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1.
Cell Genom ; : 100609, 2024 Jul 12.
Article in English | MEDLINE | ID: mdl-39019033

ABSTRACT

Little is known about the role of non-coding regions in the etiology of autism spectrum disorder (ASD). We examined three classes of non-coding regions: human accelerated regions (HARs), which show signatures of positive selection in humans; experimentally validated neural VISTA enhancers (VEs); and conserved regions predicted to act as neural enhancers (CNEs). Targeted and whole-genome analysis of >16,600 samples and >4,900 ASD probands revealed that likely recessive, rare, inherited variants in HARs, VEs, and CNEs substantially contribute to ASD risk in probands whose parents share ancestry, which enriches for recessive contributions, but modestly contribute, if at all, in simplex family structures. We identified multiple patient variants in HARs near IL1RAPL1 and in VEs near OTX1 and SIM1 and showed that they change enhancer activity. Our results implicate both human-evolved and evolutionarily conserved non-coding regions in ASD risk and suggest potential mechanisms of how regulatory changes can modulate social behavior.

2.
medRxiv ; 2024 Jun 19.
Article in English | MEDLINE | ID: mdl-38946951

ABSTRACT

In recent years, there has been increased focus on exploring the role the non-protein-coding genome plays in Mendelian disorders. One class of particular interest is long non-coding RNAs (lncRNAs), which has recently been implicated in the regulation of diverse molecular processes. However, because lncRNAs do not encode protein, there is uncertainty regarding what constitutes a pathogenic lncRNA variant, and thus annotating such elements is challenging. The Developmental Genome Anatomy Project (DGAP) and similar projects recruit individuals with apparently balanced chromosomal abnormalities (BCAs) that disrupt or dysregulate genes in order to annotate the human genome. We hypothesized that rearrangements disrupting lncRNAs could be the underlying genetic etiology for the phenotypes of a subset of these individuals. Thus, we assessed 279 cases with BCAs and selected 191 cases with simple BCAs (breakpoints at only two genomic locations) for further analysis of lncRNA disruptions. From these, we identified 66 cases in which the chromosomal rearrangements directly disrupt lncRNAs. Strikingly, the lncRNAs MEF2C-AS1 and ENSG00000257522 are each disrupted in two unrelated cases. Furthermore, in 30 cases, no genes of any other class aside from lncRNAs are directly disrupted, consistent with the hypothesis that lncRNA disruptions could underly the phenotypes of these individuals. To showcase the power of this genomic approach for annotating lncRNAs, here we focus on clinical reports and genetic analysis of two individuals with BCAs and additionally highlight six individuals with likely developmental etiologies due to lncRNA disruptions.

3.
bioRxiv ; 2024 Jun 10.
Article in English | MEDLINE | ID: mdl-38915567

ABSTRACT

The human cerebral cortex, pivotal for advanced cognitive functions, is composed of six distinct layers and dozens of functionally specialized areas1,2. The layers and areas are distinguished both molecularly, by diverse neuronal and glial cell subtypes, and structurally, through intricate spatial organization3,4. While single-cell transcriptomics studies have advanced molecular characterization of human cortical development, a critical gap exists due to the loss of spatial context during cell dissociation5,6,7,8. Here, we utilized multiplexed error-robust fluorescence in situ hybridization (MERFISH)9, augmented with deep-learning-based cell segmentation, to examine the molecular, cellular, and cytoarchitectural development of human fetal cortex with spatially resolved single-cell resolution. Our extensive spatial atlas, encompassing 16 million single cells, spans eight cortical areas across four time points in the second and third trimesters. We uncovered an early establishment of the six-layer structure, identifiable in the laminar distribution of excitatory neuronal subtypes by mid-gestation, long before the emergence of cytoarchitectural layers. Notably, while anterior-posterior gradients of neuronal subtypes were generally observed in most cortical areas, a striking exception was the sharp molecular border between primary (V1) and secondary visual cortices (V2) at gestational week 20. Here we discovered an abrupt binary shift in neuronal subtype specification at the earliest stages, challenging the notion that continuous morphogen gradients dictate mid-gestation cortical arealization6,10. Moreover, integrating single-nuclei RNA-sequencing and in situ whole transcriptomics revealed an early upregulation of synaptogenesis in V1-specific Layer 4 neurons, suggesting a role of synaptogenesis in this discrete border formation. Collectively, our findings underscore the crucial role of spatial relationships in determining the molecular specification of cortical layers and areas. This work not only provides a valuable resource for the field, but also establishes a spatially resolved single-cell analysis paradigm that paves the way for a comprehensive developmental atlas of the human brain.

