 fatty acids especially docosahexaenoic acid and the resultant increased homocysteine concentrations in pre-eclampsia. Future studies need to examine if docosahexaenoic acid supplementation during pregnancy reduces homocysteine levels and ameliorates the risk of developing pre-eclampsia., (Copyright © 2010 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

The human interferon alpha 2b (IFN alpha2b) belongs to the interferon family of cytokines that exerts many biological functions like inhibition of virus multiplication, repression of tumour growth and other immunological functions. Herein, a synthetic gene coding for human IFN alpha2b was cloned and integrated into a methylotropic yeast-Pichiapastoris. The recombinant human IFN alpha2b protein (approximately 19kDa) could be successfully expressed in Pichiapastoris to a level of nearly 300mg/L with nearly 93% recovery on purification using a single anion exchange chromatography step. A novel media component dimethyl sulphoxide (DMSO) was found to aid in expression of rightly processed IFN alpha2b form with dramatic reduction in the expression of a 20kDa IFN isoform contaminant frequently observed by other workers. The identity of the 20kDa isoform was confirmed by N terminal sequencing which showed extra eleven amino acids at the N terminal portion of the IFN molecule obtained due to incorrect processing by the host KEX2 protease. The purified IFN alpha2b (19kDa) preparation was confirmed by N terminal sequencing, and characterized by MALDI-TOF and Agilent 2100 Bioanalyzer. The bioassay of the recombinant protein gave a specific activity of >2x10(8)IU/mg.

Paratuberculosis or Johne's disease is a chronic gastric disease of ruminants. For this disease there is no effective treatment or preventive measure available. 16.8 kDa protein is an immunogenic protein of Mycobacterium avium paratuberculosis and can be an ideal candidate for developing a DNA vaccine construct. In present study a bicistronic DNA vaccine construct pIR16.8/IFN was developed using eukaryotic vector pIRES 6.1. Two genes MPT (expressing 16.8 kDa protein) and murine IFNgamma were cloned, expressed and immunoreactivity was studied in murine model. Immunoreactivity was also compared with monocistronic construct pIR16.8 expressing 16.8 kDa protein. Both pIR16.8 and pIR16.8/IFN showed eukaryotic expression of respective proteins in BHK21 cells. The expressed proteins also showed immunoreactivity when reacted with hyperimmune sera raised against recombinant 16.8 kDa protein in western blot assay and immunofluorence assay. Both constructs were used as DNA vaccine in murine model and immunogenecity was studied by DTH, lymphocyte proliferation assay and NO determination. DTH reaction was significantly high in pIR16.8/IFN than pIR16.8 group, similarly lymphocyte proliferation and NO release was higher in pIR16.8/IFN group than pIR16.8 group. This indicated T cell epitopic nature of 16.8 kDa protein. The study also showed that co-expression of IFNgamma with mycobacterial gene can enhance immunogenecity of DNA vaccine and can be used as immunoadjuvant.

The first simple and efficient approach towards one step synthesis of 2-amino-5-cyano-6-hydroxy-4-aryl pyrimidines has been developed by three component condensation of aromatic aldehydes, ethyl cyanoacetate and guanidine hydrochloride in alkaline ethanol. The synthesized compounds evaluated for their anti-bacterial activity against gram-positive and gram-negative bacteria. The some of the compounds showed excellent zone of inhibition against tested bacteria.

Of 340 patients undergoing elective cholecystectomy for gallstone disease, 41 (12%) required an abdominal drain and 22 (65%) required a nasogastric tube postoperatively to control vomiting. Eighty six percent patients were discharged on the third post-operative day; 53% were satisfied with the early discharge. In our opinion, routine use of nasogastric tube and abdominal drain is not necessary and patients can be safely discharged on the third postoperative day after an uncomplicated cholecystectomy.