Lung Function and Respiratory Morbidity Among Informal Workers Exposed to Cement Dust: A Comparative Cross-Sectional Study.

Background: Cement dust is a significant source of occupational exposure affecting lung function and respiratory health. A higher burden of respiratory morbidity is known among factory workers involved in cement production. Globally or from India, there are no estimates of this burden from informal workers exposed to cement dust. Objective: To assess difference in lung function and respiratory symptoms among informal workers exposed to cement and those unexposed, using a comparative community based cross-sectional study from purposively selected areas in Delhi, India. Methods: Using a portable spirometer we measured lung function and collected respiratory symptoms from conveniently sampled informal workers (n = 100) exposed to cement dust, 50 indoor informal workers (tailors), and 50 outdoor (vegetable) vendors. Regression analyses were performed to compare respiratory symptom score and lung function parameters, adjusted for age, body mass index, smoking, socioeconomic status, and years of occupational exposure. Findings: Exposed workers had significantly lower lung function (PEF = -750 ml/s and -810 ml/s and FEV1/FVC (%) = -3.87 and -2.11) compared to indoor and outdoor groups, with three times higher chronic respiratory symptoms when compared to the unexposed groups. The cement dust exposure was observed to be associated with PEF (mean difference (MD) = -0.75L, 95%CI = -1.36 to -0.15, p = 0.01), %FEV1/FVC (MD = -3.87, 95%CI = -6.77 to -0.96, p = 0.03) and respiratory symptoms (p < 0.001). Conclusion: This study generates evidence regarding the respiratory burden of occupational exposure among vulnerable informal workers. There is an urgent need for policy reforms to safeguard health from occupational exposures, especially among informal workers.

Incidence of vitreous loss and visual outcome following cataract surgery by surgeons with various levels of experience at a tertiary eye care center in North India.

Purpose: To determine the incidence of vitreous loss and visual outcome after a vitreous loss during cataract surgery performed by surgeons with various levels of experience in adults >40 years of age at a tertiary eye care center in North India. Methods: The study was conducted at a tertiary eye care center in North India. This was an observational, retrospective, cross-sectional study of patients who underwent cataract surgery from August 1, 2011 to July 31, 2014. All adult cataract cases who were operated on from August 1, 2011 to July 31, 2014 and who experienced vitreous loss during their surgery were included in the study. The visual outcomes of these patients who experienced vitreous loss during cataract surgery in uncomplicated cataract and were managed using standard automated vitrectomy techniques were assessed for different cataract surgical techniques (extracapsular, small-incision, and phacoemulsification) as well as at different levels of skill of the operative surgeon (consultant, short term fellow, and long-term fellow). Details of the postoperative period and best-corrected visual acuity (BCVA) were collected from patient records by the principal investigator on day 1, 1 week, 4 weeks, 6 weeks, and 3 months post cataract surgery. Results: Vitreous loss occurred in 374 out of 18,430 patients who underwent cataract surgery from August 1, 2011 to July 31, 2014. The overall incidence of vitreous loss in our study was found to be 2.03% with consultants having a rate of 1.66%, short-term fellows at 5.19%, and long-term fellows at 2.02%. Two hundred eighty-eight patients of the 374 cases followed up for 3 months at the hospital and 75.69% of these patients had a final visual acuity of ≥6/18. Conclusion: In an institute with a structured training program for residents/trainees, the vitreous loss rate is low during cataract surgery. Early intervention and proper management with the standard microsurgical technique by experienced hands can improve the final visual outcome in eyes with vitreous loss. Cystoid macular edema and corneal edema were the most common causes of poor postoperative vision.

Methotrexate negatively acts on inflammatory responses triggered in Drosophila larva with hyperactive JAK/STAT pathway.

Drosophila is a valuable paradigm for studying tumorigenesis and cancer. Mutations causing hematopoietic aberrations and melanotic-blood-tumors found in Drosophila mutants are vastly studied. Clear understanding about the blood cells, signaling pathways and the tissues affected during hematopoietic tumor formation provide an opportunity to delineate the effects of cancer therapeutics. Using this simple hematopoietic archetype, we elucidated the effects of the anti-cancer drug, Methotrexate (MTX) on immune responses in two scenarios i.e. against wasp infection and in hematopoietic mutant, hopTum-l. Through this in vivo study we show that MTX impedes the immune responses against wasp infection including the encapsulation response. We further observed that MTX reduces the tumor penetrance in gain-of-function mutants of JAK/STAT pathway, hopTum-l. MTX is anti-inflammatory as it hinders not only the immune responses of acute inflammation as observed after wasp infestation, but also chronic inflammatory responses associated with constitutively activated JAK/STAT pathway mutant (hopTum-l) carrying blood tumors.

