Publications by authors named "Sumana Chakravarty"

107 Publications

A Mosquito Pick-and-Place System for PfSPZ-based Malaria Vaccine Production.

IEEE Trans Autom Sci Eng 2021 Jan 19;18(1):299-310. Epub 2020 May 19.

H. Phalen, P. Vagdargi, G. S. Chirikjian, I. Iordachita, and R. H. Taylor are with the Laboratory for Computational Sensing and Robotics (LCSR) at the Johns Hopkins University in Baltimore, MD, USA. Previously, M. L. Schrum, A. Canezin, M. Pozin, and S. Coemert were also with the LCSR. Now, M. L. Schrum is with Georgia Tech, A. Canezin is with Accenture, M. Pozin is with Auris Health, and S. Coemert is with the Technical University of Munich. G. S. Chirikjian is currently at the National University of Singapore, Department of Mechanical Engineering, 117575, Singapore. S. Chakravarty and S. L. Hoffman are with Sanaria, Inc. in Rockville, MD, USA.

The treatment of malaria is a global health challenge that stands to benefit from the widespread introduction of a vaccine for the disease. A method has been developed to create a live organism vaccine using the sporozoites (SPZ) of the parasite (Pf), which are concentrated in the salivary glands of infected mosquitoes. Current manual dissection methods to obtain these PfSPZ are not optimally efficient for large-scale vaccine production. We propose an improved dissection procedure and a mechanical fixture that increases the rate of mosquito dissection and helps to deskill this stage of the production process. We further demonstrate the automation of a key step in this production process, the picking and placing of mosquitoes from a staging apparatus into a dissection assembly. This unit test of a robotic mosquito pick-and-place system is performed using a custom-designed micro-gripper attached to a four degree of freedom (4-DOF) robot under the guidance of a computer vision system. Mosquitoes are autonomously grasped and pulled to a pair of notched dissection blades to remove the head of the mosquito, allowing access to the salivary glands. Placement into these blades is adapted based on output from computer vision to accommodate for the unique anatomy and orientation of each grasped mosquito. In this pilot test of the system on 50 mosquitoes, we demonstrate a 100% grasping accuracy and a 90% accuracy in placing the mosquito with its neck within the blade notches such that the head can be removed. This is a promising result for this difficult and non-standard pick-and-place task.

Note To Practitioners—: Automated processes could help increase malaria vaccine production to global scale. Currently, production requires technicians to manually dissect mosquitoes, a process that is slow, tedious, and requires a lengthy training regimen. This paper presents an an improved manual fixture and procedure that reduces technician training time. Further, an approach to automate this dissection process is proposed and the critical step of robotic manipulation of the mosquito with the aid of computer vision is demonstrated. Our approach may serve as a useful example of system design and integration for practitioners that seek to perform new and challenging pick-and-place tasks with small, non-uniform, and highly deformable objects.
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http://dx.doi.org/10.1109/tase.2020.2992131DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7978227PMC
January 2021

Proteome profile of telencephalon associates attenuated neurogenesis with chronic stress induced mood disorder phenotypes in zebrafish model.

Pharmacol Biochem Behav 2021 May 5;204:173170. Epub 2021 Mar 5.

Applied Biology, CSIR-Indian Institute of Chemical Technology (IICT), Tarnaka, Uppal Road, Hyderabad 500007, India; Academy of Scientific and Industrial Research, Ghaziabad 201002, India. Electronic address:

Debilitating mental illness like depression and related mood disorders is due to the disruption in circuitry that controls emotion, motivation, and reward, characterized by disparate phenotypes like decrease in socialization, motivation, threshold for threat apprehension, etc. Chronic stress is a major factor in the etiology of these disorders. Here, using a chronic unpredictable stress (CUS) paradigm the characterization of an array of mood disorder phenotypes in adult zebrafish, in comparison to normal control unstressed fish, was achieved using a battery of behavioral assays including novel ones comprising social interaction test, feed approach test, threat response test and novel tank test. For the predictive validity of the model for mood disorders, the mitigative role of a slow (imipramine) and fast (ketamine) acting antidepressant was assessed. The molecular changes associated with CUS-induced mood disorder phenotype was investigated utilizing a high throughput method called isobaric tag for relative and absolute quantification (iTRAQ) in telencephalon, the region critically associated with the processing of emotional information in the fish brain. Out of 222 proteins identified to be significantly altered, 58 were differentially expressed across the stress and antidepressant-treatment groups at more than one fold (in log2) change. Of these proteins, some were implicated in earlier studies on mood disorders such as CABP1, PER2, mTOR, etc. The enrichment of altered proteins by Ingenuity Pathway Analysis (IPA) led us to mTOR and opioid signaling pathways, the top canonical pathways affected in the fish telencephalon. Interestingly, most of the pathways affected converge at the one controlling cell proliferation thus indicating altered neurogenesis, which was validated using immunohistochemistry for cell proliferation markers BrdU, SOX2, and BLBP. The study concludes that molecules that regulate telencephalon neural progenitor cell proliferation or neurogenesis are crucially involved in chronic stress-induced mood disorders by affecting the circuitry that controls emotion and reward.
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http://dx.doi.org/10.1016/j.pbb.2021.173170DOI Listing
May 2021

Therapeutic angiogenesis using zinc oxide nanoflowers for the treatment of hind limb ischemia in rat model.

Biomed Mater 2021 Mar 3. Epub 2021 Mar 3.

Biomaterials Group, LST Division, CSIR-Indian Institute of Chemical Technology, Uppal Road, Tarnaka, Hyderabad 500007, AP, Hyderabad, Andhra Pradesh, 500007, INDIA.

Critical limb ischemia (CLI) is considered as a severe type of peripheral artery diseases (PADs) which occurs due to the inadequate supply of blood to the limb extremities. CLI patients often suffer from extreme cramping pain, impaired wound healing, immobility, cardiovascular complications, amputation of the affected limb and even death. The conventional therapy for the treatment of CLI includes surgical revascularization as well as restoring angiogenesis using growth factor therapy. However, surgical revascularization is suitable for only a minor percentage of CLI patients and it is associated with high perioperative mortality rate. The use of growth factors is also limited in terms of their poor therapeutic angiogenesis potential as observed by the earlier clinical studies, which could be attributed to their poor bio-availability and non-specificity issues. Therefore, to outweigh the aforesaid disadvantages of the conventional strategies, there is an utmost need for the advancement of new alternative therapeutic biomaterials to treat CLI. Since past few decades, various research groups including ours have been involved in developing different pro-angiogenic nanomaterials. Among them, zinc oxide nanoflowers (ZONF), established in our laboratory, are considered as one of the potent nanoparticles to induce therapeutic angiogenesis. In our earlier studies, we have depicted that ZONF promote angiogenesis by inducing the formation of reactive oxygen species (ROS) and nitric oxide (NO) as well as activating Akt/MAPK/eNOS cell signaling pathways in the endothelial cells. Recently, we have also reported the therapeutic potential of ZONF to treat cerebral ischemia through their neuritogenic and neuroprotective properties, exploiting angio-neural cross talk. Considering the excellent pro-angiogenic properties of ZONF and importance of revascularization for the recovery of CLI, in this present study, we have comprehensively explored the therapeutic potential of ZONF in a rat hind limb ischemia model (established by ligating the femoral artery of hind limb), an animal model that mimics CLI in humans. The behavioural studies, laser Doppler perfusion imaging, histopathology, immunofluorescence as well as estimation of serum NO level depicted that the administration of ZONF could ameliorate the ischemic conditions in rats at a faster rate by promoting therapeutic angiogenesis to the ischemic sites. Altogether, the present study offers an alternative nanomedicine approach employing ZONF for the treatment of PADs.
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http://dx.doi.org/10.1088/1748-605X/abebd1DOI Listing
March 2021

