• Metabolic Control of Autoimmunity in the Liver

      Perl, Andras; Oaks, Zachary (2016)
      Autophagy,literally meaning “self-eating,” is an integral part of cellularturnover of damaged organelles and proteins.This process is inextricably linked to mitochondrial function and turnover. Mitochondria can be degraded viaautophagy, known as mitophagy, as well as donate lipid membraneto generate autophagosomes fordigestingother organelles and proteins. On a larger scale, autophagy is essential for organ homeostasis. In the liver, autophagy ensures the turnover of damaged mitochondria that may otherwise increase oxidative stress which modifies DNA, proteins, and lipids resulting in the production of autoantigens or neoplasia. We investigated the role of autophagy and mitochondrial dysfunction prior to disease onset in mouse models of systemic lupus erythematosus (SLE). Patients and mice with SLE exhibit overexpression of transaldolase (TAL) and show predisposition to anti-phospholipid antibody production and associated liver diseases, including hepatocellular carcinoma. Wediscovered deficient mitophagy in the liver of lupus-prone mice prior to disease onset. Furthermore, these mice had increased mitochondrial respirationwith concomitant inner membrane hyperpolarization. These changes were coupled to overexpression of Rab4A, which depletes Drp1and thus inhibitsmitophagy.In addition,activation of complex I of the mechanistic target of rapamycin (mTORC1)was noted along with enhanced production of autoantibodies against mitochondrial phospholipids in lupus-prone mice. These changes were reversed by blockade of mTORC1 by rapamycin treatment in vivo. We then examined the role of TAL, a key enzyme of the pentose phosphate pathway (PPP) in mitochondrial dysfunction and oxidative stress. TAL-deficientmice showedincreased mitochondrial electron transport chain (ETC) activity and mTORC1 activation andreduced autophagy.Since inactivation of TAL caused oxidative stress via depletion of NADPH, we tested the hypothesis that aldose reductase(AR), a NADPH dependent enzymecan correct this metabolic defect without reversing the accumulation of TAL-specific substrates, sedoheptulose 7-phosphate and erythrose 4-phosphate. Moreover, deletion of AR reversed mTORC1 activation without affecting enhanced mitochondrial ETC activity or diminished autophagy. On a more global scale, predisposition to neoplasia and acetaminophen-induced liver failurewere reversed, while anti-phospholipid autoantibody production and liver fibrosis persisted in TAL/AR double-knockout mice indicatingthat the PPPmay act as a metabolic rheostat of organ-specific disease pathogenesis.
    • Metabolic Control of Autoimmunity Through Autophagy

      Choudhary, Gourav (2019)
      Metabolism plays a key role in immune cell activation and differentiation. Immune cell activation depending on their biosynthetic and bioenergetic needs leads to profound metabolic reprograming. Proinflammatory subsets of immune system cells such as effector T cells show dependency on glycolysis, whereas, regulatory T cells rely on oxidative phosphorylation. Under metabolic stress, immune cells utilize autophagy to overcome nutrient scarcity, an alternate method of recycling amino acids and other metabolic precursors. Limitation of nutrients such as amino acids activates mechanistic target of rapamycin (mTOR) in the immune cells. mTOR acts as a metabolic mediator, associated with mitochondria and metabolic needs of the immune cells. Homeostasis between mTOR activation and autophagy decides the fate and functionality of specific immune cells. The activation of mTOR is widely acknowledged in the pathogenesis of SLE, whereas, autophagy has been linked with antigen processing, presentation, and immunoregulation. In this study, we focused on Rab4A, an endosomal GTPase and Transaldolase, a rate limiting enzyme of the pentose phosphate pathway (PPP). Rab4A is over expressed in SLE T cells and facilitates lysosomal degradation of CD4 and CD3. Transaldolase is also overexpressed in T cells from SLE patients and SLE prone mice. First, we examined the role of Rab4A in a pristane-induced mouse model of SLE. Since Rab4A protects from pristane-induced alveolar lung hemorrhage, we tested the hypothesis that Rab4A will also protect from pristane-induced lupus nephritis. We found that overexpression of a constitutively active form of Rab4A limits antinuclear antibody production. Further, we found that Rab4A protects from pristane-induced renal injury by restricting immune complex depositions in the kidney. In additions, we found that Rab4A abrogates kidney-infiltration by lymphocytes and protects from podocyte injury. Furthermore, Rab4A facilitates the lysosomal mediated activation of mTOR. Possibly, the Rab4A mediated activation of mTOR in regulatory T cells leads to suppression of pristane-induced pro-inflammation signaling. In the second part, we investigated if aldose reductase (AR) deficiency can protect from Transaldolase mediated pathogenesis of liver disease. We found a coordinated regulation between AR and TAL, leading to the disease progression.
    • MITOCHONDRIAL ELECTRON TRANSPORT CHAIN ACTIVITY IN SYSTEMIC LUPUS ERYTHEMATOSUS