Endocannabinoid system: Role in blood cell development, neuroimmune interactions and associated disorders.

The endocannabinoid system (ECS) is a complex physiological network involved in creating homeostasis and maintaining human health. Studies of the last 40 years have shown that endocannabinoids (ECs), a group of bioactive lipids, together with their set of receptors, function as one of the most important physiologic systems in human body. ECs and cannabinoid receptors (CBRs) are found throughout the body: in the brain tissues, immune cells, and in the peripheral organs and tissues as well. In recent years, ECs have emerged as key modulators of affect, neurotransmitter release, immune function, and several other physiological functions. This modulatory homoeostatic system operates in the regulation of brain activity and states of physical health and disease. In several research studies and patents the ECS has been recognised with neuro-protective properties thus it might be a target in neurodegenerative diseases. Most immune cells express these bioactive lipids and their receptors, recent data also highlight the immunomodulatory effects of endocannabinoids. Interplay of immune and nervous system has been recognized in past, recent studies suggest that ECS function as a bridge between neuronal and immune system. In several ongoing clinical trial studies, the ECS has also been placed in the anti-cancer drugs spotlight. This review summarizes the literature of cannabinoid ligands and their biosynthesis, cannabinoid receptors and their distribution, and the signaling pathways initiated by the binding of cannabinoid ligands to cannabinoid receptors. Further, this review highlights the functional role of cannabinoids and ECS in blood cell development, neuroimmune interactions and associated disorders. Moreover, we highlight the current state of knowledge of cannabinoid ligands as the mediators of neuroimmune interactions, which can be therapeutically effective for neuro-immune disorders and several diseases associated with neuroinflammation.

Comparative hematopoiesis and signal transduction in model organisms.

Hematopoiesis is a continuous phenomenon involving the formation of hematopoietic stem cells (HSCs) giving rise to diverse functional blood cells. This developmental process of hematopoiesis is evolutionarily conserved, yet comparably different in various model organisms. Vertebrate HSCs give rise to all types of mature cells of both the myeloid and the lymphoid lineages sequentially colonizing in different anatomical tissues. Signal transduction in HSCs facilitates their potency and specifies branching of lineages. Understanding the hematopoietic signaling pathways is crucial to gain insights into their deregulation in several blood-related disorders. The focus of the review is on hematopoiesis corresponding to different model organisms and pivotal role of indispensable hematopoietic pathways. We summarize and discuss the fundamentals of blood formation in both invertebrate and vertebrates, examining the requirement of key signaling nexus in hematopoiesis. Knowledge obtained from such comparative studies associated with developmental dynamics of hematopoiesis is beneficial to explore the therapeutic options for hematopoietic diseases.

Structural insights into histone chaperone Asf1 and its characterization from Plasmodium falciparum.

Asf1 is a highly conserved histone chaperone that regulates tightly coupled nucleosome assembly/disassembly process. We observed that Plasmodium falciparum Asf1 (PfAsf1) is ubiquitously expressed in different stages of the life cycle of the parasite. To gain further insight into its biological activity, we solved the structure of N-terminal histone chaperone domain of PfAsf1 (1-159 amino acids) by X-ray crystallography to a resolution of 2.4 Å. The structure is composed of two beta-sheet to form a beta-sandwich, which resembles an immunoglobulin-like fold. The surface-charge distribution of PfAsf1 is distinct from yAsf1 and hAsf1 although the core-structure shows significant similarity. The crystal-structure indicated that PfAsf1 may exist in a dimeric-state which was further confirmed by solution cross-linking experiment. PfAsf1 was found to specifically interact with Plasmodium histone H3 and H4 and was able to deposit H3/H4 dimer onto DNA-template to form disomes, showing its characteristic histone chaperone activity. We mapped the critical residues of PfAsf1 involved in histone H3/H4 interaction and confirmed by site-directed mutagenesis. Further analysis indicates that histone interacting surface of Asf1 is highly conserved while the dimerization interface is variable. Our results identify the role of PfAsf1 as a mediator of chromatin assembly in Plasmodium falciparum, which is the causative agent of malignant malaria in humans.

