Nanoinformatics based insights into the interaction of blood plasma proteins with carbon based nanomaterials: Implications for biomedical applications.

In the past three decades, interest in using carbon-based nanomaterials (CBNs) in biomedical application has witnessed remarkable growth. Despite the rapid advancement, the translation of laboratory experimentation to clinical applications of nanomaterials is one of the major challenges. This might be attributed to poor understanding of bio-nano interface. Arguably, the most significant barrier is the complexity that arises by interplay of several factors like properties of nanomaterial (shape, size, surface chemistry), its interaction with suspending media (surface hydration and dehydration, surface reconstruction and release of free surface energy) and the interaction with biomolecules (conformational change in biomolecules, interaction with membrane and receptor). Tailoring a nanomaterial that minimally interacts with protein and lipids in the medium while effectively acts on target site in biological milieu has been very difficult. Computational methods and artificial intelligence techniques have displayed potential in effectively addressing this problem. Through predictive modelling and deep learning, computer-based methods have demonstrated the capability to create accurate models of interactions between nanoparticles and cell membranes, as well as the uptake of nanomaterials by cells. Computer-based simulations techniques enable these computational models to forecast how making particular alterations to a material's physical and chemical properties could enhance functional aspects, such as the retention of drugs, the process of cellular uptake and biocompatibility. We review the most recent progress regarding the bio-nano interface studies between the plasma proteins and CBNs with a special focus on computational simulations based on molecular dynamics and density functional theory.

Novel furan chalcone modulates PHD-2 induction to impart antineoplastic effect in mammary gland carcinoma.

Normoxic inactivation of prolyl hydroxylase-2 (PHD-2) in tumour microenvironment paves the way for cancer cells to thrive under the influence of HIF-1α and NF-κB. Henceforth, the present study is aimed to identify small molecule activators of PHD-2. A virtual screening was conducted on a library consisting of 265,242 chemical compounds, with the objective of identifying molecules that exhibit structural similarities to the furan chalcone scaffold. Further, PHD-2 activation potential of screened compound was determined using in vitro 2-oxoglutarate assay. The cytotoxic activity and apoptotic potential of screened compound was determined using various staining techniques, including 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide, 4',6-diamidino-2-phenylindole (DAPI), 1,1',3,3'-tetraethylbenzimi-dazolylcarbocyanine iodide (JC-1), and acridine orange/ethidium bromide (AO/EB), against MCF-7 cells. 7,12-Dimethylbenz[a]anthracene (DMBA) model of mammary gland cancer was used to study the in vivo antineoplastic efficacy of screened compound. [(E)-1-(4-fluorophenyl)-3-(furan-2-yl) prop-2-en-1-one] (BBAP-7) was screened and validated as a PHD-2 activator by an in vitro 2-oxo-glutarate assay. The IC50 of BBAP-7 on MCF-7 cells is 18.84 µM. AO/EB and DAPI staining showed nuclear fragmentation, blebbing and condensation in MCF-7 cells following BBAP-7 treatment. The red-to-green intensity ratio of JC-1 stained MCF-7 cells decreased after BBAP-7 treatment, indicating mitochondrial-mediated apoptosis. DMBA caused mammary gland dysplasia, duct hyperplasia and ductal carcinoma in situ. Carmine staining, histopathology, and scanning electron microscopy demonstrated that BBAP-7, alone or with tirapazamine, restored mammary gland surface morphology and structural integrity. Additionally, BBAP-7 therapy significantly reduced oxidative stress and glycolysis. The findings reveal that BBAP-7 activates PHD-2, making it a promising anticancer drug.

The Microbiome Modulates the Immune System to Influence Cancer Therapy.

The gut microbiota composition can affect the tumor microenvironment and its interaction with the immune system, thereby having implications for treatment predictions. This article reviews the studies available to better understand how the gut microbiome helps the immune system fight cancer. To describe this fact, different mechanisms and approaches utilizing probiotics to improve advancements in cancer treatment will be discussed. Moreover, not only calorie intake but also the variety and quality of diet can influence cancer patients' immunotherapy treatment because dietary patterns can impair immunological activities either by stimulating or suppressing innate and adaptive immunity. Therefore, it is interesting and critical to understand gut microbiome composition as a biomarker to predict cancer immunotherapy outcomes and responses. Here, more emphasis will be given to the recent development in immunotherapies utilizing microbiota to improve cancer therapies, which is beneficial for cancer patients.

