Cerebrospinal fluid evaluation as a diagnosis and prognosis tool: a bibliometric analysis of the 100 most cited articles / Avaliação do líquido cefalorraquidiano enquanto ferramenta diagnóstica e prognóstica: uma análise bibliométrica dos 100 artigos mais citados / Evaluación del líquido cefalorraquídeo como herramienta de diagnóstico y pronóstico: un análisis bibliométrico de los 100 artículos más citados

Introduction: Cerebrospinal fluid (CSF) analysis is critical in the diagnosis, prognosis, and treatment of a wide range of diseases, including multiple sclerosis, encephalitis, meningitis, brain tumors, Creutzfeldt-Jakob disease, Alzheimer's disease, and other neurodegenerative conditions. Objective: Bibliometric analysis of the 100 most cited articles to obtain deeper insights into the status of research in this sector, in order to provide support for evidence-based medicine (EBM). Methodology: The main collection of the Web of Science was used to collect relevant studies on the topic, and the VOSviewer software was employed to build bibliometric networks. The examination did not include materials from editorials, books, patents, or research with unspecified designs. The articles chosen are in the time range from 1991 to 2020. Results: It was noted that most of the articles were human observational studies focusing on the diagnosis of neurodegenerative diseases, specifically Alzheimer's, which were published in neurology and/or Alzheimer's-related journals, mainly in the United States of America. We discovered forward-looking research hotspots and trends in this domain, which can serve as an important guide to neurological research, generating subsidies for medical decision- making. Conclusion: The number of primary articles on the subject points to the need for further future research on CSF associated, mainly, with other neurodegenerative diseases, in addition to Alzheimer's, sustaining the diagnostic efficacy and EBM.

Introdução: A análise do líquido cefalorraquidiano (LCR) é fundamental no diagnóstico, prognóstico e tratamento de uma ampla gama de doenças, incluindo esclerose múltipla, encefalite, meningite, tumores cerebrais, doença de Creutzfeldt-Jakob, doença de Alzheimer e outras condições neurodegenerativas. Objetivo: Análise bibliométrica dos 100 artigos mais citados para obter insights mais aprofundados sobre o status da pesquisa nesse setor, a fim de fornecer subsídios para a medicina baseada em evidências (MBE). Metodologia: O acervo principal da Web of Science foi utilizado para coletar estudos relevantes sobre o tema, e o software VOSviewer foi empregado para construir redes bibliométricas. O exame não incluiu materiais de editoriais, livros, patentes ou pesquisas com desenhos não especificados. Os artigos escolhidos estão no intervalo de tempo de 1991 a 2020. Resultados: Observou-se que a maioria dos artigos eram estudos observacionais humanos com foco no diagnóstico de doenças neurodegenerativas, especificamente Alzheimer, que foram publicados em revistas de neurologia e/ou relacionadas ao Alzheimer, principalmente nos Estados Unidos da América. Descobrimos focos de pesquisa prospectivos e tendências nesse domínio, que podem servir como um importante guia para a pesquisa neurológica, gerando subsídios para a tomada de decisões médicas. Conclusão: O número de artigos primários sobre o tema aponta para a necessidade de novas pesquisas futuras sobre LCR associado, principalmente, a outras doenças neurodegenerativas, além da doença de Alzheimer, sustentando a eficácia diagnóstica e a BEM.

Introducción: El análisis del líquido cefalorraquídeo (LCR) es crítico en el diagnóstico, pronóstico y tratamiento de una amplia gama de enfermedades, incluyendo esclerosis múltiple, encefalitis, meningitis, tumores cerebrales, enfermedad de Creutzfeldt-Jakob, enfermedad de Alzheimer y otras afecciones neurodegenerativas. Objetivo: Análisis bibliométrico de los 100 artículos más citados para profundizar en el estado de la investigación en este sector, con el fin de dar soporte a la medicina basada en la evidencia (MBE). Metodología: Se utilizó la colección principal de la Web of Science para recopilar estudios relevantes sobre el tema, y se empleó el software VOSviewer para construir redes bibliométricas. El examen no incluyó materiales de editoriales, libros, patentes o investigaciones con diseños no especificados. Los artículos elegidos están en el rango de tiempo de 1991 a 2020. Resultados: Se observó que la mayoría de los artículos eran estudios observacionales en humanos centrados en el diagnóstico de enfermedades neurodegenerativas, específicamente Alzheimer, que fueron publicados en revistas de neurología y/o relacionadas con el Alzheimer, principalmente en los Estados Unidos de América. Descubrimos puntos calientes de investigación con visión de futuro y tendencias en este dominio, que pueden servir como una guía importante para la investigación neurológica, generando subsidios para la toma de decisiones médicas. Conclusión: El número de artículos primarios sobre el tema apunta a la necesidad de futuras investigaciones sobre el LCR asociadas, principalmente, con otras enfermedades neurodegenerativas, además del Alzheimer, manteniendo la eficacia diagnóstica y la MBE.

