An increasing number of de novo missense variants have been identified in the GRIN family of genes encoding glutamate receptors, which play multiple roles in the central nervous system including mediation of a slow, calcium permeable component of synaptic transmission. This presentation will introduce the NMDA receptor family and summarize broadly what is known about the GRIN variants across multiple genes. The rationale underlying functional analysis both in vitro and in vivo will be presented, along with a snapshot of the procedures utilized by the Center for Functional Evaluation of Rare Variants. The terms “gain-of-function” and “loss-of-function” will be considered in the context of functional data, and specific data provided illustrating how these properties can vary with gene, location of the variant, and altered function among multiple properties of NMDA receptors.
The main idea for developing this project is to replace existing manual compliant system with online service support.
This system will increase corporation reputation by providing better services and request feedback from people.
Administrator can view the status of compliant registered by people.
Summary reports periodically forward to respective department.
Hepatocellular carcinoma is one of the most common malignancies worldwide, with over 1 million new cases annually. Risk factors include cirrhosis from hepatitis B or C, alcohol consumption, and non-alcoholic steatohepatitis. Symptoms vary and include abdominal pain, weight loss, jaundice, and cirrhosis symptoms. Staging systems include Okuda and CLIP classifications which consider tumor extent, ascites, bilirubin and albumin levels, and portal vein thrombosis. Treatment depends on staging and liver function but may include surgical resection, ablation, transarterial chemoembolization, radiation, chemotherapy, or liver transplant. Early stage 1-2 HCC is typically treated
This document discusses genitourinary trauma, focusing on injuries to the upper and lower urinary tract. It covers the etiology, clinical findings, imaging, and management of renal injuries, ureteral injuries, and bladder injuries. Renal injuries are the most common genitourinary injuries and are often caused by blunt trauma from motor vehicle accidents. Contrast-enhanced CT is the preferred imaging method to evaluate renal injuries. Most renal injuries can be managed non-operatively with bed rest and IV fluids, while operative management is indicated for persistent bleeding or expanding hematomas.
The main idea for developing this project is to replace existing manual compliant system with online service support.
This system will increase corporation reputation by providing better services and request feedback from people.
Administrator can view the status of compliant registered by people.
Summary reports periodically forward to respective department.
Hepatocellular carcinoma is one of the most common malignancies worldwide, with over 1 million new cases annually. Risk factors include cirrhosis from hepatitis B or C, alcohol consumption, and non-alcoholic steatohepatitis. Symptoms vary and include abdominal pain, weight loss, jaundice, and cirrhosis symptoms. Staging systems include Okuda and CLIP classifications which consider tumor extent, ascites, bilirubin and albumin levels, and portal vein thrombosis. Treatment depends on staging and liver function but may include surgical resection, ablation, transarterial chemoembolization, radiation, chemotherapy, or liver transplant. Early stage 1-2 HCC is typically treated
This document discusses genitourinary trauma, focusing on injuries to the upper and lower urinary tract. It covers the etiology, clinical findings, imaging, and management of renal injuries, ureteral injuries, and bladder injuries. Renal injuries are the most common genitourinary injuries and are often caused by blunt trauma from motor vehicle accidents. Contrast-enhanced CT is the preferred imaging method to evaluate renal injuries. Most renal injuries can be managed non-operatively with bed rest and IV fluids, while operative management is indicated for persistent bleeding or expanding hematomas.
1. Nocturia is defined as waking at night to void where the individual is both preceded and followed by sleep. It is clinically significant when there are two or more voids per night.
2. Nocturia can negatively impact quality of life by reducing sleep efficiency and increasing fatigue. It is associated with increased risks of falls, fractures, cardiovascular disease and mortality.
3. The prevalence of nocturia increases with age, affecting about 25-31% of adults overall and about 3 in 5 people over age 70. Evaluation involves a medical history, physical exam, and a 24-hour voiding diary to determine the underlying cause.
This document discusses the definitions, causes, evaluation, and management of urinary retention and anuria. It defines urinary retention as the inability to pass urine despite an urge to void, while anuria is the lack of urine production or passage. The causes of retention are discussed for different age groups and include conditions like urethral stricture, enlarged prostate, neurogenic bladder, bladder stones, and drugs. Evaluation involves history, examination, urinalysis, renal function tests, ultrasound, and urodynamics. Management depends on whether it is acute or chronic retention and may include catheterization, treating underlying causes, and surgery in some cases. Anuria is evaluated and managed based on whether its cause is pre-renal
The document provides an agenda for a presentation on blockchain technology and its applications in the energy industry. The presentation will cover fundamentals of blockchain like digital wallets and transactions, how blockchains work through mining and consensus mechanisms, and introduce smart contracts on the Ethereum network. It will also discuss how blockchain can help modernize the electricity grid and provide an ecosystem of players and platforms in the energy sector, highlighting challenges and benefits of implementing blockchain technology.
Presentation to the New York Association for Energy Economics on October 12th 2017 on how blockchain and distributed ledger technology is being applied to the power sector. The talk focused on examining emerging applications, the limitations of the technology, while also looking to the future of distributed ledgers and their potential impact on the energy value chain.