Virodhamine, an endocannabinoid, induces megakaryocyte differentiation by regulating MAPK activity and function of mitochondria.

Endocannabinoids are well-known regulators of neurotransmission by activating the cannabinoid (CB) receptors. Endocannabinoids are being used extensively for the treatment of various neurological disorders such as Alzheimer's and Parkinson's diseases. Although endocannabinoids are well studied in cell survival, proliferation, and differentiation in various neurological disorders and several cancers, the functional role in the regulation of blood cell development is less examined. In the present study, virodhamine, which is an agonist of CB receptor-2, was used to examine its effect on megakaryocytic development from a megakaryoblastic cell. We observed that virodhamine increases cell adherence, cell size, and cytoplasmic protrusions. Interestingly, we have also observed large nucleus and increased expression of megakaryocytic marker (CD61), which are the typical hallmarks of megakaryocytic differentiation. Furthermore, the increased expression of CB2 receptor was noticed in virodhamine-induced megakaryocytic cells. The effect of virodhamine on megakaryocytic differentiation could be mediated through CB2 receptor. Therefore, we have studied virodhamine induced molecular regulation of megakaryocytic differentiation; mitogen-activated protein kinase (MAPK) activity, mitochondrial function, and reactive oxygen species (ROS) production were majorly affected. The altered mitochondrial functions and ROS production is the crucial event associated with megakaryocytic differentiation and maturation. In the present study, we report that virodhamine induces megakaryocytic differentiation by triggering MAPK signaling and ROS production either through MAPK effects on ROS-generating enzymes or by the target vanilloid receptor 1-mediated regulation of mitochondrial function.

Elucidating the functional aspects of different domains of bean common mosaic virus coat protein.

The coat protein (CP) is the only structural protein present in the polyprotein of bean common mosaic virus. The well known characteristics of the CP are self-oligomerization and nucleic acid binding activity. The studies of the coat protein mutants revealed that the oligomeric property of CP solely depends on the amino-terminal residues and the nucleic acid binding domain present at the 194-202 residue position. The 3'UTR RNA of the virus showed high binding affinity with the RNA binding domain as compared to the 5'UTR RNA. Further, the intrinsic fluorescence study of the CP also suggested that the N- and C-terminal of CP contains a highly disordered region. The present study also illustrates that the coat protein contains a conserved RNA binding pocket among the potyviruses, but displays divergent oligomerization propensities due to the difference in residue at the N- and C-terminal.

Atypical plant homeodomain of UBR7 functions as an H2BK120Ub ligase and breast tumor suppressor.

The roles of Plant Homeodomain (PHD) fingers in catalysis of histone modifications are unknown. We demonstrated that the PHD finger of Ubiquitin Protein Ligase E3 Component N-Recognin7 (UBR7) harbors E3 ubiquitin ligase activity toward monoubiquitination of histone H2B at lysine120 (H2BK120Ub). Purified PHD finger or full-length UBR7 monoubiquitinated H2BK120 in vitro, and loss of UBR7 drastically reduced H2BK120Ub genome-wide binding sites in MCF10A cells. Low UBR7 expression was correlated with occurrence of triple-negative breast cancer and metastatic tumors. Consistently, UBR7 knockdown enhanced the invasiveness, induced epithelial-to-mesenchymal transition and promoted metastasis. Conversely, ectopic expression of UBR7 restored these cellular phenotypes and reduced tumor growth. Mechanistically, UBR7 loss reduced H2BK120Ub levels on cell adhesion genes, including CDH4, and upregulated the Wnt/ß-Catenin signaling pathway. CDH4 overexpression could partially revert UBR7-dependent cellular phenotypes. Collectively, our results established UBR7 as a histone H2B monoubiquitin ligase that suppresses tumorigenesis and metastasis of triple-negative breast cancer.

MicroRNA function in megakaryocytes.