Impact of Adolescent Personality Disorders on Obesity 17 Years Later.

OBJECTIVES: To investigate associations between adolescent personality disorder (PD) and obesity 17 years later. METHODS: The Children in the Community is a longitudinal study based on a randomly sampled cohort of families, in effect since 1975. PDs were assessed in youths by self-report and mother report in 1985 to 1986, when participants were at an average age of 16 years. Obesity was assessed in 2001 to 2004 when participants were an average age of 33 years (n = 621). RESULTS: Prevalence of obesity was 16.59% (103/621) at an average age of 33 years. Prevalence of any adolescent PD was 17.55% (109/621) at an average age of 16 years. Adolescents who had any PD were 1.84 (95% confidence interval [CI] = 1.05-3.22) times as likely to be obese 17 years later after adjusting for demographic variables and known risk factors. Paranoid, histrionic, and obsessive-compulsive PDs in adolescence were significantly associated with obesity in adulthood, with odds ratios of 3.45 (95% CI = 1.46-8.17), 4.49 (95% CI = 1.91-10.53), and 6.80 (95% CI = 2.50-18.55), respectively. CONCLUSIONS: This is the first study to report a significant independent long-term association based on prospective data between adolescent PDs and adult obesity in a community-based sample. Findings will contribute to the design of preventive measures against the development of obesity.

Decreased adipogenesis and adipose tissue in mice with inactivated protein phosphatase 5.

Glucocorticoids play an important role in the treatment of inflammation and immune disorders, despite side effects, which include metabolic derangements such as central adiposity. These studies examine the role of protein phosphatase 5 (Ppp5) in glucocorticoid receptor (GR) complexes which mediate response to glucocorticoids. Mice homozygous for inactivated Ppp5 (Ppp5D274A/D274A) exhibit decreased adipose tissue surrounding the gonads and kidneys compared with wild-type mice. Adipocyte size is smaller, more preadipocytes/stromal cell are present in their gonadal fat tissue and differentiation of preadipocytes to adipocytes is retarded. Glucocorticoid levels are raised and the GR is hyperphosphorylated in adipose tissue of Ppp5D274A/D274A mice at Ser212 and Ser220 (orthologous to human Ser203 and Ser211) in the absence of glucocorticoids. Preadipocyte cultures from Ppp5D274A/D274A mice show decreased down regulation of Delta-like protein-1/preadipocyte factor-1, hyperphosphorylation of extra-cellular signal regulated kinase 2 (ERK2) and increased concentration of (sex determining region Y)-box 9 (SOX9), changes in a pathway essential for preadipocyte differentiation, which leads to decreased concentrations of the transcription factors CEBPß and CEBPα necessary for the later stages of adipogenesis. The data indicate that Ppp5 plays a crucial role in modifying GR-mediated initiation of adipose tissue differentiation, suggesting that inhibition of Ppp5 may potentially be beneficial to prevent obesity during glucocorticoid treatment.

The efficacy of religious service attendance in reducing depressive symptoms.

PURPOSE: To examine whether religiosity may help people ward off depression, we investigated the association between religious service attendance and depressive symptom scores in a community-based 30-year follow-up longitudinal study. METHODS: This study used data on 754 subjects followed over 30 years and evaluated at four time points. Linear mixed effects models were used to assess the association between religious service attendance and depressive symptoms development; frequency of attendance and age also were used as predictors. Demographic factors, life-time trauma, family socioeconomic status, and recent negative events were considered as control variables. RESULTS: Depressive symptom scores were reduced by an average of 0.518 units (95 % CI from -0.855 to -0.180, p < 0.005) each year in subjects who attended religious services as compared with subjects who did not. The more frequent the religious service attendance, the stronger the influence on depressive symptoms when compared with non-attendance. Yearly, monthly, and weekly religious service attendance reduced depression scores by 0.474 (95 % CI from -0.841 to -0.106, p < 0.01), 0.495 (95 % CI from -0.933 to -0.057, p < 0.05) and 0.634 (95 % CI from -1.056 to -0.212, p < 0.005) units on average, respectively, when compared with non-attendance after controlling for other covariates. CONCLUSION: Religious service attendance may reduce depressive symptoms significantly, with more frequent attendance having an increasingly greater impact on symptom reduction in this 30-year community-based longitudinal study.