Harnessing two-dimensional nanomaterials for diagnosis and therapy in neurodegenerative diseases: Advances, challenges and prospects.

Neurodegenerative diseases (NDDs) are specific brain disorders characterized by the progressive deterioration of different motor activities as well as several cognitive functions. Current conventional therapeutic options for NDDs are limited in addressing underlying causes, delivering drugs to specific neuronal targets, and promoting tissue repair following brain injury. Due to the paucity of plausible theranostic options for NDDs, nanobiotechnology has emerged as a promising field, offering an interdisciplinary approach to create nanomaterials with high diagnostic and therapeutic efficacy for these diseases. Recently, two-dimensional nanomaterials (2D-NMs) have gained significant attention in biomedical and pharmaceutical applications due to their precise drug-loading capabilities, controlled release mechanisms, enhanced stability, improved biodegradability, and reduced cell toxicity. Although various studies have explored the diagnostic and therapeutic potential of different nanomaterials in NDDs, there is a lack of comprehensive review addressing the theranostic applications of 2D-NMs in these neuronal disorders. Therefore, this concise review aims to provide a state-of-the-art understanding of the need for these ultrathin 2D-NMs and their potential applications in biosensing and bioimaging, targeted drug delivery, tissue engineering, and regenerative medicine for NDDs.

Prospecting the Potential of Plant Growth-Promoting Microorganisms for Mitigating Drought Stress in Crop Plants.

Drought is a global phenomenon affecting plant growth and productivity, the severity of which has impacts around the whole world. A number of approaches, such as agronomic, conventional breeding, and genetic engineering, are followed to increase drought resilience; however, they are often time consuming and non-sustainable. Plant growth-promoting microorganisms are used worldwide to mitigate drought stress in crop plants. These microorganisms exhibit multifarious traits, which not only help in improving plant and soil health, but also demonstrate capabilities in ameliorating drought stress. The present review highlights various adaptive strategies shown by these microbes in improving drought resilience, such as modulation of various growth hormones and osmoprotectant levels, modification of root morphology, exopolysaccharide production, and prevention of oxidative damage. Gene expression patterns providing an adaptive edge for further amelioration of drought stress have also been studied in detail. Furthermore, the practical applications of these microorganisms in soil are highlighted, emphasizing their potential to increase crop productivity without compromising long-term soil health. This review provides a comprehensive coverage of plant growth-promoting microorganisms-mediated drought mitigation strategies, insights into gene expression patterns, and practical applications, while also guiding future research directions.

HIV cure: Are we going to make history?

BACKGROUND: At present, combination antiretroviral therapy (cART) is the mainstay for the treatment of people living with HIV/AIDS. cART can suppress the viral load to a minimal level; however, the possibility of the emergence of full-blown AIDS is always there. In the latter part of the first decade of the 21st century, an HIV-positive person received stem cell transplantation (SCT) for treatment of his haematological malignancy. The patient was able to achieve remission of the haematological condition as well as of HIV following SCT. Thorough investigations of various samples including blood and biopsy could not detect the virus in the person's body. The person was declared to be the first cured case of HIV. LITERATURE SEARCH: Over the next decade, a few more similar cases were observed and have recently been declared cured of the infection. A comprehensive search was performed in PubMed, Cochrane library and Google Scholar. Four such additional cases were found in literature. DESCRIPTION & DISCUSSION: These cases all share a common proposed mechanism for the HIV cure, that is, transplantation of stem cells from donors carrying a homozygous mutation in a gene encoding for CCR5 (receptor utilized by HIV for entry into the host cell), denoted as CCR5△32. This mutation makes the host immune cells devoid of CCR5, causing the host to acquire resistance against HIV. To the best of our knowledge, this is the first review to look at relevant and updated information of all cured cases of HIV as well as the related landmarks in history and discusses the underlying mechanism(s).

