gene

Could Your Genes Influence How You Vote?

Title: Could Your Genes Influence How You Vote?
Category: Health News
Created: 8/27/2012 4:05:00 PM
Last Editorial Review: 8/28/2012 12:00:00 AM




gene

Scientists ID 'Happy' Gene in Women

Title: Scientists ID 'Happy' Gene in Women
Category: Health News
Created: 8/29/2012 4:05:00 PM
Last Editorial Review: 8/30/2012 12:00:00 AM




gene

Gene Study Helps Advance Diagnosis of Cystic Fibrosis

Title: Gene Study Helps Advance Diagnosis of Cystic Fibrosis
Category: Health News
Created: 8/26/2013 2:36:00 PM
Last Editorial Review: 8/27/2013 12:00:00 AM




gene

Gene May Raise Diabetics' Chances of Heart Disease

Title: Gene May Raise Diabetics' Chances of Heart Disease
Category: Health News
Created: 8/27/2013 4:35:00 PM
Last Editorial Review: 8/28/2013 12:00:00 AM




gene

Experimental Drug Shows Promise for Rare Genetic Disorder

Title: Experimental Drug Shows Promise for Rare Genetic Disorder
Category: Health News
Created: 8/29/2013 12:35:00 PM
Last Editorial Review: 8/30/2013 12:00:00 AM




gene

Gene Tweak Boosts Lifespan by 20 Percent in Mice

Title: Gene Tweak Boosts Lifespan by 20 Percent in Mice
Category: Health News
Created: 8/29/2013 12:35:00 PM
Last Editorial Review: 8/30/2013 12:00:00 AM




gene

Scientists Spot Genetic Clues to Crohn's Disease

Title: Scientists Spot Genetic Clues to Crohn's Disease
Category: Health News
Created: 8/27/2014 9:35:00 AM
Last Editorial Review: 8/27/2014 12:00:00 AM




gene

Gene Research Yields Insights Into Ebola Virus

Title: Gene Research Yields Insights Into Ebola Virus
Category: Health News
Created: 8/28/2014 2:36:00 PM
Last Editorial Review: 8/29/2014 12:00:00 AM




gene

Black Women at Raised Risk of Carrying Breast Cancer Genes

Title: Black Women at Raised Risk of Carrying Breast Cancer Genes
Category: Health News
Created: 8/27/2015 12:00:00 AM
Last Editorial Review: 8/28/2015 12:00:00 AM




gene

Genes Might Explain Hispanics' Added Longevity

Title: Genes Might Explain Hispanics' Added Longevity
Category: Health News
Created: 8/19/2016 12:00:00 AM
Last Editorial Review: 8/22/2016 12:00:00 AM




gene

Gene Test Might Quickly ID Baby's Infection

Title: Gene Test Might Quickly ID Baby's Infection
Category: Health News
Created: 8/23/2016 12:00:00 AM
Last Editorial Review: 8/24/2016 12:00:00 AM




gene

Autism-Linked Genes Often Differ Between Siblings

Title: Autism-Linked Genes Often Differ Between Siblings
Category: Health News
Created: 8/25/2016 12:00:00 AM
Last Editorial Review: 8/26/2016 12:00:00 AM




gene

First Gene Therapy Approved in U.S.

Title: First Gene Therapy Approved in U.S.
Category: Health News
Created: 8/30/2017 12:00:00 AM
Last Editorial Review: 8/31/2017 12:00:00 AM




gene

Gene 'Editing' in Dog Study Shows Promise for Kids With Muscular Dystrophy

Title: Gene 'Editing' in Dog Study Shows Promise for Kids With Muscular Dystrophy
Category: Health News
Created: 8/30/2018 12:00:00 AM
Last Editorial Review: 8/31/2018 12:00:00 AM




gene

There Is No 'Gay Gene,' Major Study Concludes

Title: There Is No 'Gay Gene,' Major Study Concludes
Category: Health News
Created: 8/29/2019 12:00:00 AM
Last Editorial Review: 8/30/2019 12:00:00 AM




gene

Gene Therapy Makes Inroads Against a Form of Hemophilia

Title: Gene Therapy Makes Inroads Against a Form of Hemophilia
Category: Health News
Created: 7/22/2022 12:00:00 AM
Last Editorial Review: 7/22/2022 12:00:00 AM




gene

Gene Tests Could Spot 1 Million Americans at Risk of High Cholesterol

Title: Gene Tests Could Spot 1 Million Americans at Risk of High Cholesterol
Category: Health News
Created: 5/18/2022 12:00:00 AM
Last Editorial Review: 5/18/2022 12:00:00 AM




gene

Major Gene Study Spots DNA Tied to Autism, Other Disorders

Title: Major Gene Study Spots DNA Tied to Autism, Other Disorders
Category: Health News
Created: 8/19/2022 12:00:00 AM
Last Editorial Review: 8/19/2022 12:00:00 AM




gene

Dynamic dysregulation of retrotransposons in neurodegenerative diseases at the single-cell level [RESOURCES]

