Practices and outcomes of responsive caregiving on child neurodevelopment and mental health across diverse global populations: a scoping review protocol.

INTRODUCTION: Responsive caregiving (RC) leads to positive outcomes in children, including secure attachment with caregivers, emotional regulation, positive social interactions and cognitive development. Through our scoping review, we aim to summarise the practices and outcomes of RC in diverse caregiver and child populations from 0 to 8 years. METHODS AND ANALYSIS: We will use the Arksey and O'Malley framework and the Joanna Briggs Institute methodology for scoping reviews. We shall present our findings as per the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines for scoping review. Only peer-reviewed, English-language articles from 1982 to 2022 will be included from PubMed, Web of Science, APA PsychInfo, APA PsycArticles, SocINDEX and Google Scholar databases. Reference lists of included articles will also be screened. The search strategy will be developed for each database, and search results will be imported into Rayyan. Screening will be done in two phases: (1) titles and abstracts will be screened by two authors and conflicts will be resolved by mutual discussion between both or by consulting with a senior author; and (2) full-texts of shortlisted studies from the first phase will then be screened using the same inclusion/exclusion criteria. A data extraction form will be developed to collate relevant information from the final list of included articles. This form will be pilot tested on the first 10 papers and iteratively refined prior to data extraction from the remaining articles. Results will be presented in figures, tables and a narrative summary. ETHICS AND DISSEMINATION: No ethics approval needed as the review shall only use already published data. We shall publish the review in an open-access, peer-reviewed journal and disseminate through newsletters, social media pages, and presentations to relevant audiences.

Using mobile health technology to assess childhood autism in low-resource community settings in India: An innovation to address the detection gap.

LAY ABSTRACT: Autism is diagnosed by highly trained professionals- but most autistic people live in parts of the world that harbour few or no such autism specialists and little autism awareness. So many autistic people go undiagnosed, misdiagnosed, and misunderstood. We designed an app (START) to identify autism and related conditions in such places, in an attempt to address this global gap in access to specialists. START uses computerised games and activities for children and a questionnaire for parents to measure social, sensory, and motor skills. To check whether START can flag undiagnosed children likely to have neurodevelopmental conditions, we tested START with children whose diagnoses already were known: Non-specialist health workers with just a high-school education took START to family homes in poor neighbourhoods of Delhi, India to work with 131 two-to-seven-year-olds. Differences between typically and atypically developing children were highlighted in all three types of skills that START assesses: children with neurodevelopmental conditions preferred looking at geometric patterns rather than social scenes, were fascinated by predictable, repetitive sensory stimuli, and had more trouble with precise hand movements. Parents' responses to surveys further distinguished autistic from non-autistic children. An artificial-intelligence technique combining all these measures demonstrated that START can fairly accurately flag atypically developing children. Health workers and families endorsed START as attractive to most children, understandable to health workers, and adaptable within sometimes chaotic home and family environments. This study provides a proof of principle for START in digital screening of autism and related conditions in community settings.

Identification of Small Molecule Inhibitors and Ligand Directed Degraders of Calcium/Calmodulin Dependent Protein Kinase Kinase 1 and 2 (CaMKK1/2).

CaMKK2 signals through AMPK-dependent and AMPK-independent pathways to trigger cellular outputs including proliferation, differentiation, and migration, resulting in changes to metabolism, bone mass accrual, neuronal function, hematopoiesis, and immunity. CAMKK2 is upregulated in tumors including hepatocellular carcinoma, prostate, breast, and gastric cancer, and genetic deletion in myeloid cells results in increased antitumor immunity in several syngeneic models. Validation of the biological roles of CaMKK2 has relied on genetic deletion or small molecule inhibitors with activity against several biological targets. We sought to generate selective inhibitors and degraders to understand the biological impact of inhibiting catalytic activity and scaffolding and the potential therapeutic benefits of targeting CaMKK2. We report herein selective, ligand-efficient inhibitors and ligand-directed degraders of CaMKK2 that were used to probe immune and tumor intrinsic biology. These molecules provide two distinct strategies for ablating CaMKK2 signaling in vitro and in vivo.

