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Mitochondria are versatile organelles that regulate several physiological functions. Many mitochondria-controlled processes are driven by mitochondrial Ca (2+) signaling. However, role of mitochondrial Ca (2+) signaling in melanosome biology remains unknown. Here, we show that pigmentation requires mitochondrial Ca (2+) uptake. In vitro gain and loss of function studies demonstrated that Mitochondrial Ca (2+) Uniporter (MCU) is crucial for melanogenesis while the MCU rheostats, MCUb and MICU1 negatively control melanogenesis. Zebrafish and mouse models showed that MCU plays a vital role in pigmentation in vivo . Mechanistically, MCU controls activation of transcription factor NFAT2 to induce expression of three keratins (keratin 5, 7 and 8), which we report as positive regulators of melanogenesis. Interestingly, keratin 5 in turn modulates mitochondrial Ca (2+) uptake thereby this signaling module acts as a negative feedback loop that fine-tunes both mitochondrial Ca (2+) signaling and melanogenesis. Mitoxantrone, an FDA approved drug that inhibits MCU, decreases physiological melanogenesis. Collectively, our data demonstrates a critical role for mitochondrial Ca (2+) signaling in vertebrate pigmentation and reveal the therapeutic potential of targeting MCU for clinical management of pigmentary disorders. Given the centrality of mitochondrial Ca (2+) signaling and keratin filaments in cellular physiology, this feedback loop may be functional in a variety of other pathophysiological conditions. HIGHLIGHTS: MCU complex mediated mitochondrial Ca (2+) uptake is a novel regulator of vertebrate pigmentation . Keratin filaments bridge mitochondrial Ca (2+) signaling to melanosome biogenesis and maturation . Transcription factor NFAT2 connects mitochondrial Ca (2+) dynamics to keratins expression . MCU-NFAT2-Keratin 5 signaling module generates a negative feedback loop to maintain mitochondrial Ca (2+) homeostasis and to ensure optimal melanogenesis . Inhibiting MCU with mitoxantrone, an FDA approved drug, leads to reduction in physiological pigmentation.

In earlier years, there was abundance of funds in banks in the form of demand and savings deposits. Hence, the focus of banks was mainly on asset management. But intense competition and volatility of interest rate due to banking reforms reduced the availability of low-cost funds and therefore, banks focused on liability management as well. These pressures call for structured and comprehensive measures and not just ad hoc action. This is how banks started to concentrate more on the management of both sides of the balance sheet. As a result, the concept of asset-liability management originated in India and introduced in the Indian banking industry since 1st April 1999 to administer the risk management aspects. This paper attempts to optimize assets and liabilities of banks using goal programming technique. Secondary data is collected from annual reports of Allahabad bank from 2010-2019 and RBI website is used for modelling. The findings show that in Allahabad bank, goal programming help in achieving optimization and increase profitability. The model incorporating constraints and set objectives. It model can support banks in decision making process, planning, budgeting, and forecasting. An attempt is made to use realistic goals and constraints after discussing with bank officials. JEL Classification Codes: C61, G21, G32.

Stromal Interaction Molecule1 (STIM1) is an endoplasmic reticulum membrane-localized calcium (Ca

Asset Liability Management has gained popularity in the banking sector. Earlier banks focused on asset allocation, but now the management of assets and liabilities is equally essential. Asset liability management targets the optimum distribution of funds in assets and managing liabilities so that banks can earn higher profits and minimize risk. In this paper, the optimization of assets and liabilities of Indian banks has been concentrated using mathematical models. Combining the Analytical Hierarchy Process (AHP) and Goal Programming (GP) model has been used to solve the optimization problem. AHP is a multi-criteria decision-making approach for deriving priority weights. Goal Programming is a linear programming model to solve complex issues having multiple objectives. In this paper, the primary data gathered from Bank senior managers have been analyzed using the AHP approach to derive weights for criteria. These weights are assigned to goals in goal programming to prioritize the goals. Secondary data on OBC bank is used in goal programming from 2010-2019 collected from OBC bank's annual reports and RBI websites. The findings show that OBC bank has the scope of improving its assets and liabilities position to increase its profit and minimize the risk. The model generates an optimum balance sheet that achieves the set goals and satisfies all the statutory and planning constraints. The same model can be useful for scheduled commercial banks in India with modifications concerning banks' targets and controls. The model developed in this paper is helpful for bank managers in planning and forecasting. AHP and GP's combined approach is unique in this paper, which uses experts' knowledge and applies it in the model. The model is created on the bank's realistic goals and constraints after carefully considering the issues faced by bank officials. The paper is limited to the Indian Banking system as other countries have different balance sheet structures and constraints.