      Perl, Andras; Doherty, Edward (2014)
      Systemic lupus erythematosus (SLE) is an autoimmune disorder, characterized by T cell and B cell dysfunction. SLE mitochondria have been shown to be dysfunctional with increased mass, mitochondrial potential, decreased ATP, elevated reactive oxygen species (ROS) and reactive nitrogen species (RNS) concentrations, and altered Ca2+ stores. Drug treatments that target the mitochondria have shown efficacy in treating SLE. Here we have investigated electron transport chain (ETC) activity in SLE, to better understand the causes of mitochondrial dysfunction in SLE. We have found that mitochondrial complexes I and IV of the ETC have elevated respiration in SLE compared to healthy controls after both overnight resting and anti-CD3/CD28 stimulation. We have also shown that SLE complex I is resistant to NO inhibition of respiration. SLE peripheral blood lymphocytes (PBL) have increased S-nitrosylation (SNO) while immunoprecipitated complex I had decreased SNO of proteins compared to healthy controls. The drug Nacetylcysteine (NAC) was able to inhibit complex I activity in SLE, and was found to reduce the amount of complex I protein NDUFS3 after 15 minutes as measured by western blotting. These results have led us to the conclusion that SLE mitochondrial complex I is in an active form which is resistant to SNO and is driving the production of ROS and RNS that are associated with SLE. The drug NAC is able to inhibit complex I respiration which may have therapeutic efficacy by reducing the ROS and RNS stress in SLE.
    • MITOCHONDRIAL PROTEINS AS TUMOR MARKERS AND ANTI-CANCER DRUG TARGETS

