The complete sequence and comparative analysis of ape sex chromosomes.

Apes possess two sex chromosomes-the male-specific Y chromosome and the X chromosome, which is present in both males and females. The Y chromosome is crucial for male reproduction, with deletions being linked to infertility1. The X chromosome is vital for reproduction and cognition2. Variation in mating patterns and brain function among apes suggests corresponding differences in their sex chromosomes. However, owing to their repetitive nature and incomplete reference assemblies, ape sex chromosomes have been challenging to study. Here, using the methodology developed for the telomere-to-telomere (T2T) human genome, we produced gapless assemblies of the X and Y chromosomes for five great apes (bonobo (Pan paniscus), chimpanzee (Pan troglodytes), western lowland gorilla (Gorilla gorilla gorilla), Bornean orangutan (Pongo pygmaeus) and Sumatran orangutan (Pongo abelii)) and a lesser ape (the siamang gibbon (Symphalangus syndactylus)), and untangled the intricacies of their evolution. Compared with the X chromosomes, the ape Y chromosomes vary greatly in size and have low alignability and high levels of structural rearrangements-owing to the accumulation of lineage-specific ampliconic regions, palindromes, transposable elements and satellites. Many Y chromosome genes expand in multi-copy families and some evolve under purifying selection. Thus, the Y chromosome exhibits dynamic evolution, whereas the X chromosome is more stable. Mapping short-read sequencing data to these assemblies revealed diversity and selection patterns on sex chromosomes of more than 100 individual great apes. These reference assemblies are expected to inform human evolution and conservation genetics of non-human apes, all of which are endangered species.

In vivo detection of DNA secondary structures using permanganate/S1 footprinting with direct adapter ligation and sequencing (PDAL-Seq).

DNA secondary structures are essential elements of the genomic landscape, playing a critical role in regulating various cellular processes. These structures refer to G-quadruplexes, cruciforms, Z-DNA or H-DNA structures, amongst others (collectively called 'non-B DNA'), which DNA molecules can adopt beyond the B conformation. DNA secondary structures have significant biological roles, and their landscape is dynamic and can rearrange due to various factors, including changes in cellular conditions, temperature, and DNA-binding proteins. Understanding this dynamic nature is crucial for unraveling their functions in cellular processes. Detecting DNA secondary structures remains a challenge. Conventional methods, such as gel electrophoresis and chemical probing, have limitations in terms of sensitivity and specificity. Emerging techniques, including next-generation sequencing and single-molecule approaches, offer promise but face challenges since these techniques are mostly limited to only one type of secondary structure. Here we describe an updated version of a technique permanganate/S1 nuclease footprinting, which uses potassium permanganate to trap single-stranded DNA regions as found in many non-B structures, in combination with S1 nuclease digest and adapter ligation to detect genome-wide non-B formation. To overcome technical hurdles, we combined this method with direct adapter ligation and sequencing (PDAL-Seq). Furthermore, we established a user-friendly pipeline available on Galaxy to standardize PDAL-Seq data analysis. This optimized method allows the analysis of many types of DNA secondary structures that form in a living cell and will advance our knowledge of their roles in health and disease.

The Complete Sequence and Comparative Analysis of Ape Sex Chromosomes.

Apes possess two sex chromosomes-the male-specific Y and the X shared by males and females. The Y chromosome is crucial for male reproduction, with deletions linked to infertility. The X chromosome carries genes vital for reproduction and cognition. Variation in mating patterns and brain function among great apes suggests corresponding differences in their sex chromosome structure and evolution. However, due to their highly repetitive nature and incomplete reference assemblies, ape sex chromosomes have been challenging to study. Here, using the state-of-the-art experimental and computational methods developed for the telomere-to-telomere (T2T) human genome, we produced gapless, complete assemblies of the X and Y chromosomes for five great apes (chimpanzee, bonobo, gorilla, Bornean and Sumatran orangutans) and a lesser ape, the siamang gibbon. These assemblies completely resolved ampliconic, palindromic, and satellite sequences, including the entire centromeres, allowing us to untangle the intricacies of ape sex chromosome evolution. We found that, compared to the X, ape Y chromosomes vary greatly in size and have low alignability and high levels of structural rearrangements. This divergence on the Y arises from the accumulation of lineage-specific ampliconic regions and palindromes (which are shared more broadly among species on the X) and from the abundance of transposable elements and satellites (which have a lower representation on the X). Our analysis of Y chromosome genes revealed lineage-specific expansions of multi-copy gene families and signatures of purifying selection. In summary, the Y exhibits dynamic evolution, while the X is more stable. Finally, mapping short-read sequencing data from >100 great ape individuals revealed the patterns of diversity and selection on their sex chromosomes, demonstrating the utility of these reference assemblies for studies of great ape evolution. These complete sex chromosome assemblies are expected to further inform conservation genetics of nonhuman apes, all of which are endangered species.