This document discusses neurogenic lower urinary tract dysfunction. It begins with an introduction and overview of classifications, causes, evaluation, and specific neurological disorders related to lower urinary tract dysfunction. Evaluation involves taking a thorough history, physical exam, bladder diary, lab tests including urine analysis and post-void residual, and urodynamic studies to assess storage and voiding functions. Lesions in different areas of the nervous system can result in distinct patterns of bladder dysfunction, with suprapontine lesions commonly causing storage issues and infrasacral lesions more often resulting in voiding problems. Treatment aims to protect the upper urinary tract and improve symptoms.
Urodynamics describes physiological tests used to investigate abnormalities of lower urinary tract function. The principles of urodynamics are simple - it involves studying the relationship between bladder pressure, volume, and flow during different stages of the micturition cycle. Both non-invasive tests like flowmetry and invasive tests like cystometry are used to evaluate patients and make a urodynamic diagnosis. Special considerations are needed when performing urodynamics on certain patient populations like those with spinal cord injuries.
Genetic variation in GRIN genes encoding N-methyl-D-aspartate receptor (NMDAR) subunits has been associated with a spectrum of neurological and neuropsychiatric disorders. This talk will focus on clinical phenotype, functional consequences, and potential rescue pharmacology of disease-associated GRIN2D missense variants. The GRIN2D variants are located in the pre-M1 helix, agonist-binding domain, transmembrane domain M3, and the intracellular CTD. Developmental and epileptic encephalopathy (DEE) is the unifying phenotype across all 13 patients. The seizure types ranged from focal seizures, atypical absence seizures, tonic or atonic seizures, to epileptic spasms. Eight patients showed certain degree of hypotonia and movement disorders, three patients have autistic behavior and one patient showed symptoms of ADHD. Functional analysis in vitro on six novel GRIN2D variants reveals that that all six variants decreased receptor surface expression, which may underline certain shared clinical symptoms. Three variants (Leu670Phe, Ala675Thr, Ala678Asp) showed significantly enhanced agonist potency, and/or increased channel open probability, while the other three (Ser573Phe, Ser1271Phe, Arg1313Trp) presented reduced
sensitivity to endogenous protons and decreased channel open probability. Three variants (Ser573Phe, Ala675Thr, Ala678Asp) significantly decrease current amplitude. GluN2D-Leu670Phe
prolongs synaptic-like response time course and increases charge transfer. GluN2D-Ala678Asp transfection significantly reduced cell viability of cultured cortical neurons. In addition, a set of FDA-approved NMDAR channel blockers were evaluated for their ability to rescue functional changes of mutant receptors. This work suggests the importance of functional and biochemical validation for each individual variant. Rescue pharmacology in vitro may provide potential benefit of precision
medicine for a subset of severe pediatric neurodevelopmental diseases.
N-methyl-D-aspartate receptors (NMDARs) mediate a slow component of excitatory synaptic transmission that plays important roles in normal brain function and development. A large number of disease-associated variants in the GRIN gene family encoding NMDAR GluN subunits have been identified in patients with various neurological and neuropsychiatric disorders. Many of these variants reduce the function of NMDARs by a range of different mechanisms, including
reduced glutamate potency, reduced glycine potency, accelerated deactivation time course, reduced current response amplitude, decreased surface expression, and/or reduced open probability. This talk will focus on three positive allosteric modulators of NMDAR receptor function (24(S)-hydroxycholesterol, pregnenolone sulfate, tobramycin) and two co-agonists (D-serine and D-cycloserine) on their ability to mitigate the diminished function of NMDARs harboring GRIN variants. We examined the effects of these modulators on NMDARs that contained 24 different loss-of-function missense variants in GRIN1, GRIN2A, or GRIN2B. The clinical phenotypes of the patients hosting these variants include epilepsy/seizures and/or developmental delay/intellectual disability. Some patients have autistic behavior or show symptoms of ADHD. For all variants, some aspect of the
reduced function was partially restored. Moreover, some variants showed enhanced sensitivity to positive allosteric modulators compared to wild type receptors. These results raise the possibility that enhancement of NMDAR function by positive allosteric modulators may be a useful therapeutic strategy.
- The document discusses the burden of diabetic kidney disease and the benefits of SGLT2 inhibitors (SGLT2i).
- It notes that progression of diabetic kidney disease depends on glomerular blood pressure and that SGLT2i lower intraglomerular pressure through their mechanisms of action.
- Clinical trials show that SGLT2i provide renal benefits including postponing end-stage renal disease and that earlier treatment provides longer-term protection of kidney function.
Effects of Sodium Glucose contransporter (SGLT2) inhibition on renal outcomes in patients with (diabetic) chronic kidney disease.
Presentation given during the East by Southwest, Annual Update in Nephrology, September 17th 2017, Santa Fe, NM
http://medicine.unm.edu/academic-divisions/nephrology/east-by-southwest.html
El lunes y martes 20 y 21 de noviembre coordinamos un simposio internacional en la Fundación Ramón Areces, sobre los defectos del transporte de aminoácidos.
1) The document discusses the double burden of diabetes and chronic kidney disease (CKD) in India. Over 50% of patients with type 2 diabetes in one study had CKD as defined by reduced eGFR or albuminuria.