Retrotransposable elements (RTEs) are common mobile genetic elements comprising ~42% of the human genome. RTEs play critical roles in gene regulation and function, but how they are specifically involved in complex diseases is largely unknown. Here, we investigate the cellular heterogeneity of RTEs using 12 single-cell transcriptome profiles covering three neurodegenerative diseases, Alzheimer's disease (AD), Parkinson's disease, and multiple sclerosis. We identify cell type marker RTEs in neurons, astrocytes, oligodendrocytes, and oligodendrocyte precursor cells that are related to these diseases. The differential expression analysis reveals the landscape of dysregulated RTE expression, especially L1s, in excitatory neurons of multiple neurodegenerative diseases. Machine learning algorithms for predicting cell disease stage using a combination of RTE and gene expression features suggests dynamic regulation of RTEs in AD. Furthermore, we construct a single-cell atlas of retrotransposable elements in neurodegenerative disease (scARE) using these data sets and features. scARE has six feature analysis modules to explore RTE dynamics in a user-defined condition. To our knowledge, scARE represents the first systematic investigation of RTE dynamics at the single-cell level within the context of neurodegenerative diseases.




gene

PWAS Hub for exploring gene-based associations of common complex diseases [RESOURCES]

PWAS (proteome-wide association study) is an innovative genetic association approach that complements widely used methods like GWAS (genome-wide association study). The PWAS approach involves consecutive phases. Initially, machine learning modeling and probabilistic considerations quantify the impact of genetic variants on protein-coding genes’ biochemical functions. Secondly, for each individual, aggregating the variants per gene determines a gene-damaging score. Finally, standard statistical tests are activated in the case-control setting to yield statistically significant genes per phenotype. The PWAS Hub offers a user-friendly interface for an in-depth exploration of gene–disease associations from the UK Biobank (UKB). Results from PWAS cover 99 common diseases and conditions, each with over 10,000 diagnosed individuals per phenotype. Users can explore genes associated with these diseases, with separate analyses conducted for males and females. For each phenotype, the analyses account for sex-based genetic effects, inheritance modes (dominant and recessive), and the pleiotropic nature of associated genes. The PWAS Hub showcases its usefulness for asthma by navigating through proteomic-genetic analyses. Inspecting PWAS asthma-listed genes (a total of 27) provide insights into the underlying cellular and molecular mechanisms. Comparison of PWAS-statistically significant genes for common diseases to the Open Targets benchmark shows partial but significant overlap in gene associations for most phenotypes. Graphical tools facilitate comparing genetic effects between PWAS and coding GWAS results, aiding in understanding the sex-specific genetic impact on common diseases. This adaptable platform is attractive to clinicians, researchers, and individuals interested in delving into gene–disease associations and sex-specific genetic effects.




gene

Complete genomes of Asgard archaea reveal diverse integrated and mobile genetic elements [RESEARCH]

Asgard archaea are of great interest as the progenitors of Eukaryotes, but little is known about the mobile genetic elements (MGEs) that may shape their ongoing evolution. Here, we describe MGEs that replicate in Atabeyarchaeia, a wetland Asgard archaea lineage represented by two complete genomes. We used soil depth–resolved population metagenomic data sets to track 18 MGEs for which genome structures were defined and precise chromosome integration sites could be identified for confident host linkage. Additionally, we identified a complete 20.67 kbp circular plasmid and two family-level groups of viruses linked to Atabeyarchaeia, via CRISPR spacer targeting. Closely related 40 kbp viruses possess a hypervariable genomic region encoding combinations of specific genes for small cysteine-rich proteins structurally similar to restriction-homing endonucleases. One 10.9 kbp integrative conjugative element (ICE) integrates genomically into the Atabeyarchaeum deiterrae-1 chromosome and has a 2.5 kbp circularizable element integrated within it. The 10.9 kbp ICE encodes an expressed Type IIG restriction-modification system with a sequence specificity matching an active methylation motif identified by Pacific Biosciences (PacBio) high-accuracy long-read (HiFi) metagenomic sequencing. Restriction-modification of Atabeyarchaeia differs from that of another coexisting Asgard archaea, Freyarchaeia, which has few identified MGEs but possesses diverse defense mechanisms, including DISARM and Hachiman, not found in Atabeyarchaeia. Overall, defense systems and methylation mechanisms of Asgard archaea likely modulate their interactions with MGEs, and integration/excision and copy number variation of MGEs in turn enable host genetic versatility.