Targeting CaMKK2 Inhibits Actin Cytoskeletal Assembly to Suppress Cancer Metastasis.

Triple-negative breast cancers (TNBC) tend to become invasive and metastatic at early stages in their development. Despite some treatment successes in early-stage localized TNBC, the rate of distant recurrence remains high, and long-term survival outcomes remain poor. In a search for new therapeutic targets for this disease, we observed that elevated expression of the serine/threonine kinase calcium/calmodulin (CaM)-dependent protein kinase kinase 2 (CaMKK2) is highly correlated with tumor invasiveness. In validation studies, genetic disruption of CaMKK2 expression or inhibition of its activity with small molecule inhibitors disrupted spontaneous metastatic outgrowth from primary tumors in murine xenograft models of TNBC. High-grade serous ovarian cancer (HGSOC), a high-risk, poor prognosis ovarian cancer subtype, shares many features with TNBC, and CaMKK2 inhibition effectively blocked metastatic progression in a validated xenograft model of this disease. Mechanistically, CaMKK2 increased the expression of the phosphodiesterase PDE1A, which hydrolyzed cyclic guanosine monophosphate (cGMP) to decrease the cGMP-dependent activity of protein kinase G1 (PKG1). Inhibition of PKG1 resulted in decreased phosphorylation of vasodilator-stimulated phosphoprotein (VASP), which in its hypophosphorylated state binds to and regulates F-actin assembly to facilitate cell movement. Together, these findings establish a targetable CaMKK2-PDE1A-PKG1-VASP signaling pathway that controls cancer cell motility and metastasis by impacting the actin cytoskeleton. Furthermore, it identifies CaMKK2 as a potential therapeutic target that can be exploited to restrict tumor invasiveness in patients diagnosed with early-stage TNBC or localized HGSOC. SIGNIFICANCE: CaMKK2 regulates actin cytoskeletal dynamics to promote tumor invasiveness and can be inhibited to suppress metastasis of breast and ovarian cancer, indicating CaMKK2 inhibition as a therapeutic strategy to arrest disease progression.

Ca 2+ /Calmodulin Dependent Protein Kinase Kinase-2 (CaMKK2) promotes Protein Kinase G (PKG)-dependent actin cytoskeletal assembly to increase tumor metastasis.

Triple-negative breast cancers (TNBCs) tend to become highly invasive early during cancer development. Despite some successes in the initial treatment of patients diagnosed with early-stage localized TNBC, the rate of metastatic recurrence remains high with poor long-term survival outcomes. Here we show that elevated expression of the serine/threonine-kinase, Calcium/Calmodulin (CaM)-dependent protein kinase kinase-2 (CaMKK2), is highly correlated with tumor invasiveness. We determined that genetic disruption of CaMKK2 expression, or inhibition of its activity, disrupted spontaneous metastatic outgrowth from primary tumors in murine xenograft models of TNBC. High-grade serous ovarian cancer (HGSOC), a high-risk, poor-prognosis ovarian cancer subtype, shares many genetic features with TNBC, and importantly, CaMKK2 inhibition effectively blocked metastatic progression in a validated xenograft model of this disease. Probing the mechanistic links between CaMKK2 and metastasis we defined the elements of a new signaling pathway that impacts actin cytoskeletal dynamics in a manner which increases cell migration/invasion and metastasis. Notably, CaMKK2 increases the expression of the phosphodiesterase PDE1A which decreases the cGMP-dependent activity of protein kinase G1 (PKG1). This inhibition of PKG1 results in decreased phosphorylation of Vasodilator-Stimulated Phosphoprotein (VASP), which in its hypophosphorylated state binds to and regulates F-actin assembly to facilitate contraction/cell movement. Together, these data establish a targetable CaMKK2-PDE1A-PKG1-VASP signaling pathway that controls cancer cell motility and metastasis. Further, it credentials CaMKK2 as a therapeutic target that can be exploited in the discovery of agents for use in the neoadjuvant/adjuvant setting to restrict tumor invasiveness in patients diagnosed with early-stage TNBC or localized HGSOC.