2) Microalbuminuria is an early marker of kidney dysfunction in patients with diabetes. Higher levels of microalbuminuria are associated with poorer glycemic control and longer duration of diabetes.
3) The CARMELINA trial evaluated the cardiovascular and kidney safety of linagliptin versus placebo in patients with type 2 diabetes at high cardiovascular risk but relatively early in their disease. Linagliptin demonstrated kidney safety and reduced the risk of microvascular outcomes.
RNA splicing mutations and human disease: Pompe disease - Emanuele Buratti
Convegno del 25 novembre "Diagnosi e management della glicogenosi tipo 2" - Centro di coordinamento regionale malattie rare FVG
The document summarizes emerging concepts around SGLT2 inhibitors and renal outcomes. It discusses the mechanism of action of SGLT2 inhibitors including reducing glucose reabsorption and increasing sodium delivery to the macula densa. A key trial on the SGLT2 inhibitor dapagliflozin showed it reduced the composite of sustained ≥50% eGFR decline, end-stage kidney disease, or renal or cardiovascular death by 39% compared to placebo in patients with chronic kidney disease. Updated guidelines now recommend SGLT2 inhibitors to reduce renal and cardiovascular risk in patients with chronic kidney disease based on these renal protection benefits shown in clinical trials.
NMDA receptors play crucial roles in excitatory synaptic transmission. Rare variants in genes that encode receptor subunits are associated with several intractable neurodevelopmental disorders, including developmental and epileptic encephalopathy (DEE). To extend understanding of these intractable childhood diseases, we have begun to model these variants in laboratory mice.
Models studied so far are a constitutive knockin for GRIN2A variant p.Ser644Gly (S644G) based on one case, and a GRIN2D variant, p.Val667Ile (V667I), noted in at least three unrelated cases. Homozygous and heterozygous Grin2a S644G mice exhibit altered hippocampal morphology at 2 weeks, and homozygotes exhibit lethal tonic-clonic seizures in week 3. Heterozygotes have a normal lifespan without spontaneous seizures, but display a variety of distinct features including
resistance to electrically induced limbic seizures, as well as hyperactivity and repetitive and reduced anxiety behaviors. Multielectrode recordings of mutant neuronal networks reveal hyperexcitability and altered bursting and synchronicity of both mutant genotypes. When expressed in heterologous cells, mutant receptors exhibit enhanced NMDAR agonist potency and slow deactivation following rapid removal of glutamate, as occurs at synapses. Consistent with this, NMDAR-mediated synaptic currents in hippocampal slices from mutant mice show a prolonged deactivation time course. Standard antiepileptic drug monotherapy was ineffective in the patient, but combined treatment of NMDAR antagonists with antiepileptic drugs substantially reduced the seizure burden albeit without appreciable developmental improvement. Chronic treatment of homozygous mutant mouse pups with NMDAR antagonists delayed the onset of lethal seizures but did not prevent them.
Grin2d V667I knockin mice are at an earlier stage of study. In contrast to Grin2a S644G, V667I heterozygous mice are severely impaired and suffer from lethal tonic-clonic seizures with an onset from about 18 days to 3 months. The impairment precludes natural mating such that the line needs to be propagated by ovary transplantation. Young heterozygotes adults in video-EEG also exhibit very frequent interictal epileptiform spiking and spike-wave discharge activity, resembling absence seizures. Preliminary histology shows significant pyknotic nuclei appearing to evidence
cell death in the cerebral cortex. Pup developmental milestones, while not evidencing significant developmental delay, show unusual features including excessive maternal separation induced pup vocalization. Further studies are ongoing. Together these efforts illustrate the power of modelling severe neurodevelopmental seizure disorders using multiple experimental modalities and suggest their utility in identifying and evaluating new therapies.
This document discusses the clinical profile and efficacy of the combination drug GLYXAMBI, which contains empagliflozin and linagliptin. It summarizes clinical trial results showing that GLYXAMBI provides significant reductions in HbA1c and body weight compared to the individual components alone in patients with type 2 diabetes. Guidelines from major diabetes organizations have been updated to recommend SGLT2 inhibitors like empagliflozin and GLP-1 receptor agonists to reduce cardiovascular risk based on positive cardiovascular outcomes trial results.
This document provides an overview of a company focused on developing transformative therapies for chronic eye diseases. It discusses the company's leadership which has expertise in ophthalmics, retinal disease, and regulatory matters. It also outlines the company's lead product NT-503, an encapsulated cell therapy for wet age-related macular degeneration, and its versatile drug delivery platform which aims to provide long-term continuous production of therapeutic proteins in the eye to treat a broad range of eye diseases.
The FIGARO-DKD trial found that:
1) Finerenone significantly reduced the risk of the primary cardiovascular outcome (composite of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, or hospitalization for heart failure) by 13% compared to placebo in patients with chronic kidney disease and type 2 diabetes.
2) The cardiovascular benefit was primarily driven by a reduction in hospitalization for heart failure despite excluding patients with symptomatic heart failure with reduced ejection fraction.