Specificity and sensitivity of the social communication questionnaire lifetime screening tool for autism spectrum disorder in a UK CAMHS service.

INTRODUCTION: The Social Communication Questionnaire is used to identify children and young people (CYP) who may require formal ASD assessment. However, there is a paucity of research on its utility in Children and Adolescent Mental Health Services. This evaluation aimed to determine the sensitivity and specificity of the Social Communication Questionnaire (SCQ) in a UK, Midlands CAMHS service. METHOD: Forty young people (mean age 13.75 years) were screened using the caregiver reported SCQ before completing 'gold standard' assessment. RESULTS: The SCQ had a sensitivity of 80% and a specificity of 25.7%. ROC curve analysis indicated low diagnostic accuracy. Differences in predictive accuracy of SCQ and diagnostic standard were statistically significant (p < 0.0001). CONCLUSION: This evaluation builds on previous research suggesting that the SCQ may not be an efficient screening tool in CAMHS settings.

Co-opting regulation bypass repair as a gene-correction strategy for monogenic diseases.

With the development of CRISPR-Cas9-mediated gene-editing technologies, correction of disease-causing mutations has become possible. However, current gene-correction strategies preclude mutation repair in post-mitotic cells of human tissues, and a unique repair strategy must be designed and tested for each and every mutation that may occur in a gene. We have developed a novel gene-correction strategy, co-opting regulation bypass repair (CRBR), which can repair a spectrum of mutations in mitotic or post-mitotic cells and tissues. CRBR utilizes the non-homologous end joining (NHEJ) pathway to insert a coding sequence (CDS) and transcription/translation terminators targeted upstream of any CDS mutation and downstream of the transcriptional promoter. CRBR results in simultaneous co-option of the endogenous regulatory region and bypass of the genetic defect. We validated the CRBR strategy for human gene therapy by rescuing a mouse model of Wolcott-Rallison syndrome (WRS) with permanent neonatal diabetes caused by either a large deletion or a nonsense mutation in the PERK (EIF2AK3) gene. Additionally, we integrated a CRBR GFP-terminator cassette downstream of the human insulin promoter in cadaver pancreatic islets of Langerhans, which resulted in insulin promoter regulated expression of GFP, demonstrating the potential utility of CRBR in human tissue gene repair.

Genetic connectivity and population structure of African savanna elephants (Loxodonta africana) in Tanzania.

Increasing human population growth, exurban development, and associated habitat fragmentation is accelerating the isolation of many natural areas and wildlife populations across the planet. In Tanzania, rapid and ongoing habitat conversion to agriculture has severed many of the country's former wildlife corridors between protected areas. To identify historically linked protected areas, we investigated the genetic structure and gene flow of African savanna elephants in Tanzania using microsatellite and mitochondrial DNA markers in 688 individuals sampled in 2015 and 2017. Our results indicate distinct population genetic structure within and between ecosystems across Tanzania, and reveal important priority areas for connectivity conservation. In northern Tanzania, elephants sampled from the Tarangire-Manyara ecosystem appear marginally, yet significantly isolated from elephants sampled from the greater Serengeti ecosystem (mean F ST = 0.03), where two distinct subpopulations were identified.Unexpectedly, elephants in the Lake Manyara region appear to be more closely related to those across the East African Rift wall in the Ngorongoro Conservation Area than they are to the neighboring Tarangire subpopulations. We concluded that the Rift wall has had a negligible influence on genetic differentiation up to this point, but differentiation may accelerate in the future because of ongoing loss of corridors in the area. Interestingly, relatively high genetic similarity was found between elephants in Tarangire and Ruaha although they are separated by >400 km. In southern Tanzania, there was little evidence of female-mediated gene flow between Ruaha and Selous, probably due to the presence of the Udzungwa Mountains between them. Despite observing evidence of significant isolation, the populations of elephants we examined generally exhibited robust levels of allelic richness (mean A R = 9.96), heterozygosity (mean µH E = 0.73), and effective population sizes (mean N e = 148). Our results may inform efforts to restore wildlife corridors between protected areas in Tanzania in order to facilitate gene flow for long-term survival of elephants and other species.