      Sheikh, Saeed; Babbar, Mansi (2017)
      Cancer is a major cause of morbidity and mortality. Identification and characterization of novel biomarkers are expected to facilitate early diagnosis and improve prognosis of human malignancies. Increasing number of studies have linked tumor progression with metabolic reprogramming. However, the players involved are not fully discovered. Therefore, understanding the cancer cell plasticity may offer a successful approach for an anti-cancer strategy. In this regard, we report the functional characterization of Coiled-coil Helix Tumor and Metabolism 1 (CHTM1) and KM1 as important regulator of cancer cell metabolism.CHTM1 is localized in cytosol and mitochondrial inter-membrane spaceand regulates mitochondrial activity. Our results demonstrate that MIA40 appears to alterCHTM1 mitochondrial localizationand stability. Further, CHTM1 cysteineresiduesinvolved in CHTM1 folding modulatescellular distributionof CHTM1. Importantly, alterations in CHTM1 expression in cancer cells affect mitochondrial activity. Given thatmitochondria play an important role in cellular response to nutrient stress, we sought to analyze the role of CHTM1 in glucose/glutamine-deprived conditions. Wehave found thatCHTM1 deficiency enhancescancer cell sensitivityto glucose/glutamine starvation and metformin treatment. Additionally, increased sensitivity of CHTM1-deficient cells to metabolic stress could be in part due to inability to activate fatty acid oxidation. Further, targeting CHTM1 expression in cancer cells reduce fatty acid oxidation causing decrease in substrate availability under metabolic stress conditions. This can explain the increase in autophagy and protein catabolism in CHTM1-deficient cancer cells under metabolic stress conditions. Mechanistic studies suggest that CHTM1-mediated alterations in cancer cell metabolism under stress conditions involve modulation of PGC1 alpha-CREB-PKC signaling.We further demonstrate that under metabolic stress, CHTM1 deficiency activates p38-AIF1pathway leading to increased cell death. CHTM1 negatively regulates p38 and interacts with AIF1 alteringAIF1release frommitochondria under metabolic stress conditions.These findings are highly significant because alterations in cancer cell metabolism are linked to pathogenesis of cancer. Most importantly, multiple human malignancies associated with breast, colon and lung tissuesshow increase in CHTM1 expression. CHTM1 appears to be a high value tumor marker, that has the potential tofacilitate earlydiagnosis of human malignancies and could also serve as a target to develop novel therapeutics to manage human malignancies. In the second part of this manuscript, we report the characterization of a novel protein temporarily named as KM1. Our results indicate that KM1 is localized inthemitochondrial inner membrane and regulates mitochondrial activity. Metabolic stress-induced increased cell death is noted in KM1 knockout cancer cells, a finding consistent with the defective mitochondria in KM1-deficient cells. Our results further demonstrate that under metabolic stress KM1 regulates mitochondrial-mediated cell death. Most importantly, KM1 levels are upregulated in breast and lung cancer tissues.Collectively, our results suggest that CHTM1 and KM1 are novel proteins and are involved in regulating cancer cell metabolism.
    • Molecular Analysisof Saccharomyc escerevisiae RNA Polymerase I Core Factor Complex and its Interaction with Promoter DNA

      Knutson, Bruce; Jackobel, Ashleigh J (2020)
      Gene transcription and protein synthesis are essential molecular processes required for all living organisms. In eukaryotes, messages encoded within DNA are transcribed by three DNA-dependent RNA polymerases (Pols I-III) into ribosomal RNA (rRNA), messenger RNA (mRNA), and transfer RNA (tRNA), respectively. General transcription factors (GTFs) help recruit Pols to their appropriate gene promoters as well as facilitate template opening and transcription start site (TSS) selection. In Saccharomyces cerevisiae, the Pol I pre-initiation complex (PIC) is formed by numerous GTFs that include Upstream Activating Factor (UAF), Core Factor (CF), TATA-binding protein (TBP), and Rrn3. This unique set of GTFs engage ribosomal DNA (rDNA) through interactions with regulatory elements of the promoter known as the Upstream Activating Sequence (UAS) and the Core Element (CE). Here, we resolve the cryo-electron microscopy (cryo-EM) structure of CF bound to the rDNA promoter at 3.8Å near-atomic resolution and determine itsDNA binding preferences in which CF preferentially binds to the GC-minor groove. Briefly, our cryo-EM studies reveal that the CF-DNA interaction is mediated by two CF subunits, Rrn7 and Rrn11. We also found that the path of promoter DNA is relatively straight in the Pol I PIC, which is strikingly different from the bent promoters observed in structures of the Pols II/III PICs. We identified three states of CF engagement with promoter DNA (States 1-3) in which CF acts as a ratchet toforceDNA into the active site of the polymerase that facilitates the melting of the double-stranded DNA template in an ATP-independent manner, another unique feature of the Pol I system. Using in vitroDNA binding assays, we have identified a 12 base pair (bp) region within the CE that is necessary and sufficient for CF binding. We have also demonstrated that the human anticancer compound CX-5461 can inhibit yeast cell growth and blocks yeast CF binding to both yeast and human rDNA promoters in vitro. Furthermore, we show that the human Core Promoter Element (CPE) can functionally replace the yeast CE in a position-dependent manner. Together, these results reveal the unique molecular architecture of the Pol I PIC and suggest a conserved sequence-independent binding mechanism of CF with promoter DNA.
    • The monoamine oxidase B gene exhibits significant association to ADHD

