Recent advances in small molecule and peptide inhibitors of glucose-regulated protein 78 for cancer therapy.

Glucose-regulated protein 78 (GRP78) is one of key endoplasmic reticulum (ER) chaperone proteins that regulates the unfolded protein response (UPR) to maintain ER homeostasis. As a core factor in the regulation of the UPR, GRP78 takes a critical part in the cellular processes required for tumorigenesis, such as proliferation, metastasis, anti-apoptosis, immune escape and chemoresistance. Overexpression of GRP78 is closely correlated with tumorigenesis and poor prognosis in various malignant tumors. Targeting GRP78 is regarded as a potentially promising therapeutic strategy for cancer therapy. Although none of the GRP78 inhibitors have been approved to date, there have been several studies of GRP78 inhibitors. Herein, we comprehensively review the structure, physiological functions of GRP78 and the recent progress of GRP78 inhibitors, and discuss the structures, in vitro and in vivo efficacies, and merits and demerits of these inhibitors to inspire further research. Additionally, the feasibility of GRP78-targeting proteolysis-targeting chimeras (PROTACs), disrupting GRP78 cochaperone interactions, or covalent inhibition are also discussed as novel strategies for drugs discovery targeting GRP78, with the hope that these strategies can provide new opportunities for targeted GRP78 antitumor therapy.

Parent- and Observer-Rated Positive Affect in Early Childhood: Genetic Overlap and Environmental Specificity.

The sources of individual differences in both observed and parent-rated positive affect (PA) were examined in a sample of 304 3-year-old twin pairs (140 MZ, 164 DZ). Based on model-fitting analyses, individual differences in observed PA were attributed to moderate genetic and high nonshared environmental factors, but not shared environmental factors. In contrast, shared environmental effects accounted for over half of the variance in parent-rated PA and genetic and nonshared environmental effects were more modest. The genetic correlation across the two measures was high, indicating substantial overlap between genetic factors influencing the two. It was these overlapping genetic effects that fully explained the phenotypic correlation between both measures. There was no significant covariance between the environmental influences on parent rated and observed PA. Thus, the two measures of PA in early childhood have common genetic underpinnings, whereas environmental influences are measure-specific. Measurement implications are discussed.

Genetic and environmental links between motor activity level and attention problems in early childhood.

Cross-lagged biometric models were used to examine genetic and environmental links between actigraph-assessed motor activity level (AL) and parent-rated attention problems (AP) in 314 same-sex twin pairs (MZ = 145, DZ = 169) at ages 2 and 3 years. At both ages, genetic correlations between AL and AP were moderate (ra2 = .35; ra3 = .39) indicating both overlap and specificity in genetic effects across the two domains. Within- and across-age phenotypic associations between AL and AP were entirely due to overlapping genetic influences. There was a unidirectional effect of AL at age 2 predicting later AP. For AP, genetic and environmental influences from age 2 were transmitted to age 3 via stability effects and from AL. For AL, across-age effects were transmitted only via stability. These results suggest that overactivity in late infancy may impact the later development of problems related to inattention, and that genetic factors explain the association between the two domains.

Difficult temperament and negative parenting in early childhood: a genetically informed cross-lagged analysis.

A genetically informed longitudinal cross-lagged model was applied to twin data to explore etiological links between difficult temperament and negative parenting in early childhood. The sample comprised 313 monozygotic (MZ) and dizygotic (DZ) twin pairs. Difficult temperament and negative parenting were assessed at ages 2 and 3 using parent ratings. Both constructs were interrelated within and across age (rs .34-.47) and showed substantial stability (rs .65-.68). Difficult temperament and negative parenting were influenced by genetic and environmental factors at ages 2 and 3. The genetic and nonshared environmental correlations (rs .21-.76) at both ages suggest overlap at the level of etiology between the phenotypes. Significant bidirectional associations between difficult temperament and negative parenting were found. The cross-lagged association from difficult temperament at age 2 to negative parenting at age 3 and from negative parenting at age 2 and difficult temperament at age 3 were due to genetic, shared environmental, and nonshared environmental factors. Substantial novel genetic and nonshared environmental influences emerged at age 3 and suggest change in the etiology of these constructs over time.

Positive affect: phenotypic and etiologic associations with prosocial behaviors and internalizing problems in toddlers.

Despite evidence for the associations of positive affect to prosocial behaviors and internalizing problems, relatively little is known about the underlying etiology. The sample comprised over 300 twin pairs at age 3. Positive affect, prosocial behaviors, and internalizing problems were assessed using the Toddler Behavior Assessment Questionnaire (Goldsmith, 1996), the Revised Rutter Parent Scale for Preschool Children (Hogg et al., 1997), and the Child Behavior Checklist for ages 1.5-5 (Achenbach, 1991), respectively. Positive affect correlated positively with prosocial behaviors, and negatively with internalizing problems. Prosocial behaviors were negatively associated with internalizing problems. The relations of positive affect to prosocial behaviors and internalizing problems were due to environmental effects (shared and non-shared). In contrast, the link between prosocial behaviors and internalizing problems was entirely explained by genetic effects. The current study has moved beyond prior emphasis on negative affect and elucidated the less understood etiology underlying the associations between positive affect, prosocial behaviors, and internalizing problems. This study could guide the development of programs for promoting prosocial behaviors and alleviating internalizing problems in children.