This study examines the efficiency of the overall Indian banking industry using Data Envelopment Analysis (DEA) and to perform a comparative efficiency analysis of public, private, and foreign banks using six varied forms. Also, providing ranks to the banks based on their efficiency. The study incorporates BCC output-oriented DEA model using a sample of 50 Indian banks (public banks = 17, private banks = 18, foreign banks = 15) for a period ranging from 2009-10 to 2018-19, hence incorporating the after-effects of the financial crisis and demonetization, this study uses panel data from 2009-10 to 2018-19. The results showed that most of the Indian banks fall on the efficient side or are near to full efficiency. However, public banks outperform private and foreign banks in terms of their average efficiency. Results also specify that the performance of banks is sensitive to input-output variables, units under evaluation, and choice of the model. The current study has just focused on the internal factors for analyzing the efficiency of Indian banks; however, certain external factors might also impact the banks’ efficiency.

Simple Summary Pancreatic cancer (PC) is one of the most lethal forms of cancers with 5-year mean survival rate of less than 10%. Most of the PC associated deaths are due to metastasis to secondary sites. Calcium (Ca2+) signaling plays a critical role in regulating hallmarks of cancer progression including cell proliferation, migration and apoptotic resistance. Here, we demonstrate that a highly Ca2+ selective plasma membrane channel Orai3 is overexpressed in PC and is associated with poor prognosis in PC patients. Our data demonstrate that Orai3 modulates PC cell proliferation, apoptosis and migration. We further reveal that Orai3 regulates PC metastasis in immune-compromised mice. Collectively, our study establishes Orai3 as an attractive therapeutic target for managing PC metastasis, which may lead to better prognosis. Abstract Store operated Ca2+ entry (SOCE) mediated by Orai1/2/3 channels is a highly regulated and ubiquitous Ca2+ influx pathway. Although the role of Orai1 channels is well studied, the significance of Orai2/3 channels is still emerging in nature. In this study, we performed extensive bioinformatic analysis of publicly available datasets and observed that Orai3 expression is inversely associated with the mean survival time of PC patients. Orai3 expression analysis in a battery of PC cell lines corroborated its differential expression profile. We then carried out thorough Ca2+ imaging experiments in six PC cell lines and found that Orai3 forms a functional SOCE channel in PC cells. Our in vitro functional assays show that Orai3 regulates PC cell cycle progression, apoptosis and migration. Most importantly, our in vivo xenograft studies demonstrate a critical role of Orai3 in PC tumor growth and secondary metastasis. Mechanistically, Orai3 controls G1 phase progression, matrix metalloproteinase expression and epithelial-mesenchymal transition in PC cells. Taken together, this study for the first-time reports that Orai3 drives aggressive phenotypes of PC cells, i.e., migration in vitro and metastasis in vivo. Considering that Orai3 overexpression leads to poor prognosis in PC patients, it appears to be a highly attractive therapeutic target.

Long non‐coding RNAs (lncRNAs) are emerging as key regulators of endothelial cell function. Here, we investigated the role of a novel vascular endothelial‐associated lncRNA (VEAL2) in regulating endothelial permeability. Precise editing of veal2 loci in zebrafish (veal2 gib005Δ8/+) induced cranial hemorrhage. In vitro and in vivo studies revealed that veal2 competes with diacylglycerol for interaction with protein kinase C beta‐b (Prkcbb) and regulates its kinase activity. Using PRKCB2 as bait, we identified functional ortholog of veal2 in humans from HUVECs and named it as VEAL2. Overexpression and knockdown of VEAL2 affected tubulogenesis and permeability in HUVECs. VEAL2 was differentially expressed in choroid tissue in eye and blood from patients with diabetic retinopathy, a disease where PRKCB2 is known to be hyperactivated. Further, VEAL2 could rescue the effects of PRKCB2‐mediated turnover of endothelial junctional proteins thus reducing hyperpermeability in hyperglycemic HUVEC model of diabetic retinopathy. Based on evidence from zebrafish and hyperglycemic HUVEC models and diabetic retinopathy patients, we report a hitherto unknown VEAL2 lncRNA‐mediated regulation of PRKCB2, for modulating junctional dynamics and maintenance of endothelial permeability., The evolutionarily conserved lncRNA VEAL2 enhances junctional integrity in developing zebrafish vasculature and in hyperglycemic vascular endothelium in humans.