Gene Expression Analysis Identifies Cholesterol Metabolism Dysregulation in Hippocampus of Phenytoin-Resistant Pentylenetetrazol-Kindled Epileptic Mice.

Neuromolecular Med 2021 Feb 18. Epub 2021 Feb 18.

Epigenetics & Neuropsychiatric Disorders Laboratory, CSIR-Centre for Cellular and Molecular Biology (CCMB), Uppal Road, Habsiguda, Hyderabad, Telangana State, 500007, India.

Pharmaco-resistant Epilepsy has been a major challenge for medical interventions in controlling seizures. To date, up to 33% of the patients with epilepsy do not show adequate response to anti-epileptic drugs even after prolonged combinatorial drug usage. Using microarray, this study explores the changes in hippocampal gene expression in the phenytoin-resistant pentylenetetrazol (PTZ)-kindled mouse model of epilepsy. Our results from mRNA microarray analysis show distinct gene expression profiles in the hippocampus of phenytoin-resistant and sensitive mice. Pathway enrichment analysis showed differential expression of genes involved in cholesterol biosynthesis in phenytoin-resistant and sensitive mice.
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http://dx.doi.org/10.1007/s12017-021-08648-0DOI Listing
February 2021

Atypical B cells are part of an alternative lineage of B cells that participates in responses to vaccination and infection in humans.

Cell Rep 2021 Feb;34(6):108684

Department of Immunology and Infectious Disease, John Curtin School of Medical Research, The Australian National University, Canberra, ACT 2601, Australia. Electronic address:

The diversity of circulating human B cells is unknown. We use single-cell RNA sequencing (RNA-seq) to examine the diversity of both antigen-specific and total B cells in healthy subjects and malaria-exposed individuals. This reveals two B cell lineages: a classical lineage of activated and resting memory B cells and an alternative lineage, which includes previously described atypical B cells. Although atypical B cells have previously been associated with disease states, the alternative lineage is common in healthy controls, as well as malaria-exposed individuals. We further track Plasmodium-specific B cells after malaria vaccination in naive volunteers. We find that alternative lineage cells are primed after the initial immunization and respond to booster doses. However, alternative lineage cells develop an atypical phenotype with repeated boosts. The data highlight that atypical cells are part of a wider alternative lineage of B cells that are a normal component of healthy immune responses.
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http://dx.doi.org/10.1016/j.celrep.2020.108684DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7873835PMC
February 2021

Silver Prussian Blue Analogue Nanoparticles: Rationally Designed Advanced Nanomedicine for Multifunctional Biomedical Applications.

ACS Biomater Sci Eng 2020 01 30;6(1):690-704. Epub 2019 Dec 30.

Department of Applied Biology, CSIR-Indian Institute of Chemical Technology, Uppal Road, Tarnaka, Hyderabad 500007, Telangana State, India.

The development of simple, cost-effective, and advanced multifunctional technology is the need of the hour to combat cancer as well as bacterial infections. There have been reports of silver nanoparticles (AgNPs), silver salts, and Prussian blue (PB) being used for medicinal purposes which are clinically approved. In this context, in the present communication, we incorporated PB and silver salts (silver nitrate) to develop silver PB analogue nanoparticles (SPBANPs), a new nanomedicine formulation as a safer and effective mode of treatment strategy (2-in-1) for both cancer and bacterial infections. Considering all fundamental issues of nanomedicine, along with understanding of the biological impact of PB, we designed a simple, fast, efficient, cheap, and eco-friendly method for the synthesis of [poly(-vinyl-2-pyrrolidone)]-stabilized silver hexacyanoferrate nanoparticles (silver PB analogue: Ag[Fe(CN)] abbreviated as SPBANPs). Various analytical tools were used to analyze and characterize the nanomaterials (SPBANPs). The SPBANPs were highly stable for several weeks in various phosphate buffers with a range of physiological pH conditions (pH = 6-8). The nanoparticles showed biocompatibility in vivo in C57BL6/J mice that encouraged us to screen the nanoparticles for various biomedical applications. The SPBANPs themselves exhibited remarkable inhibition of cancer cell proliferation (B16F10, A549, MCF-7, and SK-OV-3) in vitro. Substantial inhibition of melanoma tumor growth was observed in the C57BL6/J mouse model (aggressive murine melanoma model: B16F10) after intraperitoneal administration of the SPBANPs without any anticancer drug. Additionally, the SPBANPs exhibited excellent antibacterial activity in various Gram-negative (, , and ) and Gram-positive () bacteria. Interestingly, this nanoformulation itself works as a drug delivery vehicle, as well as an anticancer and antibacterial agent. The in vitro and in vivo results together demonstrate that this biocompatible nanoformulation (SPBANPs) without an anticancer drug or antibiotic could be explored to develop as a multifunctional therapeutic agent (2-in-1) for the treatment of cancer and bacterial infections in the near future.
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http://dx.doi.org/10.1021/acsbiomaterials.9b01693DOI Listing
January 2020

Differential modulation of GR signaling and HDACs in the development of resilient/vulnerable phenotype and antidepressant-like response of vorinostat.

Psychoneuroendocrinology 2021 Feb 1;124:105083. Epub 2020 Dec 1.

Applied Biology Division, CSIR- Indian Institute of Chemical Technology (IICT), Hyderabad 500007, Telangana, India. Electronic address:

The present study explored the antidepressant potential of vorinostat (VOR) against chronic social defeat stress (CSDS) in mice. Since this model has the remarkable capacity to delineate the resilient and the defeated mice, we also looked for their molecular deviations. Defeated mice showed classical phenotypic alterations such as anhedonia, social avoidance, anxiety and despair. Whereas, resilient mice were immune to the development of those. Both defeated and resilient mice demonstrated marked CORT elevation in blood. Development of resilience vs. defeat to CSDS was found to be associated with the differential nuclear levels of GR, HDAC3 and HDAC6 in the hippocampus. Activation of a stress responsive adaptive mechanism involving these mediators at the nuclear level might be offering resilience while maladaptive mechanisms leading to defeat. Interestingly, an elevated hippocampal HDAC6 level in defeated mice was also observed, which was restored by VOR treatment. Further studies will be necessary to delineate the HDAC6 associated antidepressant mechanisms. As HDAC3 and HDAC6 are crucial mediators of GR signaling, further molecular studies may aid in understanding the basis of development of resilience to target MDD with new prospective.
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http://dx.doi.org/10.1016/j.psyneuen.2020.105083DOI Listing
February 2021

Histone Lysine Demethylase JMJD2D/KDM4D and Family Members Mediate Effects of Chronic Social Defeat Stress on Mouse Hippocampal Neurogenesis and Mood Disorders.

