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Category: genetics – Page 6

Abstract: Uncovering a novel disease mechanism in partial lipodystrophy syndrome disease

Here, Elif A. Oral & team describe a nonsense variant in EBF2 in a patient with an atypical form of partial lipodystrophy and establish a mouse model—linking the EBF2 p. E165X variant to impaired adipogenesis and adipose tissue function.

The image shows inguinal adipose tissue from the EBF2 p. E165X knock-in mouse, demonstrating prominent accumulation of collagen fibers (blue) and elastin-rich eosinophilic material (purple).

1Caswell Diabetes Institute and Metabolism, Endocrinology and Diabetes Division, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, USA.

2Department of Clinical and Translational Sciences, University of Pisa, Pisa, Italy.

3Division of Genetics and Genomics, Boston Children’s Hospital, Boston, Massachusetts, USA.

FOXJ3 gene variants linked to drug-resistant focal epilepsy

Researchers have discovered that mutations in the FOXJ3 gene act as a “master switch” failure, disrupting how the brain builds its layers and leading to FCD, a primary cause of drug-resistant epilepsy. The study reveals how FOXJ3 controls the formation of brain cortical layers during brain development by regulating the PTEN–mTOR signaling pathway.

The PTEN-mTOR signaling pathway acts as a critical control system for cell growth, proliferation, metabolism, and survival. When this system malfunctions, it causes many neurological disorders including FCD, tuberous sclerosis complex and neurofibromatosis. The discovery of FOXJ3, a transcription factor (a protein that regulates gene activity), as a new cause of these “mTOR pathway diseases” (mTORpathies) provides new insight into the biological origins of epilepsy and cortical malformations, as well as potential new treatments.

The research team by studying families with inherited focal epilepsy alongside mouse and single-cell analysis, uncovered how FOXJ3 mutations disrupt how brain cells move to their correct locations and take on their proper roles during early brain development.

“Focal cortical dysplasia is one of the most common causes of epilepsy that does not respond to medication, yet in many patients the underlying cause remains unknown,” said the corresponding author. “Our findings identify FOXJ3 as the critical genetic and molecular link between abnormal brain development and epilepsy.” ScienceMission sciencenewshighlights.

Dendritic cell immunotherapy induces anti-tumor effect in a transgenic mouse model of pancreatic ductal adenocarcinoma

The promise of dendritic cell (DC)-based immunotherapy has been established by two decades of translational research. However, long-term benefits of DC vaccination are reported in only scattered patients with pancreatic ductal adenocarcinoma (PDAC). Here we optimize DC vaccination and evaluate its safety and antitumor efficacy in the genetically engineered PDAC model (KrasLSL-G12D p53LSL-R172H Pdx-1-Cre (KPC mice)). KPC transgenic mice and orthotopic models using KPC cell lines were treated with DC vaccine via an intraperitoneal route. Tumor growth and microenvironment were dynamically monitored by magnetic resonance imaging (MRI). Histological analysis and flow cytometry were used to evaluate tumor-directed T cell immunity of these mice. DC vaccine via intraperitoneal injection suppressed tumor progression (P = 0.030) and significantly prolonged survival time (P = 0.028) in KPC mice. Vaccinated KPC mice displayed an increased antitumor T cell response indicated by a higher IFN-γ production (P = 0.016) and tumor-specific cytotoxicity (P = 0.027). Particularly, the mean apparent diffusion coefficient (ADC) values of KPC tumor calculated from diffusion weighted MRI (DW-MRI) were significantly higher in DC vaccine group than that in control group (P < 0.001). More interestingly, we observed that ADC positively correlated with fibrosis in KPC tumor (R2 = 0.463, P = 0.015). Our study demonstrated that the immunization with our improved DC vaccine can elicit a strong tumor-specific immune response and tumor suppression in PDAC.

Glutamine metabolism tunes myeloid responses to drive resolution of inflammation during skin repair

Xu et al. uncover how metabolites regulate cellular communication during inflammatory resolution and tissue repair in vivo. They find that glutamine metabolism alters chromatin accessibility and suppresses neutrophil chemotaxis gene transcription to resolve inflammation and drive tissue repair.

Dick Van Dyke Credits His Longevity to One Habit, And Science Supports It

Dick Van Dyke, the legendary American actor and comedian who starred in classics such as Mary Poppins and Chitty Chitty Bang Bang, turned 100 on December 13. The beloved actor credits his remarkable longevity to his positive outlook and never getting angry.

While longevity of course comes down to many factors – including genetics and lifestyle – there is some truth to Van Dyke’s claims.

Numerous studies have shown that keeping stress levels low and maintaining a positive, optimistic outlook are correlated with longevity.

Why You Should Question Genetic Risk Scores

Whole genome sequencing is powerful but still very new. Many companies offer genetic predictions for diseases without clearly explaining how those models are built or validated. Most people don’t ask basic questions like: How accurate is this? What data was used? What are the limitations? In this video, we break down why transparency matters and why you should always question genetic risk scores before trusting them. Youtube Video: https://www.youtube.com/LongevityScienceNews/membership Patreon: https://www.patreon.com/posts/polygenic-scores-152170836?utm…=join_link https://www.herasight.com/

Abstract: Patients with recurrent kidney stone disease stand to benefit from personalized diagnostics

In this Research Article, Ruxandra Bachmann-Gagescu & team integrate blood and urine biochemistry with genetics to improve interpretation of genetic findings in adults with kidney stone disease—the approach has prognostic value, enabling personalized risk assessment.

3Department of Molecular Life Sciences, University of Zurich, Zurich, Switzerland.

4National Center of Competence in Research (NCCR) Kidney. CH, Bern, Switzerland.

5Department of Nephrology and Hypertension, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.

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