Influence of Vitamin D Level on Inflammatory and Prognostic Markers in COVID-19 - A Retrospective Study.

OBJECTIVE: The ongoing pandemic of severe acute respiratory syndrome coronavirus 2019 (SARS-CoV-2) has caused an immense public health crisis worldwide. Emerging evidence has suggested that inflammatory response plays a critical role in the pathogenesis and prognosis of the disease. As vitamin D can modulate the immune system, this study has been designed to correlate vitamin D with inflammatory and prognostic markers in COVID-19 patients. METHODS: The present study is a retrospective study examining the relationship between vitamin D levels and inflammatory markers in the COVID-19 disease. COVID-19 patients who were investigated for vitamin D, ferritin, D-dimer, C-reactive protein (CRP), and procalcitonin (PCT) level were only included. The patients were divided into hypovitaminosis D, and normal vitamin D. Correlation and logistic regression analyses were carried out to identify the strength and association of hypovitaminosis D with inflammatory markers in COVID-19 disease. RESULTS: The hypovitaminosis D group had significantly higher inflammatory markers compared to the normal vitamin D group. The correlation between hypovitaminosis D and procalcitonin was negative (r = -0.433), with a strong and significant association (p = 0.002). The correlation between hypovitaminosis D, CRP, and ferritin was weak and insignificant. The logistic regression between hypovitaminosis D and procalcitonin established a significant regression equation, leading to a significant linear model. CONCLUSION: This study concludes that patients with hypovitaminosis D should be treated with vitamin D therapy to reduce the severity of COVID-19 disease.

A Randomized Controlled Study Comparing the Efficacy of 75mg Versus 150mg Aspirin for the Prevention of Preeclampsia in High-Risk Pregnant Women.

Background Preeclampsia is a major factor in both maternal and fetal morbidity and mortality. The most widely investigated preeclampsia prevention medication is low dose Aspirin. However, guidelines differ considerably regarding the prophylactic dose of Aspirin for preeclampsia. Objective The objective is to compare the efficacy of 150mg versus 75mg Aspirin for the prevention of preeclampsia in pregnant women at high risk of preeclampsia. Methodology This was a parallel, open-label, randomized control trial carried over a period of one year and three months at a tertiary care center of Eastern India. Block randomization was done and block sizes of 2 and 4 were used to ensure balanced distributions within the study arms. Primary outcome was the development of preeclampsia and secondary outcomes were fetomaternal complications in both groups. Results The present clinical trial was conducted on 116 pregnant women with a risk factor of preeclampsia and they were randomly assigned to receive either 150mg or 75mg of Aspirin daily beginning from 12 to 16 weeks of gestation till 36 weeks' gestation. A significantly greater number of pregnant females who received Aspirin 75mg (33.92%) developed preeclampsia in contrast to those who received Aspirin 150mg (8.77%), p=0.001, OR = 5.341, 95%CI = 1.829-15.594. There was an insignificant difference in fetomaternal outcome among both the groups of women. Conclusion Among women who are at high risk of developing preeclampsia, Aspirin 150 mg once a day at bedtime is more effective than Aspirin 75 mg once a day at bedtime in preventing preeclampsia with similar fetomaternal outcomes (NICU admission, IUGR, neonatal death, still birth, eclampsia, HELLP syndrome, placental abruption and pulmonary edema).

Impact of crystal structure on optical properties and temperature sensing behavior of NaYF4:Yb3+/Er3+ nanoparticles.

