@article {1458, title = {The Hox gene uses Doublesex as a cofactor to promote neuroblast apoptosis in the central nervous system [Transgenic Fly Facility]}, journal = {Development}, volume = {146}, year = {2019}, month = {2019 08 22}, abstract = {

Highly conserved DM domain-containing transcription factors (Doublesex/MAB-3/DMRT1) are responsible for generating sexually dimorphic features. In the central nervous system, a set of Doublesex (Dsx)-expressing neuroblasts undergo apoptosis in females whereas their male counterparts proliferate and give rise to serotonergic neurons crucial for adult mating behaviour. Our study demonstrates that the female-specific isoform of Dsx collaborates with Hox gene () to bring about this apoptosis. Biochemical results suggest that proteins AbdB and Dsx interact through their highly conserved homeodomain and DM domain, respectively. This interaction is translated into a cooperative binding of the two proteins on the apoptotic enhancer in the case of females but not in the case of males, resulting in female-specific activation of apoptotic genes. The capacity of AbdB to use the sex-specific isoform of Dsx as a cofactor underlines the possibility that these two classes of protein are capable of cooperating in selection and regulation of target genes in a tissue- and sex-specific manner. We propose that this interaction could be a common theme in generating sexual dimorphism in different tissues across different species.

}, keywords = {Animals, Apoptosis, DNA-Binding Proteins, Drosophila, Drosophila Proteins, Female, Gene Expression Regulation, Developmental, Genes, Homeobox, Homeodomain Proteins, Male, Neural Stem Cells, Protein Isoforms, Sex Characteristics}, issn = {1477-9129}, doi = {10.1242/dev.175158}, author = {Ghosh, Neha and Bakshi, Asif and Khandelwal, Risha and Rajan, Sriivatsan Govinda and Joshi, Rohit} } @article {1231, title = {A sleep-inducing gene, nemuri, links sleep and immune function in Drosophila [Transgenic Fly Facility]}, journal = {Science}, volume = {363}, year = {2019}, month = {2019 02 01}, pages = {509-515}, abstract = {

Sleep remains a major mystery of biology. In particular, little is known about the mechanisms that account for the drive to sleep. In an unbiased screen of more than 12,000 lines, we identified a single gene, , that induces sleep. The NEMURI protein is an antimicrobial peptide that can be secreted ectopically to drive prolonged sleep (with resistance to arousal) and to promote survival after infection. Loss of increased arousability during daily sleep and attenuated the acute increase in sleep induced by sleep deprivation or bacterial infection. Conditions that increase sleep drive induced expression of in a small number of fly brain neurons and targeted it to the sleep-promoting, dorsal fan-shaped body. We propose that NEMURI is a bona fide sleep homeostasis factor that is particularly important under conditions of high sleep need; because these conditions include sickness, our findings provide a link between sleep and immune function.

}, keywords = {Animals, Antimicrobial Cationic Peptides, Arousal, Bacterial Infections, Brain, Drosophila melanogaster, Drosophila Proteins, Female, Gain of Function Mutation, Gene Knockout Techniques, Homeostasis, Immune System, Male, Neurons, Sleep}, issn = {1095-9203}, doi = {10.1126/science.aat1650}, author = {Toda, Hirofumi and Williams, Julie A and Gulledge, Michael and Sehgal, Amita} } @article {683, title = {Combinatorial action of Grainyhead, Extradenticle and Notch in regulating Hox mediated apoptosis in Drosophila larval CNS.}, journal = {PLoS Genet}, volume = {13}, year = {2017}, month = {2017 Oct}, pages = {e1007043}, abstract = {