3) Finerenone did not significantly reduce the risk of a sustained 40% decline in eGFR but did trend toward improving the clinically accepted outcome of a sustained 57% decline in eGFR compared to placebo.
1. Nocturia is defined as waking at night to void where the individual is both preceded and followed by sleep. It is clinically significant when there are two or more voids per night.
2. Nocturia can negatively impact quality of life by reducing sleep efficiency and increasing fatigue. It is associated with increased risks of falls, fractures, cardiovascular disease and mortality.
3. The prevalence of nocturia increases with age, affecting about 25-31% of adults overall and about 3 in 5 people over age 70. Evaluation involves a medical history, physical exam, and a 24-hour voiding diary to determine the underlying cause.
This document discusses the definitions, causes, evaluation, and management of urinary retention and anuria. It defines urinary retention as the inability to pass urine despite an urge to void, while anuria is the lack of urine production or passage. The causes of retention are discussed for different age groups and include conditions like urethral stricture, enlarged prostate, neurogenic bladder, bladder stones, and drugs. Evaluation involves history, examination, urinalysis, renal function tests, ultrasound, and urodynamics. Management depends on whether it is acute or chronic retention and may include catheterization, treating underlying causes, and surgery in some cases. Anuria is evaluated and managed based on whether its cause is pre-renal
The document provides an agenda for a presentation on blockchain technology and its applications in the energy industry. The presentation will cover fundamentals of blockchain like digital wallets and transactions, how blockchains work through mining and consensus mechanisms, and introduce smart contracts on the Ethereum network. It will also discuss how blockchain can help modernize the electricity grid and provide an ecosystem of players and platforms in the energy sector, highlighting challenges and benefits of implementing blockchain technology.
Presentation to the New York Association for Energy Economics on October 12th 2017 on how blockchain and distributed ledger technology is being applied to the power sector. The talk focused on examining emerging applications, the limitations of the technology, while also looking to the future of distributed ledgers and their potential impact on the energy value chain.
This document discusses neurogenic lower urinary tract dysfunction. It begins with an introduction and overview of classifications, causes, evaluation, and specific neurological disorders related to lower urinary tract dysfunction. Evaluation involves taking a thorough history, physical exam, bladder diary, lab tests including urine analysis and post-void residual, and urodynamic studies to assess storage and voiding functions. Lesions in different areas of the nervous system can result in distinct patterns of bladder dysfunction, with suprapontine lesions commonly causing storage issues and infrasacral lesions more often resulting in voiding problems. Treatment aims to protect the upper urinary tract and improve symptoms.
Urodynamics describes physiological tests used to investigate abnormalities of lower urinary tract function. The principles of urodynamics are simple - it involves studying the relationship between bladder pressure, volume, and flow during different stages of the micturition cycle. Both non-invasive tests like flowmetry and invasive tests like cystometry are used to evaluate patients and make a urodynamic diagnosis. Special considerations are needed when performing urodynamics on certain patient populations like those with spinal cord injuries.
Genetic variation in GRIN genes encoding N-methyl-D-aspartate receptor (NMDAR) subunits has been associated with a spectrum of neurological and neuropsychiatric disorders. This talk will focus on clinical phenotype, functional consequences, and potential rescue pharmacology of disease-associated GRIN2D missense variants. The GRIN2D variants are located in the pre-M1 helix, agonist-binding domain, transmembrane domain M3, and the intracellular CTD. Developmental and epileptic encephalopathy (DEE) is the unifying phenotype across all 13 patients. The seizure types ranged from focal seizures, atypical absence seizures, tonic or atonic seizures, to epileptic spasms. Eight patients showed certain degree of hypotonia and movement disorders, three patients have autistic behavior and one patient showed symptoms of ADHD. Functional analysis in vitro on six novel GRIN2D variants reveals that that all six variants decreased receptor surface expression, which may underline certain shared clinical symptoms. Three variants (Leu670Phe, Ala675Thr, Ala678Asp) showed significantly enhanced agonist potency, and/or increased channel open probability, while the other three (Ser573Phe, Ser1271Phe, Arg1313Trp) presented reduced
sensitivity to endogenous protons and decreased channel open probability. Three variants (Ser573Phe, Ala675Thr, Ala678Asp) significantly decrease current amplitude. GluN2D-Leu670Phe
prolongs synaptic-like response time course and increases charge transfer. GluN2D-Ala678Asp transfection significantly reduced cell viability of cultured cortical neurons. In addition, a set of FDA-approved NMDAR channel blockers were evaluated for their ability to rescue functional changes of mutant receptors. This work suggests the importance of functional and biochemical validation for each individual variant. Rescue pharmacology in vitro may provide potential benefit of precision
medicine for a subset of severe pediatric neurodevelopmental diseases.