      Li, Jun; Wang, Yufeng; Hu, Songnian; Zhou, Rulun; Yu, Xiaomin; Wang, Bing; Guan, Lili; Yang, Li; Zhang, Feng; Faraone, Stephen V. (Wiley, 2008)
      Attention deficit hyperactivity disorder (ADHD) is a common neuropsychiatric condition with strong genetic basis. Recent work in China indicated that ADHD may be linked to Xp1–2 in the Han Chinese population. The gene encoding monoamine oxidase B (MAOB), the main enzyme degrading dopamine in the human brain, is located in this region. The current study sequenced the exons and the 50 and 30 flanking regions of theMAOBgene and found four common variants including 2276C>T and 2327C>T in exon 15, rs1799836 in intron 13 and rs1040399 in 30-UTR. We assessed the association of these variants with ADHD in 548 trios collected from 468 males and 80 females probands. TDT analysis showed that alleles of each polymorphism were preferentially transmitted to probands (rs1799836, P¼3.28E-15; rs1040399, P¼1.87E-6; 2276T>C or 2327T>C, P¼2.20E-6) and haplotype-based TDT analyses also found distorted transmission. In conclusion, this study provides the strongest evidence for the involvement of MAOB gene in the etiology of ADHD to date, at least in Han Chinese population.
    • MULTI-FUNCTIONAL EFFECTOR RESPONSES ELICITED FROM IgM MEMORY STEM CELLS

      Winslow, Gary; Kenderes, Kevin (2017)
      The response of memory B cells to challenge infection is fundamental to longterm protection against pathogens. Following challenge, memory B cells can rapidly differentiate into antibody-secreting cells (ASCs) to produce a secondary antibody response. Memory B cells have also been shown to re-enter into germinal centers and undergo additional rounds of affinity maturation. Both the isotype of the B cell and the signals that generated the B cell have been proposed to modulate how memory B cells respond. Initial studies proposed BCR-intrinsic factors are responsible for the differentiation of memory cells. IgM memory cells undergo differentiation in GCs following antigen challenge, while IgG memory cells rapidly differentiate into ASCs. Other studies found no link-between BCR isotype and differentiation. We investigated the differentiation of T-bet+ CD11c+ IgM memory B cells following challenge infection. IgM memory cells differentiated into IgM-producing plasmablasts. Other IgM memory B cells entered germinal centers, underwent class switching, and became switched memory cells. Yet other donor cells were maintained as IgM memory cells. The IgM memory cells also retained their multi-lineage potential following serial transfer. The kinetics of the IgM memory response mimicked the kinetics of the primary response. Thus, IgM memory cells can differentiate into all effector B cell lineages, and undergo self-renewal, properties that are characteristic of stem cells; however, differentiation occurs with the same kinetics of the primary response. We propose that memory B cells have varying degrees of stem cell likeness. IgM memory stem cells retain the most differentiating capacity but respond to challenge similarly to naïve cells, while IgG effector memory cells are primed to rapidly differentiate into IgG ASCs.
    • The multidimensionality of schizotypy in nonpsychotic relatives of patients with schizophrenia and its applications in ordered subsets linkage analysis of schizophrenia