4.
bioRxiv ; 2023 Dec 07.
Article in English | MEDLINE | ID: mdl-38105981

ABSTRACT

The human brain expresses thousands of different long noncoding RNAs (lncRNAs), and aberrant expression of specific lncRNAs has been associated with cognitive and psychiatric disorders. While a growing number of lncRNAs are now known to regulate neural cell development and function, relatively few have been shown to underlie animal behavior, particularly with genetic strategies that establish lncRNA function in trans. Pnky is an evolutionarily conserved, neural lncRNA that regulates brain development. Using mouse genetic strategies, we show that Pnky has sex-specific roles in mouse behavior and that this lncRNA underlies specific behavior by functioning in trans. Male Pnky-knockout (KO) mice have deficits in cued fear recall, a type of Pavlovian associative memory. In female Pnky-KO mice, the acoustic startle response (ASR) is increased and accompanied by a decrease in prepulse inhibition (PPI), both of which are behaviors altered in affective disorders. Remarkably, expression of Pnky from a bacterial artificial chromosome (BAC) transgene reverses the ASR phenotype of female Pnky-KO mice, demonstrating that Pnky underlies specific animal behavior by functioning in trans. More broadly, these data provide genetic evidence that a lncRNA gene and its function in trans can play a key role in the behavior of adult mammals, contributing fundamental knowledge to our growing understanding of the association between specific lncRNAs and disorders of cognition and mood.

5.
BMC Immunol ; 24(1): 45, 2023 11 16.
Article in English | MEDLINE | ID: mdl-37974069

ABSTRACT

BACKGROUND: SARS-CoV-2 remains a world-wide health issue. SARS-CoV-2-specific immunity is induced upon both infection and vaccination. However, defining the long-term immune trajectory, especially after infection, is limited. In this study, we aimed to further the understanding of long-term SARS-CoV-2-specific immune response after infection. RESULTS: We conducted a longitudinal cohort study among 93 SARS-CoV-2 recovered individuals. Immune responses were continuously monitored for up to 20 months after infection. The humoral responses were quantified by Spike- and Nucleocapsid-specific IgG levels. T cell responses to Spike- and non-Spike epitopes were examined using both intercellular cytokine staining (ICS) assay and Activation-Induced marker (AIM) assay with quantification of antigen-specific IFNγ production. During the 20 months follow-up period, Nucleocapsid-specific antibody levels and non-Spike-specific CD4 + and CD8 + T cell frequencies decreased in the blood. However, a majority of participants maintained a durable immune responses 20 months after infection: 59% of the participants were seropositive for Nucleocapsid-specific IgG, and more than 70% had persisting non-Spike-specific T cells. The Spike-specific response initially decreased but as participants were vaccinated against COVID-19, Spike-specific IgG levels and T cell frequencies were boosted reaching similar or higher levels compared to 1 month post-infection. The trajectory of infection-induced SARS-CoV-2-specific immunity decreases, but for the majority of participants it persists beyond 20 months. The T cell response displays a greater durability. Vaccination boosts Spike-specific immune responses to similar or higher levels as seen after primary infection. CONCLUSIONS: For most participants, the response persists 20 months after infection, and the cellular response appears to be more long-lived compared to the circulating antibody levels. Vaccination boosts the S-specific response but does not affect the non-S-specific response. Together, these findings support the understanding of immune contraction, and with studies showing the immune levels required for protection, adds to the knowledge of durability of protection against future SARS-CoV-2.


Subject(s)
COVID-19 , Humans , Longitudinal Studies , SARS-CoV-2 , Immunity, Cellular , Immunoglobulin G , Antibodies, Viral , Immunity, Humoral , Vaccination
6.
medRxiv ; 2023 Sep 22.
Article in English | MEDLINE | ID: mdl-37790480

ABSTRACT

Little is known about the role of noncoding regions in the etiology of autism spectrum disorder (ASD). We examined three classes of noncoding regions: Human Accelerated Regions (HARs), which show signatures of positive selection in humans; experimentally validated neural Vista Enhancers (VEs); and conserved regions predicted to act as neural enhancers (CNEs). Targeted and whole genome analysis of >16,600 samples and >4900 ASD probands revealed that likely recessive, rare, inherited variants in HARs, VEs, and CNEs substantially contribute to ASD risk in probands whose parents share ancestry, which enriches for recessive contributions, but modestly, if at all, in simplex family structures. We identified multiple patient variants in HARs near IL1RAPL1 and in a VE near SIM1 and showed that they change enhancer activity. Our results implicate both human-evolved and evolutionarily conserved noncoding regions in ASD risk and suggest potential mechanisms of how changes in regulatory regions can modulate social behavior.