The current landscape and future of tablet-based cognitive assessments for children in low-resourced settings.

Interest in measuring cognition in children in low-resourced settings has increased in recent years, but options for cognitive assessments are limited. Researchers are faced with challenges when using existing assessments in these settings, such as trained workforce shortages, less relevant testing stimuli, limitations of proprietary assessments, and inadequate parental knowledge of cognitive milestones. Tablet-based direct child assessments are emerging as a practical solution to these challenges, but evidence of their validity and utility in cross-cultural settings is limited. In this overview, we introduce key concepts of this field while exploring the current landscape of tablet-based assessments for low-resourced settings. We also make recommendations for future directions of this relatively novel field. We conclude that tablet-based assessments are an emerging and promising method of assessing cognition in young children. Further awareness and dissemination of validated tablet-based assessments may increase capacity for child development research and clinical practice in low-resourced settings.

SGC-CAMKK2-1: A Chemical Probe for CAMKK2.

The serine/threonine protein kinase calcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2) plays critical roles in a range of biological processes. Despite its importance, only a handful of inhibitors of CAMKK2 have been disclosed. Having a selective small molecule tool to interrogate this kinase will help demonstrate that CAMKK2 inhibition can be therapeutically beneficial. Herein, we disclose SGC-CAMKK2-1, a selective chemical probe that targets CAMKK2.

Increased CaMKK2 Expression Is an Adaptive Response That Maintains the Fitness of Tumor-Infiltrating Natural Killer Cells.

Calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2) is a key regulator of energy homeostasis in several cell types. Expression of this enzyme in tumor cells promotes proliferation and migration, and expression in tumor-associated immune cells facilitates M2 macrophage polarization and the development of myeloid-derived suppressor cells. Thus, there has been interest in developing CaMKK2 inhibitors as potential anticancer therapeutics. One impediment to clinical development of these agents is that the roles of CaMKK2 in other cellular compartments within the tumor immune microenvironment remain to be established. We report herein that CaMKK2 is expressed at low basal levels in natural killer (NK) cells but is upregulated in tumor-infiltrating NK cells where it suppresses apoptosis and promotes proliferation. NK cell-intrinsic deletion of CaMKK2 increased metastatic progression in several murine models, establishing a critical role for this enzyme in NK cell-mediated antitumor immunity. Ablation of the CaMKK2 protein, but not inhibition of its kinase activity, resulted in decreased NK-cell survival. These results indicate an important scaffolding function for CaMKK2 in NK cells and suggest that competitive CaMKK2 inhibitors and ligand-directed degraders (LDD) are likely to have distinct therapeutic utilities. Finally, we determined that intracellular lactic acid is a key driver of CaMKK2 expression, suggesting that upregulated expression of this enzyme is an adaptive mechanism by which tumor-infiltrating NK cells mitigate the deleterious effects of a lactic acid-rich tumor microenvironment. The findings of this study should inform strategies to manipulate the CaMKK2-signaling axis as a therapeutic approach in cancer.

Digital tools for direct assessment of autism risk during early childhood: A systematic review.