Brain Sci 2020 Nov 9;10(11). Epub 2020 Nov 9.

Epigenetics & Neuropsychiatric Disorders Laboratory, CSIR-Centre for Cellular and Molecular Biology (CCMB), Uppal Road, Habsiguda, Hyderabad, Telangana 500007, India.

Depression, anxiety and related mood disorders are major psychiatric illnesses worldwide, and chronic stress appears to be one of the primary underlying causes. Therapeutics to treat these debilitating disorders without a relapse are limited due to the incomplete molecular understanding of their etiopathology. In addition to the well-studied genetic component, research in the past two decades has implicated diverse epigenetic mechanisms in mediating the negative effects of chronic stressful events on neural circuits. This includes the cognitive circuitry, where the dynamic hippocampal dentate gyrus (DG) neurogenesis gets affected in depression and related affective disorders. Most of these epigenetic studies have focused on the impact of acetylation/deacetylation and methylation of several histone lysine residues on neural gene expression. However, there is a dearth of investigation into the role of demethylation of these lysine residues in chronic stress-induced changes in neurogenesis that results in altered behaviour. Here, using the chronic social defeat stress (CSDS) paradigm to induce depression and anxiety in C57BL/6 mice and DG neural stem/progenitor cell (NSCs/NPCs) culture we show the role of the members of the JMJD2/KDM4 family of histone lysine demethylases (KDMs) in mediating stress-induced changes in DG neurogenesis and mood disorders. The study suggests a critical role of JMJD2D in DG neurogenesis. Altered enrichment of JMJD2D on the promoters of (inhibitor of differentiation 2) and (SRY-Box Transcription Factor 2) was observed during proliferation and differentiation of NSCs/NPCs obtained from the DG. This would affect the demethylation of repressive epigenetic mark H3K9, thus activating or repressing these and possibly other genes involved in regulating proliferation and differentiation of DG NSCs/NPCs. Treatment of the NSCs/NPCs culture with Dimethyloxallyl Glycine (DMOG), an inhibitor of JMJDs, led to attenuation in their proliferation capacity. Additionally, systemic administration of DMOG in mice for 10 days induced depression-like and anxiety-like phenotype without any stress exposure.
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http://dx.doi.org/10.3390/brainsci10110833DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7695311PMC
November 2020

Multidose Priming and Delayed Boosting Improve PfSPZ Vaccine Efficacy against Heterologous P. falciparum Controlled Human Malaria Infection.

Clin Infect Dis 2020 Sep 12. Epub 2020 Sep 12.

Naval Medical Research Center Malaria Department, Silver Spring, MD.

Background: A live-attenuated Plasmodium falciparum (Pf) sporozoite (SPZ) vaccine (PfSPZ Vaccine) has shown up to 100% protection against controlled human malaria infection (CHMI) using homologous parasites (same Pf strain as in the vaccine). Using a more stringent CHMI, with heterologous parasites (different Pf strain), we assessed the impact of higher PfSPZ doses, a novel multi-dose prime regimen, and a delayed vaccine boost upon vaccine efficacy.

Methods: Four groups of 15 healthy, malaria-naïve adults were immunized. Group (Grp) 1 received five doses of 4.5x10 5 PfSPZ (days 1, 3, 5, 7; week 16). Grps 2, 3 and 4 received three doses (weeks 0, 8, 16) with Gp 2 receiving 9.0×10 5/dose, Grp 3 receiving 18.0×10 5/dose, and Grp 4 receiving 27.0×10 5 for dose 1 and 9.0×10 5 for doses 2 and 3. VE was assessed by heterologous CHMI after 12 or 24 weeks. Volunteers not protected at 12 weeks were boosted prior to repeat CHMI at 24 weeks.

Results: At 12-week CHMI, 6/15 (40%) Group 1 (P=0.04), 3/15 (20%) Group 2 vs. 0/8 controls remained aparasitemic. At 24-week CHMI, 3/13 (23%) Group 3, 3/14 (21%) Group 4 vs. 0/8 controls remained aparasitemic (Groups 2-4, VE not significant). Post-boost, 9/14 (64%) vs. 0/8 controls remained aparasitemic (3/6 Group 1, P=0.025; 6/8 Group 2, P=0.002).

Conclusions: Four stacked, priming injections (multi-dose priming) showed 40% VE against heterologous CHMI, while dose escalation of PfSPZ using single dose priming was not significantly protective. Boosting unprotected subjects improved VE at 24 weeks to 64%.
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http://dx.doi.org/10.1093/cid/ciaa1294DOI Listing
September 2020

Molecular Basis of Sex Difference in Neuroprotection induced by Hypoxia Preconditioning in Zebrafish.

Mol Neurobiol 2020 Dec 29;57(12):5177-5192. Epub 2020 Aug 29.

Applied Biology, CSIR-Indian Institute of Chemical Technology (IICT), Hyderabad, India.

Hypoxia, the major cause of ischemic injury, leads to debilitating disease in infants via birth asphyxia and cerebral palsy, whereas in adults via heart attack and stroke. A widespread, natural protective phenomenon termed 'hypoxic preconditioning' (PH) occurs when prior exposures to hypoxia eventually result in robust hypoxia resistance. Accordingly, we have developed and optimized a novel model of hypoxic preconditioning in adult zebrafish to mimic the tolerance of mini stroke(s) in human, which appears to protect against the severe damage inflicted by a major stroke event. Here, we observed a remarkable difference in the progression pattern of neuroprotection between preconditioning hypoxia followed by acute hypoxia (PH) group, and acute hypoxia (AH) only group, with noticeable sex difference when compared with normoxia behaviour upon recovery. Since gender difference has been reported in stroke risk factors and disease history, it was pertinent to investigate whether any such sex difference also exists in PH's protective mechanism against acute ischemic stroke. In order to elucidate the neural molecular mechanisms behind sex difference in neuroprotection induced by PH, a high throughput proteomics approach utilizing iTRAQ was performed, followed by protein enrichment analysis using ingenuity pathway analysis (IPA) tool. Out of thousands of significantly altered proteins in zebrafish brain, the ones having critical role either in neuroglial proliferation/differentiation or neurotrophic functions were validated by analyzing their expression levels in preconditioned (PH), acute hypoxia (AH), and normoxia groups. The data indicate that female zebrafish brains are more protected against the severity of AH when exposed to the hypoxic preconditioning. The study also sheds light on the involvement of many signalling pathways underlying sex difference in preconditioning-induced neuroprotective mechanism, which can be further validated for the therapeutic approach.
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http://dx.doi.org/10.1007/s12035-020-02091-1DOI Listing
December 2020

Rapid acting antidepressants in the mTOR pathway: Current evidence.

