Frontotemporal dementia-like disease progression elicited by seeded aggregation and spread of FUS.

RNA binding proteins have emerged as central players in the mechanisms of many neurodegenerative diseases. In particular, a proteinopathy of fu sed in s arcoma (FUS) is present in some instances of familial Amyotrophic lateral sclerosis (ALS) and about 10% of sporadic FTLD. Here we establish that focal injection of sonicated human FUS fibrils into brains of mice in which ALS-linked mutant or wild-type human FUS replaces endogenous mouse FUS is sufficient to induce focal cytoplasmic mislocalization and aggregation of mutant and wild-type FUS which with time spreads to distal regions of the brain. Human FUS fibril-induced FUS aggregation in the mouse brain of humanized FUS mice is accelerated by an ALS-causing FUS mutant relative to wild-type human FUS. Injection of sonicated human FUS fibrils does not induce FUS aggregation and subsequent spreading after injection into naïve mouse brains containing only mouse FUS, indicating a species barrier to human FUS aggregation and its prion-like spread. Fibril-induced human FUS aggregates recapitulate pathological features of FTLD including increased detergent insolubility of FUS and TAF15 and amyloid-like, cytoplasmic deposits of FUS that accumulate ubiquitin and p62, but not TDP-43. Finally, injection of sonicated FUS fibrils is shown to exacerbate age-dependent cognitive and behavioral deficits from mutant human FUS expression. Thus, focal seeded aggregation of FUS and further propagation through prion-like spread elicits FUS-proteinopathy and FTLD-like disease progression.

Frontotemporal dementia-like disease progression elicited by seeded aggregation and spread of FUS.

RNA binding proteins have emerged as central players in the mechanisms of many neurodegenerative diseases. In particular, a proteinopathy of fused in sarcoma (FUS) is present in some instances of familial Amyotrophic lateral sclerosis (ALS) and about 10% of sporadic Frontotemporal lobar degeneration (FTLD). Here we establish that focal injection of sonicated human FUS fibrils into brains of mice in which ALS-linked mutant or wild-type human FUS replaces endogenous mouse FUS is sufficient to induce focal cytoplasmic mislocalization and aggregation of mutant and wild-type FUS which with time spreads to distal regions of the brain. Human FUS fibril-induced FUS aggregation in the mouse brain of humanized FUS mice is accelerated by an ALS-causing FUS mutant relative to wild-type human FUS. Injection of sonicated human FUS fibrils does not induce FUS aggregation and subsequent spreading after injection into naïve mouse brains containing only mouse FUS, indicating a species barrier to human FUS aggregation and its prion-like spread. Fibril-induced human FUS aggregates recapitulate pathological features of FTLD including increased detergent insolubility of FUS and TAF15 and amyloid-like, cytoplasmic deposits of FUS that accumulate ubiquitin and p62, but not TDP-43. Finally, injection of sonicated FUS fibrils is shown to exacerbate age-dependent cognitive and behavioral deficits from mutant human FUS expression. Thus, focal seeded aggregation of FUS and further propagation through prion-like spread elicits FUS-proteinopathy and FTLD-like disease progression.

Implications of the Immune Polymorphisms of the Host and the Genetic Variability of SARS-CoV-2 in the Development of COVID-19.

The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is responsible for the current pandemic affecting almost all countries in the world. SARS-CoV-2 is the agent responsible for coronavirus disease 19 (COVID-19), which has claimed millions of lives around the world. In most patients, SARS-CoV-2 infection does not cause clinical signs. However, some infected people develop symptoms, which include loss of smell or taste, fever, dry cough, headache, severe pneumonia, as well as coagulation disorders. The aim of this work is to report genetic factors of SARS-CoV-2 and host-associated to severe COVID-19, placing special emphasis on the viral entry and molecules of the immune system involved with viral infection. Besides this, we analyze SARS-CoV-2 variants and their structural characteristics related to the binding to polymorphic angiotensin-converting enzyme type 2 (ACE2). Additionally, we also review other polymorphisms as well as some epigenetic factors involved in the immunopathogenesis of COVID-19. These factors and viral variability could explain the increment of infection rate and/or in the development of severe COVID-19.

Wild-type FUS corrects ALS-like disease induced by cytoplasmic mutant FUS through autoregulation.