gene

Wonca Europe 2023 Definition of General Practice/Family Medicine: New Needs New Content




gene

Performance Evaluation of the Generative Pre-trained Transformer (GPT-4) on the Family Medicine In-Training Examination

Objective:

In this study, we sought to comprehensively evaluate GPT-4 (Generative Pre-trained Transformer)’s performance on the 2022 American Board of Family Medicine’s (ABFM) In-Training Examination (ITE), compared with its predecessor, GPT-3.5, and the national family residents’ performance on the same examination.

Methods:

We utilized both quantitative and qualitative analyses. First, a quantitative analysis was employed to evaluate the model's performance metrics using zero-shot prompt (where only examination questions were provided without any additional information). After this, qualitative analysis was executed to understand the nature of the model's responses, the depth of its medical knowledge, and its ability to comprehend contextual or new information through chain-of-thoughts prompts (interactive conversation) with the model.

Results:

This study demonstrated that GPT-4 made significant improvement in accuracy compared with GPT-3.5 over a 4-month interval between their respective release dates. The correct percentage with zero-shot prompt increased from 56% to 84%, which translates to a scaled score growth from 280 to 690, a 410-point increase. Most notably, further chain-of-thought investigation revealed GPT-4’s ability to integrate new information and make self-correction when needed.

Conclusions:

In this study, GPT-4 has demonstrated notably high accuracy, as well as rapid reading and learning capabilities. These results are consistent with previous research indicating GPT-4's significant potential to assist in clinical decision making. Furthermore, the study highlights the essential role of physicians' critical thinking and lifelong learning skills, particularly evident through the analysis of GPT-4's incorrect responses. This emphasizes the indispensable human element in effectively implementing and using AI technologies in medical settings.




gene

A germline PAF1 paralog complex ensures cell type-specific gene expression [Research Papers]

Animal germline development and fertility rely on paralogs of general transcription factors that recruit RNA polymerase II to ensure cell type-specific gene expression. It remains unclear whether gene expression processes downstream from such paralog-based transcription is distinct from that of canonical RNA polymerase II genes. In Drosophila, the testis-specific TBP-associated factors (tTAFs) activate over a thousand spermatocyte-specific gene promoters to enable meiosis and germ cell differentiation. Here, we show that efficient termination of tTAF-activated transcription relies on testis-specific paralogs of canonical polymerase-associated factor 1 complex (PAF1C) proteins, which form a testis-specific PAF1C (tPAF). Consequently, tPAF mutants show aberrant expression of hundreds of downstream genes due to read-in transcription. Furthermore, tPAF facilitates expression of Y-linked male fertility factor genes and thus serves to maintain spermatocyte-specific gene expression. Consistently, tPAF is required for the segregation of meiotic chromosomes and male fertility. Supported by comparative in vivo protein interaction assays, we provide a mechanistic model for the functional divergence of tPAF and the PAF1C and identify transcription termination as a developmentally regulated process required for germline-specific gene expression.




gene

Decoding genetic susceptibility to Pseudomonas aeruginosa infections in cystic fibrosis

Extract

In cystic fibrosis (CF), Pseudomonas aeruginosa acquisition represents a turning point in disease progression. The presence of chronic P. aeruginosa infection is associated with worsening lung function and increased risk of earlier death, whereas treatment substantially improves lung function and survival [1, 2]. Efforts to diagnose and eradicate early P. aeruginosa provide lasting benefits for children with CF [3, 4]. However, the timing of infection varies considerably between individuals with CF, treatment centres [5, 6], and different birth cohorts of people with the disease [7, 8].




gene

The Induction of Drug Uptake Transporter Organic Anion Transporting Polypeptide 1A2 by Radiation Is Mediated by the Nonreceptor Tyrosine Kinase v-YES-1 Yamaguchi Sarcoma Viral Oncogene Homolog 1 [Articles]