LAY ABSTRACT: The challenge of finding autistic children, and finding them early enough to make a difference for them and their families, becomes all the greater in parts of the world where human and material resources are in short supply. Poverty of resources delays interventions, translating into a poverty of outcomes. Digital tools carry potential to lessen this delay because they can be administered by non-specialists in children's homes, schools or other everyday environments, they can measure a wide range of autistic behaviours objectively and they can automate analysis without requiring an expert in computers or statistics. This literature review aimed to identify and describe digital tools for screening children who may be at risk for autism. These tools are predominantly at the 'proof-of-concept' stage. Both portable (laptops, mobile phones, smart toys) and fixed (desktop computers, virtual-reality platforms) technologies are used to present computerised games, or to record children's behaviours or speech. Computerised analysis of children's interactions with these technologies differentiates children with and without autism, with promising results. Tasks assessing social responses and hand and body movements are the most reliable in distinguishing autistic from typically developing children. Such digital tools hold immense potential for early identification of autism spectrum disorder risk at a large scale. Next steps should be to further validate these tools and to evaluate their applicability in a variety of settings. Crucially, stakeholders from underserved communities globally must be involved in this research, lest it fail to capture the issues that these stakeholders are facing.

The effect of cumulative early life adversities, and their differential mediation through hair cortisol levels, on childhood growth and cognition: Three-year follow-up of a birth cohort in rural India.

Background: Early adversities negatively impact children's growth and development, putatively mediated by chronic physiological stress resulting from these adverse experiences. We aimed to estimate the associations between prospectively measured cumulative early adversities with growth and cognition outcomes in rural Indian preschool children and to explore if hair cortisol concentration (HCC), a measure of chronic physiological stress, mediated the above association. Methods: Participants were recruited from the SPRING cRCT in rural Haryana, India. Adversities experienced through pregnancy and the first year of life were measured in 1304 children at 12-months. HCC was measured at 12-months in 845 of them. Outcome measures were height-for-age-z-score (HAZ), weight-for-age-z-score (WAZ) and cognition, measured in 1124 children followed up at 3-years. Cognition was measured using a validated tablet-based gamified tool named DEEP. Results: Cumulative adversities at 12-months were inversely associated with all outcomes measures at 3-years. Each unit increase in adversity score led to a decrease of 0·08 units [95% confidence interval (CI):-0·11,-0·06] in DEEP-z-score; 0·12 units [-0·14,-0·09] in HAZ and 0·11 units [-0·13,-0·09] in WAZ. 12-month HCC was inversely associated with DEEP-z-score (-0·09 [-0·16,-0·01]) and HAZ (-0·12 [-0·20,-0·04]), but the association with WAZ was not significant (p = 0·142). HCC marginally mediated the association between cumulative adversities and HAZ (proportion mediated = 0·06, p = 0·014). No evidence of mediation was found for the cognition outcome. Conclusions: Cumulative early adversities and HCC measured at 12-months have persistent negative effects on child growth and cognition at 3-years. The association between adversities and these two child outcomes were differentially mediated by HCC, with no evidence of mediation observed for the cognitive outcome. Future studies should focus on other stress biomarkers, and alternate pathways such as the immune, inflammation and cellular ageing pathways, to unpack key mechanisms underlying the established relationship between early adversities and poor child outcomes.

Engineering of graphene quantum dots by varying the properties of graphene oxide for fluorescence detection of picric acid.

The study examines the effect of different forms of graphene oxide (GO) on the synthesis of graphene quantum dots (GQD). GO synthesized at various temperatures i.e. 30, 50, 110 °C possessed different structural and functional properties and was used as a substrate for GQD preparation. Thorough characterization of the GQDs in terms of their structural, morphological, functional, and optical properties was performed. The GQDs exhibited variation in their size and fluorescence properties depending upon the type of GO used. Hydrothermal reduction of GO, prepared at an oxidation temperature of 50 °C (GO-50), minimized the particle size (3.6 nm) and maximized the photoluminescence (PL) intensity and quantum yield (64.8%) of the GQD (GQD-50). GQD-50 was found to detect picric acid (PA) in an aqueous solution via 'turn-off' fluorescence quenching, unlike the other GQDs where the initial precursor is synthesized at 30, 110 °C. Experimental studies summarize that interaction between the fluorophore-quencher resulted in static quenching. The limit of detection was estimated to be 1.2 µM with a detection range of 0-200 µM. The work concludes that optimization of the substrate i.e. GO can result in the development of a simple, non-toxic, cost-effective GQD based sensor for PA detection. The study eliminates the need for doping/functionalization of GQDs as reported previously, and hence finds a promising impact on the development of sensors.