Glucose-6-phosphate-mediated activation of liver glycogen synthase plays a key role in hepatic glycogen synthesis.

The liver responds to an increase in blood glucose levels in the postprandial state by uptake of glucose and conversion to glycogen. Liver glycogen synthase (GYS2), a key enzyme in glycogen synthesis, is controlled by a complex interplay between the allosteric activator glucose-6-phosphate (G6P) and reversible phosphorylation through glycogen synthase kinase-3 and the glycogen-associated form of protein phosphatase 1. Here, we initially performed mutagenesis analysis and identified a key residue (Arg(582)) required for activation of GYS2 by G6P. We then used GYS2 Arg(582)Ala knockin (+/R582A) mice in which G6P-mediated GYS2 activation had been profoundly impaired (60-70%), while sparing regulation through reversible phosphorylation. R582A mutant-expressing hepatocytes showed significantly reduced glycogen synthesis with glucose and insulin or glucokinase activator, which resulted in channeling glucose/G6P toward glycolysis and lipid synthesis. GYS2(+/R582A) mice were modestly glucose intolerant and displayed significantly reduced glycogen accumulation with feeding or glucose load in vivo. These data show that G6P-mediated activation of GYS2 plays a key role in controlling glycogen synthesis and hepatic glucose-G6P flux control and thus whole-body glucose homeostasis.

Protein phosphatase 4 is phosphorylated and inactivated by Cdk in response to spindle toxins and interacts with γ-tubulin.

Many pharmaceuticals used to treat cancer target the cell cycle or mitotic spindle dynamics, such as the anti-tumor drug, paclitaxel, which stabilizes microtubules. Here we show that, in cells arrested in mitosis with the spindle toxins, nocodazole, or paclitaxel, the endogenous protein phosphatase 4 (Ppp4) complex Ppp4c-R2-R3A is phosphorylated on its regulatory (R) subunits, and its activity is inhibited. The phosphorylations are blocked by roscovitine, indicating that they may be mediated by Cdk1-cyclin B. Endogenous Ppp4c is enriched at the centrosomes in the absence and presence of paclitaxel, nocodazole, or roscovitine, and the activity of endogenous Ppp4c-R2-R3A is inhibited from G 1/S to the G 2/M phase of the cell cycle. Endogenous γ-tubulin and its associated protein, γ-tubulin complex protein 2, both of which are essential for nucleation of microtubules at centrosomes, interact with the Ppp4 complex. Recombinant γ-tubulin can be phosphorylated by Cdk1-cyclin B or Brsk1 and dephosphorylated by Ppp4c-R2-R3A in vitro. The data indicate that Ppp4c-R2-R3A regulates microtubule organization at centrosomes during cell division in response to stress signals such as spindle toxins, paclitaxel, and nocodazole, and that inhibition of the Ppp4 complex may be advantageous for treatment of some cancers.

Impact of early adolescent anxiety disorders on self-esteem development from adolescence to young adulthood.

PURPOSE: To examine the association between early adolescent anxiety disorders and self-esteem development from early adolescence through young adulthood. METHODS: Self-esteem was measured at mean ages 13, 16, and 22 for 821 participants from the Children in the Community Study, a population-based longitudinal cohort. Anxiety disorders were measured at mean age 13 years. Multilevel growth models were employed to analyze the change in self-esteem from early adolescence to young adulthood and to evaluate whether adolescent anxiety disorders predict both average and slope of self-esteem development. RESULTS: Self-esteem increased during adolescence and continued to increase in young adulthood. Girls had lower average self-esteem than boys, but this difference disappeared when examining the effect of anxiety. Adolescents with anxiety disorder had lower self-esteem, on average, compared with healthy adolescents (effect size [ES] = -.35, p < .01). Social phobia was found to have the greatest relative impact on average self-esteem (ES = -.30, p < .01), followed by overanxious disorder (ES = -.17, p < .05), and simple phobia (ES = -.17, p < .05). Obsessive compulsive-disorder (OCD) predicted a significant decline in self-esteem from adolescence to young adulthood (ß = -.1, p < .05). Separation anxiety disorder was not found to have any significant impact on self-esteem development. CONCLUSIONS: All but one of the assessed adolescent anxiety disorders were related to lower self-esteem, with social phobia having the greatest impact. OCD predicted a decline in self-esteem trajectory with age. The importance of raising self-esteem in adolescents with anxiety and other mental disorders is discussed.