We report a comprehensive study of the structural, morphological, and optical properties, and UC-based ratiometric temperature sensing behavior of (α) cubic and (ß) hexagonal phases of NaYF4:Yb3+/Er3+ nanoparticles. The α-NaYF4:Yb3+/Er3+ and ß-NaYF4:Yb3+/Er3+ nanoparticles were synthesized using co-precipitation and hydrothermal methods, respectively. Powder X-ray diffraction studies confirmed the phase purity of the samples. The morphological studies show uniform particle sizes of both phases; the average particle size of α-NaYF4:Yb3+/Er3+ and ß-NaYF4:Yb3+/Er3+ was 9.2 nm and 29 nm, respectively. The Raman spectra reveal five sharp peaks at 253 cm-1, 307 cm-1, 359 cm-1, 485 cm-1, and 628 cm-1 for ß-NaYF4:Yb3+/Er3+, whereas α-NaYF4:Yb3+/Er3+ shows two broad peaks centred at 272 cm-1 and 721 cm-1. The optical property measurements show that α- and ß-NaYF4:Yb3+/Er3+ phases have distinct upconversion emission and temperature sensing behavior. The upconversion emission measurements show that ß-NaYF4:Yb3+/Er3+ has higher overall emission intensities and green/red emission intensity ratio. The temperature-dependent upconversion emission measurements show that α-NaYF4:Yb3+/Er3+ has higher energy separation between 2H11/2 and 4S3/2 energy states. The temperature sensing performed utilizing these thermally coupled energy levels shows a maximum sensitivity of 0.0069 K-1 at 543 K and 0.016 K-1 at 422 K for ß-NaYF4:Yb3+/Er3+ and α-NaYF4:Yb3+/Er3+, respectively.

Interplay between MAP kinases and tumor microenvironment: Opportunity for immunotherapy in pancreatic cancer.

Pancreatic Ductal Adenocarcinoma (PDAC), commonly called pancreatic cancer, is aggressive cancer usually detected at a late stage, limiting treatment options with modest clinical responses. It is projected that by 2030, PDAC will be the second most common cause of cancer-related mortality in the United States. Drug resistance in PDAC is common and significantly affects patients' overall survival (OS). Oncogenic KRAS mutations are nearly uniform in PDAC, affecting over 90% of patients. However, effective drugs directed to target prevalent KRAS mutants in pancreatic cancer are not in clinical practice. Accordingly, efforts are continued on identifying alternative druggable target(s) or approaches to improve patient outcomes with PDAC. In most PDAC cases, the KRAS mutations turn-on the RAF-MEK-MAPK pathways, leading to pancreatic tumorigenesis. The MAPK signaling cascade (MAP4K→MAP3K→MAP2K→MAPK) plays a central role in the pancreatic cancer tumor microenvironment (TME) and chemotherapy resistance. The immunosuppressive pancreatic cancer TME is another unfavorable factor affecting the therapeutic efficacy of chemotherapy and immunotherapy. The immune checkpoint proteins (ICPs), including CTLA-4, PD-1, PD-L1, and PD-L2, are critical players in T cell dysfunction and pancreatic tumor cell growth. Here, we review the activation of MAPKs, a molecular trait of KRAS mutations and their impact on pancreatic cancer TME, chemoresistance, and expression of ICPs that could influence the clinical outcomes in PDAC patients. Therefore, understanding the interplay between MAPK pathways and TME could help to design rational therapy combining immunotherapy and MAPK inhibitors for pancreatic cancer treatment.

Exploring the role of microbes for the management of persistent organic pollutants.

Persistent organic pollutants (POPs) are chemicals which have been persisting in the environment for many years due to their longer half-lives. POPs have gained attention over the last few decades due to the unsustainable management of chemicals which led to their widespread and massive contamination of biota from different strata and environments. Due to the widespread distribution, bio-accumulation and toxic behavior, POPs have become a risk for organisms and environment. Therefore, a focus is required to eliminate these chemicals from the environment or transform into non-toxic forms. Among the available techniques for the removal of POPs, most of them are inefficient or incur high operational costs. As an alternative to this, microbial bioremediation of POPs such as pesticides, polycyclic aromatic hydrocarbons, polychlorinated biphenyls, pharmaceuticals and personal care products is much more efficient and cost-effective. Additionally, bacteria play a vital role in the biotransformation and solubilization of POPs, which reduces their toxicity. This review specifies the Stockholm Convention that evaluates the risk profile for the management of existing as well as emerging POPs. The sources, types and persistence of POPs along with the comparison of conventional elimination and bioremediation methods of POPs are discussed comprehensively. This study demonstrates the existing bioremediation techniques of POPs and summaries the potential of microbes which serve as enhanced, cost-effective, and eco-friendly approach for POPs elimination.