In the neural crest lineage, progressive fate-restriction and stem cell assignment are critical for both development and regeneration. While the fate-commitment events have distinct transcriptional footprints, fate-biasing is often transitory and metastable, and is thought to be moulded by epigenetic programs. Hence molecular basis of specification is difficult to define. In this study, we establish a role of a histone variant H2a.z.2 in specification of melanocyte lineage from multipotent neural crest cells. Silencing of H2a.z.2 reduces the number of melanocyte precursors in developing zebrafish embryos, and from mouse embryonic stem cells in vitro. We demonstrate that this histone variant occupies nucleosomes in the promoter of key melanocyte determinant Mitf, and enhances its induction. CRISPR-Cas9 based targeted mutagenesis of this gene in zebrafish drastically reduces adult melanocytes, as well as their regeneration. Thereby our study establishes the role of a histone variant upstream to the core gene regulatory network in the neural crest lineage. This epigenetic mark is a key determinant of cell fate and facilitates gene activation by external instructive signals thereby establishing melanocyte fate identity.

Store Operated Ca2+ Entry (SOCE) mediated by Orai channels is a ubiquitous Ca2+ influx pathway that regulates several cellular functions. We have earlier reported that Orai3, the mammalian specific Orai1 homolog, plays a critical role in breast cancer progression. More recently, Orai3 was demonstrated to regulate prostate and lung tumorigenesis. Although the tumorigenic potential of Orai3 is associated with increase in its expression, the molecular machinery regulating its expression remains largely unexplored. Here, by performing extensive bioinformatics analysis and functional studies, we identify and characterize micro-RNAs (miRNAs) that regulate Orai3 expression and function. We demonstrate that miR18a and miR18b positively regulate Orai3 whereas miR34a represses Orai3 expression and function. All these miRs exert their effect on Orai3 by virtue of their direct action on Orai3 3'UTR. These miRs provide novel opportunities for targeting Orai3 for better management of cancer. This study further opens up the possibility of targeting specific Orai homologs by different miRs in tissue and disease specific context.

Viral infections are one of the leading causes of human illness. Viruses take over host cell signaling cascades for their replication and infection. Calcium (Ca2+) is a versatile and ubiquitous second messenger that modulates plethora of cellular functions. In last two decades, a critical role of host cell Ca2+ signaling in modulating viral infections has emerged. Furthermore, recent literature clearly implicates a vital role for the organellar Ca2+ dynamics (influx and efflux across organelles) in regulating virus entry, replication and severity of the infection. Therefore, it is not surprising that a number of viral infections including current SARS-CoV-2 driven COVID-19 pandemic are associated with dysregulated Ca2+ homeostasis. The focus of this review is to first discuss the role of host cell Ca2+ signaling in viral entry, replication and egress. We further deliberate on emerging literature demonstrating hijacking of the host cell Ca2+ dynamics by viruses. In particular, a variety of viruses including SARS-CoV-2 modulate lysosomal and cytosolic Ca2+ signaling for host cell entry and replication. Moreover, we delve into the recent studies, which have demonstrated the potential of several FDA-approved drugs targeting Ca2+ handling machinery in inhibiting viral infections. Importantly, we discuss the prospective of targeting intracellular Ca2+ signaling for better management and treatment of viral pathogenesis including COVID-19. Finally, we highlight the key outstanding questions in the field that demand critical and timely attention.

In the neural crest lineage, progressive fate-restriction and stem cell assignment are critical for both development and regeneration. While the fate-commitment events have distinct transcriptional footprints, fate-biasing is often transitory and metastable, and is thought to be moulded by epigenetic programs. Hence molecular basis of specification is difficult to define. In this study, we establish a role of a histone variantH2a.z.2in specification of melanocyte lineage from multipotent neural crest cells. Silencing ofH2a.z.2reduces the number of melanocyte precursors in developing zebrafish embryos, and from mouse embryonic stem cellsin vitro. We demonstrate that this histone variant occupies nucleosomes in the promoter of key melanocyte determinantMitf, and enhances its induction. CRISPR-Cas9 based targeted mutagenesis of this gene in zebrafish drastically reduces adult melanocytes, as well as their regeneration. Thereby our study establishes a histone based specification code upstream to the core gene regulatory network in the neural crest lineage of melanocytes. This epigenetic code renders a poised state to the promoter of key determinant and enhances activation by external instructive signals thereby establishing melanocyte fate identity.