Organic anion transporting polypeptides (OATP, gene symbol SLCO) are well-recognized key determinants for the absorption, distribution, and excretion of a wide spectrum of endogenous and exogenous compounds including many antineoplastic agents. It was therefore proposed as a potential drug target for cancer therapy. In our previous study, it was found that low-dose X-ray and carbon ion irradiation both upregulated the expression of OATP family member OATP1A2 and in turn, led to a more dramatic killing effect when cancer cells were cotreated with antitumor drugs such as methotrexate. In the present study, the underlying mechanism of the phenomenon was explored in breast cancer cell line MCF-7. It was found that the nonreceptor tyrosine kinase v-YES-1 Yamaguchi sarcoma viral oncogene homolog 1 (YES-1) was temporally coordinated with the change of OATP1A2 after irradiation. The overexpression of YES-1 significantly increased OATP1A2 both at the mRNA and protein level. The signal transducer and activator of transcription 3 (STAT3) pathway is likely the downstream target of YES-1 because phosphorylation and nuclear accumulation of STAT3 were both enhanced after overexpressing YES-1 in MCF-7 cells. Further investigation revealed that there are two possible binding sites of STAT3 localized at the upstream sequence of SLCO1A2, the encoding gene of OATP1A2. Electrophoretic mobility shift assay and chromatin immunoprecipitation analysis suggested that these two sites bound to STAT3 specifically and the overexpression of YES-1 significantly increased the association of the transcription factor with the putative binding sites. Finally, inhibition or knockdown of YES-1 attenuated the induction effect of radiation on the expression of OATP1A2.

SIGNIFICANCE STATEMENT

The present study found that the effect of X-rays on v-YES-1 Yamaguchi sarcoma viral oncogene homolog 1 (YES-1) and organic anion transporting polypeptides (OATP)1A2 was temporally coordinated. YES-1 phosphorylates and increases the nuclear accumulation of signal transducer and activator of transcription 3, which in turn binds to the upstream regulatory sequences of SLCO1A2, the coding gene for OATP1A2. Hence, inhibitors of YES-1 may suppress the radiation induction effect on OATP1A2.




gene

Characterizing the Distribution of a Stimulator of Interferon Genes Agonist and Its Metabolites in Mouse Liver by Matrix-Assisted Laser Desorption/Ionization Imaging Mass Spectrometry [Special Section on New and Emerging Areas and Technologies in Drug Met

A STING (stimulator of interferon genes) agonist GSK3996915 under investigation in early discovery for hepatitis B was orally dosed to a mouse model for understanding the parent drug distribution in liver, the target organ. Matrix-assisted laser desorption/ionization (MALDI) imaging mass spectrometry (IMS) was used to quantify the distribution of GSK3996915 in liver collected from mice administered a single oral dose at 90 mg/kg. GSK3996915 was detected with a zonal distribution localized in the portal triad and highly concentrated in the main bile ducts, indicating clearance through biliary excretion. High spatial resolution imaging showed the distribution of the parent drug localized to the cellular populations in the sinusoids, including the Kupffer cells. Additionally, a series of drug-related metabolites were observed to be localized in the central zones of the liver. These results exemplify the potential of utilizing MALDI IMS for measuring not only quantitative drug distribution and target exposure but also drug metabolism and elimination in a single suite of experiments.

SIGNIFICANCE STATEMENT

An integrated imaging approach utilizing matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI IMS) complemented with immunohistochemistry (IHC) and histology was used to address the question of target exposure at the cellular level. Localized quantification of the parent drug in the target organ and identification of potential metabolites in the context of tissue histology were also achieved in one experimental suite to support characterization of pharmacokinetic properties of the drug in the early discovery stage.:




gene

Factors Influencing the Central Nervous System (CNS) Distribution of the Ataxia Telangiectasia Mutated and Rad3-Related Inhibitor Elimusertib (BAY1895344): Implications for the Treatment of CNS Tumors [Metabolism, Transport, and Pharmacogenetics]