Brain Res Bull 2020 10 31;163:170-177. Epub 2020 Jul 31.

Applied Biology Division, CSIR- Indian Institute of Chemical Technology, Tarnaka, Uppal Road, Hyderabad, 500007, India. Electronic address:

Despite the growing burden of major depressive disorder (MDD) on the society, therapeutic management that is mostly based on the conventional monoaminergic mechanisms, is significantly delimited especially from low response rate and time lag for treatment response; thus, often prolonging the distress for patients. The mechanistic exploration of drug candidates that could exert antidepressant effects rapidly has highlighted the significance of modulating mammalian target of rapamycin (mTOR) pathway in MDD. Fast acting antidepressants acts at different receptors, subunits and sites, including NMDA, AMPA, m1ACh, mGluR2/3 and GluN2B to enhance mTOR function, leading to increase in synaptic protein synthesis, synaptogenesis and spine-remodeling, which in turn contribute to the rapid antidepressant effects. This review focuses on the preclinical and clinical evidences on the fast acting antidepressants that can modulate mTOR pathway. It can be understood that modulating mTOR pathway for rapid onset of antidepressant effect in MDD is not without challenges as some of the drugs have failed in advanced stages of clinical trials. However, considering the recent approval of esketamine as a breakthrough in decades, fast acting antidepressants in the mTOR pathway may have promising prospects in the drug discovery pipeline.
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http://dx.doi.org/10.1016/j.brainresbull.2020.07.022DOI Listing
October 2020

Antibody Feedback Limits the Expansion of B Cell Responses to Malaria Vaccination but Drives Diversification of the Humoral Response.

Cell Host Microbe 2020 10 21;28(4):572-585.e7. Epub 2020 Jul 21.

Department of Immunology and Infectious Disease, John Curtin School of Medical Research, the Australian National University, Canberra, ACT 2601, Australia. Electronic address:

Generating sufficient antibody to block infection is a key challenge for vaccines against malaria. Here, we show that antibody titers to a key target, the repeat region of the Plasmodium falciparum circumsporozoite protein (PfCSP), plateaued after two immunizations in a clinical trial of the radiation-attenuated sporozoite vaccine. To understand the mechanisms limiting vaccine responsiveness, we developed immunoglobulin (Ig)-knockin mice with elevated numbers of PfCSP-binding B cells. We determined that recall responses were inhibited by antibody feedback, potentially via epitope masking of the immunodominant PfCSP repeat region. Importantly, the amount of antibody that prevents boosting is below the amount of antibody required for protection. Finally, while antibody feedback limited responses to the PfCSP repeat region in vaccinated volunteers, potentially protective subdominant responses to PfCSP C-terminal regions expanded with subsequent boosts. These data suggest that antibody feedback drives the diversification of immune responses and that vaccination for malaria will require targeting multiple antigens.
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http://dx.doi.org/10.1016/j.chom.2020.07.001DOI Listing
October 2020

Advances in histone deacetylase inhibitors in targeting glioblastoma stem cells.

Cancer Chemother Pharmacol 2020 08 7;86(2):165-179. Epub 2020 Jul 7.

CSIR-Centre for Cellular and Molecular Biology, Habsiguda, Uppal Road, Hyderabad, 500007, Telangana, India.

Glioblastoma multiforme (GBM) is a lethal grade IV glioma (WHO classification) and widely prevalent primary brain tumor in adults. GBM tumors harbor cellular heterogeneity with the presence of a small subpopulation of tumor cells, described as GBM cancer stem cells (CSCs) that pose resistance to standard anticancer regimens and eventually mediate aggressive relapse or intractable progressive GBM. Existing conventional anticancer therapies for GBM do not target GBM stem cells and are mostly palliative; therefore, exploration of new strategies to target stem cells of GBM has to be prioritized for the development of effective GBM therapy. Recent developments in the understanding of GBM pathophysiology demonstrated dysregulation of epigenetic mechanisms along with the genetic changes in GBM CSCs. Altered expression/activity of key epigenetic regulators, especially histone deacetylases (HDACs) in GBM stem cells has been associated with poor prognosis; inhibiting the activity of HDACs using histone deacetylase inhibitors (HDACi) has been promising as mono-therapeutic in targeting GBM and in sensitizing GBM stem cells to an existing anticancer regimen. Here, we review the development of pan/selective HDACi as potential anticancer agents in targeting the stem cells of glioblastoma as a mono or combination therapy.
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http://dx.doi.org/10.1007/s00280-020-04109-wDOI Listing
August 2020

Potential Therapeutic Application of Zinc Oxide Nanoflowers in the Cerebral Ischemia Rat Model through Neuritogenic and Neuroprotective Properties.

Bioconjug Chem 2020 03 25;31(3):895-906. Epub 2020 Feb 25.

Department of Applied Biology, CSIR-Indian Institute of Chemical Technology, Uppal Road, Tarnaka, Hyderabad 500007, India.

Neuritogenesis, a complex process of the sprouting of neurites, plays a vital role in the structural and functional restoration of cerebral ischemia-injured neuronal tissue. Practically, there is no effective long-term treatment strategy for cerebral ischemia in clinical practice to date due to several limitations of conventional therapies, facilitating the urgency to develop new alternative therapeutic approaches. Herein, for the first time we report that pro-angiogenic nanomaterials, zinc oxide nanoflowers (ZONF), exhibit neuritogenic activity by elevating mRNA expression of different neurotrophins, following PI3K/Akt-MAPK/ERK signaling pathways. Further, ZONF administration to global cerebral ischemia-induced Fischer rats shows improved neurobehavior and enhanced synaptic plasticity of neurons via upregulation of Neurabin-2 and NT-3, revealing their neuroprotective activity. Altogether, this study offers the basis for exploitation of angio-neural cross talk of other pro-angiogenic nano/biomaterials for future advancement of alternative treatment strategies for cerebral ischemia, where neuritogenesis and neural repair are highly critical.
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http://dx.doi.org/10.1021/acs.bioconjchem.0c00030DOI Listing
March 2020

Improved delivery of doxorubicin using rationally designed PEGylated platinum nanoparticles for the treatment of melanoma.

Mater Sci Eng C Mater Biol Appl 2020 Mar 5;108:110375. Epub 2019 Nov 5.