The MAOA gene predicts happiness in women.

Psychologists, quality of life and well-being researchers have grown increasingly interested in understanding the factors that are associated with human happiness. Although twin studies estimate that genetic factors account for 35-50% of the variance in human happiness, knowledge of specific genes is limited. However, recent advances in molecular genetics can now provide a window into neurobiological markers of human happiness. This investigation examines association between happiness and monoamine oxidase A (MAOA) genotype. Data were drawn from a longitudinal study of a population-based cohort, followed for three decades. In women, low expression of MAOA (MAOA-L) was related significantly to greater happiness (0.261 SD increase with one L-allele, 0.522 SD with two L-alleles, P=0.002) after adjusting for the potential effects of age, education, household income, marital status, employment status, mental disorder, physical health, relationship quality, religiosity, abuse history, recent negative life events and self-esteem use in linear regression models. In contrast, no such association was found in men. This new finding may help explain the gender difference on happiness and provide a link between MAOA and human happiness.

On the Origins of Disorganized Attachment and Internal Working Models: Paper II. An Empirical Microanalysis of 4-Month Mother-Infant Interaction.

A microanalysis of 4-month mother-infant face-to-face communication predicted 12-month infant disorganized (vs. secure) attachment outcomes in an urban community sample. We documented a dyadic systems view of the roles of both partners, the roles of both self- and interactive contingency, and the importance of attention, orientation and touch, and as well as facial and vocal affect, in the co-construction of attachment disorganization. The analysis of different communication modalities identified striking intrapersonal and interpersonal intermodal discordance or conflict, in the context of intensely distressed infants, as the central feature of future disorganized dyads at 4 months. Lowered maternal contingent coordination, and failures of maternal affective correspondence, constituted maternal emotional withdrawal from distressed infants. This maternal withdrawal compromises infant interactive agency and emotional coherence. We characterize of the nature of emerging internal working models of future disorganized infants as follows: Future disorganized infants represent states of not being sensed and known by their mothers, particularly in moments of distress; they represent confusion about both their own and their mothers' basic emotional organization, and about their mothers' response to their distress. This internal working model sets a trajectory in development which may disturb the fundamental integration of the person. The remarkable specificity of our findings has the potential to lead to more finely-focused clinical interventions.

Early cannabis use and schizotypal personality disorder symptoms from adolescence to middle adulthood.

BACKGROUND: While increasing evidence suggests that cannabis use may play a role in the development of schizophrenia in some young people, less is known about the strength and specificity of its relationship to latent schizophrenia liability, i.e., schizotypal personality disorder traits. AIMS: Determine the predictive value of cannabis use during childhood and early adolescence on schizotypal personality disorder (SPD) symptoms projecting into adulthood, using a community-based longitudinal cohort from upstate New York. METHOD: Prospective data from 804 participants was used to determine associations between early cannabis use and later schizotypal symptoms, accounting for important potential confounds (e.g., adolescent schizotypal symptoms). RESULTS: Cannabis use with onset prior to age 14 strongly predicted SPD symptoms in adulthood, independent of early adolescent SPD symptoms, major depression, anxiety disorder, other drug use, and cigarette use. There was no interaction effect of early cannabis use and early adolescent SPD symptoms on SPD symptoms into adulthood. CONCLUSIONS: Our data provide further support for a strong association of early cannabis use with the development of symptoms characteristic of schizophrenia spectrum disorders. As with studies in schizophrenia, early SPD symptoms could not fully explain the association of early cannabis use with later schizotypal symptoms. The mechanisms that underlie the association of cannabis use and schizotypal symptoms in a developmental context deserve further exploration.