From manageable to losing control: a grounded theory study of psychosis risk syndrome.

AIM: The purpose of this study is to develop a theoretical explanation of the prodromal schizophrenia process, or so-called psychosis risk syndrome, by describing patients' own experiences with symptoms, thoughts and feelings. METHODS: A total of 40 interviews were conducted in Taiwan. A Grounded Theory method was selected because of its demonstrated effectiveness in generating theory around dynamic and complex processes on which little is known, all of which is the case with psychosis risk syndrome. Constant comparison analysis, memo writing, member checking, and theoretical sampling were adopted. RESULTS: A core theoretical framework was developed in which the process of the psychosis risk syndrome is described as proceeding from manageable to uncontrollable. Four stages emerged from the analysis: (1) something is wrong, (2) boiling up, (3) breaking point, and (4) losing control. CONCLUSIONS: The framework resulting from this Grounded Theory research is innovative in presenting patterns and clinical staging that marks the progression from premorbid stage to full-blown psychosis. In addition to specifying the detailed process through in-depth interviews, this research makes two fundamental contributions by: (1) adding evidence to current science and (2) taking patients' experience into consideration to improve the validity of screening tools and design appropriate intervention programs for people with early warning signs of developing schizophrenia.

The protein kinase PERK/EIF2AK3 regulates proinsulin processing not via protein synthesis but by controlling endoplasmic reticulum chaperones.

Loss-of-function mutations of the protein kinase PERK (EIF2AK3) in humans and mice cause permanent neonatal diabetes and severe proinsulin aggregation in the endoplasmic reticulum (ER), highlighting the essential role of PERK in insulin production in pancreatic ß cells. As PERK is generally known as a translational regulator of the unfolded protein response (UPR), the underlying cause of these ß cell defects has often been attributed to derepression of proinsulin synthesis, resulting in proinsulin overload in the ER. Using high-resolution imaging and standard protein fractionation and immunological methods we have examined the PERK-dependent phenotype more closely. We found that whereas proinsulin aggregation requires new protein synthesis, global protein and proinsulin synthesis are down-regulated in PERK-inhibited cells, strongly arguing against proinsulin overproduction being the root cause of their aberrant ER phenotype. Furthermore, we show that PERK regulates proinsulin proteostasis by modulating ER chaperones, including BiP and ERp72. Transgenic overexpression of BiP and BiP knockdown (KD) both promoted proinsulin aggregation, whereas ERp72 overexpression and knockdown rescued it. These findings underscore the importance of ER chaperones working in concert to achieve control of insulin production and identify a role for PERK in maintaining a functional balance among these chaperones.

PERK regulates Gq protein-coupled intracellular Ca2+ dynamics in primary cortical neurons.

PERK (EIF2AK3) is an ER-resident eIF2α kinase required for behavioral flexibility and metabotropic glutamate receptor-dependent long-term depression via its translational control. Motivated by the recent discoveries that PERK regulates Ca2+ dynamics in insulin-secreting ß-cells underlying glucose-stimulated insulin secretion, and modulates Ca2+ signals-dependent working memory, we explored the role of PERK in regulating Gq protein-coupled Ca2+ dynamics in pyramidal neurons. We found that acute PERK inhibition by the use of a highly specific PERK inhibitor reduced the intracellular Ca2+ rise stimulated by the activation of acetylcholine, metabotropic glutamate and bradykinin-2 receptors in primary cortical neurons. More specifically, acute PERK inhibition increased IP3 receptor mediated ER Ca2+ release, but decreased receptor-operated extracellular Ca2+ influx. Impaired Gq protein-coupled intracellular Ca2+ rise was also observed in genetic Perk knockout neurons. Taken together, our findings reveal a novel role of PERK in neurons, which is eIF2α-independent, and suggest that the impaired working memory in forebrain-specific Perk knockout mice may stem from altered Gq protein-coupled intracellular Ca2+ dynamics in cortical pyramidal neurons.