N-methyl-D-aspartate receptors (NMDARs) mediate a slow component of excitatory synaptic transmission that plays important roles in normal brain function and development. A large number of disease-associated variants in the GRIN gene family encoding NMDAR GluN subunits have been identified in patients with various neurological and neuropsychiatric disorders. Many of these variants reduce the function of NMDARs by a range of different mechanisms, including
reduced glutamate potency, reduced glycine potency, accelerated deactivation time course, reduced current response amplitude, decreased surface expression, and/or reduced open probability. This talk will focus on three positive allosteric modulators of NMDAR receptor function (24(S)-hydroxycholesterol, pregnenolone sulfate, tobramycin) and two co-agonists (D-serine and D-cycloserine) on their ability to mitigate the diminished function of NMDARs harboring GRIN variants. We examined the effects of these modulators on NMDARs that contained 24 different loss-of-function missense variants in GRIN1, GRIN2A, or GRIN2B. The clinical phenotypes of the patients hosting these variants include epilepsy/seizures and/or developmental delay/intellectual disability. Some patients have autistic behavior or show symptoms of ADHD. For all variants, some aspect of the
reduced function was partially restored. Moreover, some variants showed enhanced sensitivity to positive allosteric modulators compared to wild type receptors. These results raise the possibility that enhancement of NMDAR function by positive allosteric modulators may be a useful therapeutic strategy.
- The document discusses the burden of diabetic kidney disease and the benefits of SGLT2 inhibitors (SGLT2i).
- It notes that progression of diabetic kidney disease depends on glomerular blood pressure and that SGLT2i lower intraglomerular pressure through their mechanisms of action.
- Clinical trials show that SGLT2i provide renal benefits including postponing end-stage renal disease and that earlier treatment provides longer-term protection of kidney function.
Effects of Sodium Glucose contransporter (SGLT2) inhibition on renal outcomes in patients with (diabetic) chronic kidney disease.
Presentation given during the East by Southwest, Annual Update in Nephrology, September 17th 2017, Santa Fe, NM
http://medicine.unm.edu/academic-divisions/nephrology/east-by-southwest.html
El lunes y martes 20 y 21 de noviembre coordinamos un simposio internacional en la Fundación Ramón Areces, sobre los defectos del transporte de aminoácidos.
1) The document discusses the double burden of diabetes and chronic kidney disease (CKD) in India. Over 50% of patients with type 2 diabetes in one study had CKD as defined by reduced eGFR or albuminuria.
2) Microalbuminuria is an early marker of kidney dysfunction in patients with diabetes. Higher levels of microalbuminuria are associated with poorer glycemic control and longer duration of diabetes.
3) The CARMELINA trial evaluated the cardiovascular and kidney safety of linagliptin versus placebo in patients with type 2 diabetes at high cardiovascular risk but relatively early in their disease. Linagliptin demonstrated kidney safety and reduced the risk of microvascular outcomes.
RNA splicing mutations and human disease: Pompe disease - Emanuele Buratti
Convegno del 25 novembre "Diagnosi e management della glicogenosi tipo 2" - Centro di coordinamento regionale malattie rare FVG
The document summarizes emerging concepts around SGLT2 inhibitors and renal outcomes. It discusses the mechanism of action of SGLT2 inhibitors including reducing glucose reabsorption and increasing sodium delivery to the macula densa. A key trial on the SGLT2 inhibitor dapagliflozin showed it reduced the composite of sustained ≥50% eGFR decline, end-stage kidney disease, or renal or cardiovascular death by 39% compared to placebo in patients with chronic kidney disease. Updated guidelines now recommend SGLT2 inhibitors to reduce renal and cardiovascular risk in patients with chronic kidney disease based on these renal protection benefits shown in clinical trials.
NMDA receptors play crucial roles in excitatory synaptic transmission. Rare variants in genes that encode receptor subunits are associated with several intractable neurodevelopmental disorders, including developmental and epileptic encephalopathy (DEE). To extend understanding of these intractable childhood diseases, we have begun to model these variants in laboratory mice.
Models studied so far are a constitutive knockin for GRIN2A variant p.Ser644Gly (S644G) based on one case, and a GRIN2D variant, p.Val667Ile (V667I), noted in at least three unrelated cases. Homozygous and heterozygous Grin2a S644G mice exhibit altered hippocampal morphology at 2 weeks, and homozygotes exhibit lethal tonic-clonic seizures in week 3. Heterozygotes have a normal lifespan without spontaneous seizures, but display a variety of distinct features including
resistance to electrically induced limbic seizures, as well as hyperactivity and repetitive and reduced anxiety behaviors. Multielectrode recordings of mutant neuronal networks reveal hyperexcitability and altered bursting and synchronicity of both mutant genotypes. When expressed in heterologous cells, mutant receptors exhibit enhanced NMDAR agonist potency and slow deactivation following rapid removal of glutamate, as occurs at synapses. Consistent with this, NMDAR-mediated synaptic currents in hippocampal slices from mutant mice show a prolonged deactivation time course. Standard antiepileptic drug monotherapy was ineffective in the patient, but combined treatment of NMDAR antagonists with antiepileptic drugs substantially reduced the seizure burden albeit without appreciable developmental improvement. Chronic treatment of homozygous mutant mouse pups with NMDAR antagonists delayed the onset of lethal seizures but did not prevent them.