Hox mediated neuroblast apoptosis is a prevalent way to pattern larval central nervous system (CNS) by different Hox genes, but the mechanism of this apoptosis is not understood. Our studies with Abdominal-A (Abd-A) mediated larval neuroblast (pNB) apoptosis suggests that AbdA, its cofactor Extradenticle (Exd), a helix-loop-helix transcription factor Grainyhead (Grh), and Notch signaling transcriptionally contribute to expression of RHG family of apoptotic genes. We find that Grh, AbdA, and Exd function together at multiple motifs on the apoptotic enhancer. In vivo mutagenesis of these motifs suggest that they are important for the maintenance of the activity of the enhancer rather than its initiation. We also find that Exd function is independent of its known partner homothorax in this apoptosis. We extend some of our findings to Deformed expressing region of sub-esophageal ganglia where pNBs undergo a similar Hox dependent apoptosis. We propose a mechanism where common players like Exd-Grh-Notch work with different Hox genes through region specific enhancers to pattern respective segments of larval central nervous system.

}, keywords = {Amino Acid Sequence, Animals, Apoptosis, Central Nervous System, DNA-Binding Proteins, Drosophila, Drosophila Proteins, Enhancer Elements, Genetic, Female, Gene Expression Regulation, Developmental, Genes, Homeobox, Homeodomain Proteins, Larva, Male, Nuclear Proteins, Receptors, Notch, Transcription Factors}, issn = {1553-7404}, doi = {10.1371/journal.pgen.1007043}, author = {Khandelwal, Risha and Sipani, Rashmi and Govinda Rajan, Sriivatsan and Kumar, Raviranjan and Joshi, Rohit} } @article {513, title = {L-Plastin S-glutathionylation promotes reduced binding to β-actin and affects neutrophil functions. (Mass Spectrometry)}, journal = {Free Radic Biol Med}, volume = {86}, year = {2015}, month = {2015 Sep}, pages = {1-15}, abstract = {

Posttranslational modifications (PTMs) of cytoskeleton proteins due to oxidative stress associated with several pathological conditions often lead to alterations in cell function. The current study evaluates the effect of nitric oxide (DETA-NO)-induced oxidative stress-related S-glutathionylation of cytoskeleton proteins in human PMNs. By using in vitro and genetic approaches, we showed that S-glutathionylation of L-plastin (LPL) and β-actin promotes reduced chemotaxis, polarization, bactericidal activity, and phagocytosis. We identified Cys-206, Cys-283, and Cys-460as S-thiolated residues in the β-actin-binding domain of LPL, where cys-460 had the maximum score. Site-directed mutagenesis of LPL Cys-460 further confirmed the role in the redox regulation of LPL. S-Thiolation diminished binding as well as the bundling activity of LPL. The presence of S-thiolated LPL was detected in neutrophils from both diabetic patients and db/db mice with impaired PMN functions. Thus, enhanced nitroxidative stress may results in LPL S-glutathionylation leading to impaired chemotaxis, polarization, and bactericidal activity of human PMNs, providing a mechanistic basis for their impaired functions in diabetes mellitus.

}, keywords = {Actins, Adult, Amino Acid Sequence, Animals, Case-Control Studies, Cell Polarity, Chemotaxis, Diabetes Mellitus, Female, Glutathione, HEK293 Cells, Humans, Male, Mice, Inbred C57BL, Mice, Obese, Microfilament Proteins, Middle Aged, Molecular Sequence Data, Neutrophils, Nitric Oxide, Oxidative Stress, Protein Binding, Protein Processing, Post-Translational, Young Adult}, issn = {1873-4596}, doi = {10.1016/j.freeradbiomed.2015.04.008}, author = {Dubey, Megha and Singh, Abhishek K and Awasthi, Deepika and Nagarkoti, Sheela and Kumar, Sachin and Ali, Wahid and Chandra, Tulika and Kumar, Vikas and Barthwal, Manoj K and Jagavelu, Kumaravelu and S{\'a}nchez-G{\'o}mez, Francisco J and Lamas, Santiago and Dikshit, Madhu} } @article {481, title = {Dysregulation of core components of SCF complex in poly-glutamine disorders. [Drosophila facility]}, journal = {Cell Death Dis}, volume = {3}, year = {2012}, month = {2012 Nov 22}, pages = {e428}, abstract = {