7.
Heliyon ; 9(2): e13122, 2023 Feb.
Article in English | MEDLINE | ID: mdl-36793967

ABSTRACT

Background: Studies show that pharmacists are unsure in their ability to screen patients for substance abuse. This study evaluates the efficacy of incorporating interprofessional education (IPE) into a substance misuse training program on pharmacy students' learning outcomes in providing screening and counseling for substance misuse. Methods: Pharmacy students from 2019 to 2020 completed 3 substance misuse training modules. Students from the class of 2020 completed an additional IPE event. Both cohorts completed pre- and post-surveys that evaluated knowledge of content and comfort level with patient screening and counseling regarding substance misuse. Paired student t-tests and difference-in-difference analyses were used to evaluate the impact of the IPE event. Findings: Both cohorts (n = 127) showed statistically significant improvement in learning outcomes in providing substance misuse screening and counseling. IPE yielded extremely positive feedback from all students, but its addition to the overall training did not improve learning outcomes. This may be attributed to the differences in baseline knowledge of each class cohort. Conclusion: Substance misuse training successfully improved pharmacy student knowledge and comfort level with providing patient screening and counseling services. Though the IPE event did not improve learning outcomes, qualitative student feedback was overwhelmingly positive and supports the continued incorporation of IPE.

8.
Surgery ; 172(6): 1860-1865, 2022 12.
Article in English | MEDLINE | ID: mdl-36192213

ABSTRACT

BACKGROUND: Retriage is the emergency transfer of severely injured patients from nontrauma and lower-level trauma centers to higher-level trauma centers. We identified the barriers to retriage at sending centers in a single health system. METHODS: We conducted a failure modes effects and criticality analysis at 4 nontrauma centers and 5 lower-level trauma centers in a single health system. Clinicians from each center described the steps in the trauma assessment and retriage process to create a process map. We used standardized scoring to characterize each failure based on frequency, impact on retriage, and prevention safeguards. We ranked each failure using the scores to calculate a risk priority number. RESULTS: We identified 26 steps and 93 failures. The highest-risk failure was refusal by higher-level trauma centers (receiving hospitals) to accept a patient. The most critical failures in the retriage process based on total risk, frequency, and safeguard scores were (1) refusal from a receiving higher-level trauma center to accept a patient (risk priority number = 191), (2) delay in a sending center's consultant examination of a patient in the emergency department (risk priority number = 177), and (3) delay in receiving hospital's consultant calling back (risk priority number = 177). CONCLUSION: We identified (1) addressing obstacles to determining clinical indications for retriage and (2) identifying receiving level I trauma centers who would accept the patient as opportunities to increase timely retriage. Establishing clear clinical indications for retriage that sending and receiving hospitals agree on represents an opportunity for intervention that could improve the retriage of injured patients.


Subject(s)
Trauma Centers , Humans , Illinois
9.
EBioMedicine ; 64: 103230, 2021 Feb.
Article in English | MEDLINE | ID: mdl-33530000