Megakaryocytes (MKs), the largest cells in the bone marrow, are generated from hematopoietic stem cells (HSCs) in a sequential process called megakaryocytopoiesis in which HSCs undergo MK-progenitor (MP) commitment and maturation to terminally differentiated MK. Megakaryocytopoiesis is controlled by a complex network of bone marrow niche factors. Traditionally, the studies on megakaryocytopoiesis were focused on different cytokines, growth factors and transcription factors as the regulators of megakaryocytopoiesis. Over the past two decades many research groups have uncovered the key role of microRNAs (miRNAs) in megakaryocytopoiesis. miRNAs are a class of small length non-coding RNAs which play key regulatory role in cellular processes such as proliferation, differentiation and development and are also known to be involved in disease development. This review summarizes the current state of knowledge of miRNAs which have changed expression during megakaryocytopoiesis, also focuses on miRNAs which are differentially regulated during developmental maturation of MKs. Further, we aimed to discuss potential mechanisms of miRNAs-mediated regulation underlying megakaryocytopoiesis and developmental maturation of MKs.

Dual histone reader ZMYND8 inhibits cancer cell invasion by positively regulating epithelial genes.

Enhanced migratory potential and invasiveness of cancer cells contribute crucially to cancer progression. These phenotypes are achieved by precise alteration of invasion-associated genes through local epigenetic modifications which are recognized by a class of proteins termed a chromatin reader. ZMYND8 [zinc finger MYND (myeloid, Nervy and DEAF-1)-type containing 8], a key component of the transcription regulatory network, has recently been shown to be a novel reader of H3.1K36Me2/H4K16Ac marks. Through differential gene expression analysis upon silencing this chromatin reader, we identified a subset of genes involved in cell proliferation and invasion/migration regulated by ZMYND8. Detailed analysis uncovered its antiproliferative activity through BrdU incorporation, alteration in the expression of proliferation markers, and cell cycle regulating genes and cell viability assays. In addition, performing wound healing and invasion/migration assays, its anti-invasive nature is evident. Interestingly, epithelial-mesenchymal transition (EMT), a key mechanism of cellular invasion, is regulated by ZMYND8 where we identified its selective enrichment on promoters of CLDN1/CDH1 genes, rich in H3K36Me2/H4K16Ac marks, leading to their up-regulation. Thus, the presence of ZMYND8 could be implicated in maintaining the epithelial phenotype of cells. Furthermore, syngeneic mice, injected with ZMYND8-overexpressed invasive breast cancer cells, showed reduction in tumor volume and weight. In concert with this, we observed a significant down-regulation of ZMYND8 in invasive ductal and lobular breast cancer tissues compared with normal tissue. Taken together, our study elucidates a novel function of ZMYND8 in regulating EMT and invasion of cancer cells, possibly through its chromatin reader function.

Selective Recognition of H3.1K36 Dimethylation/H4K16 Acetylation Facilitates the Regulation of All-trans-retinoic Acid (ATRA)-responsive Genes by Putative Chromatin Reader ZMYND8.

ZMYND8 (zinc finger MYND (Myeloid, Nervy and DEAF-1)-type containing 8), a newly identified component of the transcriptional coregulator network, was found to interact with the Nucleosome Remodeling and Deacetylase (NuRD) complex. Previous reports have shown that ZMYND8 is instrumental in recruiting the NuRD complex to damaged chromatin for repressing transcription and promoting double strand break repair by homologous recombination. However, the mode of transcription regulation by ZMYND8 has remained elusive. Here, we report that through its specific key residues present in its conserved chromatin-binding modules, ZMYND8 interacts with the selective epigenetic marks H3.1K36Me2/H4K16Ac. Furthermore, ZMYND8 shows a clear preference for canonical histone H3.1 over variant H3.3. Interestingly, ZMYND8 was found to be recruited to several developmental genes, including the all-trans-retinoic acid (ATRA)-responsive ones, through its modified histone-binding ability. Being itself inducible by ATRA, this zinc finger transcription factor is involved in modulating other ATRA-inducible genes. We found that ZMYND8 interacts with transcription initiation-competent RNA polymerase II phosphorylated at Ser-5 in a DNA template-dependent manner and can alter the global gene transcription. Overall, our study identifies that ZMYND8 has CHD4-independent functions in regulating gene expression through its modified histone-binding ability.