      Lien, Yin-Ju; Tsuang, Hui-Chun; Chiang, Abigail; Liu, Chih-Min; Hsieh, Ming H.; Hwang, Tzung-Jeng; Liu, Shi K.; Hsiao, Po-Chang; Faraone, Stephen V.; Tsuang, Ming T.; et al. (Wiley, 2009)
      This study aimed to examine the multidimensionality of schizotypy and validate the structure using ordered subset linkage analyses on information from both relatives’ schizotypy and probands’ schizophrenia symptoms. A total of 203 and 1,310 nonpsychotic first-degree relatives from simplex and multiplex schizophrenia families, respectively, were interviewed with the Diagnostic Interview for Genetic Studies, which contains a modified Structured Interview for Schizotypy. Using Mplus program with categorical factor indicators, a four-factor model (Negative Schizotypy, Positive Schizotypy, Interpersonal Sensitivity, and Social Isolation/Introversion) was extracted by exploratory factor analysis from relatives of simplex families and was confirmed in relatives of multiplex families. The validity of each factor was supported by distinct linkage findings resulting from ordered subset analysis based on different combinations of schizophrenia–schizotypy factors. Six chromosomal regions with significant increase in nonparametric linkage z score (NPL-Z) were found as follows: 15q21.1 (NPLZ ¼3.60) for Negative Schizophrenia–Negative Schizotypy, 10q22.3 (NPL-Z¼3.83) and 15q21.3 (NPL-Z¼3.36) for Negative Schizophrenia–Social Isolation/Introversion, 5q14.2 (NPL-Z¼3.20) and 11q23.3 (NPL-Z¼3.31) for Positive Schizophrenia–Positive Schizotypy, and 4q32.1 (NPL-Z¼3.31- ) for Positive Schizophrenia–Interpersonal Sensitivity. The greatest NPL-Z of 3.83 on 10q22.3 in the subset was significantly higher than the greatest one of 2.88 in the whole sample (empirical P-value¼0.04). We concluded that a consistent four-factor model of schizotypy could be derived in nonpsychotic relatives across families of patients with different genetic loadings in schizophrenia. Their differential relations to linkage signals have etiological implications and provide further evidence for their validity. 2009 Wiley-Liss, Inc.
    • NEAR-ATOMIC RESOLUTION STRUCTURE OF THE YEAST VACUOLAR (V-) ATPASE MEMBRANE SECTOR Vo IN LIPID NANODISC

      Wilkens, Stephan; Stam, Nicholas J (2020-04-10)
      Vacuolar ATPase (V-ATPase) is a large multisubunit enzyme that acidifies subcellular organelles and the extracellular space. Its activity is regulated by reversible disassembly, causing V-ATPase dissociation into soluble V1-ATPase and membrane-integral Voproton channel sectors.The goal of this thesis project was to observethe yeast Voin a physiologically relevant, auto-inhibited state, i.e. in its form dissociated from the ATPase sector, V1, in order to better visualizethe closed pore and to identify testable hypotheses on why the pore remains closed following dissociation from V1. Towards this aim we present two chapters:In Chapter 1, we detail a single-particle negative stain EM study of lipid nanodisc reconstituted Vo,which suggesteddissociated Vois halted in theso-called rotational state 3 of the holo-enzyme.We performed site directed mutagenesis and binding studies of subunits aand dto test and validate this hypothesis.In Chapter 2,we further detaillipid nanodisc reconstitutedVoin a high-resolutioncryoEM structure,confirmingour earlier identification of Voresting in rotational state 3, andproviding structural information of the sectorat the amino acid level. Through this work we proposed apossible mechanism for transmembrane proton transport in the V-ATPaseandidentifieda new subunit member of Vo, assembly factor Voa1.The studies shown here highlight the potential of lipid nanodisc reconstitution of membrane protein complexes, give insight into a conformational mismatch between autoinhibited V1and halted Vowith the implication that the mismatch may serve to prevent unintended reassembly of V-ATPase upon activity silencing, and propose a chemical basis for transmembrane proton transport in the Voproton pore.
    • Neuropsychological intra-individual variability explains unique genetic variance of ADHD and shows suggestive linkage to chromosomes 12, 13, and 17