Link of the short-term temporal trends of Sr and Nd isotopic composition of aeolian dust over the Arabian Sea with the source emissions.

Aeolian transport of continental dust from the Middle East and South Asia to the Arabian Sea (AS) is an important route for delivering key trace metals and nutrients. Despite being surrounded by several deserts, it is not clear which dust source is most likely contributing to mineral aerosols over this marine basin in winter. Substantial information on dust source emissions and transport pathways over the AS is, thus, needed for better constraining the biogeochemical effects in the sunlit surface waters. Here, we investigated the Sr and Nd isotopic composition (87Sr/86Sr and εNd(0)), respectively) of dust samples collected over the AS during a GEOTRACES-India expedition (GI-10: 13 January-10 February 2020). Both tracers, 87Sr/86Sr (0.70957-0.72495) and εNd(0) (-24.0 to -9.3), showed pronounced spatial variability. These proxies were further tagged with their source profiles of surrounding land masses based on the origin of air mass back trajectories (AMBTs). We also encountered two dust storms (DS), one on 27 January 2020 (87Sr/86Sr: 0.70957; εNd(0): -9.3) and the second one on 10 February 2020 (87Sr/86Sr: 0.71474, εNd(0):-12.5), which showed distinct isotopic signatures. AMBTs and satellite imagery together revealed that DS1 is from the Arabian Peninsula and DS2 is from Iran and/or the Indo-Gangetic Plain. Notably, the Sr and Nd isotope composition of DS1 is further consistent with other dust samples collected over the pelagic waters, suggesting the impact of dust outbreaks from the Arabian Peninsula during winter season. Such documentation based on the 87Sr/86Sr and εNd(0) over the Arabian Sea, hitherto, is lacking in literature and, thus, highlights the need for more measurements.

Approach to Cystic Lesions of the Pancreas: Review of Literature.

Pancreatic cystic lesions (PCL) have a wide range of demographical, clinical, morphological and histological characteristics. The distinction between these lesions is of paramount importance due to the risk of malignancy in specific categories of PCL. Considering the malignant potential for pancreatic cystic neoplasm (PCN) lesions, guidelines have been made to balance unnecessary treatment and manage the progression to malignancy. Various surgical procedures can be done for PCN depending on the location and size of the cyst; pancreatoduodenectomy is done for PCN located in the head of the uncinate process, whereas distal pancreatectomy is done for PCN in the body or tail. In the neck and proximal body of the pancreas, less extensive resections such as central pancreatectomy can be performed. Active surveillance of PCN is typically offered to asymptomatic PCNs of subtype intraductal papillary mucinous neoplasms (IPMN) and mucinous cystic neoplasms (MCN) without any concerning features. In recent years, numerous guidelines have been created to augment PCN diagnosis, classification and management. Despite this, the management of PCNs remains complex. Thus, discussions with multidisciplinary teams involving surgeons, gastroenterologists, pathologists, and radiologists are required to ensure optimum care for the patient.

Molecular Insights of MAP4K4 Signaling in Inflammatory and Malignant Diseases.

Mitogen-activated protein kinase (MAPK) cascades are crucial in extracellular signal transduction to cellular responses. The classical three-tiered MAPK cascades include signaling through MAP kinase kinase kinase (MAP3K) that activates a MAP kinase kinase (MAP2K), which in turn induces MAPK activation and downstream cellular responses. The upstream activators of MAP3K are often small guanosine-5'-triphosphate (GTP)-binding proteins, but in some pathways, MAP3K can be activated by another kinase, which is known as a MAP kinase kinase kinase kinase (MAP4K). MAP4K4 is one of the widely studied MAP4K members, known to play a significant role in inflammatory, cardiovascular, and malignant diseases. The MAP4K4 signal transduction plays an essential role in cell proliferation, transformation, invasiveness, adhesiveness, inflammation, stress responses, and cell migration. Overexpression of MAP4K4 is frequently reported in many cancers, including glioblastoma, colon, prostate, and pancreatic cancers. Besides its mainstay pro-survival role in various malignancies, MAP4K4 has been implicated in cancer-associated cachexia. In the present review, we discuss the functional role of MAP4K4 in malignant/non-malignant diseases and cancer-associated cachexia and its possible use in targeted therapy.