Department of Applied Biology, CSIR-Indian Institute of Chemical Technology, Uppal Road, Tarnaka, Hyderabad, 500007, Telangana State, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India. Electronic address:

Efficient delivery of chemotherapeutic drugs to tumor cells is one of the crucial issues for modern day cancer therapy. In this article, we report the synthesis of poly ethylene glycol (PEG) assisted colloidal platinum nanoparticles (PtNPs) by borohydride reduction method at room temperature. PtNPs are stable at room temperature for more than 2 years and are stable in serum and phosphate buffer (pH = 7.4) solution for one week. PtNPs show biocompatibility in different normal cell lines (in vitro) and chicken egg embryonic model (ex vivo). Further, we designed and fabricated PtNPs-based drug delivery systems (DDS: PtNPs-DOX) using doxorubicin (DOX), a FDA approved anticancer drug. Various analytical techniques were applied to characterize the nanomaterials (PtNPs) and DDS (PtNPs-DOX). This DDS exhibits inhibition of cancer cell (B16F10 and A549) proliferation, observed by different in vitro assays. PtNPs-DOX induces apoptosis in cancer cells observed by annexin-V staining method. Intraperitoneal (IP) administration of PtNPs-DOX shows substantial reduction of tumor growth in subcutaneous murine melanoma tumor model compared to control group with free drug. Up-regulation of tumor suppressor protein p53 and down regulation of SOX2 and Ki-67 proliferation markers in melanoma tumor tissues (as observed by immunofluorescence and western blot analysis) indicates probable molecular mechanism for the anticancer activity of DDS. Considering the in vitro and pre-clinical (in vivo) results in murine melanoma, it is believed that platinum nanoparticle-based drug delivery formulation could be exploited to develop an alternative therapeutic nanomedicine for cancer therapy in the near future.
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http://dx.doi.org/10.1016/j.msec.2019.110375DOI Listing
March 2020

Increase of Dose Associated With Decrease in Protection Against Controlled Human Malaria Infection by PfSPZ Vaccine in Tanzanian Adults.

Clin Infect Dis 2020 Dec;71(11):2849-2857

Sanaria Inc., Rockville, Maryland, USA.

Background: A vaccine would be an ideal tool for reducing malaria's impact. PfSPZ Vaccine (radiation attenuated, aseptic, purified, cryopreserved Plasmodium falciparum [Pf] sporozoites [SPZ]) has been well tolerated and safe in >1526 malaria-naive and experienced 6-month to 65-year-olds in the United States, Europe, and Africa. When vaccine efficacy (VE) of 5 doses of 2.7 × 105 PfSPZ of PfSPZ Vaccine was assessed in adults against controlled human malaria infection (CHMI) in the United States and Tanzania and intense field transmission of heterogeneous Pf in Mali, Tanzanians had the lowest VE (20%).

Methods: To increase VE in Tanzania, we increased PfSPZ/dose (9 × 105 or 1.8 × 106) and decreased numbers of doses to 3 at 8-week intervals in a double blind, placebo-controlled trial.

Results: All 22 CHMIs in controls resulted in parasitemia by quantitative polymerase chain reaction. For the 9 × 105 PfSPZ group, VE was 100% (5/5) at 3 or 11 weeks (P < .000l, Barnard test, 2-tailed). For 1.8 × 106 PfSPZ, VE was 33% (2/6) at 7.5 weeks (P = .028). VE of dosage groups (100% vs 33%) was significantly different (P = .022). Volunteers underwent repeat CHMI at 37-40 weeks after last dose. 6/6 and 5/6 volunteers developed parasitemia, but time to first parasitemia was significantly longer than controls in the 9 × 105 PfSPZ group (10.89 vs 7.80 days) (P = .039), indicating a significant reduction in parasites in the liver. Antibody and T-cell responses were higher in the 1.8 × 106 PfSPZ group.

Conclusions: In Tanzania, increasing the dose from 2.7 × 105 to 9 × 105 PfSPZ increased VE from 20% to 100%, but increasing to 1.8 × 106 PfSPZ significantly reduced VE.

Clinical Trials Registration: NCT02613520.
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http://dx.doi.org/10.1093/cid/ciz1152DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7947995PMC
December 2020

Crafting Carbazole-Based Vorinostat and Tubastatin-A-like Histone Deacetylase (HDAC) Inhibitors with Potent in Vitro and in Vivo Neuroactive Functions.

ACS Omega 2019 Oct 7;4(17):17279-17294. Epub 2019 Oct 7.

Applied Biology Division and Fluoro and Agrochemical Division, CSIR-Indian Institute of Chemical Technology, Tarnaka, Uppal Road, Hyderabad 500007, Telangana, India.

Small-molecule inhibitors of HDACs (HDACi) induce hyperacetylation of histone and nonhistone proteins and have emerged as potential therapeutic agents in most animal models tested. The established HDACi vorinostat and tubastatin-A alleviate neurodegenerative and behavioral conditions in animal models of neuropsychiatric disorders restoring the neurotrophic milieu. In spite of the neuroactive pharmacological role of HDACi (vorinostat and tubastatin-A), they are limited by efficacy and toxicity. Considering these limitations and concern, we have designed novel compounds - as potential HDACi based on the strategic crafting of the key pharmacophoric elements of vorinostat and tubastatin-A into architecting a single molecule. The molecules - were synthesized through a multistep reaction sequence starting from carbazole and were fully characterized by NMR and mass spectral analysis. The novel molecules - showed remarkable pan HDAC inhibition and the potential to increase the levels of acetyl H3 and acetyl tubulin. In addition, few novel HDAC inhibitors -, , and exhibited significant neurite outgrowth-promoting activity with no observable cytotoxic effects, and interestingly, compound has shown comparably more neurite growth than the parent compounds vorinostat and tubastatin-A. Also, compound was evaluated for possible mood-elevating effects in a chronic unpredictable stress model of Zebrafish. It showed potent anxiolytic and antidepressant-like effects in the novel tank test and social interaction test, respectively. Furthermore, the potent in vitro and in vivo neuroactive compound has shown selectivity for class II over class I HDACs. Our results suggest that the novel carbazole-based HDAC inhibitors, crafted with vorinostat and tubastatin-A pharmacophoric moieties, have potent neurite outgrowth activity and potential to be developed as therapeutics to treat depression and related psychiatric disorders.
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http://dx.doi.org/10.1021/acsomega.9b01950DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6811854PMC
October 2019

An Overview of the Heterogeneity of Major Depressive Disorder: Current Knowledge and Future Prospective.

Curr Neuropharmacol 2020 ;18(3):168-187

Applied Biology Division, CSIR-Indian Institute of Chemical Technology, Tarnaka, Uppal Road, Hyderabad 500007, India.