      Frazier-Wood, Alexis C.; Bralten, Janita; Arias-Vasquez, Alejandro; Luman, Marjolein; Ooterlaan, Jaap; Sergeant, Joseph; Faraone, Stephen V.; Buitelaar, Jan; Franke, Barbara; Kuntsi, Jonna; et al. (Wiley, 2012-01-05)
      Attention-deficit/hyperactivity disorder (ADHD) is a highly heritable neuropsychiatric disorder that is usually accompanied by neuropsychological impairments. The use of heritable, psychometrically robust traits that show association with the disorder of interest can increase the power of gene-finding studies. Due to the robust association of intra-individual variability with ADHD on a phenotypic and genetic level, intra-individual variability is a prime candidate for such an attempt. We aimed to combine intra-individual variability measures across tasks into one more heritable measure, to examine the relatedness to other cognitive factors, and to explore the genetic underpinnings through quantitative trait linkage analysis. Intra-individual variability measures from seven tasks were available for 238 ADHD families (350 ADHD-affected and 195 non-affected children) and 147 control families (271 children). Intra-individual variability measures from seven different tasks shared common variance and could be used to construct an aggregated measure. This aggregated measure was largely independent from other cognitive factors related to ADHD and showed suggestive linkage to chromosomes 12q24.3 (LOD ¼ 2.93), 13q22.2 (LOD ¼ 2.36), and 17p13.3 (LOD ¼ 2.00). A common intra-individual variability construct can be extracted from very diverse neuropsychological tasks; this construct taps into unique genetic aspects of ADHD and may relate to loci conferring risk for ADHD (12q24.3 and 17p13.3) and possibly autism (12q24.3). Given that joining of data across sites boosts the power for genetic analyses, our findings are promising in showing that intra-individual variability measures are viable candidates for across site analyses where different tasks have been used.
    • The new neuropsychiatric genetics

      Faraone, Stephen V.; Smoller, J.W.; Pato, C.N.; Sullivan, P.; Tsuang, M.T. (Wiley, 2008-01-05)
    • NIMH genetics initiative millennium schizophrenia consortium: Linkage analysis of African-American pedigrees

      Kaufmann, Charles A.; Suarez, Brian; Malaspina, Dolores; Pepple, John; Svrakic, Dragan; Markel, Paul D.; Meyer, Joanne; Zambuto, Christopher T.; Schmitt, Karin; Matise, Tara Cox; et al. (Wiley, 1998-07-10)
      The NIMH Genetics Initiative is a multi-site collaborative study designed to create a national resource for genetic studies of complex neuropsychiatric disorders. Schizophrenia pedigrees have been collected at three sites: Washington University, Columbia University, and Harvard University. This article—one in a series that describes the results of a genome-wide scan with 459 short-tandem repeat (STR) markers for susceptibility loci in the NIMH Genetics Initiative schizophrenia sample—presents results for African-American pedigrees. The African-American sample comprises 30 nuclear families and 98 subjects. Seventy-nine of the family members were considered affected by virtue of having received a DSMIII-R diagnosis of schizophrenia (n = 71) or schizoaffective disorder, depressed (n = 8). The families contained a total of 42 independent sib pairs. While no region demonstrated evidence of significant linkage using the criteria suggested by Lander and Kruglyak, several regions, including chromosomes 6q16-6q24, 8pter-8q12, 9q32-9q34, and 15p13-15q12, showed evidence consistent with linkage (P = 0.01–0.05), providing independent support of findings reported in other studies. Moreover, the fact that different genetic loci were identified in this and in the European-American samples, lends credence to the notion that these genetic differences together with differences in environmental exposures may contribute to the reported differences in disease prevalence, severity, comorbidity, and course that has been observed in different racial groups in the United States and elsewhere. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 81:282–289, 1998. © 1998 Wiley-Liss, Inc.
    • The p53-Zn2+ Energy Landscape and Metallochaperone Hypothesis