Glioblastoma (GBM) is a disease of the whole brain, with infiltrative tumor cells protected by an intact blood-brain barrier (BBB). GBM has a poor prognosis despite aggressive treatment, in part due to the lack of adequate drug permeability at the BBB. Standard of care GBM therapies include radiation and cytotoxic chemotherapy that lead to DNA damage. Subsequent activation of DNA damage response (DDR) pathways can induce resistance. Various DDR inhibitors, targeting the key regulators of these pathways such as ataxia telangiectasia mutated and Rad3-related (ATR), are being explored as radio- and chemosensitizers. Elimusertib, a novel ATR kinase inhibitor, can prevent repair of damaged DNA, increasing efficacy of DNA-damaging cytotoxic therapies. Robust synergy was observed in vitro when elimusertib was combined with the DNA-damaging agent temozolomide; however, we did not observe improvement with this combination in in vivo efficacy studies in GBM orthotopic tumor-bearing mice. This in vitro–in vivo disconnect was explored to understand factors influencing central nervous system (CNS) distribution of elimusertib and reasons for lack of efficacy. We observed that elimusertib is rapidly cleared from systemic circulation in mice and would not maintain adequate exposure in the CNS for efficacious combination therapy with temozolomide. CNS distribution of elimusertib is partially limited by P-glycoprotein efflux at the BBB, and high binding to CNS tissues leads to low levels of pharmacologically active (unbound) drug in the brain. Acknowledging the potential for interspecies differences in pharmacokinetics, these data suggest that clinical translation of elimusertib in combination with temozolomide for treatment of GBM may be limited.

SIGNIFICANCE STATEMENT

This study examined the disconnect between the in vitro synergy and in vivo efficacy of elimusertib/temozolomide combination therapy by exploring systemic and central nervous system (CNS) distributional pharmacokinetics. Results indicate that the lack of improvement in in vivo efficacy in glioblastoma (GBM) patient-derived xenograft (PDX) models could be attributed to inadequate exposure of pharmacologically active drug concentrations in the CNS. These observations can guide further exploration of elimusertib for the treatment of GBM or other CNS tumors.




gene

Analgesic Properties of Next-Generation Modulators of Endocannabinoid Signaling: Leveraging Modern Tools for the Development of Novel Therapeutics [Special Section: Cannabinoid Signaling in Human Health and Disease-Minireview]

Targeting the endocannabinoid (eCB) signaling system for pain relief is an important treatment option that is only now beginning to be mechanistically explored. In this review, we focus on two recently appreciated cannabinoid-based targeting strategies, treatments with cannabidiol (CBD) and α/β-hydrolase domain containing 6 (ABHD6) inhibitors, which have the exciting potential to produce pain relief through distinct mechanisms of action and without intoxication. We review evidence on plant-derived cannabinoids for pain, with an emphasis on CBD and its multiple molecular targets expressed in pain pathways. We also discuss the function of eCB signaling in regulating pain responses and the therapeutic promises of inhibitors targeting ABHD6, a 2-arachidonoylglycerol (2-AG)-hydrolyzing enzyme. Finally, we discuss how the novel cannabinoid biosensor GRABeCB2.0 may be leveraged to enable the discovery of targets modulated by cannabinoids at a circuit-specific level.

SIGNIFICANCE STATEMENT

Cannabis has been used by humans as an effective medicine for millennia, including for pain management. Recent evidence emphasizes the therapeutic potential of compounds that modulate endocannabinoid signaling. Specifically, cannabidiol and inhibitors of the enzyme ABHD6 represent promising strategies to achieve pain relief by modulating endocannabinoid signaling in pain pathways via distinct, nonintoxicating mechanisms of action.




gene

The Updated Registry of Fast Myocardial Perfusion Imaging with Next-Generation SPECT (REFINE SPECT 2.0)

The Registry of Fast Myocardial Perfusion Imaging with Next-Generation SPECT (REFINE SPECT) has been expanded to include more patients and CT attenuation correction imaging. We present the design and initial results from the updated registry. Methods: The updated REFINE SPECT is a multicenter, international registry with clinical data and image files. SPECT images were processed by quantitative software and CT images by deep learning software detecting coronary artery calcium (CAC). Patients were followed for major adverse cardiovascular events (MACEs) (death, myocardial infarction, unstable angina, late revascularization). Results: The registry included scans from 45,252 patients from 13 centers (55.9% male, 64.7 ± 11.8 y). Correlating invasive coronary angiography was available for 3,786 (8.4%) patients. CT attenuation correction imaging was available for 13,405 patients. MACEs occurred in 6,514 (14.4%) patients during a median follow-up of 3.6 y (interquartile range, 2.5–4.8 y). Patients with a stress total perfusion deficit of 5% to less than 10% (unadjusted hazard ratio [HR], 2.42; 95% CI, 2.23–2.62) and a stress total perfusion deficit of at least 10% (unadjusted HR, 3.85; 95% CI, 3.56–4.16) were more likely to experience MACEs. Patients with a deep learning CAC score of 101–400 (unadjusted HR, 3.09; 95% CI, 2.57–3.72) and a CAC of more than 400 (unadjusted HR, 5.17; 95% CI, 4.41–6.05) were at increased risk of MACEs. Conclusion: The REFINE SPECT registry contains a comprehensive set of imaging and clinical variables. It will aid in understanding the value of SPECT myocardial perfusion imaging, leverage hybrid imaging, and facilitate validation of new artificial intelligence tools for improving prediction of adverse outcomes incorporating multimodality imaging.