Genetic and environmental influences on individual differences in emotion regulation and its relation to working memory in toddlerhood.

This is the first study to explore genetic and environmental contributions to individual differences in emotion regulation in toddlers, and the first to examine the genetic and environmental etiology underlying the association between emotion regulation and working memory. In a sample of 304 same-sex twin pairs (140 MZ, 164 DZ) at age 3, emotion regulation was assessed using the Behavior Rating Scale of the Bayley Scales of Infant Development (BRS; Bayley, 1993), and working memory was measured by the visually cued recall (VCR) task (Zelazo, Jacques, Burack, & Frye, 2002) and several memory tasks from the Mental Scale of the BSID. Based on model-fitting analyses, both emotion regulation and working memory were significantly influenced by genetic and nonshared environmental factors. Shared environmental effects were significant for working memory, but not for emotion regulation. Only genetic factors significantly contributed to the covariation between emotion regulation and working memory.

Genetic and environmental contributions to stability and change of sleep problems in toddlerhood.

OBJECTIVE: To examine genetic and environmental contributions to stability and change in sleep problems (SP) in early childhood. METHODS: The sample comprised over 300 twin pairs assessed at ages 2 and 3 years. Parents rated SP on the Sleep Problems subscale of the Child Behavior Checklist for ages 1.5-5 years. RESULTS: Longitudinal quantitative genetic analyses indicated that SP were genetically influenced at both ages. The stability of SP from ages 2 to 3 years was largely due to genetic factors common to both ages. Nonshared environmental influences displayed modest continuity across age. New genetic and nonshared environmental factors emerged at age 3 years. CONCLUSIONS: Genetic factors contribute to the stability in SP, whereas change is due to both genetic and nonshared environmental influences. Early interventions on SP and individualized treatments based on children's unique environmental experiences may be fruitful.

Mutation frequency for Charcot-Marie-Tooth disease type 1 in the Chinese population is similar to that in the global ethnic patients.

PURPOSE: To investigate the genetic loci/mutations among the Chinese Charcot-Marie-Tooth disease type 1 (CMT1), which accounts for approximately 70% of Charcot-Marie-Tooth; and to study the genetic heterogeneity and mutation frequency. METHODS: CMT1A duplication and mutations at loci of MPZ, Cx32/GJB1, EGR2, and LITAF/SIMPLE were analyzed among 32 clinically diagnosed CMT1 patients of Chinese ancestry. RESULTS: The CMT1A duplication was detected in 62.5% (20/32) CMT1 patients. This duplication accounts for the major mutation for Chinese CMT1. Among 12 cases that have no CMT1A duplication detected, three point mutations including one (3.1%) in MPZ and two (6.3%) in Cx32 were identified. No mutation was detected in genes PMP22, EGR2 and LITAF among the remaining nine (28.1%) CMT1 patients. CONCLUSION: The mutation frequency for the Chinese CMT1 is similar to that seen in the global ethnic population. Molecular testing of the CMT1A duplication, along with the loci of MPZ and Cx32, may detect the majority of Chinese CMT1 patients.

No mutation was detected in the LMNA gene among sporadic Charcot-Marie-Tooth patients.

OBJECTIVE: To intensively investigate sporadic CMT patients, we have analyzed the LMNA gene in this study in a series of 32 unrelated CMT patients. METHODS: Twelve exons of the LMNA gene were amplified from genetic DNA. PCR products of each exon were analyzed by single strand conformational polymorphism (SSCP). RESULTS: No abnormal SSCP pattern, suggesting no mutation in our CMT patients, was detected. CONCLUSION: The CMT diseases resulted from the mutations of LMNA gene were rare.

Principal genetic syndromes and autism: from phenotypes, proteins to genes.

Autism is a neurodevelopmental disorder characterized by impairments in social skills, language, and behavior. It is now clear that autism is not a disease, but a syndrome characterized by phenotypic and genetic complexity. The etiology of autism is still poorly understood. Available evidence from a variety of sources strongly suggests that many genetic disorders are frequently associated with autism for their similar phenotypes. Based on this fact, this review begins by highlighting several principal genetic syndromes consistently associated with autism (fragile X, tuberous sclerosis, Angelman syndrome, Pader-Willi syndrome, Rett syndrome, Down syndrome and Turner syndrome). These genetic disorders include both chromosome disorders and single gene disorders. By comparing the similar phenotype, protein marker and candidate genes, we might make some breakthrough in the mechanism of autism and other genetic disorders.