      Loh, Stewart; Blanden, Adam (2017)
      p53 is a tumor suppressor protein found mutated in essentially half of human cancers, and dysfunctional in nearly all human cancers. Each DNA-binding domain of the protein contains a critical tetrahedrally coordinated Zn2+. In this work, we present a quantitative thermodynamic model describing the energetics of the p53-Zn2+ interaction, as well as the mechanism of action of a new class of therapeutic compounds we call synthetic zinc metallochaperones (ZMC) that restore proper structure and function to many mutant p53s by delivering Zn2+ to the protein in the cell. We combine recombinant protein expression and in vitrobiophysical characterization with cell biology, molecular biology, medicinal chemistry, and live cell imaging to address these issues. Our model for both the mechanism of action of ZMCs and the p53-Zn2+interaction are broadly based on the Metallochaperone Hypothesis originally proposed by our group in 2010. We find that the core tenants of the Metallochaperone Hypothesis are accurate, and have expanded that model to quantitatively describe the link between p53-Zn2+ binding and protein stability noted for decades in the field. We find that at physiological temperature and Zn2+ concentrations, wild-type p53 has a folding energy of ~0 kcal mol-1, and as such is exquisitely sensitive to inactivation by mutation, and rapidly changes the fraction folded in response to changes in Zn2+ concentration. We demonstrate that ZMCs are ionophores, transport Zn2+ from the extracellular space into cells, and rescue mutant p53 by increasing the intracellular free Zn2+ concentration. This increase in Zn2+ stabilizes the mutant proteins via the same mechanism previously described for substrate stabilization of enzymes, and is only seen in a "Goldilocks Zone" of Zn2+ concentrations and ZMC Kds. This presents a fundamentally new way to interact with and reactivate mutant p53s, and raises questions about the potential for biological exploitation of this interaction for signaling or other functions.
    • Patterns of Psychopathology and Dysfunction in High-Risk Children of Parents With Panic Disorder and Major Depression

      Biederman, Joseph; Faraone, Stephen V.; Hirshfeld-Becker, Dina R.; Friedman, Deborah; Robin, Joanna A.; Rosenbaum, Jerrold F. (American Psychiatric Association Publishing, 2001-01)
      Objective: The purpose of the study was to evaluate 1) whether an underlying familial predisposition is shared by all anxiety disorders or whether specific risks are associated with specific disorders, and 2) whether panic disorder and major depression have a familial link. Method: The study compared four groups of children: 1) offspring of parents with panic disorder and comorbid major depression (N=179), 2) offspring of parents with panic disorder without comorbid major depression (N=29), 3) offspring of parents with major depression without comorbid panic disorder (N=59), and 4) offspring of parents with neither panic disorder nor major depression (N=113). Results: Parental panic disorder, regardless of comorbidity with major depression, was associated with an increased risk for panic disorder and agoraphobia in offspring. Parental major depression, regardless of comorbidity with panic disorder, was associated with increased risks for social phobia, major depression, disruptive behavior disorders, and poorer social functioning in offspring. Both parental panic disorder and parental major depression, individually or comorbidly, were associated with increased risk for separation anxiety disorder and multiple (two or more) anxiety disorders in offspring. Conclusions: These findings confirm and extend previous results documenting significant associations between the presence of panic disorder and major depression in parents and patterns of psychopathology and dysfunction in their offspring.
    • Pediatric mania: a developmental subtype of bipolar disorder?

      Biederman, Joseph; Mick, Eric; Faraone, Stephen V.; Spencer, Thomas; Wilens, Timothy E; Wozniak, Janet (Elsevier BV, 2000-09)
      Despite ongoing controversy, the view that pediatric mania is rare or nonexistent has been increasingly challenged not only by case reports, but also by systematic research. This research strongly suggests that pediatric mania may not be rare but that it may be difficult to diagnose. Since children with mania are likely to become adults with bipolar disorder, the recognition and characterization of childhood-onset mania may help identify a meaningful developmental subtype of bipolar disorder worthy of further investigation. The major difficulties that complicate the diagnosis of pediatric mania include: 1) its pattern of comorbidity may be unique by adult standards, especially its overlap with attention-deficit/hyperactivity disorder, aggression, and conduct disorder; 2) its overlap with substance use disorders; 3) its association with trauma and adversity; and 4) its response to treatment is atypical by adult standards. Biol Psychiatry 2000;48: 458–466 © 2000 Society of Biological Psychiatry.
    • Pediatric mania: a developmental subtype of bipolar disorder?