The Acceptability, Feasibility, and Utility of Portable Electroencephalography to Study Resting-State Neurophysiology in Rural Communities.

Electroencephalography (EEG) provides a non-invasive means to advancing our understanding of the development and function of the brain. However, the majority of the world's population residing in low and middle income countries has historically been limited from contributing to, and thereby benefiting from, such neurophysiological research, due to lack of scalable validated methods of EEG data collection. In this study, we establish a standard operating protocol to collect approximately 3 min each of eyes-open and eyes-closed resting-state EEG data using a low-cost portable EEG device in rural households through formative work in the community. We then evaluate the acceptability of these EEG assessments to young children and feasibility of administering them through non-specialist workers. Finally, we describe properties of the EEG recordings obtained using this novel approach to EEG data collection. The formative phase was conducted with 9 families which informed protocols for consenting, child engagement strategies and data collection. The protocol was then implemented on 1265 families. 977 children (Mean age = 38.8 months, SD = 0.9) and 1199 adults (Mean age = 27.0 years, SD = 4) provided resting-state data for this study. 259 children refused to wear the EEG cap or removed it, and 58 children refused the eyes-closed recording session. Hardware or software issues were experienced during 30 and 25 recordings in eyes-open and eyes-closed conditions respectively. Disturbances during the recording sessions were rare and included participants moving their heads, touching the EEG headset with their hands, opening their eyes within the eyes-closed recording session, and presence of loud sounds in the testing environment. Similar to findings in laboratory-based studies from high-income settings, the percentage of recordings which showed an alpha peak was higher in eyes-closed than eyes-open condition, with the peak occurring most frequently in electrodes at O1 and O2 positions, and the mean frequency of the alpha peak was found to be lower in children (8.43 Hz, SD = 1.73) as compared to adults (10.71 Hz, SD = 3.96). We observed a deterioration in the EEG signal with prolonged device usage. This study demonstrates the acceptability, feasibility and utility of conducting EEG research at scale in a rural low-resource community, while highlighting its potential limitations, and offers the impetus needed to further refine the methods and devices and validate such scalable methods to overcome existing research inequity.

KLF8 promotes invasive outgrowth of breast cancer by inducing filopodium-like protrusions via CXCR4.

Post-therapeutic relapse remains the biggest challenge to breast cancer management. The re-initiation of proliferation of dormant tumor cells in either metastatic or primary tumor location marks the final rate-limiting step of malignancy and mortality. The underlying molecular mechanisms remain poorly understood. We have recently demonstrated that KLF8 promotes breast cancer metastasis via CXCR4 upregulation. Here we report a role and mechanisms for KLF8 in driving the recurrence-like tumor outgrowth in both secondary and primary sites in a CXCR4-dependent manner. Treatment of an MDA-MB-231 breast cancer cell variant with the CXCR4 ligand, CXCL12, induces formation of filopodia in monolayer culture and filopodium-like protrusions (FLPs) in 3D culture. The FLP+ cells proliferate significantly faster than FLP- cells in the 3D culture supplemented with CXCL12. Both the FLP formation and enhanced proliferation in the 3D culture can be prevented by silencing KLF8 expression in the cells. From this prevention, the cells can be rescued by overexpressing wild-type CXCR4 but not its inactive mutant form in the cells. Overexpression of KLF8 or CXCR4 in the cells dramatically enhances their invasive outgrowth and metastasis after being implanted into immunocompromised mice. Mechanistically, we found that the activated FAK was recruited to the nascent FLPs and that proliferation of the cells was completely prevented with a FAK-specific inhibitor. Taken together, these results shed new light on the role of KLF8 in promoting breast cancer recurrence, the fatal episode of the disease, by inducing CXCR4-dependent FLP formation.

