Genetically modified organisms: adapting regulatory frameworks for evolving genome editing technologies.

Genetic modification of living organisms has been a prosperous activity for research and development of agricultural, industrial and biomedical applications. Three decades have passed since the first genetically modified products, obtained by transgenesis, become available to the market. The regulatory frameworks across the world have not been able to keep up to date with new technologies, monitoring and safety concerns.

Prevention of Cardiorenal Complications with Sodium-Glucose Cotransporter Type 2 Inhibitors: A Narrative Review.

Heart failure (HF) and chronic kidney disease (CKD) are the most frequent first cardiorenal conditions in patients with type 2 diabetes (T2D), which can be exacerbated by other comorbidities, such as hypertension, dyslipidemia, and obesity. To improve their clinical outcomes, patients with T2D need to achieve and maintain glycemic targets, as well as prevent cardiorenal disease onset and progression. Several clinical trials evaluating the sodium-glucose cotransporter type 2 inhibitors (SGLT2i) dapagliflozin, empagliflozin, canagliflozin, and ertugliflozin have shown consistent risk reduction in major adverse cardiovascular events and/or hospitalization for HF, together with lower risk of kidney disease progression.

Critical roles of protein disulfide isomerases in balancing proteostasis in the nervous system.

Protein disulfide isomerases (PDIs) constitute a family of oxidoreductases promoting redox protein folding and quality control in the endoplasmic reticulum. PDIs catalyze disulfide bond formation, isomerization, and reduction, operating in concert with molecular chaperones to fold secretory cargoes in addition to directing misfolded proteins to be refolded or degraded. Importantly, PDIs are emerging as key components of the proteostasis network, integrating protein folding status with central surveillance mechanisms to balance proteome stability according to cellular needs.

Mutation in protein disulfide isomerase A3 causes neurodevelopmental defects by disturbing endoplasmic reticulum proteostasis.

Recessive gene mutations underlie many developmental disorders and often lead to disabling neurological problems. Here, we report identification of a homozygous c.170G>A (p.

Protein disulfide isomerase ERp57 protects early muscle denervation in experimental ALS.

Amyotrophic lateral sclerosis (ALS) is a progressive fatal neurodegenerative disease that affects motoneurons. Mutations in superoxide dismutase 1 (SOD1) have been described as a causative genetic factor for ALS. Mice overexpressing ALS-linked mutant SOD1 develop ALS symptoms accompanied by histopathological alterations and protein aggregation.

Improving the standard of care for patients with spondyloarthritis-related immune inflammatory conditions: results of a Delphi study and proposal for early detection.

Background: Our objective was to provide consensus recommendations on the optimal management of the immune-mediated inflammatory diseases (IMIDs) seen in patients with spondyloarthritis (SpA) using a multidisciplinary approach, and to develop a simple tool to help earlier recognition and referral of coexisting IMIDs in patients who already have one type of IMID.

Methods: A total of 28 experts in the multidisciplinary management of the SpA-associated IMIDs assessed two questionnaires: one with statements focused on the multidisciplinary management of IMIDs, and a second questionnaire focused on questions useful for early recognition and referral. Panelists assessed the statements with a 9-point ordinal scale (1 = strongly disagree, 9 = strongly agree) using a modified Delphi methodology.

Endoplasmic reticulum stress leads to accumulation of wild-type SOD1 aggregates associated with sporadic amyotrophic lateral sclerosis.

Abnormal modifications to mutant superoxide dismutase 1 (SOD1) are linked to familial amyotrophic lateral sclerosis (fALS). Misfolding of wild-type SOD1 (SOD1) is also observed in postmortem tissue of a subset of sporadic ALS (sALS) cases, but cellular and molecular mechanisms generating abnormal SOD1 species are unknown. We analyzed aberrant human SOD1 species over the lifetime of transgenic mice and found the accumulation of disulfide-cross-linked high-molecular-weight SOD1 aggregates during aging.

Clinical value of Flash glucose monitoring in patients with type 1 diabetes treated with continuous subcutaneous insulin infusion.

Aim: To analyze the clinical impact of the Flash glucose monitoring system in patients with type 1 diabetes mellitus (T1DM) treated with continuous subcutaneous insulin infusion (CSII).

Methods: A 24-week retrospective cohort study in CSII-treated T1DM patients exposed (1:1) to the Flash glucose monitoring system vs. self-monitoring of capillary blood glucose (SMBG).

Disulfide cross-linked multimers of TDP-43 and spinal motoneuron loss in a TDP-43 ALS/FTD mouse model.

Tar DNA binding protein 43 (TDP-43) is the principal component of ubiquitinated protein inclusions present in nervous tissue of most cases of both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Previous studies described a TDP-43 transgenic mouse model that develops progressive motor dysfunction in the absence of protein aggregation or significant motoneuron loss, questioning its validity to study ALS. Here we have further characterized the course of the disease in TDP-43 mice using a battery of tests and biochemical approaches.

The ER proteostasis network in ALS: Determining the differential motoneuron vulnerability.

Amyotrophic lateral sclerosis (ALS) is a fatal late-onset neurodegenerative disease characterized by the selective loss of motoneurons. The mechanisms underlying neuronal degeneration in ALS are starting to be elucidated, highlighting abnormal protein aggregation and altered mRNA metabolism as common phenomena. ALS involves the selective vulnerablility of a subpopulation of motoneurons, suggesting that intrinsic factors may determine ALS pathogenesis.

Targeted overexpression of tumor necrosis factor-α increases cyclin-dependent kinase 5 activity and TRPV1-dependent Ca2+ influx in trigeminal neurons.

We reported earlier that TNF-α, a proinflammatory cytokine implicated in many inflammatory disorders causing orofacial pain, increases the activity of Cdk5, a key kinase involved in brain development and function and recently found to be involved in pain signaling. To investigate a potential mechanism underlying inflammatory pain in trigeminal ganglia (TGs), we engineered a transgenic mouse model (TNF) that can conditionally overexpresses TNF-α upon genomic recombination by Cre recombinase. TNF mice were bred with Nav1.

ALS-linked protein disulfide isomerase variants cause motor dysfunction.

Disturbance of endoplasmic reticulum (ER) proteostasis is a common feature of amyotrophic lateral sclerosis (ALS). Protein disulfide isomerases (PDIs) areERfoldases identified as possibleALSbiomarkers, as well as neuroprotective factors. However, no functional studies have addressed their impact on the disease process.

Functional Role of the Disulfide Isomerase ERp57 in Axonal Regeneration.

ERp57 (also known as grp58 and PDIA3) is a protein disulfide isomerase that catalyzes disulfide bonds formation of glycoproteins as part of the calnexin and calreticulin cycle. ERp57 is markedly upregulated in most common neurodegenerative diseases downstream of the endoplasmic reticulum (ER) stress response. Despite accumulating correlative evidence supporting a neuroprotective role of ERp57, the contribution of this foldase to the physiology of the nervous system remains unknown.

The Protein-disulfide Isomerase ERp57 Regulates the Steady-state Levels of the Prion Protein.

Although the accumulation of a misfolded and protease-resistant form of the prion protein (PrP) is a key event in prion pathogenesis, the cellular factors involved in its folding and quality control are poorly understood. PrP is a glycosylated and disulfide-bonded protein synthesized at the endoplasmic reticulum (ER). The ER foldase ERp57 (also known as Grp58) is highly expressed in the brain of sporadic and infectious forms of prion-related disorders.