Grin2d V667I knockin mice are at an earlier stage of study. In contrast to Grin2a S644G, V667I heterozygous mice are severely impaired and suffer from lethal tonic-clonic seizures with an onset from about 18 days to 3 months. The impairment precludes natural mating such that the line needs to be propagated by ovary transplantation. Young heterozygotes adults in video-EEG also exhibit very frequent interictal epileptiform spiking and spike-wave discharge activity, resembling absence seizures. Preliminary histology shows significant pyknotic nuclei appearing to evidence
cell death in the cerebral cortex. Pup developmental milestones, while not evidencing significant developmental delay, show unusual features including excessive maternal separation induced pup vocalization. Further studies are ongoing. Together these efforts illustrate the power of modelling severe neurodevelopmental seizure disorders using multiple experimental modalities and suggest their utility in identifying and evaluating new therapies.
This document discusses the clinical profile and efficacy of the combination drug GLYXAMBI, which contains empagliflozin and linagliptin. It summarizes clinical trial results showing that GLYXAMBI provides significant reductions in HbA1c and body weight compared to the individual components alone in patients with type 2 diabetes. Guidelines from major diabetes organizations have been updated to recommend SGLT2 inhibitors like empagliflozin and GLP-1 receptor agonists to reduce cardiovascular risk based on positive cardiovascular outcomes trial results.
This document provides an overview of a company focused on developing transformative therapies for chronic eye diseases. It discusses the company's leadership which has expertise in ophthalmics, retinal disease, and regulatory matters. It also outlines the company's lead product NT-503, an encapsulated cell therapy for wet age-related macular degeneration, and its versatile drug delivery platform which aims to provide long-term continuous production of therapeutic proteins in the eye to treat a broad range of eye diseases.
The FIGARO-DKD trial found that:
1) Finerenone significantly reduced the risk of the primary cardiovascular outcome (composite of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, or hospitalization for heart failure) by 13% compared to placebo in patients with chronic kidney disease and type 2 diabetes.
2) The cardiovascular benefit was primarily driven by a reduction in hospitalization for heart failure despite excluding patients with symptomatic heart failure with reduced ejection fraction.
3) Finerenone did not significantly reduce the risk of a sustained 40% decline in eGFR but did trend toward improving the clinically accepted outcome of a sustained 57% decline in eGFR compared to placebo.
Advances in LC/MS methodologies for the characterisation of complex glycoprot...Quality Assistance s.a.
Dr. Arnaud Delobel from Quality Assistance spoke on "Advances in LC/MS methodologies for the characterisation of complex glycoproteins (case study: Etanercept)" at the "Challenges and Opportunities in Protein Analytics" day in Brussels.
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Quality Assistance S.A. is a leading European Contract Research Organisation providing the pharmaceutical industry with all the analytical services required by EMA and FDA regulations for the development and marketing of innovative human medicinal products.
We assist our clients from candidate selection, through non-clinical and clinical studies, to marketing authorisation, using our state-of-the-art, product-dedicated expertise in analytical sciences.
For each customer and each project, we design customised solutions, define analytical protocols, develop and validate specific new analytical methods and perform characterisation, stability, pharmacokinetic, biomarker and immunogenicity studies as well as batch release testing, in order to evaluate the Quality, Safety and Efficacy of the given drugs.
This document summarizes the results of a survey of 51 individuals with GRIN2B variants and their families from 15 countries. It finds that most common symptoms include intellectual disability, delayed communication, physical delays, sleep problems, hypotonia, constipation, strabismus and sensory processing disorder. The majority had normal MRI results but abnormal EEGs. Over half had issues with strabismus, digestion and toileting. Communication delays and minimal speech were common, with many nonverbal past age 4.
GRIN-related epileptic encephalopathy can present early in life with intellectual disability, continuous spike-and-wave during sleep syndrome (CSWS), or epilepsy-aphasia spectrum phenotypes such as in Landau-Kleffner syndrome. Efficacy of IVIG treatment was recently reported in a patient with LKS related to GRIN2A mutation.
We describe our experience with IVIG therapy in 5 patients (4 males, age range 6 months-13 years) with confirmed GRIN-related epileptic encephalopathy (4 with GRIN2A mutations presenting with epilepsy-aphasia spectrum/epileptic encephalopathy with CSWS and verbal, communicative and
behavioural regression, and one patient with GRIN2D mutation who presented with early infantile developmental-epileptic encephalopathy). All patients had global developmental delay/ intellectual disability in various degrees and were resistant to anticonvulsants. None of the patients had clinical seizures as a hallmark. All patients received monthly infusion of IVIG 2 g/ kg for 6 months; 2 patients were also treated with high-dose corticosteroids. No seizures were observed during the treatment
period in any of these patients. Marked electrographical improvement was noted in 4/5 patients, with complete normalization of the EEG in 2 patients. Expressive and receptive verbal abilities, communication skills and behaviour (hyperactivity, impulsivity and attention disorders) improved. However, visuospatial perceptual/spatial abilities, as well as executive functions and attention span remained significantly impaired.
Conclusion: IVIG should be considered in the treatment of GRIN-related epileptic encephalopathy and may lead to EEG normalization. Early treatment is advocated to rescue developmental milestones and improve developmental potential. Autoimmune mechanism in GRIN-related diseases should be further investigated.