Major depressive disorder (MDD) is estimated to impose maximum debilitating effects on the society by 2030, with its critical effects on health, functioning, quality of life and concomitant high levels of morbidity and mortality. Yet, the disease is inadequately understood, diagnosed and treated. Moreover, with the recent drastic rise in the pace of life, stress has materialized as one of the most potent environmental factors for depression. In this scenario, it is important to understand the modern pathogenetic hypotheses and mechanisms, and possibly try to shift from the traditional approaches in depression therapy. These include the elaboration of pathophysiological changes in heterogeneous systems such as genetic, epigenetic, serotonergic, noradrenergic, gammaaminobutyric acid, glutamatergic and endocannabinoid systems, neurotrophic factors, HPA axis, immune system as well as cellular stress mechanisms. These components interact with each other in a complex matrix and further elucidation of their mechanism and cascade pathways are needed. This might aid in the identification of MDD subtypes as well as the development of sophisticated biomarkers. Further, characterization might also aid in developing multitargeted therapies that hold much promise as compared to the conventional monoamine based treatment. New candidate pharmacons, refined psychotherapeutic modalities, advanced neuro-surgical and imaging techniques as well as the implementation of pharmacokinetic, pharmacogenetic prescribing guidelines constitute the emerging expanses of MDD treatment.
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http://dx.doi.org/10.2174/1570159X17666191001142934DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7327947PMC
November 2020

Plasmodium vivax chloroquine resistance links to pvcrt transcription in a genetic cross.

Nat Commun 2019 09 20;10(1):4300. Epub 2019 Sep 20.

Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, 20892, USA.

Mainstay treatment for Plasmodium vivax malaria has long relied on chloroquine (CQ) against blood-stage parasites plus primaquine against dormant liver-stage forms (hypnozoites), however drug resistance confronts this regimen and threatens malaria control programs. Understanding the basis of P. vivax chloroquine resistance (CQR) will inform drug discovery and malaria control. Here we investigate the genetics of P. vivax CQR by a cross of parasites differing in drug response. Gametocytogenesis, mosquito infection, and progeny production are performed with mixed parasite populations in nonhuman primates, as methods for P. vivax cloning and in vitro cultivation remain unavailable. Linkage mapping of progeny surviving >15 mg/kg CQ identifies a 76 kb region in chromosome 1 including pvcrt, an ortholog of the Plasmodium falciparum CQR transporter gene. Transcriptional analysis supports upregulated pvcrt expression as a mechanism of CQR.
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http://dx.doi.org/10.1038/s41467-019-12256-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6754410PMC
September 2019

Revealing sex-specific molecular changes in hypoxia-ischemia induced neural damage and subsequent recovery using zebrafish model.

Neurosci Lett 2019 11 10;712:134492. Epub 2019 Sep 10.

Applied Biology, CSIR-Indian Institute of Chemical Technology (IICT), Hyderabad, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, U.P, India. Electronic address:

Functional recovery from hypoxia-ischemia depends on an individual's response to the ischemic damage and recovery. Many of the neurological disorders, including cerebral stroke have sex-specific characteristics. Deciphering the differential molecular mechanisms of sex-specific recovery from hypoxic-ischemic insult can improve medical practice in the treatment of cerebral stroke. In the present study, we describe the establishment of a sex-specific global hypoxia-ischemia neural damage and repair model in zebrafish. During hypoxic exposure a delayed behavioural response was observed in female fish that resumed normal swimming pattern earlier than their male counterparts. Moreover, female appeared more affected as they showed restricted locomotor and exploratory behaviour in novel tank test, reduced mitochondrial enzyme activity, enhanced DNA damage, and cell death after hypoxia insult. However, they showed a faster recovery as compared to male. Analysis of mRNA and protein expression levels of some characteristic hypoxic-ischemic markers showed notable sex-specific differences. Using zebrafish model, we have uncovered cellular and molecular differences in sex-specific systemic responses during the post-hypoxia recovery. This insight might help in devising better therapeutic strategy for stroke in female patients.
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http://dx.doi.org/10.1016/j.neulet.2019.134492DOI Listing
November 2019

miR-30 Family miRNAs Mediate the Effect of Chronic Social Defeat Stress on Hippocampal Neurogenesis in Mouse Depression Model.

Front Mol Neurosci 2019 8;12:188. Epub 2019 Aug 8.

Epigenetics and Neuropsychiatric Disorders' Laboratory, CSIR-Centre for Cellular and Molecular Biology (CCMB), Hyderabad, India.

Depression is a debilitating psychiatric disorder with a high rate of relapse and a low rate of response to antidepressant treatment. There is a dearth of new antidepressants due to an incomplete understanding of the molecular mechanisms involved in its etiopathology. Chronic stress appears to be one of the foremost underlying causes of depression. Studies in animal models in the past decade have implicated epigenetic mechanisms in mediating the negative effects of chronic stressful events on the progression/manifestation of depression and other co-morbid neuropsychiatric disorders. However, non-coding RNAs, another layer of epigenetic regulation is relatively less studied in depression. Here, using the chronic social defeat stress (CSDS)-induced depression model, we hypothesized dysregulation in miRNA-mRNA networks in the neurogenic dentate gyrus (DG) region of male C57BL/6 mice. Among several dysregulated miRNAs identified miRNA arrays, the most striking finding was the downregulation of miRNAs of the miR-30 family in stressed/defeated mice. To investigate miRNAs in the DG-resident neural stem/progenitor cells (NSCs/NPCs), we used the neurosphere culture, where proliferating NSCs/NPCs were subjected to differentiation. Among several differentially expressed miRNAs, we observed an upregulation of miR-30 family miRNAs upon differentiation. To search for the gene targets of these miRNAs, we performed gene arrays followed by bioinformatics analysis, miRNA manipulations and luciferase assays. Our results suggest that miR-30 family miRNAs mediate chronic stress-induced depression-like phenotype by altering hippocampal neurogenesis and neuroplasticity controlling the epigenetic and transcription regulators such as and ; and cell signaling regulators like , and .
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http://dx.doi.org/10.3389/fnmol.2019.00188DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6694739PMC
August 2019

Beyond Blood Smears: Qualification of 18S rRNA as a Biomarker for Controlled Human Malaria Infections.

Am J Trop Med Hyg 2019 06;100(6):1466-1476

Department of Microbiology, University of Washington, Seattle, Washington.

18S rRNA is a biomarker that provides an alternative to thick blood smears in controlled human malaria infection (CHMI) trials. We reviewed data from CHMI trials at non-endemic sites that used blood smears and 18S rRNA/rDNA biomarker nucleic acid tests (NATs) for time to positivity. We validated a multiplex quantitative reverse transcription-polymerase chain reaction (qRT-PCR) for 18S rRNA, prospectively compared blood smears and qRT-PCR for three trials, and modeled treatment effects at different biomarker-defined parasite densities to assess the impact on infection detection, symptom reduction, and measured intervention efficacy. Literature review demonstrated accelerated NAT-based infection detection compared with blood smears (mean acceleration: 3.2-3.6 days). For prospectively tested trials, the validated 18S rRNA qRT-PCR positivity was earlier (7.6 days; 95% CI: 7.1-8.1 days) than blood smears (11.0 days; 95% CI: 10.3-11.8 days) and significantly preceded the onset of grade 2 malaria-related symptoms (12.2 days; 95% CI: 10.6-13.3 days). Discrepant analysis showed that the risk of a blood smear-positive, biomarker-negative result was negligible. Data modeling predicted that treatment triggered by specific biomarker-defined thresholds can differentiate complete, partial, and non-protective outcomes and eliminate many grade 2 and most grade 3 malaria-related symptoms post-CHMI. 18S rRNA is a sensitive and specific biomarker that can justifiably replace blood smears for infection detection in CHMI trials in non-endemic settings. This study led to biomarker qualification through the U.S. Food and Drug Administration for use in CHMI studies at non-endemic sites, which will facilitate biomarker use for the qualified context of use in drug and vaccine trials.
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http://dx.doi.org/10.4269/ajtmh.19-0094DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6553913PMC
June 2019

Safety and Differential Antibody and T-Cell Responses to the Sporozoite Malaria Vaccine, PfSPZ Vaccine, by Age in Tanzanian Adults, Adolescents, Children, and Infants.