gene

Intrapatient Intermetastatic Heterogeneity Determined by Triple-Tracer PET Imaging in mCRPC Patients and Correlation to Survival: The 3TMPO Cohort Study

Intrapatient intermetastatic heterogeneity (IIH) has been demonstrated in metastatic castration-resistant prostate cancer (mCRPC) patients and is of the utmost importance for radiopharmaceutical therapy (RPT) eligibility. This study was designed to determine the prevalence of IIH and RPT eligibility in mCRPC patients through a triple-tracer PET imaging strategy. Methods: This was a multisite prospective observational study in which mCRPC patients underwent both 18F-FDG and 68Ga-prostate-specific membrane antigen (PSMA)–617 PET/CT scans. A third scan with 68Ga-DOTATATE, a potential biomarker of neuroendocrine differentiation, was performed if an 18F-FDG–positive/68Ga-PSMA–negative lesion was found. Per-tracer lesion positivity was defined as having an uptake at least 50% above that of the liver. IIH prevalence was defined as the percentage of participants having at least 2 lesions with discordant features on multitracer PET. Results: IIH was observed in 81 patients (82.7%), and at least 1 18F-FDG–positive/68Ga-PSMA–negative lesion was found in 45 patients (45.9%). Of the 37 participants who also underwent 68Ga-DOTATATE PET/CT, 6 (16.2%) had at least 1 68Ga-DOTATATE–positive lesion. In total, 12 different combinations of lesion imaging phenotypes were observed. On the basis of our prespecified criteria, 52 (53.1%) participants were determined to be eligible for PSMA RPT, but none for DOTATATE RPT. Patients with IIH had a significantly shorter median overall survival than patients without IIH (9.5 mo vs. not reached; log-rank P = 0.03; hazard ratio, 2.7; 95% CI, 1.1–6.8). Conclusion: Most mCRPC patients showed IIH, which was associated with shorter overall survival. On the basis of a triple-tracer PET approach, multiple phenotypic combinations were found. Correlation of these imaging phenotypes with genomics and treatment response will be relevant for precision medicine.




gene

Posttranslational Modifications of {alpha}-Synuclein, Their Therapeutic Potential, and Crosstalk in Health and Neurodegenerative Diseases [Review Article]

α-Synuclein (α-Syn) aggregation in Lewy bodies and Lewy neurites has emerged as a key pathogenetic feature in Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. Various factors, including posttranslational modifications (PTMs), can influence the propensity of α-Syn to misfold and aggregate. PTMs are biochemical modifications of a protein that occur during or after translation and are typically mediated by enzymes. PTMs modulate several characteristics of proteins including their structure, activity, localization, and stability. α-Syn undergoes various posttranslational modifications, including phosphorylation, ubiquitination, SUMOylation, acetylation, glycation, O-GlcNAcylation, nitration, oxidation, polyamination, arginylation, and truncation. Different PTMs of a protein can physically interact with one another or work together to influence a particular physiological or pathological feature in a process known as PTMs crosstalk. The development of detection techniques for the cooccurrence of PTMs in recent years has uncovered previously unappreciated mechanisms of their crosstalk. This has led to the emergence of evidence supporting an association between α-Syn PTMs crosstalk and synucleinopathies. In this review, we provide a comprehensive evaluation of α-Syn PTMs, their impact on misfolding and pathogenicity, the pharmacological means of targeting them, and their potential as biomarkers of disease. We also highlight the importance of the crosstalk between these PTMs in α-Syn function and aggregation. Insight into these PTMS and the complexities of their crosstalk can improve our understanding of the pathogenesis of synucleinopathies and identify novel targets of therapeutic potential.