PERK Regulates Working Memory and Protein Synthesis-Dependent Memory Flexibility.

PERK (EIF2AK3) is an ER-resident eIF2α kinase required for memory flexibility and metabotropic glutamate receptor-dependent long-term depression, processes known to be dependent on new protein synthesis. Here we investigated PERK's role in working memory, a cognitive ability that is independent of new protein synthesis, but instead is dependent on cellular Ca2+ dynamics. We found that working memory is impaired in forebrain-specific Perk knockout and pharmacologically PERK-inhibited mice. Moreover, inhibition of PERK in wild-type mice mimics the fear extinction impairment observed in forebrain-specific Perk knockout mice. Our findings reveal a novel role of PERK in cognitive functions and suggest that PERK regulates both Ca2+ -dependent working memory and protein synthesis-dependent memory flexibility.

Giraffe genome sequence reveals clues to its unique morphology and physiology.

The origins of giraffe's imposing stature and associated cardiovascular adaptations are unknown. Okapi, which lacks these unique features, is giraffe's closest relative and provides a useful comparison, to identify genetic variation underlying giraffe's long neck and cardiovascular system. The genomes of giraffe and okapi were sequenced, and through comparative analyses genes and pathways were identified that exhibit unique genetic changes and likely contribute to giraffe's unique features. Some of these genes are in the HOX, NOTCH and FGF signalling pathways, which regulate both skeletal and cardiovascular development, suggesting that giraffe's stature and cardiovascular adaptations evolved in parallel through changes in a small number of genes. Mitochondrial metabolism and volatile fatty acids transport genes are also evolutionarily diverged in giraffe and may be related to its unusual diet that includes toxic plants. Unexpectedly, substantial evolutionary changes have occurred in giraffe and okapi in double-strand break repair and centrosome functions.

Perk gene dosage regulates glucose homeostasis by modulating pancreatic ß-cell functions.

BACKGROUND: Insulin synthesis and cell proliferation are under tight regulation in pancreatic ß-cells to maintain glucose homeostasis. Dysfunction in either aspect leads to development of diabetes. PERK (EIF2AK3) loss of function mutations in humans and mice exhibit permanent neonatal diabetes that is characterized by insufficient ß-cell mass and reduced proinsulin trafficking and insulin secretion. Unexpectedly, we found that Perk heterozygous mice displayed lower blood glucose levels. METHODOLOGY: Longitudinal studies were conducted to assess serum glucose and insulin, intracellular insulin synthesis and storage, insulin secretion, and ß-cell proliferation in Perk heterozygous mice. In addition, modulation of Perk dosage specifically in ß-cells showed that the glucose homeostasis phenotype of Perk heterozygous mice is determined by reduced expression of PERK in the ß-cells. PRINCIPAL FINDINGS: We found that Perk heterozygous mice first exhibited enhanced insulin synthesis and secretion during neonatal and juvenile development followed by enhanced ß-cell proliferation and a substantial increase in ß-cell mass at the adult stage. These differences are not likely to entail the well-known function of PERK to regulate the ER stress response in cultured cells as several markers for ER stress were not differentially expressed in Perk heterozygous mice. CONCLUSIONS: In addition to the essential functions of PERK in ß-cells as revealed by severely diabetic phenotype in humans and mice completely deficient for PERK, reducing Perk gene expression by half showed that intermediate levels of PERK have a profound impact on ß-cell functions and glucose homeostasis. These results suggest that an optimal level of PERK expression is necessary to balance several parameters of ß-cell function and growth in order to achieve normoglycemia.

A journey of suffering: living with amyotrophic lateral sclerosis in South Korea.

Amyotrophic lateral sclerosis presents significant challenges for patients because of the devastating disease characteristics and the fact that there is no treatment available. In this article, we explored the illness experiences from the perspectives of patients with amyotrophic lateral sclerosis in the sociocultural context of South Korea. Fifteen patients were observed and interviewed between September 2009 and July 2010 in the metropolitan area of South Korea. We used an ethnographic approach for data collection and analysis. The meta-theme generated was "a journey of suffering," and three themes emerged: (a) off the course, (b) drifting, and (c) on a new boat. Participants experienced multidimensional suffering as the disease progressed. Healthcare professionals should understand that, for many patients, this disease is a process or a series of experiences rather than a single diagnosis. This knowledge would allow healthcare providers to help patients prepare for those needs that arise as the disease worsens.