Ion channels in particular Calcium (Ca2+) channels play a critical role in physiology by regulating plethora of cellular processes ranging from cell proliferation, differentiation, transcriptional regulation and programmed cell death. One such physiologically important and highly Ca2+ selective channel family is Orai channels consisting of three homologs Orai1, Orai2 and Orai3. Orai channels are responsible for Ca2+ influx across the plasma membrane in response to decrease in Endoplasmic Reticulum (ER) Ca2+ stores. STIM1/STIM2 proteins sense the reduction in ER Ca2+ levels and activate Orai channels for restoring ER Ca2+ as well as for driving cellular functions. This signaling cascade is known as Store Operated Ca2+ Entry (SOCE). Although Orai1 is the ubiquitous SOCE channel protein, Orai2 and Orai3 mediate SOCE in certain specific tissues. Further, mammalian specific homolog Orai3 forms heteromultimeric channel with Orai1 for constituting Arachidonic acid regulated Ca2+ (ARC) channels or arachidonic acid metabolite Leukotriene C4 (LTC4) regulated Ca2+ (LRC) channels. Literature suggests that Orai3 regulates Breast, Prostate, Lung and Gastrointestinal cancers by either forming Store Operated Ca2+ (SOC) or ARC/LRC channels in the cancerous cells but not in healthy tissue. In this review, we would discuss the role of Orai3 in these cancers and would highlight the potential of therapeutic targeting of Orai3 for better management and treatment of cancer. Finally, we will deliberate on key outstanding questions in the field that demand critical attention and further studies.

Endoplasmic reticulum (ER)–plasma membrane (PM) junctions form functionally active microdomains that connect intracellular and extracellular environments. While the key role of these interfaces in maintenance of intracellular Ca 2+ levels has been uncovered in recent years, the functional significance of ER‐PM junctions in non‐excitable cells has remained unclear. Here, we show that the ER calcium sensor protein STIM1 (stromal interaction molecule 1) interacts with the plasma membrane‐localized adenylyl cyclase 6 (ADCY6) to govern melanogenesis. The physiological stimulus α‐melanocyte‐stimulating hormone (αMSH) depletes ER Ca 2+ stores, thus recruiting STIM1 to ER‐PM junctions, which in turn activates ADCY6. Using zebrafish as a model system, we further established STIM19s significance in regulating pigmentation in vivo . STIM1 domain deletion studies reveal the importance of Ser/Pro‐rich C‐terminal region in this interaction. This mechanism of cAMP generation creates a positive feedback loop, controlling the output of the classical αMSH‐cAMP‐MITF axis in melanocytes. Our study thus delineates a signaling module that couples two fundamental secondary messengers to drive pigmentation. Given the central role of calcium and cAMP signaling pathways, this module may be operative during various other physiological processes and pathological conditions.

Store-operated Ca

Store-operated Ca2+ entry (SOCE) mediated by STIM and Orai proteins is a highly regulated and ubiquitous signaling pathway that plays an important role in various cellular and physiological functions. Endoplasmic reticulum (ER) serves as the major site for intracellular Ca2+ storage. Stromal Interaction Molecule 1/2 (STIM1/2) sense decrease in ER Ca2+ levels and transmits the message to plasma membrane Ca2+ channels constituted by Orai family members (Orai1/2/3) resulting in Ca2+ influx into the cells. This increase in cytosolic Ca2+ in turn activates a variety of signaling cascades to regulate a plethora of cellular functions. Evidence from the literature suggests that SOCE dysregulation is associated with several pathophysiologies, including vascular disorders. Interestingly, recent studies have suggested that STIM proteins may also regulate vascular functions independent of their contribution to SOCE. In this updated book chapter, we will focus on the physiological role of STIM and Orai proteins in the vasculature (endothelial cells and vascular smooth muscle cells). We will further retrospect the literature implicating a critical role for these proteins in vascular disease.