Significance Statement

α-Synuclein is a key pathogenic protein in Parkinson’s disease and other synucleinopathies, making it a leading therapeutic target for disease modification. Multiple posttranslational modifications occur at various sites in α-Synuclein and alter its biophysical and pathological properties, some interacting with one another to add to the complexity of the pathogenicity of this protein. This review details these modifications, their implications in disease, and potential therapeutic opportunities.




gene

Glatiramer Acetate for the Treatment of Multiple Sclerosis: From First-Generation Therapy to Elucidation of Immunomodulation and Repair [Review Article]

Multiple sclerosis (MS) is a chronic inflammatory demyelinating and neurodegenerative disease of the central nervous system (CNS), with a putative autoimmune origin and complex pathogenesis. Modification of the natural history of MS by reducing relapses and slowing disability accumulation was first attained in the 1990 s with the development of the first-generation disease-modifying therapies. Glatiramer acetate (GA), a copolymer of L-alanine, L-lysine, L-glutamic acid, and L-tyrosine, was discovered due to its ability to suppress the animal model of MS, experimental autoimmune encephalomyelitis. Extensive clinical trials and long-term assessments established the efficacy and the safety of GA. Furthermore, studies of the therapeutic processes induced by GA in animal models and in MS patients indicate that GA affects various levels of the innate and the adaptive immune response, generating deviation from proinflammatory to anti-inflammatory pathways. This includes competition for binding to antigen presenting cells; driving dendritic cells, monocytes, and B-cells toward anti-inflammatory responses; and stimulating T-helper 2 and T-regulatory cells. The immune cells stimulated by GA reach the CNS and secrete in situ anti-inflammatory cytokines alleviating the pathological processes. Furthermore, cumulative findings reveal that in addition to its immunomodulatory effect, GA promotes neuroprotective repair processes such as neurotrophic factors secretion, remyelination, and neurogenesis. This review aims to provide an overview of MS pathology diagnosis and treatment as well as the diverse mechanism of action of GA.

Significance Statement

Understanding the complex MS immune pathogenesis provided multiple targets for therapeutic intervention, resulting in a plethora of agents, with various mechanisms of action, efficacy, and safety profiles. However, promoting repair beyond the body’s limited spontaneous extent is still a major challenge. GA, one of the first approved disease-modifying therapies, induces diverse immunomodulatory effects. Furthermore, GA treatment results in elevated neurotrophic factors secretion, remyelination and neurogenesis, supporting the notion that immunomodulatory treatment can support in situ a growth-promoting and repair environment.




gene

Ependymal Tumors: Overview of the Recent World Health Organization Histopathologic and Genetic Updates with an Imaging Characteristic [CLINICAL PRACTICE]

SUMMARY:

The 2021 World Health Organization Classification of Tumors of the Central Nervous System (CNS5), introduced significant changes, impacting tumors ranging from glial to ependymal neoplasms. Ependymal tumors were previously classified and graded based on histopathology, which had limited clinical and prognostic utility. The updated CNS5 classification now divides ependymomas into 10 subgroups based on anatomic location (supratentorial, posterior fossa, and spinal compartment) and genomic markers. Supratentorial tumors are defined by zinc finger translocation associated (ZFTA) (formerly v-rel avian reticuloendotheliosis viral oncogene [RELA]), or yes-associated protein 1 (YAP1) fusion; posterior fossa tumors are classified into groups A (PFA) and B (PFB), spinal ependymomas are defined by MYCN amplification. Subependymomas are present across all these anatomic compartments. The new classification kept an open category of "not elsewhere classified" or "not otherwise specified" if no pathogenic gene fusion is identified or if the molecular diagnosis is not feasible. Although there is significant overlap in the imaging findings of these tumors, a neuroradiologist needs to be familiar with updated CNS5 classification to understand tumor behavior, for example, the higher tendency for tumor recurrence along the dural flap for ZFTA fusion-positive ependymomas. On imaging, supratentorial ZFTA-fused ependymomas are preferentially located in the cerebral cortex, carrying predominant cystic components. YAP1-MAMLD1-fused ependymomas are intra- or periventricular with prominent multinodular solid components and have significantly better prognosis than ZFTA-fused counterparts. PFA ependymomas are aggressive paramedian masses with frequent calcification, seen in young children, originating from the lateral part of the fourth ventricular roof. PFB ependymomas are usually midline, noncalcified solid-cystic masses seen in adolescents and young adults arising from the fourth ventricular floor. PFA has a poorer prognosis, higher recurrence, and higher metastatic rate than PFB. Myxopapillary spinal ependymomas are now considered grade II due to high recurrence rates. Spinal-MYCN ependymomas are aggressive tumors with frequent leptomeningeal spread, relapse, and poor prognosis. Subependymomas are noninvasive, intraventricular, slow-growing benign tumors with an excellent prognosis. Currently, the molecular classification does not enhance the clinicopathologic understanding of subependymoma and myxopapillary categories. However, given the molecular advancements, this will likely change in the future. This review provides an updated molecular classification of ependymoma, discusses the individual imaging characteristics, and briefly outlines the latest targeted molecular therapies.