Unveiling the mechanism of platelet dysfunction in Parkinson's disease: The effect of 6-hydroxydopamine on human blood platelets.

INTRODUCTION: Parkinson's disease (PD) is a progressive neuronal illness often linked to increased cardiovascular complications, such as myocardial infarction, cardiomyopathy, congestive heart failure, and coronary heart disease. Platelets, which are the essential components of circulating blood, are considered potential players in regulating these complications, as platelet dysfunction is evident in PD. These tiny blood cell fragments are supposed to play a crucial role in these complications, but the underlying molecular processes are still obscure. METHODS: To gain a better understanding of platelet dysfunction in PD, we investigated the impact of 6-hydroxydopamine (6-OHDA), an analog of dopamine that simulates PD by destroying dopaminergic neurons, on human blood platelets. The levels of intraplatelet reactive oxygen species (ROS) were assessed using H2DCF-DA (20 µM), while mitochondrial ROS was evaluated using MitoSOX™ Red (5 µM), and intracellular Ca2+ was measured with Fluo-4-AM (5 µM). The data were acquired through the use of both a multimode plate reader and a laser-scanning confocal microscope. RESULTS: Our findings showed that 6-OHDA treatment increased the production of ROS in human blood platelets. The increase in ROS was confirmed by the ROS scavenger, NAC, and was also reduced by inhibiting the NOX enzyme with apocynin. Additionally, 6-OHDA potentiated mitochondrial ROS production in platelets. Furthermore, 6-OHDA triggered the intraplatelet Ca2+ elevation. This effect was mitigated by the Ca2+ chelator BAPTA, which decreased the ROS production triggered by 6-OHDA in human blood platelets, while the IP3 receptor blocker, 2-APB, reduced the formation of ROS induced by 6-OHDA. CONCLUSION: Our findings suggest that the 6-OHDA-induced ROS production is regulated by the IP3 receptor-Ca2+-NOX signaling axis in human blood platelets, where the platelet mitochondria also play a significant role. This observation provides a crucial mechanistic understanding of the altered platelet activities that are commonly observed in PD patients.

Enhancing the temperature sensing property of a Ca0.79-xBixEr0.01Yb0.2MoO4 phosphor via local symmetry distortion and reduction in non-radiative channels.

We demonstrate an enhancement in the upconversion (UC) emission and temperature sensing property of a CaMoO4:Er/Yb phosphor via distortion of the local symmetry environments and reduction in no-radiative channels. Bi3+ ion co-doping creates a local distortion while the average tetragonal structure of CaMoO4 remains intact. This creates asymmetry around the Er3+ ions which improves the UC emission. Furthermore, our calculations on XRD data show a reduction in the dislocation density and the micro-strain in the crystal with the introduction of Bi3+, which also favours the enhancement of UC emission as it reduces the non-radiative channels. Furthermore, the effect of this enhancement on the temperature sensing property of Er3+ ion has also been revealed. Our results show that the UC emission is enhanced about 25 times for Bi3+ co-doped samples which improves the temperature sensitivity significantly. The samples, both with and without Bi3+ co-doping, exhibited relative sensitivities of 0.0068 K-1 at 300 K and 0.0057 K-1 at 298 K which is a significant improvement and indicates the potential of the material for temperature sensing applications. This proof-of-concept provides a deeper understanding of the effect of Bi3+ doping on UC emission and opens new avenues for the development of high-performance temperature sensing materials.

Understanding Mutations in Human SARS-CoV-2 Spike Glycoprotein: A Systematic Review & Meta-Analysis.