Do Thai parents discuss sex and AIDS with young adolescents? A qualitative study.

This qualitative study explored parents' and young adolescents' perceptions of communication related to sex and HIV/AIDS. Focus group discussions and group discussion were conducted among 67 adolescents and 30 parents. For the adolescents, group discussion using participatory activities was conducted, followed by five focus group discussions. Group discussions using participatory activities were conducted among parents. Thematic analysis indicated that the adolescents received inadequate information about sex and AIDS from their parents, whom they feared as providing negative judgment, and this represented a key barrier to such discussions. Their parents, on the other hand, reported that they believed their children were still too young to learn about and engage in sexual activities. The parents perceived barriers to communication included a lack of confidence and feelings of embarrassment. Nevertheless, they also recognized their important role in their child's sexual education. Collectively, these results draw attention to the need for a culturally appropriate program to strengthen parent-child communication skills for the topics of sex and HIV/AIDS.

The localisation of inflammatory cells and expression of associated proteoglycans in response to implanted chitosan.

Implantation of a foreign material almost certainly results in the formation of a fibrous capsule around the implant however, mechanistic events leading to its formation are largely unexplored. Mast cells are an inflammatory cell type known to play a role in the response to material implants, through the release of pro-inflammatory proteases and cytokines from their α-granules following activation. This study examined the in vivo and in vitro response of mast cells to chitosan, through detection of markers known to be produced by mast cells or involved with the inflammatory response. Mast cells, identified as Leder stained positive cells, were shown to be present in response to material implants. Additionally, the mast cell receptor, c-kit, along with collagen, serglycin, perlecan and chondroitin sulphate were detected within the fibrous capsules, where distribution varied between material implants. In conjunction, rat mast cells (RBL-2H3) were shown to be activated following exposure to chitosan as indicated by the release of ß-hexosaminidase. Proteoglycan and glycosaminoglycans produced by the cells showed similar expression and localisation when in contact with chitosan to when chemically activated. These data support the role that mast cells play in the inflammatory host response to chitosan implants, where mediators released from their α-granules impact on the formation of a fibrous capsule by supporting the production and organisation of collagen fibres.

GCN2 in the brain programs PPARγ2 and triglyceride storage in the liver during perinatal development in response to maternal dietary fat.

The liver plays a central role in regulating lipid metabolism and facilitates efficient lipid utilization and storage. We discovered that a modest increase in maternal dietary fat in mice programs triglyceride storage in the liver of their developing offspring. The activation of this programming is not apparent, however, until several months later at the adult stage. We found that the perinatal programming of adult hepatic triglyceride storage was controlled by the eIF2α kinase GCN2 (EIF2AK4) in the brain of the offspring, which stimulates epigenetic modification of the Pparγ2 gene in the neonatal liver. Genetic ablation of Gcn2 in the offspring exhibited reduced hepatic triglyceride storage and repressed expression of the peroxisome proliferator-activated receptor gamma 2 (Pparγ2) and two lipid droplet protein genes, Fsp27 and Cidea. Brain-specific, but not liver-specific, Gcn2 KO mice exhibit these same defects demonstrating that GCN2 in the developing brain programs hepatic triglyceride storage. GCN2 and nutrition-dependent programming of Pparγ2 is correlated with trimethylation of lysine 4 of histone 3 (H3K4me3) in the Pparγ2 promoter region during neonatal development. In addition to regulating hepatic triglyceride in response to modest changes in dietary fat, Gcn2 deficiency profoundly impacts the severity of the obese-diabetic phenotype of the leptin receptor mutant (db/db) mouse, by reducing hepatic steatosis and obesity but exacerbating the diabetic phenotype. We suggest that GCN2-dependent perinatal programming of hepatic triglyceride storage is an adaptation to couple early nutrition to anticipated needs for hepatic triglyceride storage in adults. However, increasing the hepatic triglyceride set point during perinatal development may predispose individuals to hepatosteatosis, while reducing circulating fatty acid levels that promote insulin resistance.

Insulin secretion and Ca2+ dynamics in ß-cells are regulated by PERK (EIF2AK3) in concert with calcineurin.

Protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) (EIF2AK3) is essential for normal development and function of the insulin-secreting ß-cell. Although genetic ablation of PERK in ß-cells results in permanent neonatal diabetes in humans and mice, the underlying mechanisms remain unclear. Here, we used a newly developed and highly specific inhibitor of PERK to determine the immediate effects of acute ablation of PERK activity. We found that inhibition of PERK in human and rodent ß-cells causes a rapid inhibition of secretagogue-stimulated subcellular Ca(2+) signaling and insulin secretion. These dysfunctions stem from alterations in store-operated Ca(2+) entry and sarcoplasmic endoplasmic reticulum Ca(2+)-ATPase activity. We also found that PERK regulates calcineurin, and pharmacological inhibition of calcineurin results in similar defects on stimulus-secretion coupling. Our findings suggest that interplay between calcineurin and PERK regulates ß-cell Ca(2+) signaling and insulin secretion, and that loss of this interaction may have profound implications in insulin secretion defects associated with diabetes.

GCN2 regulates the CCAAT enhancer binding protein beta and hepatic gluconeogenesis.

Mice deficient for general control nondepressible-2 (Gcn2) either globally or specifically in the liver display reduced capacity to maintain glucose homeostasis during fasting, suggesting the hypothesis that GCN2 may regulate gluconeogenesis (GNG), which normally plays a key role maintaining peripheral glucose homeostasis. Gcn2-deficient mice exhibit normal insulin sensitivity and plasma insulin but show reduced GNG when administered pyruvate, a gluconeogenic substrate. The basal expression of phosphoenolpyruvate carboxykinase, a rate-limiting enzyme in GNG, is abnormally elevated in Gcn2 knockout (KO) mice in the fed state but fails to be further induced during fasting. The level of tricarboxylic acid cycle intermediates, including malate and oxaloacetate, and the NADH-to-NAD(+) ratio are perturbed in the liver of Gcn2 KO mice either in the fed or fasted state, which may directly impinge upon GNG. Additionally, the expression of the CCAAT enhancer-binding protein-ß (C/EBPß) in the liver fails to be induced in Gcn2 KO mice after 24 h fasting, and the liver-specific Cebpß KO mice show reduced fasting GNG similar to that seen in Gcn2-deficient mice. Our study demonstrates that GCN2 is important in maintaining GNG in the liver, which is likely to be mediated through regulation of C/EBPß.

Perspectives on provider behaviors: a qualitative study of sexual and gender minorities regarding quality of care.

Lesbian, gay, bisexual, transgender, and queer (LGBTQ) identified patients report receiving substandard care from healthcare providers. They face the fear and disturbing reality of discrimination when accessing health care. Without culturally sensitive treatment, nursing and other health professions do not properly care for this population. Following the recent trend towards awareness and need for inclusion of LGBTQ populations in healthcare, this paper provides a summary of the current literature on the treatment and needs of LGBTQ people and describes focus groups conducted to explore perceptions regarding provider behaviors. It concludes with a list of behaviors that enhance or impede quality care that can serve as a guide for healthcare professionals.

Hyperthermia induces the ER stress pathway.

BACKGROUND: The ER chaperone GRP78/BiP is a homolog of the Hsp70 family of heat shock proteins, yet GRP78/BiP is not induced by heat shock but instead by ER stress. However, previous studies had not considered more physiologically relevant temperature elevation associated with febrile hyperthermia. In this report we examine the response of GRP78/BiP and other components of the ER stress pathway in cells exposed to 40°C. METHODOLOGY: AD293 cells were exposed to 43°C heat shock to confirm inhibition of the ER stress response genes. Five mammalian cell types, including AD293 cells, were then exposed to 40°C hyperthermia for various time periods and induction of the ER stress pathway was assessed. PRINCIPAL FINDINGS: The inhibition of the ER stress pathway by heat shock (43°C) was confirmed. In contrast cells subjected to more mild temperature elevation (40°C) showed either a partial or full ER stress pathway induction as determined by downstream targets of the three arms of the ER stress pathway as well as a heat shock response. Cells deficient for Perk or Gcn2 exhibit great sensitivity to ER stress induction by hyperthermia. CONCLUSIONS: The ER stress pathway is induced partially or fully as a consequence of hyperthermia in parallel with induction of Hsp70. These findings suggest that the ER and cytoplasm of cells contain parallel pathways to coordinately regulate adaptation to febrile hyperthermia associated with disease or infection.