Am J Trop Med Hyg 2019 06;100(6):1433-1444

Sanaria, Inc., Rockville, Maryland.

In 2016, there were more cases and deaths caused by malaria globally than in 2015. An effective vaccine would be an ideal additional tool for reducing malaria's impact. Sanaria PfSPZ Vaccine, composed of radiation-attenuated, aseptic, purified, cryopreserved (Pf) sporozoites (SPZ) has been well tolerated and safe in malaria-naïve and experienced adults in the United States and Mali and protective against controlled human malaria infection with Pf in the United States and field transmission of Pf in Mali, but had not been assessed in younger age groups. We, therefore, evaluated PfSPZ Vaccine in 93 Tanzanians aged 45 years to 6 months in a randomized, double-blind, normal saline placebo-controlled trial. There were no significant differences in adverse events between vaccinees and controls or between dosage regimens. Because all age groups received three doses of 9.0 × 10 PfSPZ of PfSPZ Vaccine, immune responses were compared at this dosage. Median antibody responses against Pf circumsporozoite protein and PfSPZ were highest in infants and lowest in adults. T-cell responses were highest in 6-10-year olds after one dose and 1-5-year olds after three doses; infants had no significant positive T-cell responses. The safety data were used to support initiation of trials in > 300 infants in Kenya and Equatorial Guinea. Because PfSPZ Vaccine-induced protection is thought to be mediated by T cells, the T-cell data suggest PfSPZ Vaccine may be more protective in children than in adults, whereas infants may not be immunologically mature enough to respond to the PfSPZ Vaccine immunization regimen assessed.
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http://dx.doi.org/10.4269/ajtmh.18-0835DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6553883PMC
June 2019

Is Saglin a mosquito salivary gland receptor for Plasmodium falciparum?

Malar J 2019 Jan 3;18(1). Epub 2019 Jan 3.

Sanaria Inc., 9800 Medical Center Drive, Suite A209, Rockville, MD, 20850, USA.

Background: Saglin, a 100 kDa protein composed of two 50 kDa homodimers, is present in the salivary glands of Anopheles gambiae and has been considered an essential receptor for sporozoites (SPZ) of Plasmodium berghei and Plasmodium falciparum (Pf), allowing SPZ to recognize, bind to, and infect mosquito salivary glands. Spatial and temporal patterns of Saglin expression reported here, however, suggest that this model does not fully describe the Saglin-SPZ interaction.

Results: Saglin protein was detected by indirect immunofluorescence microscopy only in the medial and proximal-lateral lobes, but not in the distal-lateral lobes, of the salivary glands of An. gambiae; the pattern of expression was independent of mosquito age or physiological state. These results were confirmed by steady-state Saglin transcript and protein expression using qRT-PCR and Western-blot analysis, respectively. Saglin was localized to the basal surface of the cells of the medial lobes and was undetectable elsewhere (intracellularly, on the lateral or apical membranes, the cells' secretory vacuoles, or in the salivary duct). In the cells of the proximal lateral lobes of the salivary glands, Saglin was distinctly intracellular and was not localized to any of the cell surfaces. Transgenic Anopheles stephensi were produced that expressed An. gambiae Saglin in the distal lateral lobes of the salivary gland. Additional Saglin expression did not enhance infection by PfSPZ compared to non-transgenic siblings fed on the same gametocyte-containing blood meal.

Conclusions: The absence of Saglin in the distal lateral lobes of the salivary glands, a primary destination for SPZ, suggests Saglin is not an essential receptor for Plasmodium SPZ. The lack of any correlation between increased Saglin expression in the distal lateral lobes of the salivary glands of transgenic An. stephensi and PfSPZ infection is also consistent with Saglin not being an essential salivary gland receptor for Plasmodium SPZ.
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http://dx.doi.org/10.1186/s12936-018-2634-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6317240PMC
January 2019

Author Correction: A human monoclonal antibody prevents malaria infection by targeting a new site of vulnerability on the parasite.

Nat Med 2019 Jan;25(1):188-189

Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.

In the version of this article originally published, data were incorrectly ascribed to monoclonal antibody CIS34 because of a labeling error. The data were generated with monoclonal antibody CIS04. Full details can be found in the correction notice.
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http://dx.doi.org/10.1038/s41591-018-0315-0DOI Listing
January 2019

Increased stress and altered expression of histone modifying enzymes in brain are associated with aberrant behaviour in vitamin B12 deficient female mice.

Nutr Neurosci 2020 Sep 25;23(9):714-723. Epub 2018 Nov 25.

National Institute of Nutrition, ICMR, Hyderabad 500007, India.

A sub-optimal nutritional environment from early life can be envisaged as a stressor that translates into mental health problems in adulthood. After considering (a) the widespread prevalence of vitamin B12 deficiency especially amongst women in developing countries and (b) the importance of vitamin B12 in normal brain function, in this study we have elucidated the behavioural correlates of chronic severe and moderate vitamin B12 deficiency in C57BL/6 mice. Female weanling mice were assigned to three dietary groups: (a) control AIN-76A diet with cellulose as dietary fibre (b) vitamin B12 restricted AIN-76A diet with pectin as dietary fibre (severe deficiency group) and (c) vitamin B12 restricted AIN-76A diet with cellulose as dietary fibre (moderate deficiency group). The mice received these diets throughout pregnancy, lactation and thereafter. Nest-building, maternal care, anxiety and depressive behaviours were evaluated. Oxidative stress, activities of antioxidant enzymes and expression of various histone modifying enzymes in brain were investigated to unravel the probable underlying mechanisms. Our data suggests that both severe and moderate vitamin B12 deficiency induced anxiety and impaired maternal care. However, only severe vitamin B12 deficiency induced depression. Oxidative stress and poor antioxidant defense underlie the deleterious effects of both severe and moderate vitamin B12 deficiency. Altered expression of histone modifying enzymes in the brain of severely deficient mice is suggestive of epigenetic reprogramming. This study suggests that chronic vitamin B12 deficiency leads to behavioural anomalies in female C57BL/6 mice and the severity of these outcomes can be correlated to the level of deficiency.
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http://dx.doi.org/10.1080/1028415X.2018.1548676DOI Listing
September 2020

Artemisinin resistance phenotypes and K13 inheritance in a cross and model.

