Neha Tiwari

The aim of our study is to compare the outcomes in unilateral and bilateral cochlear implants in pediatric age and also between simultaneous and sequential cochlear implant surgery. This retrospective study was carried out with 83 children aged between 12 months to 2.5 years which included 41 children with bilateral Cochlear implants and 42 with unilateral implants. Out of these 41 children, 21 were simultaneous and 20 were sequential cochlear implant. All the children were operated at civil hospital Gandhinagar, Gujarat, India. CAP, SIR, localization, traffic noise and speech in noise scores were assessed at regular intervals over the period of 4 years. Also the drug administration time, surgical time, operating room time were assessed for simultaneous and sequential cochlear implant surgery. Children with bilateral simultaneous implants fared significantly better with CAP, SIR, localization, speech noise and traffic noise scores than sequential bilateral implants and unilateral implants with a significant difference of means t tests between the two groups. Simultaneous cochlear implant surgery is associated with reduced surgical time, operating room time, it shortens the total in patient stay. There is less of drug administration and bilateral ones are stimulated simultaneously. Bilateral cochlear implants perform better with respect to auditory perception skills and spontaneous speech when compared with unilateral implants, but simultaneous surgery is better and safe option for pediatric cochlear implantation.

The set of events that convert adherent epithelial cells into migratory cells are collectively known as epithelial–mesenchymal transition (EMT). EMT is involved during development, for example, in triggering neural crest migration, and in pathogenesis such as metastasis. Here we discover FBXO32, an E3 ubiquitin ligase, to be critical for hallmark gene expression and phenotypic changes underlying EMT. Interestingly, FBXO32 directly ubiquitinates CtBP1, which is required for its stability and nuclear retention. This is essential for epigenetic remodeling and transcriptional induction of CtBP1 target genes, which create a suitable microenvironment for EMT progression. FBXO32 is also amplified in metastatic cancers and its depletion in a NSG mouse xenograft model inhibits tumor growth and metastasis. In addition, FBXO32 is essential for neuronal EMT during brain development. Together, these findings establish that FBXO32 acts as an upstream regulator of EMT by governing the gene expression program underlying this process during development and disease.

Pax6 is a highly conserved transcription factor among vertebrates and is important in various aspects of the central nervous system development. However, the gene regulatory circuitry of Pax6 underlying these functions remains elusive. We find that Pax6 targets a large number of promoters in neural progenitors cells. Intriguingly, many of these sites are also bound by another progenitor factor, Sox2, which cooperates with Pax6 in gene regulation. A combinatorial analysis of Pax6-binding data set with transcriptome changes in Pax6-deficient neural progenitors reveals a dual role for Pax6, in which it activates the neuronal (ectodermal) genes while concurrently represses the mesodermal and endodermal genes, thereby ensuring the unidirectionality of lineage commitment towards neuronal differentiation. Furthermore, Pax6 is critical for inducing activity of transcription factors that elicit neurogenesis and repress others that promote non-neuronal lineages. In addition to many established downstream effectors, Pax6 directly binds and activates a number of genes that are specifically expressed in neural progenitors but have not been previously implicated in neurogenesis. The in utero knockdown of one such gene, Ift74, during brain development impairs polarity and migration of newborn neurons. These findings demonstrate new aspects of the gene regulatory circuitry of Pax6, revealing how it functions to control neuronal development at multiple levels to ensure unidirectionality and proper execution of the neurogenic program.

The epithelial to mesenchymal transition (EMT) is a biological process in which cells lose cell–cell contacts and become motile. EMT is used during development, for example, in triggering neural crest migration, and in cancer metastasis. Despite progress, the dynamics of JNK signaling, its role in genomewide transcriptional reprogramming, and involved downstream effectors during EMT remain largely unknown. Here, we show that JNK is not required for initiation, but progression of phenotypic changes associated with EMT. Such dependency resulted from JNK‐driven transcriptional reprogramming of critical EMT genes and involved changes in their chromatin state. Furthermore, we identified eight novel JNK‐induced transcription factors that were required for proper EMT. Three of these factors were also highly expressed in invasive cancer cells where they function in gene regulation to maintain mesenchymal identity. These factors were also induced during neuronal development and function in neuronal migration in vivo. These comprehensive findings uncovered a kinetically distinct role for the JNK pathway in defining the transcriptome that underlies mesenchymal identity and revealed novel transcription factors that mediate these responses during development and disease. Synopsis Combining transcriptome analysis and patient data, this study illustrates how JNK signaling drives EMT progression via a panel of specific transcription factors, several of which are linked to EMT for the first time. JNK signaling is essential for progression of epithelial to mesenchymal transition (EMT). EMT relies on JNK‐dependent transcriptional reprogramming of many crucial EMT genes. JNK‐induced novel transcription factors are critically required for acquisition and maintenance of the mesenchymal fate. These novel factors are highly expressed in invasive cancer cells where they function in gene regulation to maintain metastatic identity. These factors were also induced during neuronal development and function in neuronal migration in vivo.

Acquiring resistance against transforming growth factor β (TGFβ)‐induced growth inhibition at early stages of carcinogenesis and shifting to TGFβ's tumour‐promoting functions at later stages is a pre‐requisite for malignant tumour progression and metastasis. We have identified the transcription factor distal‐less homeobox 2 (Dlx2) to exert critical functions during this switch. Dlx2 counteracts TGFβ‐induced cell‐cycle arrest and apoptosis in mammary epithelial cells by at least two molecular mechanisms: Dlx2 acts as a direct transcriptional repressor of TGFβ receptor II ( TGF β RII ) gene expression and reduces canonical, Smad‐dependent TGFβ signalling and expression of the cell‐cycle inhibitor p21CIP1 and increases expression of the mitogenic transcription factor c‐Myc. On the other hand, Dlx2 directly induces the expression of the epidermal growth factor (EGF) family member betacellulin, which promotes cell survival by stimulating EGF receptor signalling. Finally, Dlx2 expression supports experimental tumour growth and metastasis of B16 melanoma cells and correlates with tumour malignancy in a variety of human cancer types. These results establish Dlx2 as one critical player in shifting TGFβ from its tumour suppressive to its tumour‐promoting functions.