      Biederman, Joseph; Mick, Eric; Faraone, Stephen V.; Spencer, Thomas; Wilens, Timothy E; Wozniak, Janet (Elsevier BV, 2000-09)
    • PHOSPHORYLATION AND UBIQUITINATION REGULATE PROTEIN PHOSPHATASE 5 ACTIVITY AND ITS PROSURVIVAL ROLE IN KIDNEY CANCER

      Mollapour, Mehdi; Dushukyan, Natela (2018)
      Protein Phosphatase 5 (PP5) is a serine/threonine phosphatase known to regulate many essential cellular functions including steroid hormone signaling, stress response, proliferation, apoptosis, and DNA repair. PP5 is a knownco-chaperone of the molecular chaperone heat shock protein 90 (Hsp90), and its regulation of Hsp90aidswiththe proper activation of Hsp90 clients and withsteroid hormone signaling.Hsp90 is also one of the strongest activators of PP5, as it releases the auto-inhibition of PP5 by interacting with the N-terminal tetratricopeptide repeat (TPR) domain of PP5. Our lab has recently shown that PP5 is phosphorylated at T362, and that this phosphorylation acts as an “on switch” resultingin the hyperactivation of PP5. Misregulation of this key phosphatase has been shown to aid in the tumor progression of ER-dependent and independent breast cancer. Elevated PP5 levels have also been linked to colorectalcancer, hepatocellular carcinoma (HCC), lymphoma, and prostate cancer. The work presented here reveals the pro-survival role that PP5 plays in kidney cancer. Clear cell renal cell carcinomas (ccRCC) are most often driven by mutations in the von Hippel-Lindau tumor suppressor (VHL). The data in this thesis shows that VHL binds and multi mono-ubiquitinates PP5 at two lysine residues K185 and K199. This post-translational modification negatively regulates PP5 likean “off switch” and ultimately leads to its degradation bythe proteasome. Mutations in the VHLgene that result in inactive mutants or a lack of VHL protein expression lead to ccRCC tumors. The data in this thesis shows that these VHL-nulltumors become dependent on elevated levels of PP5, and that both PP5 knockdown and inhibition lead to cancer cell death. The data further shows that the decrease in PP5 activity in VHL-null cells results in the induction of the extrinsic apoptotic pathway with a dramatic increase in the cleavage of PARP and caspases 3, 7, and 8.
    • Placebo and nocebo responses in randomised, controlled trials of medications for ADHD: a systematic review and meta-analysis

      Faraone, Stephen V.; Newcorn, Jeffrey H.; Cipriani, Andrea; Brandeis, Daniel; Kaiser, Anna; Hohmann, Sarah; Haege, Alexander; Cortese, Samuele (Springer Science and Business Media LLC, 2021-05-10)
      The nature and magnitude of placebo and nocebo responses to ADHD medications and the extent to which response to active medications and placebo are inter-correlated is unclear. To assess the magnitude of placebo and nocebo responses to ADHD and their association with active treatment response. We searched literature until June 26, 2019, for published/ unpublished double-blind, randomised placebo-controlled trials (RCTs) of ADHD medication. Authors were contacted for additional data. We assessed placebo effects on efficacy and nocebo effects on tolerability using random effects metaanalysis. We assessed the association of study design and patient features with placebo/nocebo response. We analysed 128 RCTs (10,578 children/adolescents and 9175 adults) and found significant and heterogenous placebo effects for all efficacy outcomes, with no publication bias. The placebo effect was greatest for clinician compared with other raters. We found nocebo effects on tolerability outcomes. Efficacy outcomes from most raters showed significant positive correlations between the baseline to endpoint placebo effects and the baseline to endpoint drug effects. Placebo and nocebo effects did not differ among drugs. Baseline severity and type of rating scale influenced the findings. Shared non-specific factors influence response to both placebo and active medication. Although ADHD medications are superior to placebo, and placebo treatment in clinical practice is not feasible, clinicians should attempt to incorporate factors associated with placebo effects into clinical care. Future studies should explore how such effects influence response to medication treatment. Upon publication, data will be available in Mendeley Data: PROSPERO (CRD42019130292).