A range of approaches to clinical trials for targeted therapy in rare diseases will be discussed, highlighting the need for natural history data to determine which outcomes are important and feasible to measure in a trial setting. Dr. Poduri will review what is needed for a robust, blinded trial as well as N of 1 treatment experiences relevant to the GRIN community. Specific examples of successful N of 1 cases will be discussed for both pharmacological and genetic approaches. Questions around
dosing, gain- and loss-of-function properties of variants, and resource requirements will be considered.
Simons Searchlight is an initiative of the Simons Foundation Autism Research Initiative (SFARI) that aims to better understand genetic neurodevelopmental conditions, including those associated with autism spectrum disorder. Over 1,500 individuals with rare disorders and their families are currently
registered in Simons Searchlight, including participants from both the GRIN2A and GRIN2B groups. These numbers are expected to grow significantly in the coming years, and so are the research opportunities for participants as well as investigators studying these conditions.
Synaptic dysfunction is implicated in a variety of neurological disorders. De novo mutations in certain synaptic proteins are pathogenic. In particular, rare variants of two NMDA receptor
subunits, GluN2A and GluN2B, underlie some cases of epilepsy and neurodevelopmental disorders.
For many years, my laboratory has worked on mechanisms regulating NMDA receptor trafficking to excitatory synapses and how synaptic localization is dynamically regulated during development and in response to experience. In particular, we have studied how the long C-terminal domains of GluN2A and GluN2B regulate trafficking through protein-protein interactions and posttranslational modifications such as phosphorylation. In particular we have evaluated a missense mutation within
the C-terminal domain of GluN2B identified in a patient with ASD and described deficits in receptor surface expression and dendritic spine density. We are moving forward to make a mouse model of this mutation. More recently we are studying a missense mutation located within the C-domain of GluN2A identified in a patient with epilepsy and intellectual disability. Thus residue is a phosphorylation site and affects receptor trafficking. Our studies validate a ‘bedside to bench’
approach of studying rare variants associated with disease to better understand the function and signaling properties of NMDA receptors. We anticipate our results will allow us to better understand the structure, function and signaling regulated by the C-termini. Importantly, by characterizing these variants, we hope to gain insight into the pathogenesis of various neurodevelopmental disorders.
The document discusses variants in the GRIN2A and GRIN2B genes. It summarizes findings from studies that analyzed 247 cases with GRIN2A variants and 91 cases with GRIN2B variants. The clinical features and severity of phenotypes associated with variants in these genes and other GRIN genes are compared. The presentation concludes by proposing the creation of a single large shared database for GRIN variants that would be accessible to researchers.
Grin1 knockdown mice (Grin1KD) have a loss-of-function mutation that is caused by the insertion of foreign DNA into an intron of the Grin1 gene. Although this mouse does not model a
specific patient variant, it is a useful model to understand how brain functions are altered by a global reduction of NMDA receptors. Grin1KD mice display many phenotypes that are similar to patient symptoms, including increased motor activity, decreased muscle tone, increased stereotypic movements,
and impairments in multiple domains of cognition. We asked whether phenotypes of Grin1KD mice could be improved by genetic rescue of the knockdown mutation in adult mice. To do this, we used a tamoxifen inducible Cre recombinase to excise the mutation and restore the Grin1 gene to a wildtype configuration. We discovered that several forms of cognition were improved or even normalized when genetic rescue was performed in adult mice. Our results suggest that the adult brain has sufficient plasticity to overcome developmental insults to NMDA receptor function, which has important implications for patients with GRIN disorders.
While gene therapy may be possible in the future, there are a number of pharmacological interventions that can be tested in this model and quickly translated to patients. As an example, we
tested the ability of a ketogenic diet or dietary ketone ester to improve behavioural phenotypes of Grin1KD mice. We discovered that either the ketogenic diet or beta-hydroxybutyrate improved the Grin1KD phenotypes of hyperactivity, sociability, sensory processing, and spatial memory. Similar studies could be used to test novel pharmacological agents that increase NMDA receptor activity.
Disease-causing variants in genes encoding subunits of the N-methyl-D-aspartate receptor (NMDAR) are an important contributor to neurodevelopmental disorders. While individually rare, GRIN-related disorders due to disease-causing variants in GRIN1, GRIN2A, GRIN2B or GRIN2D collectively represent 5% of all individuals with a positive genetic diagnosis in our ongoing natural history of genetic epilepsies and neurodevelopmental disorders at the Children’s Hospital of Philadelphia.
By systematically assessing the disease course of individuals with GRIN-related disorders in this cohort, we delineated shared and distinct phenotypic features in this disease group in comparison to other genetic epilepsies and neurodevelopmental disorders using large-scale electronic medical record data.
In our overall cohort of 800 individuals with more than 100 distinct genetic etiologies in 250 individuals, the 12 individuals with GRIN-related disorders showed 32 specific gene-phenotype associations that stood out from the remainder of the cohort. These included associations of GRIN2A and dyslexia
(p=0.005), GRIN1 with absent speech (p= 0.008) and GRIN1 with generalized hypotonia (p=0.009) as the three most significant findings. Both GRIN2A and GRIN2B displayed an association with focal impaired awareness seizures (p=0.03), while GRIN2B was associated with epileptic encephalopathy
(p=0.02) but no specific seizure types. We did not find an association between GRIN-related disorders and the use of specific anti-seizure medications. Our data provide a general overview how GRIN associated disorders relate to the wider range of genetic epilepsies and neurodevelopmental disorders,
which is an important prerequisite for understanding the specificity of phenotypic features and outcome measures for precision medicine trials.