Genetic variant(s) of concern (VoC) of SARS-CoV-2 have been emerging worldwide due to mutations in the gene encoding spike glycoprotein. We performed comprehensive analyses of spike protein mutations in the significant variant clade of SARS-CoV-2, using the data available on the Nextstrain server. We selected various mutations, namely, A222V, N439K, N501Y, L452R, Y453F, E484K, K417N, T478K, L981F, L212I, N856K, T547K, G496S, and Y369C for this study. These mutations were chosen based on their global entropic score, emergence, spread, transmission, and their location in the spike receptor binding domain (RBD). The relative abundance of these mutations was mapped with global mutation D614G as a reference. Our analyses suggest the rapid emergence of newer global mutations alongside D614G, as reported during the recent waves of COVID-19 in various parts of the world. These mutations could be instrumentally imperative for the transmission, infectivity, virulence, and host immune system's evasion of SARS-CoV-2. The probable impact of these mutations on vaccine effectiveness, antigenic diversity, antibody interactions, protein stability, RBD flexibility, and accessibility to human cell receptor ACE2 was studied in silico. Overall, the present study can help researchers to design the next generation of vaccines and biotherapeutics to combat COVID-19 infection.

Multi-stimuli-responsive and dynamic color tunable security ink for multilevel anticounterfeiting.

Luminescent security features have been used for anticounterfeiting for a long time. However, constant effort is required to strengthen these security features to be ahead of counterfeiters. Here, we developed a multi-stimuli-responsive luminescent security ink containing Tb(ASA)3Phen, K2SiF6:Mn4+,and NaYF4:Yb3+/Er3+luminescent materials in PVC gold medium. Tb(ASA)3Phen complex shows a broad excitation band in the UV region; upon UV light radiation it shows strong greenish emission of Tb3+ions through the antenna effect. K2SiF6:Mn4+, on the other hand, has three excitation bands with maxima at 248, 354, and 454 nm which emit red light after excitation through these bands. NaYF4:Yb3+/Er3+is used as an upconverting nanophosphor showing green emission under 976 nm laser excitation. Thus, the multi-stimuli-responsive luminescent security ink shows greenish, red, and green emissions under 367 nm, 450 nm, and 976 nm excitations, respectively. Furthermore, the distinct lifetimes of the activators in Tb(ASA)3Phen and K2SiF6:Mn4+, i.e. 0.1708 ms and 8.165 ms, respectively, under 380 nm excitation make this ink suitable for dynamic anticounterfeiting as well. The ink shows a change in the emission color with time delay, after the removal of the 380 nm excitation source, from greenish yellow (at 0 delays) to reddish color after a delay of 7.5 ms. These unique optical features along with excellent photo-, chemical- and environmental stability make this ink useful for advanced-level anticounterfeiting.

TrkA expression directs the anti-neoplastic activity of MLK3 inhibitors in triple-negative breast cancer.

Mixed Lineage Kinase 3 (MLK3) is a viable target for neoplastic diseases; however, it is unclear whether its activators or inhibitors can act as anti-neoplastic agents. We reported that the MLK3 kinase activity was higher in triple-negative (TNBC) than in hormone receptor-positive human breast tumors, where estrogen inhibited MLK3 kinase activity and provided a survival advantage to ER+ breast cancer cells. Herein, we show that in TNBC, the higher MLK3 kinase activity paradoxically promotes cancer cell survival. Knockdown of MLK3 or MLK3 inhibitors, CEP-1347 and URMC-099, attenuated tumorigenesis of TNBC cell line and Patient-Derived (PDX) xenografts. The MLK3 kinase inhibitors decreased both the expression and activation of MLK3, PAK1, and NF-kB protein and caused cell death in TNBC breast xenografts. RNA-seq analysis identified several genes downregulated by MLK3 inhibition, and the NGF/TrkA MAPK pathway was significantly enriched in tumors sensitive to growth inhibition by MLK3 inhibitors. The TNBC cell line unresponsive to kinase inhibitor had substantially lower TrkA, and overexpression of TrkA restored the sensitivity to MLK3 inhibition. These results suggest that the functions of MLK3 in breast cancer cells depend on downstream targets in TNBC tumors expressing TrkA, and MLK3 kinase inhibition may provide a novel targeted therapy.