ABSTRACT

BACKGROUND: Upon SARS-CoV-2 infection, most individuals develop neutralizing antibodies and T-cell immunity. However, some individuals reportedly remain SARS-CoV-2 PCR positive by pharyngeal swabs weeks after recovery. Whether viral RNA in these persistent carriers is contagious and stimulates SARS-CoV-2-specific immune responses is unknown. METHODS: This cohort study was conducted between April 3rd-July 9th 2020, recruiting COVID-19 recovered individuals that were symptom-free for at least 14 days. We collected serum for SARS-CoV-2-specific total Ig, IgA and IgM detection by ELISA, pharyngeal swabs (two time points) for ddPCR and PBMCs for anti-SARS-CoV-2 CD8 T-cell dextramer analyses. FINDINGS: We enrolled 203 post-symptomatic participants with a previous RT-PCR-verified SARS-CoV-2 infection. At time point 1, a median of 23 days (range 15-44) after recovery, 26 individuals (12⋅8%) were PCR positive. At time point 2, 90 days (median, range 85-105) after recovery, 5 (5⋅3%) were positive. There was no difference in SARS-CoV-2 antibody levels between the PCR negative and positive group. The persistent PCR positive group however, had SARS-CoV-2-specific CD8 T-cell responses of significantly increased breadth and magnitude. Assisted contact tracing among persistent PCR positive individuals revealed zero new COVID-19 diagnoses among 757 close contacts. INTERPRETATION: Persistent pharyngeal SARS-CoV-2 PCR positivity in post-symptomatic individuals is associated with elevated cellular immune responses and thus, the viral RNA may represent replicating virus. However, transmission to close contacts was not observed indicating that persistent PCR positive individuals are not contagious at the post-symptomatic stage of the infection.


Subject(s)
CD8-Positive T-Lymphocytes/immunology , COVID-19 Nucleic Acid Testing , COVID-19/immunology , RNA, Viral/immunology , Reverse Transcriptase Polymerase Chain Reaction , SARS-CoV-2/immunology , Adult , Aged , Aged, 80 and over , CD8-Positive T-Lymphocytes/metabolism , COVID-19/blood , Female , Humans , Male , Middle Aged , RNA, Viral/blood , SARS-CoV-2/metabolism
10.
Science ; 368(6486): 48-53, 2020 04 03.
Article in English | MEDLINE | ID: mdl-32241942

ABSTRACT

Neural stem cells (NSCs) in the developing and postnatal brain have distinct positional identities that dictate the types of neurons they generate. Although morphogens initially establish NSC positional identity in the neural tube, it is unclear how such regional differences are maintained as the forebrain grows much larger and more anatomically complex. We found that the maintenance of NSC positional identity in the murine brain requires a mixed-lineage leukemia 1 (Mll1)-dependent epigenetic memory system. After establishment by sonic hedgehog, ventral NSC identity became independent of this morphogen. Even transient MLL1 inhibition caused a durable loss of ventral identity, resulting in the generation of neurons with the characteristics of dorsal NSCs in vivo. Thus, spatial information provided by morphogens can be transitioned to epigenetic mechanisms that maintain regionally distinct developmental programs in the forebrain.


Subject(s)
Genomic Imprinting , Histone-Lysine N-Methyltransferase/physiology , Myeloid-Lymphoid Leukemia Protein/physiology , Neural Stem Cells/physiology , Neurogenesis/genetics , Prosencephalon/cytology , Prosencephalon/embryology , Thyroid Nuclear Factor 1/genetics , Animals , Hedgehog Proteins/metabolism , Histone-Lysine N-Methyltransferase/genetics , Mice , Mice, Mutant Strains , Myeloid-Lymphoid Leukemia Protein/genetics , Neural Stem Cells/cytology , Transcriptome
11.
Ann Pharmacother ; 54(3): 262-276, 2020 03.
Article in English | MEDLINE | ID: mdl-31537106

ABSTRACT

Objective: To review the pharmacology, pharmacokinetics, efficacy, safety, dosing, and cost information of glecaprevir/pibrentasvir in the treatment of hepatitis C virus (HCV). Data Sources: A literature search was conducted between September 2018 and July 2019 using PubMed and Google Scholar with the search terms glecaprevir, pibrentasvir, Mavyret, Maviret, and hepatitis C. Clinicaltrials.gov was searched using the same terms. References of published articles were assessed for additional information. Study Selection and Data Extraction: English-language preclinical and clinical studies on the chemistry, pharmacology, pharmacokinetics, safety, and efficacy of glecaprevir/pibrentasvir were evaluated. Data Synthesis: Food and Drug Administration-approved glecaprevir/pibrentasvir is considered both safe and efficacious for the treatment of HCV genotypes 1 to 6 and in several patient populations, such as those with treatment-naïve or treatment-experienced HCV; with or without compensated cirrhosis, HIV-1 coinfection, or renal impairment; post-liver or post-kidney transplant; and ≥12 years of age. Sustained virological response rates ranged from 83% to 100% in clinical trials, and safety outcomes appear similar to other guideline-recommended HCV treatment options. Relevance to Patient Care and Clinical Practice: This review discusses the pharmacological, efficacy, and safety data found in glecaprevir/pibrentasvir clinical trials and relates this to guideline recommendations and the practical use of this medication for treatment of HCV. Conclusions: With HCV infection rates remaining elevated, it is important to have safe and efficacious treatment options. Glecaprevir/pibrentasvir is a safe and efficacious guideline-recommended, 8-week treatment for HCV in several patient populations, with these populations likely growing in the near future given ongoing and future studies.