When I was asked to give a companion lecture in support of ‘The Philosophy of Science’ (https://shorturl.at/4pUXz) I decided not to walk through the detail of the many methodologies in order of use. Instead, I chose to employ a long standing, and ongoing, scientific development as an exemplar. And so, I chose the ever evolving story of Thermodynamics as a scientific investigation at its best.
Conducted over a period of >200 years, Thermodynamics R&D, and application, benefitted from the highest levels of professionalism, collaboration, and technical thoroughness. New layers of application, methodology, and practice were made possible by the progressive advance of technology. In turn, this has seen measurement and modelling accuracy continually improved at a micro and macro level.
Perhaps most importantly, Thermodynamics rapidly became a primary tool in the advance of applied science/engineering/technology, spanning micro-tech, to aerospace and cosmology. I can think of no better a story to illustrate the breadth of scientific methodologies and applications at their best.
Sexuality - Issues, Attitude and Behaviour - Applied Social Psychology - Psyc...PsychoTech Services
A proprietary approach developed by bringing together the best of learning theories from Psychology, design principles from the world of visualization, and pedagogical methods from over a decade of training experience, that enables you to: Learn better, faster!
The binding of cosmological structures by massless topological defectsSérgio Sacani
Assuming spherical symmetry and weak field, it is shown that if one solves the Poisson equation or the Einstein field
equations sourced by a topological defect, i.e. a singularity of a very specific form, the result is a localized gravitational
field capable of driving flat rotation (i.e. Keplerian circular orbits at a constant speed for all radii) of test masses on a thin
spherical shell without any underlying mass. Moreover, a large-scale structure which exploits this solution by assembling
concentrically a number of such topological defects can establish a flat stellar or galactic rotation curve, and can also deflect
light in the same manner as an equipotential (isothermal) sphere. Thus, the need for dark matter or modified gravity theory is
mitigated, at least in part.
Travis Hills of MN is Making Clean Water Accessible to All Through High Flux ...Travis Hills MN
By harnessing the power of High Flux Vacuum Membrane Distillation, Travis Hills from MN envisions a future where clean and safe drinking water is accessible to all, regardless of geographical location or economic status.
The technology uses reclaimed CO₂ as the dyeing medium in a closed loop process. When pressurized, CO₂ becomes supercritical (SC-CO₂). In this state CO₂ has a very high solvent power, allowing the dye to dissolve easily.
The cost of acquiring information by natural selectionCarl Bergstrom
This is a short talk that I gave at the Banff International Research Station workshop on Modeling and Theory in Population Biology. The idea is to try to understand how the burden of natural selection relates to the amount of information that selection puts into the genome.
It's based on the first part of this research paper:
The cost of information acquisition by natural selection
Ryan Seamus McGee, Olivia Kosterlitz, Artem Kaznatcheev, Benjamin Kerr, Carl T. Bergstrom
bioRxiv 2022.07.02.498577; doi: https://doi.org/10.1101/2022.07.02.498577
Current Ms word generated power point presentation covers major details about the micronuclei test. It's significance and assays to conduct it. It is used to detect the micronuclei formation inside the cells of nearly every multicellular organism. It's formation takes place during chromosomal sepration at metaphase.
Authoring a personal GPT for your research and practice: How we created the Q...Leonel Morgado
Thematic analysis in qualitative research is a time-consuming and systematic task, typically done using teams. Team members must ground their activities on common understandings of the major concepts underlying the thematic analysis, and define criteria for its development. However, conceptual misunderstandings, equivocations, and lack of adherence to criteria are challenges to the quality and speed of this process. Given the distributed and uncertain nature of this process, we wondered if the tasks in thematic analysis could be supported by readily available artificial intelligence chatbots. Our early efforts point to potential benefits: not just saving time in the coding process but better adherence to criteria and grounding, by increasing triangulation between humans and artificial intelligence. This tutorial will provide a description and demonstration of the process we followed, as two academic researchers, to develop a custom ChatGPT to assist with qualitative coding in the thematic data analysis process of immersive learning accounts in a survey of the academic literature: QUAL-E Immersive Learning Thematic Analysis Helper. In the hands-on time, participants will try out QUAL-E and develop their ideas for their own qualitative coding ChatGPT. Participants that have the paid ChatGPT Plus subscription can create a draft of their assistants. The organizers will provide course materials and slide deck that participants will be able to utilize to continue development of their custom GPT. The paid subscription to ChatGPT Plus is not required to participate in this workshop, just for trying out personal GPTs during it.
Mending Clothing to Support Sustainable Fashion_CIMaR 2024.pdfSelcen Ozturkcan
Ozturkcan, S., Berndt, A., & Angelakis, A. (2024). Mending clothing to support sustainable fashion. Presented at the 31st Annual Conference by the Consortium for International Marketing Research (CIMaR), 10-13 Jun 2024, University of Gävle, Sweden.