Proc Natl Acad Sci U S A 2018 12 19;115(49):12513-12518. Epub 2018 Nov 19.

Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892;

Concerns about malaria parasite resistance to treatment with artemisinin drugs (ARTs) have grown with findings of prolonged parasite clearance s (>5 h) and their association with mutations in Kelch-propeller protein K13. Here, we describe a laboratory cross of K13 C580Y mutant with C580 wild-type parasites to investigate ART response phenotypes in vitro and in vivo. After genotyping >400 isolated progeny, we evaluated 20 recombinants in vitro: IC measurements of dihydroartemisinin were at similar low nanomolar levels for C580Y- and C580-type progeny (mean ratio, 1.00; 95% CI, 0.62-1.61), whereas, in a ring-stage survival assay, the C580Y-type progeny had 19.6-fold (95% CI, 9.76-39.2) higher average counts. In splenectomized monkeys treated with three daily doses of i.v. artesunate, calculations by three different methods yielded mean differences of 0.01 h (95% CI, -3.66 to 3.67), 0.80 h (95% CI, -0.92 to 2.53), and 2.07 h (95% CI, 0.77-3.36) between C580Y and C580 infections. Incidences of recrudescence were 57% in C580Y (4 of 7) versus 70% in C580 (7 of 10) infections (-13% difference; 95% CI, -58% to 35%). Allelic substitution of C580 in a C580Y-containing progeny clone (76H10) yielded a transformant (76H10) that, in an infected monkey, recrudesced regularly 13 times over 500 d. Frequent recrudescences of ART-treated infections occur with or without K13 mutations and emphasize the need for improved partner drugs to effectively eliminate the parasites that persist through the ART component of combination therapy.
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http://dx.doi.org/10.1073/pnas.1813386115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6298093PMC
December 2018

Fellutamide B Synthetic Path Intermediates with in Vitro Neuroactive Function Shows Mood-Elevating Effect in Stress-Induced Zebrafish Model.

ACS Omega 2018 Sep 5;3(9):10534-10544. Epub 2018 Sep 5.

Chemical Biology and Natural Products Chemistry, CSIR-Indian Institute of Chemical Technology, Tarnaka, Uppal Road, Hyderabad 500007, India.

Fellutamide B is reported to have cytotoxic and proteasome inhibitory activity. Interestingly, fellutamide B and its simplified analogues have also been observed for the neurotrophic activity by stimulating the synthesis and secretion of neurotrophins. Owing to the interesting structural and potent neurotrophic role of fellutamide B (a lipopeptide aldehyde), we have assessed the synthetic path intermediates (compounds A-D) of fellutamide B for their neuroactive potential (in vitro and in vivo). We have observed few compounds (comp #A-D) to have potential neurite outgrowth activity in Neuro2a cells with no observable negative effect on the cell viability. In addition, most compounds (comp #A, C, and D) have shown neurogenic activity ex vivo in hippocampal neurosphere culture, with increased acetyl H3 and acetyl H4 induction ability (comp #C). Furthermore, the intermediate product comp #C has shown anxiolytic and antidepressant-like activity in novel tank test and social interaction test, in the chronic unpredictable stress model of zebrafish mood disorder, inducing BDNF gene expression in the telencephalon region of the fish brain. Our results thus demonstrate that the fellutamide B synthetic path intermediates have potential neurotrophic, neurogenic, and mood-elevating effects and thus good prospect to be developed as potential therapeutics to treat psychiatric disorders.
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http://dx.doi.org/10.1021/acsomega.8b00456DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6173481PMC
September 2018

Mice With Partial Deletion of Y-Heterochromatin Exhibits Stress Vulnerability.

Front Behav Neurosci 2018 21;12:215. Epub 2018 Sep 21.

CSIR-Centre for Cellular and Molecular Biology, Hyderabad, India.

The role of Y chromosome in sex determination and male fertility is well established. It is also known that infertile men are prone to psychological disturbances. Earlier studies in the laboratory identified genes expressed in testes that are putatively regulated by Y chromosome in man and mouse. With the availability of a Y-deleted mouse model, that is subfertile, we studied the effect of a partial deletion of Y-chromosomal heterochromatin on mouse behavior when compared to its wild type. The partial Y-deleted mice exhibited anxiety like phenotype under stress when different anxiety (open field test and elevated plus maze, EPM test) and depression related tests (tail suspension and force swim) were performed. The mutant mice also showed reduction in hippocampal neurogenesis and altered expression of neurogenesis markers such as Nestin, , and using quantitative real time PCR (qPCR) analysis. The genes with altered expression contained short stretches of homology to Y-derived transcripts only in their Untranslated Regions (UTRs). Our study suggests putative regulation of these genes by the Y chromosome in mouse brain altering stress related behavior.
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http://dx.doi.org/10.3389/fnbeh.2018.00215DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6160548PMC
September 2018

Plasmodium 18S rRNA of intravenously administered sporozoites does not persist in peripheral blood.

Malar J 2018 Jul 27;17(1):275. Epub 2018 Jul 27.

Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Building 40, Room 3512, 40 Convent Drive, Bethesda, MD, 20814, USA.

Background: Plasmodium 18S rRNA is a biomarker used to monitor blood-stage infections in malaria clinical trials. Plasmodium sporozoites also express this biomarker, and there is conflicting evidence about how long sporozoite-derived 18S rRNA persists in peripheral blood. If present in blood for an extended timeframe, sporozoite-derived 18S rRNA could complicate use as a blood-stage biomarker.

Methods: Blood samples from Plasmodium yoelii infected mice were tested for Plasmodium 18S rRNA and their coding genes (rDNA) using sensitive quantitative reverse transcription PCR and quantitative PCR assays, respectively. Blood and tissues from Plasmodium falciparum sporozoite (PfSPZ)-infected rhesus macaques were similarly tested.

Results: In mice, when P. yoelii sporozoite inoculation and blood collection were performed at the same site (tail vein), low level rDNA positivity persisted for 2 days post-infection. Compared to intact parasites with high rRNA-to-rDNA ratios, this low level positivity was accompanied by no increase in rRNA-to-rDNA, indicating detection of residual, non-viable parasite rDNA. When P. yoelii sporozoites were administered via the retro-orbital vein and blood sampled by cardiac puncture, neither P. yoelii 18S rRNA nor rDNA were detected 24 h post-infection. Similarly, there was no P. falciparum 18S rRNA detected in blood of rhesus macaques 3 days after intravenous injection with extremely high doses of PfSPZ. Plasmodium 18S rRNA in the rhesus livers increased by approximately 101-fold from 3 to 6 days post infection, indicating liver-stage proliferation.

Conclusions: Beyond the first few hours after injection, sporozoite-derived Plasmodium 18S rRNA was not detected in peripheral blood. Diagnostics based on 18S rRNA are unlikely to be confounded by sporozoite inocula in human clinical trials.
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http://dx.doi.org/10.1186/s12936-018-2422-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6062992PMC
July 2018