Subject(s)
Antiviral Agents/therapeutic use , Benzimidazoles/therapeutic use , Hepacivirus/drug effects , Hepatitis C, Chronic/drug therapy , Quinoxalines/therapeutic use , Sulfonamides/therapeutic use , Adult , Aminoisobutyric Acids , Antiviral Agents/administration & dosage , Antiviral Agents/adverse effects , Antiviral Agents/pharmacokinetics , Benzimidazoles/administration & dosage , Benzimidazoles/adverse effects , Benzimidazoles/pharmacokinetics , Child , Clinical Trials as Topic , Coinfection/drug therapy , Cyclopropanes , Drug Combinations , Female , Genotype , Hepacivirus/genetics , Hepatitis C, Chronic/complications , Hepatitis C, Chronic/virology , Humans , Lactams, Macrocyclic , Leucine/analogs & derivatives , Liver Cirrhosis/complications , Liver Cirrhosis/drug therapy , Male , Middle Aged , Proline/analogs & derivatives , Pyrrolidines , Quinoxalines/administration & dosage , Quinoxalines/adverse effects , Quinoxalines/pharmacokinetics , Sulfonamides/administration & dosage , Sulfonamides/adverse effects , Sulfonamides/pharmacokinetics
12.
Dev Cell ; 49(4): 632-642.e7, 2019 05 20.
Article in English | MEDLINE | ID: mdl-31112699

ABSTRACT

While it is now appreciated that certain long noncoding RNAs (lncRNAs) have important functions in cell biology, relatively few have been shown to regulate development in vivo, particularly with genetic strategies that establish cis versus trans mechanisms. Pnky is a nuclear-enriched lncRNA that is transcribed divergently from the neighboring proneural transcription factor Pou3f2. Here, we show that conditional deletion of Pnky from the developing cortex regulates the production of projection neurons from neural stem cells (NSCs) in a cell-autonomous manner, altering postnatal cortical lamination. Surprisingly, Pou3f2 expression is not disrupted by deletion of the entire Pnky gene. Moreover, expression of Pnky from a BAC transgene rescues the differential gene expression and increased neurogenesis of Pnky-knockout NSCs, as well as the developmental phenotypes of Pnky-deletion in vivo. Thus, despite being transcribed divergently from a key developmental transcription factor, the lncRNA Pnky regulates development in trans.


Subject(s)
Cerebral Cortex/embryology , Neural Stem Cells/metabolism , RNA, Long Noncoding/genetics , Animals , Brain/metabolism , Cerebral Cortex/metabolism , Female , Interneurons/metabolism , Male , Mice , Mice, Inbred C57BL , Nerve Tissue Proteins/genetics , Neurogenesis/genetics , Neurons/metabolism , POU Domain Factors/genetics , RNA, Long Noncoding/metabolism , Trans-Activators/genetics , Trans-Activators/metabolism , Transcription Factors/metabolism
13.
J Biol Chem ; 294(16): 6405-6415, 2019 04 19.
Article in English | MEDLINE | ID: mdl-30733336

ABSTRACT

Upon phagocytosis into macrophages, the intracellular bacterial pathogen Legionella pneumophila secretes effector proteins that manipulate host cell components, enabling it to evade lysosomal degradation. However, the bacterial proteins involved in this evasion are incompletely characterized. Here we show that the L. pneumophila effector protein RavD targets host membrane compartments and contributes to the molecular mechanism the pathogen uses to prevent encounters with lysosomes. Protein-lipid binding assays revealed that RavD selectively binds phosphatidylinositol-3-phosphate (PI(3)P) in vitro We further determined that a C-terminal RavD region mediates the interaction with PI(3)P and that this interaction requires Arg-292. In transiently transfected mammalian cells, mCherry-RavD colocalized with the early endosome marker EGFP-Rab5 as well as the PI(3)P biosensor EGFP-2×FYVE. However, treatment with the phosphoinositide 3-kinase inhibitor wortmannin did not disrupt localization of mCherry-RavD to endosomal compartments, suggesting that RavD's interaction with PI(3)P is not necessary to anchor RavD to endosomal membranes. Using superresolution and immunogold transmission EM, we observed that, upon translocation into macrophages, RavD was retained onto the Legionella-containing vacuole and was also present on small vesicles adjacent to the vacuole. We also report that despite no detectable effects on intracellular growth of L. pneumophila within macrophages or amebae, the lack of RavD significantly increased the number of vacuoles that accumulate the late endosome/lysosome marker LAMP-1 during macrophage infection. Together, our findings suggest that, although not required for intracellular replication of L. pneumophila, RavD is a part of the molecular mechanism that steers the Legionella-containing vacuole away from endolysosomal maturation pathways.