Advancements in visible light responsive MOF composites for photocatalytic decontamination of textile wastewater: A review.

Heterogeneous photocatalysis using metal-organic frameworks (MOFs) is expected to provide a pivotal solution for the remediation of toxic dyes and heavy metals from textile wastewater. However, MOFs often suffer from a low removal efficiency, due to the rapid recombination between holes and electrons, generated upon photoexcitation. Additionally, the MOFs exhibit poor water stability, which restricts their large-scale application. In this regard, various approaches (i.e. doping of metal nanoparticle, semiconductor, quantum dot, and ligand functionalization) have been adopted for the formation of multifunctional composites. The MOF-composites possess suitable photochemical, surface, optical, and electronic properties, resulting in enhanced water stability, visible light absorption, and reduced recombination between photogenerated species. This comprehensive review targets to provide an insight into the synthesis and subsequent application of various MOF composites for photocatalytic removal of organic contaminants (dyes) and inorganic (Cr(VI)) contaminants from water. MOFs/graphene oxide composites possess improved surface area and reusability whereas noble metal incorporated MOFs composites suffer from photocorrosion and are relatively costly. Zr and Ti based MOFs exhibit tuning from UV to visible light response and surpass the poor water stability upon binary/ternary composite formation. The role of the dopants in enhancing the efficiency of the composites; the effect of influencing factors such as solution pH, pollutant concentration; the mechanism, and the kinetics of reactions have been outlined. In spite of many advancements, the article also summarizes some roadblocks that need to be unraveled to achieve the energy-water-environment nexus and scope for future breakthrough research in this field.

Inhibition of estrogen signaling in myeloid cells increases tumor immunity in melanoma.

Immune checkpoint blockade (ICB) therapies have significantly prolonged patient survival across multiple tumor types, particularly in melanoma. Interestingly, sex-specific differences in response to ICB have been observed, with males receiving a greater benefit from ICB than females, although the mechanism or mechanisms underlying this difference are unknown. Mining published transcriptomic data sets, we determined that the response to ICBs is influenced by the functionality of intratumoral macrophages. This puts into context our observation that estrogens (E2) working through the estrogen receptor α (ERα) stimulated melanoma growth in murine models by skewing macrophage polarization toward an immune-suppressive state that promoted CD8+ T cell dysfunction and exhaustion and ICB resistance. This activity was not evident in mice harboring macrophage-specific depletion of ERα, confirming a direct role for estrogen signaling within myeloid cells in establishing an immunosuppressed state. Inhibition of ERα using fulvestrant, a selective estrogen receptor downregulator (SERD), decreased tumor growth, stimulated adaptive immunity, and increased the antitumor efficacy of ICBs. Further, a gene signature that determines ER activity in macrophages predicted survival in patients with melanoma treated with ICB. These results highlight the importance of E2/ER signaling as a regulator of intratumoral macrophage polarization, an activity that can be therapeutically targeted to reverse immune suppression and increase ICB efficacy.

The association of a novel digital tool for assessment of early childhood cognitive development, 'DEvelopmental assessment on an E-Platform (DEEP)', with growth in rural India: A proof of concept study.