Poly-glutamine (polyQ) diseases are neurodegenerative disorders characterised by expanded CAG repeats in the causative genes whose proteins form inclusion bodies. Various E3 ubiquitin ligases are implicated in neurodegenerative disorders. We report that dysfunction of the SCF (Skp1-Cul1-F-box protein) complex, one of the most well-characterised ubiquitin ligases, is associated with pathology in polyQ diseases like Huntington{\textquoteright}s disease (HD) and Machado-Joseph disease (MJD). We found that Cullin1 (Cul1) and Skp1, core components of the SCF complex, are reduced in HD mice brain. A reduction in Cul1 levels was also observed in cellular HD model and fly models of both HD and MJD. We show that Cul1 is able to genetically modify mutant huntingtin aggregates because its silencing results in increased aggregate load in cultured cells. Moreover, we demonstrate that silencing dCul1 and dSkp1 in Drosophila results in increased aggregate load and enhanced polyQ-induced toxicity. Our results imply that reduced levels of SCF complex might contribute to polyQ disease pathology.

}, keywords = {Animals, Cullin Proteins, Drosophila, Female, Humans, Huntington Disease, Machado-Joseph Disease, Male, Mice, Mice, Transgenic, Peptides, SKP Cullin F-Box Protein Ligases}, issn = {2041-4889}, doi = {10.1038/cddis.2012.166}, author = {Bhutani, S and Das, A and Maheshwari, M and Lakhotia, S C and Jana, N R} } @article {719, title = {Functional tumor infiltrating TH1 and TH2 effectors in large early-stage cervical cancer are suppressed by regulatory T cells.}, journal = {Int J Gynecol Cancer}, volume = {22}, year = {2012}, month = {2012 Sep}, pages = {1130-7}, abstract = {

OBJECTIVE: Analysis of tumor-infiltrating lymphocytes (TILs) is one of the cornerstones for the understanding of immune responses prevailing in the tumor microenvironment. We studied TILs from squamous cell carcinoma of the cervix ex vivo without proliferating them in vitro before analysis.

METHODS: Whereas TILs were magnetic activated cell separation enriched and flow sorted into CD4 CD25 (regulatory T cells [Tregs]), CD4 CD25 (effector T cells [Teffs]) were directly purified by flow cytometry, and both these subsets were characterized phenotypically and functionally. Tissue sections were probed for interleukin 4 (IL-4) and interferon γ.

RESULTS: Effector T cells constitutively expressed both interferon γ and IL-4 prototypical cytokines of TH1 and TH2, respectively, and were able to proliferate and secrete higher quantities of both cytokines in response to anti-CD3/anti-CD28 and autologous tumor lysates. Only 53\% of cervical cancer Tregs were FOXP3, elaborated transforming growth factor β1, and IL-10 and were able to inhibit both T helper subsets.

CONCLUSIONS: Intratumoral Teffs represented functionally active subsets of both TH1 and TH2 that were not anergic but were suppressed by multiple Treg subsets, which comprised FOXP3 + Tregs and Tregs secreting transforming growth factor β1 and IL-10. These results imply that the microenvironment of cervical carcinomas harbored both TH1 and TH2 subsets of CD4 Teffs that were functionally active but were perhaps unable to perform because of the overpowering effect of Tregs.

}, keywords = {Carcinoma, Squamous Cell, Cytokines, Female, Flow Cytometry, Humans, Immune Tolerance, Interferon-gamma, Lymphocyte Activation, Lymphocytes, Tumor-Infiltrating, Neoplasm Staging, T-Lymphocytes, Regulatory, Th1 Cells, Th2 Cells, Uterine Cervical Neoplasms}, issn = {1525-1438}, doi = {10.1097/IGC.0b013e318262aa53}, author = {Adurthi, Sreenivas and Mukherjee, Geetashree and Krishnamurthy, H and Sudhir, Krishna and Bafna, Uttamchand D and Umadevi, Kswamy and Jayshree, Rudrapatna Subramanyam} }