Calcium concentration modulation both inside and outside cell is of considerable interest for nervous system function in normal and pathological conditions. MRI has potential for very high spatial resolution at molecular/cellular level. Design, synthesis and evaluation of Gd-DO3A-AME-NPHE, a calcium responsive MRI contrast agent is presented. The probe is comprised of a Gd(3+)-DO3A core coupled to iminoacetate coordinating groups for calcium induced relaxivity switching. In the absence of Ca(2+) ions, inner sphere water binding to the Gd-DO3A-AME-NPHE is restricted with longitudinal relaxivity, r1 = 4.37 mM(-1) s(-1) at 4.7 T. However, addition of Ca(2+) triggers a marked enhancement in r1 = 6.99 mM(-1) s(-1) at 4.7 T (60% increase). The construct is highly selective for Ca(2+) over competitive metal ions at extracellular concentration. The r1 is modulated by changes in the hydration number (0.2 to 1.05), which was confirmed by luminescence emission lifetimes of the analogous Eu(3+) complex. T1 phantom images establish the capability of complex of visualizing changes in [Ca(2+)] by MRI.

A bis-polyazamacrocycle, 10'-bis(acetamido)ethane-bis[1,4,7-tri(carboxymethane)-1,4,7,10-tetraazacyclododecane] (DO3A-AME-DO3A) was synthesized for application in magnetic resonance imaging. The efficacy of DO3A-AME-DO3A as non ionic magnetic contrast agent was tested by performing relaxometric studies on its gadolinium complex. The longitudinal relaxivity, r(1) and transverse relaxivity, r(2) values were found to be 5.84 mM(-1)s(-1) and 6.82 mM(-1)s(-1), per Gd(III) at pH 7.0, 37 °C. The luminescence properties of europium complex of DO3A-AME-DO3A were investigated in aqueous medium. The lifetime of Eu(2)-DO3A-AME-DO3A in water was found to be 0.786 ms. Emission and luminescence lifetime measurements on the europium complex of DO3A-AME-DO3A gives a hydration number of q = 1.9. The reaction enthalpy and entropy were found to be, ΔH(0) = -(6.2 ± 2) kJ mol(-1), ΔS(0) = - (1.8 ± 0.4) kJ mol(-1)K(-1), and K(Eu)(298) = (1.8 ± 0.1).

A phosphonate derivative 10'-bis(acetamido)-ethane-bis[1,4,7-tri(methylene phosphonic acid)-1,4,7,10-tetraazacyclododecane] (DO3P-AME-DO3P), was synthesized with 90% yield in high purity. It was labeled with (99m)Tc in 97.5% efficiency and specific activity of 112-250 MBq/μmol. The binding affinity of (99m)Tc-DO3P-AME-DO3P towards bone minerals was tested in vitro by using hydroxy apatite as a bone model with absorption of 93% during the first hour of the experiment. Receptor binding assay on human bone cell line SAOS-2 demonstrated K(d) value of 1.07 nM. Cell binding studies of DO3P-AME-DO3P on osteoblasts and osteoclasts cells performed in vitro displayed preferential affinity of the compound towards osteoclast (167.95 ± 3.56% dose/mg protein). The serum stability of (99m)Tc complex was found to be 96.8% after 24 h. Blood kinetics of (99m)Tc-DO3P-AME-DO3P performed on normal rabbits showed fast clearance with t(1/2)(F) = 15 min ± 0.014 min and t(1/2)(S) = 4 h 3 min ± 0.09 min. Biodistribution studies carried out in normal BALB/c mice showed bone-to-blood ratio of 20 and bone-to-muscle ratio of 33. The bone tissue demonstrated highest concentration of bound radioactivity with 10.73% ID/g at 1 h post injection. The protonation and stability constants were determined by pH-potentiometry titrations. The stability constants of DO3P-AME-DO3P with Lu(III), Sm(III), and Ho(III) were 19.7, 21.8, and 20.2 determined by "out of cell" method. The excellent bone seeking properties of DO3P-AME-DO3P make it a candidate of choice for SPECT imaging and preferential uptake of the compound in osteoclasts in comparison to osteoblasts; BMM and BMC can be used to understand the pathway of pathogenesis of osteoporosis and skeletal metastases.