BACKGROUND: There is an urgent need to fill the gap of scalable cognitive assessment tools for preschool children to enable identification of children at-risk of sub-optimal development and to support their timely referral into interventions. We present the associations between growth in early childhood, a well-established marker of cognitive development, and scores on a novel digital cognitive assessment tool called DEvelopmental Assessment on an E-Platform (DEEP) on a sample of 3-year old pre-schoolers from a rural region in north India. METHODS: Between February 2018 and March 2019, 1359 children from the Sustainable Programme Incorporating Nutrition and Games (SPRING) programme were followed up at 3-years age and data on DEEP, anthropometry and a clinical developmental assessment, the Bayley's Scale of Infant and Toddler Development, 3rd edition (BSID-III) was collected. DEEP data from 200 children was used to train a machine learning algorithm to predict their score on the cognitive domain of BSID-III. The DEEP score of the remaining 1159 children was then predicted using this algorithm to examine the cross-sectional and prospective association of growth with the DEEP score. FINDINGS: The magnitude of the concurrent positive association between height-for-age and cognitive z-scores in 3-year olds was similar when cognition was measured by BSID-III (0.20 standard deviations increase for every unit change in specifically age-adjusted height (HAZ), 95% CI = 0.06-0.35) and DEEP (0.26 CI, 0.11-0.41). A similar positive prospective relationship was found between growth at 18 (0.21 CI, 0.17-0.26) and 12-months (0.18 CI, 0.13-0.23) and DEEP score measured at 3-years. Additionally, the relationship between growth and cognitive development was found to be dependant on socioeconomic status (SES). INTERPRETATION: In this study, we suggest the utility of DEEP, a scalable, digital cognitive assessment tool, to measure cognition in preschool children. Further validation in different and larger datasets is necessary to confirm our findings. FUNDING: The SPRING Programme was funded through a Wellcome Trust programme grant and the follow-up study by the Corporate Social Responsibility initiative grant from Madura Microfinance Ltd.

Role of krüppel-like factor 8 for therapeutic drug-resistant multi-organ metastasis of breast cancer.

Metastasis and drug resistance are intertwined processes that are responsible for the vast majority of patient deaths from breast cancer. The underlying mechanisms remain incompletely understood. We previously demonstrated that KLF8 activates CXCR4 transcription in metastatic breast cancer. Here, we report a novel role of KLF8-CXCR4 signaling for converting single organ metastasis into multiple organ metastasis associated with chemotherapeutic resistance. We show that KLF8 expression in metastatic breast cancer cells can be over-induced by chemotherapeutic drugs. Analysis of data from large-cohorts of patients indicates that post-chemotherapy there is a close correlation between the aberrant high levels of KLF8 and CXCR4 and that this correlation is well associated with drug resistance, metastasis, and poor prognosis. To mimic their aberrant high levels, we overexpressed KLF8 or CXCR4 in a human breast cancer cell line known to metastasize only to the lungs after intravenous injection in nude mice. As expected, these cells become more resistant to chemotherapeutic drugs. Surprisingly, these KLF8 or CXCR4 overexpressing cells, even implanted orthotopically, metastasized extensively to multiple organs particularly the CXCL12-rich organs. Tube formation assay, Ki67 staining and Western blotting revealed that KLF8 or CXCR4 overexpression enhanced angiogenesis involving increased expression and secretion of VEGF protein. We also found that KLF8 or CXCR4 overexpression strongly enhanced formation of filopodium-like protrusions and proliferation via CXCR4 stimulation in a 3D culture model mimicking the colonization step of metastasis. Taken together, these results suggest that the chemo-induction of KLF8 upregulation be critical for drug resistance and systemic metastasis through enhanced tumor angiogenesis and colonization via CXCR4 over-activation and that KLF8-CXCR4 signaling axis may be a new therapeutic target for drug-resistant breast cancer metastasis.

Potential Anti-leishmanial Activity of a Semi-purified Fraction Isolated from the Leaves of Parthenium hysterophorus.