Subject(s)
Bacterial Proteins/metabolism , Endosomes/metabolism , Legionella pneumophila/metabolism , Legionnaires' Disease/metabolism , Lysosomes/metabolism , Macrophages/metabolism , Vacuoles/metabolism , Bacterial Proteins/genetics , Endosomes/genetics , Endosomes/ultrastructure , HEK293 Cells , HeLa Cells , Humans , Legionella pneumophila/genetics , Legionella pneumophila/pathogenicity , Legionnaires' Disease/genetics , Legionnaires' Disease/pathology , Lysosomal Membrane Proteins/genetics , Lysosomal Membrane Proteins/metabolism , Lysosomes/genetics , Lysosomes/ultrastructure , Macrophages/microbiology , Macrophages/ultrastructure , Phosphatidylinositol 3-Kinases/genetics , Phosphatidylinositol 3-Kinases/metabolism , Phosphatidylinositol Phosphates/antagonists & inhibitors , Phosphatidylinositol Phosphates/genetics , Phosphatidylinositol Phosphates/metabolism , U937 Cells , Vacuoles/genetics , Vacuoles/microbiology , Vacuoles/ultrastructure , Wortmannin/pharmacology , rab5 GTP-Binding Proteins/genetics , rab5 GTP-Binding Proteins/metabolism
14.
Cell Tissue Res ; 371(1): 55-71, 2018 01.
Article in English | MEDLINE | ID: mdl-29079882

ABSTRACT

During both development and adulthood, the human brain expresses many thousands of long noncoding RNAs (lncRNAs), and aberrant lncRNA expression has been associated with a wide range of neurological diseases. Although the biological significance of most lncRNAs remains to be discovered, it is now clear that certain lncRNAs carry out important functions in neurodevelopment, neural cell function, and perhaps even diseases of the human brain. Given the relatively inclusive definition of lncRNAs-transcripts longer than 200 nucleotides with essentially no protein coding potential-this class of noncoding transcript is both large and very diverse. Furthermore, emerging data indicate that lncRNA genes can act via multiple, non-mutually exclusive molecular mechanisms, and specific functions are difficult to predict from lncRNA expression or sequence alone. Thus, the different experimental approaches used to explore the role of a lncRNA might each shed light upon distinct facets of its overall molecular mechanism, and combining multiple approaches may be necessary to fully illuminate the function of any particular lncRNA. To understand how lncRNAs affect brain development and neurological disease, in vivo studies of lncRNA function are required. Thus, in this review, we focus our discussion upon a small set of neural lncRNAs that have been experimentally manipulated in mice. Together, these examples illustrate how studies of individual lncRNAs using multiple experimental approaches can help reveal the richness and complexity of lncRNA function in both neurodevelopment and diseases of the brain.


Subject(s)
Brain Diseases/metabolism , Brain/growth & development , Brain/metabolism , RNA, Long Noncoding/metabolism , Alleles , Animals , Brain Diseases/genetics , Gene Expression Regulation , Humans , Interneurons/physiology , Mice , Mice, Transgenic , Models, Animal , Mutation , Neurons/physiology , RNA, Long Noncoding/genetics
15.
Pharmacogenomics ; 17(4): 417-34, 2016 Mar.
Article in English | MEDLINE | ID: mdl-26871520

ABSTRACT

Cancer patients frequently suffer from disease- and treatment-related pain, nausea and depression, which severely reduces patients' quality of life. It is critical that clinicians are aware of drug-gene interactions and recognize the utility of applying pharmacogenetic information to personalize and improve supportive care. Pharmacogenetic-based algorithms may enhance clinical outcomes by allowing the clinician to select the 'least genetically vulnerable' drug. This review summarizes clinically relevant drug-gene interactions and presents pharmacogenetic-driven treatment pathways for depression, nausea/vomiting and pain. Ideally, this review provides a resource for clinicians to consult when selecting pharmacotherapy for a patient who presents with limited pharmacogenetic test results, with the hope of better controlling burdensome symptoms and improving the quality of life for cancer patients.