Contribution of family violence to the intergenerational transmission of externalizing behavior.

Research finds that early antisocial behavior is a risk for later intimate partner violence (IPV) perpetration and victimization, and that children's exposure to their parents' IPV is a risk for subsequent behavior problems. This study tests whether intimate violence (IPV) between partners contributes independently to the intergenerational transmission of antisocial behavior, using the Children in the Community Study, a representative sample (N = 821) followed for over 25 years in 6 assessments. The present study includes a subsample of parents (N = 678) and their offspring (N = 396). We test the role of three mechanisms by which IPV may influence child antisocial behavior-parental psychopathology, parenting practices, and child self-regulation. Results suggest that IPV independently increased the risk for offspring externalizing problems, net of the effects of parental history of antisocial behavior and family violence. IPV also increased the risk for parental post traumatic stress disorder (PTSD) and alcohol use disorder 2 years later, but not for major depressive disorder. Alcohol use disorder independently increased the risk for offspring externalizing behavior, but IPV continued to predict offspring externalizing net of parental alcohol use. Parenting, particularly low satisfaction with the child, was significantly associated with both IPV and externalizing behavior, but did not mediate the effects of IPV on externalizing. IPV predicted higher levels of emotional expressivity, aggression and hostile reactivity, and depressive mood in offspring. Implications for future research and prevention are discussed.

Exposure to intimate partner violence, peer relations, and risk for internalizing behaviors: a prospective longitudinal study.

The present study examines the quality of peer relations as a mediator between exposure to IPV (intimate partner violence) and internalizing behaviors in a sample of 129 preadolescents and adolescents (ages 10-18), who were interviewed via telephone as part of a multigenerational, prospective, longitudinal study. Relational victimization is also examined as a moderator of IPV exposure on internalizing behaviors. Results demonstrate a significant association of exposure to severe IPV and internalizing behaviors. Relational victimization is found to moderate the effects of exposure to severe IPV on internalizing behaviors. The present findings suggest that the effects of exposure to IPV had a particularly important effect on the risk for internalizing problems if the adolescent also experienced relational victimization. Conversely, the receipt of prosocial behaviors buffer against the effects of IPV exposure on internalizing symptoms in teen girls.

Direct and indirect transmission of relationship functioning across generations.

Relationship functioning is assumed to propagate across subsequent generations, but most studies have lacked appropriate methodologies to test this assumption prospectively. In a randomly selected sample of youth (N = 821) followed prospectively for over 25 years across multiple generations, we examined the association of romantic engagement (i.e., emotional involvement and closeness) between parents with offspring romantic relationship quality. We tested two developmental pathways linking parents' romantic engagement with offspring adult romantic relationship quality, the first operating via parenting practices, and the second operating via adolescent depression. Parents' romantic engagement predicted offspring romantic relationship quality a mean of 17 years later, net age and socioeconomic status. Results supported a developmental pathway from parents' romantic engagement at offspring mean age 14, to parenting at offspring mean age 16, to offspring socioemotional functioning at mean age 22, and offspring romantic relationship quality at mean age 33. However, the influence of parents' romantic engagement on offsprings' adult romantic relationship quality does not appear to operate via a pathway of adolescent depression. Implications for prevention are discussed.

Parenting behaviours associated with the development of adaptive and maladaptive offspring personality traits.

OBJECTIVES: To investigate the associations of beneficial parenting behaviours with adaptive and maladaptive offspring personality traits that persist into adulthood among individuals in the community. METHODS: Families (n = 669) participating in the Children in the Community Study were interviewed during the childhood, adolescence, emerging adulthood, and adulthood of the offspring at the mean ages of 6, 14, 16, 22, and 33 years. RESULTS: Twelve types of beneficial maternal and paternal child-rearing behaviour, reported by offspring at the mean age of 16 years, were associated with elevated offspring personality resiliency, at the mean ages of 22 and 33 years, and with low offspring personality disorder trait levels. These longitudinal associations remained significant when histories of childhood behaviour problems and parental psychiatric disorder were controlled statistically. Similar linear (that is, dose-dependent) associations were observed between the number of beneficial parenting behaviours during childhood and adaptive and maladaptive offspring traits at the mean ages of 22 and 33 years. Maternal and paternal behaviours were independently associated with both adaptive and maladaptive offspring traits. CONCLUSIONS: Beneficial maternal and paternal child-rearing behaviours may promote the development of adaptive offspring personality traits that endure into adulthood, and they may be prospectively associated with reduced levels of maladaptive offspring traits. These associations may not be attributable to childhood behaviour problems or parental psychiatric disorders, and they may be equally evident during early and middle adulthood.