PURPOSE: In the present perspective, emergence of resistant strains of Leishmania donovani and severe side effects resulting from the use of conventional anti-leishmanial therapies present an urgent need for developing novel agents against this parasite. We have explored the effectiveness of secondary plant metabolites as alternative choices in the treatment for visceral leishmaniasis (vl). METHODS: The plant Parthenium hysterophorus L. (Asteraceae) was collected from the West Bengal State University Campus, Barasat, West Bengal, India. The leaves of this plant were extracted by different solvents, such as ethyl acetate, water, petroleum ether and hexane. Gas chromatography-mass spectrometry (GC-MS) analysis was also carried out for the identification of compounds in the hexane soluble fraction (PHFd) with substantial anti-leishmanial activities. The antipromastigote activity and cytotoxicity of this fraction were evaluated by the tetrazolium MTT assay. Other biochemical and physiological parameters were studied by microscopic observation and flow cytometric analyses. RESULTS: PHFd showed considerable activity against L. donovani promastigotes (IC50: 20 µg/ml). The PHFd also inhibited in vitro growth of L. major LV39 promastigotes dose dependently with an IC50 of 40 µg/ml. The GC-MS studies of this particular fraction revealed the presence of four major compounds with different retention times (RT) of 26.08, 33.11, 36.41, and 41.20 min. In this study, we also established that PHFd could induce DNA damage and subsequent apoptosis of L. donovani promastigotes with a concomitant increase in generations of reactive oxygen species (ROS) in a time-dependent manner. This fraction was also found to be effective in nitric oxide-mediated inhibition of intracellular amastigotes (IC50:12.5 µg/ml) without any noticeable cytotoxicity towards murine splenocytes in vitro. CONCLUSION: This study provides the basis for additional phytochemical and pharmacological studies on the antiprotozoal applications of P. hysterophorus.

Engineering of Interfacial Energy Bands for Synthesis of Photoluminescent 0D/2D Coupled MOF Heterostructure with Enhanced Selectivity toward the Proton-Exchange Membrane.

Engineering of the interface for tuning the structural, functional, and electronic properties of materials via the formation of heterostructure composites exhibits immense potential in the current research scenario. This study reports a novel ternary composite synthesized by decoration of zero-dimensional Pd nanoparticles (NPs) and two-dimensional (2D) graphite oxide (GO) sheets in the UiO-66 metal-organic framework (MOF). A mixed matrix membrane was fabricated by incorporating this composite in the SPEEK polymer matrix, which exhibited higher selectivity compared to commercial Nafion 117. The synthesized composite and fabricated membranes were thoroughly characterized in terms of their chemical structures, microstructural morphologies, physicochemical, thermal, photo-electrochemical, and optical properties, ion-exchange capacity, proton conductivity, and methanol permeability. As per our knowledge, this is the first study which explores the effect of noble metal NPs and carbon 2D material simultaneously on the electronic structure of the MOF, resulting in improved selectivity. The electron-accepting nature of GO and surface plasmon resonance effect of Pd alter the energy band positions and scavenge the electrons, improving the proton conduction of the composite. The introduction of oxygen vacancies in lattice leads to efficient charge separation. The formation of a Schottky junction results in the localized electric field effect due to electron density fluctuation which aids in ion transport. The current study opens up a new route to overcome the major challenge associated with direct methanol fuel cells (DMFCs), that is, high/low methanol crossover by improving the proton conduction.

Targeting the Trypanothione Reductase of Tissue-Residing Leishmania in Hosts' Reticuloendothelial System: A Flexible Water-Soluble Ferrocenylquinoline-Based Preclinical Drug Candidate.

Since inception, the magic bullets developed against leishmaniasis traveled a certain path and then dropped down due to either toxicity or the emergence of resistance. The route of administration is also an important concern. We developed a series of water-soluble ferrocenylquinoline derivatives, targeting Leishmania donovani, among which CQFC1 showed the highest efficacy even in comparison to other drugs, in use or used, both in oral and intramuscular routes. It did not induce any toxicity to splenocytes and on hematopoiesis, induced protective cytokines, and did not hamper the drug-metabolizing enzymes in hosts. It acts through the reduction and the inhibition of parasites' survival enzyme trypanothione reductase of replicating amastigotes in hosts' reticuloendothelial tissues. Unlike conventional drugs, this molecule did not induce the resistance-conferring genes in laboratory-maintained resistant L. donovani lines. Experimentally, this easily bioavailable preclinical drug candidate overcame all of the limitations causing the discontinuation of the other conventional antileishmanial drugs.