gene

Novel pathogenic PDX1 gene variant in a Korean family with maturity-onset diabetes of the young [VARIANT DISCREPANCY RESOLUTION]

The diagnosis of maturity-onset diabetes of the young (MODY), a monogenic form of diabetes mellitus caused by a mutation in a single gene, is often uncertain until genetic testing is performed. We report a 13-yr-old Korean boy who was initially diagnosed with type 2 diabetes (T2DM). MODY was suspected because of his nonobese body habitus and family history of multiple affected members. Targeted panel sequencing of all MODY-related genes was performed using the NextSeq 550Dx platform (Illumina). Sanger sequencing was performed using blood samples from the parents, siblings, and other relatives. A frameshift variant in the 3' region of the last exon of PDX1 was detected in the patient and his family members with diabetes. PP1_Moderate criterion was applied and this variant was confirmed to be the genetic cause of diabetes in the family and classified as likely pathogenic. The study highlights the importance of genetic testing for nonobese, early-onset diabetic patients with multiple affected family members. Increased awareness and aggressive genetic testing for MODY are needed.




gene

General practice should tackle healthcare inequalities but not health inequalities




gene

Maternal postnatal care in general practice: steps forward




gene

[Neuroscience] Generation of Mammalian Astrocyte Functional Heterogeneity

Mammalian astrocytes have regional roles within the brain parenchyma. Indeed, the notion that astrocytes are molecularly heterogeneous could help explain how the central nervous system (CNS) retains embryonic positional information through development into specialized regions into adulthood. A growing body of evidence supports the concept of morphological and molecular differences between astrocytes in different brain regions, which might relate to their derivation from regionally patterned radial glia and/or local neuron inductive cues. Here, we review evidence for regionally encoded functions of astrocytes to provide an integrated concept on lineage origins and heterogeneity to understand regional brain organization, as well as emerging technologies to identify and further investigate novel roles for astrocytes.




gene

RPG Cast – Episode 563: “Isn’t Compile Heart Jail Against the Geneva Convention?”

We can't believe we have to say this, but this week Chris tries to understand water vapor. Anna Marie takes a week off to go date some demons. Josh frequents a sex shop to pick up some weapons. Pascal starts vaping in his Xbox. And Robert and Kelley are testing the jiggle physics of sacks in World of Warcraft.

The post RPG Cast – Episode 563: “Isn’t Compile Heart Jail Against the Geneva Convention?” appeared first on RPGamer.



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gene

Generative AI creates playable version of Doom game with no code

A neural network can recreate the classic computer game Doom despite using none of its code or graphics, hinting that generative AI could be used to create games from scratch in future




gene

How to avoid being fooled by AI-generated misinformation

Advances in generative AI mean fake images, videos, audio and bots are now everywhere. But studies have revealed the best ways to tell if something is real




gene

How to spot deepfakes and AI-generated images

It can be difficult to spot AI generated videos known as deepfakes, but there are ways to spot one if you know what to look for




gene

The AI expert who says artificial general intelligence is nonsense

Artificial intelligence has more in common with ants than humans, says Neil Lawrence. Only by taking a more nuanced view of intelligence can we see how machines will truly transform society




gene

Google tool makes AI-generated writing easily detectable

Google DeepMind has been using its AI watermarking method on Gemini chatbot responses for months – and now it’s making the tool available to any AI developer




gene

Exclusive: Liz Truss urged to act with Britain facing biggest loss of sports facilities in a generation




gene

Rise of the superbaby? US startup offers genetic IQ screening for wealthy elite: report

U.S.-based startup company Heliospect Genomics reportedly is offering wealthy couples embryo screening for IQ and other traits at $50,000 for 100 embryos.



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gene

Next-generation technology is a critical mid-step in dementia care

New technologies will radically change the experience of living with and caring for someone with Alzheimer's, says Professor Fiona Carragher, chief policy and research officer at Alzheimer's Society, UK





gene

Genetic Discrimination Coming for Us All...


Genetic Discrimination Coming for Us All...


(First column, 14th story, link)





gene

Contest invites teams to design a 'generation starship' for a 250-year journey

A voyage in this kind of spacecraft — while still conceptual — would take multiple lifetimes, crossing unimaginable gulfs of interstellar space. The theoretical exercise puts aside technical problems, including the propulsion system, and focusses on the design of the habitat and society.



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