R3F, a novel membrane-associated glycogen targeting subunit of protein phosphatase 1 regulates glycogen synthase in astrocytoma cells in response to glucose and extracellular signals.

Abnormal regulation of brain glycogen metabolism is believed to underlie insulin-induced hypoglycaemia, which may be serious or fatal in diabetic patients on insulin therapy. A key regulator of glycogen levels is glycogen targeted protein phosphatase 1 (PP1), which dephosphorylates and activates glycogen synthase (GS) leading to an increase in glycogen synthesis. In this study, we show that the gene PPP1R3F expresses a glycogen-binding protein (R3F) of 82.8 kDa, present at the high levels in rodent brain. R3F binds to PP1 through a classical 'RVxF' binding motif and substitution of Phe39 for Ala in this motif abrogates PP1 binding. A hydrophobic domain at the carboxy-terminus of R3F has similarities to the putative membrane binding domain near the carboxy-terminus of striated muscle glycogen targeting subunit G(M)/R(GL), and R3F is shown to bind not only to glycogen but also to membranes. GS interacts with PP1-R3F and is hyperphosphorylated at glycogen synthase kinase-3 sites (Ser640 and Ser644) when bound to R3F(Phe39Ala). Deprivation of glucose or stimulation with adenosine or noradrenaline leads to an increased phosphorylation of PP1-R3F bound GS at Ser640 and Ser644 curtailing glycogen synthesis and facilitating glycogen degradation to provide glucose in astrocytoma cells. Adenosine stimulation also modulates phosphorylation of R3F at Ser14/Ser18.

Relative impact of Axis I mental disorders on quality of life among adults in the community.

BACKGROUND: Little is known about the relative impact of different mental disorders on adult quality of life (QOL). This study estimated associations between several mental disorders and QOL in a representative American community sample. METHODS: The QOL instrument was administered to 640 adult participants in the Children in the Community Study, a population-based longitudinal study. DSM-Axis I and Axis II mental disorder diagnoses were assessed by psychiatric interview. RESULTS: Poorer QOL was strongly associated with having a mood disorder, especially major depression disorder (MDD) (effect size, ES = -0.57, p < 0.01), whereas poorer quality social relationships were associated with having dysthymia and bipolar disorders (ES = -0.92, p < 0.01; ES = -0.80, p < 0.05, respectively). Most anxiety disorders were not independently related to QOL with the exception of post traumatic stress disorder (PTSD), which was significantly related to poorer physical health (ES = -0.78, p < 0.01) and psychological well-being (ES = -0.73, p < 0.01) and to less overall QOL (ES = -0.57, p < 0.01). CONCLUSIONS: MDD and PTSD are independently related to impaired QOL and dysthymia and bipolar disorder negatively influence social relationships.

Identification of the human testis protein phosphatase 1 interactome.

Protein phosphorylation is a critical regulatory mechanism in cellular signalling. To this end, PP1 is a major eukaryotic serine/threonine-specific phosphatase whose cellular functions, in turn, depend on complexes it forms with PP1 interacting proteins-PIPs. The importance of the testis/sperm-enriched variant, PP1γ2, in sperm motility and spermatogenesis has previously been shown. Given the key role of PIPs, it is imperative to identify the physiologically relevant PIPs in testis and sperm. Hence, we performed Yeast Two-Hybrid screens of a human testis cDNA library using as baits the different PP1 isoforms and also a proteomic approach aimed at identifying PP1γ2 binding proteins. To the best of our knowledge this is the largest data set of the human testis PP1 interactome. We report the identification of 77 proteins in human testis and 7 proteins in human sperm that bind PP1. The data obtained increased the known PP1 interactome by reporting 72 novel interactions. Confirmation of the interaction of PP1 with 5 different proteins was also further validated by co-immunoprecipitation or protein overlays. The data here presented provides important insights towards the function of these proteins and opens new possibilities for future research. In fact, such diversity in PP1 regulators makes them excellent targets for pharmacological intervention.