Subject(s)
Antineoplastic Agents/adverse effects , Neoplasms/drug therapy , Quality of Life , Depression/drug therapy , Depression/genetics , Depression/psychology , Drug Interactions , Humans , Nausea/chemically induced , Nausea/drug therapy , Nausea/genetics , Neoplasms/genetics , Neoplasms/physiopathology , Neoplasms/psychology , Pain/drug therapy , Pain/genetics , Pharmacogenetics , Polymorphism, Genetic , Precision Medicine , Vomiting/chemically induced , Vomiting/drug therapy , Vomiting/genetics
17.
Genes Dev ; 29(8): 817-31, 2015 Apr 15.
Article in English | MEDLINE | ID: mdl-25846796

ABSTRACT

The bone microenvironment is composed of niches that house cells across variable oxygen tensions. However, the contribution of oxygen gradients in regulating bone and blood homeostasis remains unknown. Here, we generated mice with either single or combined genetic inactivation of the critical oxygen-sensing prolyl hydroxylase (PHD) enzymes (PHD1-3) in osteoprogenitors. Hypoxia-inducible factor (HIF) activation associated with Phd2 and Phd3 inactivation drove bone accumulation by modulating osteoblastic/osteoclastic cross-talk through the direct regulation of osteoprotegerin (OPG). In contrast, combined inactivation of Phd1, Phd2, and Phd3 resulted in extreme HIF signaling, leading to polycythemia and excessive bone accumulation by overstimulating angiogenic-osteogenic coupling. We also demonstrate that genetic ablation of Phd2 and Phd3 was sufficient to protect ovariectomized mice against bone loss without disrupting hematopoietic homeostasis. Importantly, we identify OPG as a HIF target gene capable of directing osteoblast-mediated osteoclastogenesis to regulate bone homeostasis. Here, we show that coordinated activation of specific PHD isoforms fine-tunes the osteoblastic response to hypoxia, thereby directing two important aspects of bone physiology: cross-talk between osteoblasts and osteoclasts and angiogenic-osteogenic coupling.


Subject(s)
Bone and Bones/enzymology , Homeostasis , Osteoprotegerin/metabolism , Oxygen/metabolism , Prolyl Hydroxylases/genetics , Prolyl Hydroxylases/metabolism , 3T3 Cells , Animals , Bone Resorption/genetics , Bone and Bones/cytology , Cell Communication , Cell Hypoxia/physiology , Cells, Cultured , Enzyme Activation , Female , Gene Silencing , Hypoxia-Inducible Factor 1/metabolism , Mice , Osteoblasts/metabolism , Osteoclasts/metabolism , Signal Transduction/genetics , Stem Cells/enzymology
18.
Cell Stem Cell ; 16(4): 439-447, 2015 Apr 02.
Article in English | MEDLINE | ID: mdl-25800779

ABSTRACT

While thousands of long noncoding RNAs (lncRNAs) have been identified, few lncRNAs that control neural stem cell (NSC) behavior are known. Here, we identify Pinky (Pnky) as a neural-specific lncRNA that regulates neurogenesis from NSCs in the embryonic and postnatal brain. In postnatal NSCs, Pnky knockdown potentiates neuronal lineage commitment and expands the transit-amplifying cell population, increasing neuron production several-fold. Pnky is evolutionarily conserved and expressed in NSCs of the developing human brain. In the embryonic mouse cortex, Pnky knockdown increases neuronal differentiation and depletes the NSC population. Pnky interacts with the splicing regulator PTBP1, and PTBP1 knockdown also enhances neurogenesis. In NSCs, Pnky and PTBP1 regulate the expression and alternative splicing of a core set of transcripts that relates to the cellular phenotype. These data thus unveil Pnky as a conserved lncRNA that interacts with a key RNA processing factor and regulates neurogenesis from embryonic and postnatal NSC populations.


Subject(s)
Brain/metabolism , Embryonic Stem Cells/physiology , Heterogeneous-Nuclear Ribonucleoproteins/metabolism , Neural Stem Cells/physiology , Neurons/physiology , Polypyrimidine Tract-Binding Protein/metabolism , RNA, Long Noncoding/metabolism , Alternative Splicing/genetics , Animals , Base Sequence , Cells, Cultured , Embryo, Mammalian , Heterogeneous-Nuclear Ribonucleoproteins/genetics , Humans , Mice , Mice, Inbred C57BL , Molecular Sequence Data , Neurogenesis/genetics , Polypyrimidine Tract-Binding Protein/genetics , RNA, Long Noncoding/genetics , RNA, Small Interfering/genetics
19.
Cell Res ; 24(12): 1381-2, 2014 Dec.
Article in English | MEDLINE | ID: mdl-25112712

ABSTRACT

Emerging evidence indicates that there are factors within the blood of young animals that have the ability to restore youthful characteristics to a number of organ systems in older animals. Growth/differentiation factor 11 (GDF11) is the first of such factors to be identified, and two new studies demonstrate that this "factor of youth" rejuvenates stem cells found in the skeletal muscle and brain of aged mice.


Subject(s)
Aging , Bone Morphogenetic Proteins/blood , Brain/cytology , Growth Differentiation Factors/blood , Muscle, Skeletal/cytology , Stem Cells/cytology , Aging/blood , Animals , Bone Morphogenetic Proteins/administration & dosage , Bone Morphogenetic Proteins/metabolism , Brain/physiology , Growth Differentiation Factors/administration & dosage , Growth Differentiation Factors/metabolism , Mice , Muscle, Skeletal/physiology , Recombinant Proteins/administration & dosage , Recombinant Proteins/blood , Recombinant Proteins/metabolism , Stem Cells/metabolism
20.
J Clin Microbiol ; 50(11): 3703-11, 2012 Nov.
Article in English | MEDLINE | ID: mdl-22972830

ABSTRACT

In 1991, multiresistant Escherichia coli O78:H10 strains caused an outbreak of urinary tract infections in Copenhagen, Denmark. The phylogenetic origin, clonal background, and virulence characteristics of the outbreak isolates, and their relationship to nonoutbreak O78:H10 strains according to these traits and resistance profiles, are unknown. Accordingly, we extensively characterized 51 archived E. coli O78:H10 isolates (48 human isolates from seven countries, including 19 Copenhagen outbreak isolates, and 1 each of calf, avian, and unknown-source isolates), collected from 1956 through 2000. E. coli O78:H10 was clonally heterogeneous, comprising one dominant clonal group (61% of isolates, including all 19 outbreak isolates) from ST10 (phylogenetic group A) plus several minor clonal groups (phylogenetic groups A and D). All ST10 isolates, versus 25% of non-ST10 isolates, were identified by molecular methods as enteroaggregative E. coli (EAEC) (P < 0.001). Genes present in >90% of outbreak isolates included fimH (type 1 fimbriae; ubiquitous in E. coli); fyuA, traT, and iutA (associated with extraintestinal pathogenic E. coli [ExPEC]); and sat, pic, aatA, aggR, aggA, ORF61, aaiC, aap, and ORF3 (associated with EAEC). An outbreak isolate was lethal in a murine subcutaneous sepsis model and exhibited characteristic EAEC "stacked brick" adherence to cultured epithelial cells. Thus, the 1991 Copenhagen outbreak was caused by a tight, non-animal-associated subset within a broadly disseminated O78:H10 clonal group (ST10; phylogenetic group A), members of which exhibit both ExPEC and EAEC characteristics, whereas O78:H10 isolates overall are phylogenetically diverse. Whether ST10 O78:H10 EAEC strains are both uropathogenic and diarrheagenic warrants further investigation.


Subject(s)
Disease Outbreaks , Escherichia coli Infections/epidemiology , Escherichia coli/classification , Escherichia coli/genetics , Molecular Typing , Urinary Tract Infections/epidemiology , Animals , Child , Cluster Analysis , Denmark/epidemiology , Disease Models, Animal , Drug Resistance, Multiple, Bacterial , Escherichia coli/isolation & purification , Escherichia coli Infections/microbiology , Genetic Variation , Genotype , Humans , Infant, Newborn , Mice , Molecular Epidemiology , Phylogeny , Sepsis/mortality , Serotyping , Survival Analysis , Urinary Tract Infections/microbiology
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