Mutations in FUS, an RNA-binding protein involved in multiple steps of RNA metabolism, are associated with the most severe forms of amyotrophic lateral sclerosis (ALS). Accumulation of cytoplasmic FUS is likely to be a major culprit in the toxicity of FUS mutations. Thus, preventing cytoplasmic mislocalization of the FUS protein may represent a valuable therapeutic strategy. FUS binds to its own pre-mRNA creating an autoregulatory loop efficiently buffering FUS excess through multiple proposed mechanisms including retention of introns 6 and/or 7. Here, we introduced a wild-type FUS gene allele, retaining all intronic sequences, in mice whose heterozygous or homozygous expression of a cytoplasmically retained FUS protein (Fus∆NLS) was previously shown to provoke ALS-like disease or postnatal lethality, respectively. Wild-type FUS completely rescued the early lethality caused by the two Fus∆NLS alleles, and improved the age-dependent motor deficits and reduced lifespan caused by heterozygous expression of mutant FUS∆NLS. Mechanistically, wild-type FUS decreased the load of cytoplasmic FUS, increased retention of introns 6 and 7 in the endogenous mouse Fus mRNA, and decreased expression of the mutant mRNA. Thus, the wild-type FUS allele activates the homeostatic autoregulatory loop, maintaining constant FUS levels and decreasing the mutant protein in the cytoplasm. These results provide proof of concept that an autoregulatory competent wild-type FUS expression could protect against this devastating, currently intractable, neurodegenerative disease.

Spinal subpial delivery of AAV9 enables widespread gene silencing and blocks motoneuron degeneration in ALS.

Gene silencing with virally delivered shRNA represents a promising approach for treatment of inherited neurodegenerative disorders. In the present study we develop a subpial technique, which we show in adult animals successfully delivers adeno-associated virus (AAV) throughout the cervical, thoracic and lumbar spinal cord, as well as brain motor centers. One-time injection at cervical and lumbar levels just before disease onset in mice expressing a familial amyotrophic lateral sclerosis (ALS)-causing mutant SOD1 produces long-term suppression of motoneuron disease, including near-complete preservation of spinal α-motoneurons and muscle innervation. Treatment after disease onset potently blocks progression of disease and further α-motoneuron degeneration. A single subpial AAV9 injection in adult pigs or non-human primates using a newly designed device produces homogeneous delivery throughout the cervical spinal cord white and gray matter and brain motor centers. Thus, spinal subpial delivery in adult animals is highly effective for AAV-mediated gene delivery throughout the spinal cord and supraspinal motor centers.

Discovering successful strategies for diabetic self-management: a qualitative comparative study.

OBJECTIVE: This project explored lifestyles of patients in good and poor control to identify naturally occurring practices and strategies that result in successful diabetes management. RESEARCH DESIGN AND METHODS: Semistructured interviews with adult patients with type 2 diabetes explored diet, food preparation, physical activity, medication use and glucose monitoring. Patients (n=56) were classified into good (A1C <7.0%), fair (7.0%8.0%) control groups and matched across groups on diabetes duration (±5 years) and medication modality (none, oral, insulin±oral) to control for non-lifestyle factors. A qualitative comparative analysis identified practices that distinguished glycemic groups. RESULTS: Good control patients were more likely to test their glucose two or more times a day and reduce their sodium intake, as well as increase fruits and vegetables and limit portion sizes, some attaining good control without exercise. Fair control patients discussed several dietary strategies including limiting sweets, drinking non-caloric beverages, reducing carbs, 'cheating' (eating only a few sweets/limiting carbs in one meal to have more in another meal) and tested their glucose once a day. Poor control patients were more likely to skip antidiabetic medications and not test their glucose. CONCLUSIONS: Although clinical trials indicate most self-management practices have limited effectiveness over time, increased glucose monitoring is a valuable component in daily management. Research is needed on effectiveness of dietary strategies that emphasize sodium monitoring and allow some degree of cheating. Reoffering diabetes education classes and providing pill boxes as memory aids may help improve poor control.

Ethnic and gender disparities in needed adolescent mental health care.

Psychological problems are overlooked and undertreated in adolescents, especially in low-income and ethnically-diverse youth. School-based health centers are one way to increase health care utilization, and may be particularly important for accessing hard-to-reach populations. The present study examines adolescents' psychological health and their experiences with receiving needed mental health care. Participants included 1,695 African-American (31%), Hispanic (38%), and White (31%) high-school students in southeast Texas. All students were from the same high school and all had access to a school-based mental health clinic. Twenty six percent of the sample had symptoms indicative of major depression, and 18% had scores consistent with subthreshold depression. Across all ethnicities, the prevalence of depressive symptoms was highest among females. Depressed White students were more likely than depressed minority youth to report having received a prior diagnosis of depression and to have been treated for depression. Thus, ethnic disparities in obtaining needed mental health care may persist even in settings where access to equivalent care is readily available.

Epileptiform activity induced by pharmacologic reduction of M-current in the developing hippocampus in vitro.

PURPOSE: Benign familial neonatal convulsions (BFNCs), an inheritable epilepsy that occurs in neonates but not in adults, is caused by hypofunctional mutations in genes codifying for the M-type K+ current. In an attempt to develop an in vitro model of this disease, we tested whether blocking M-current with linopirdine induces epileptiform activity in brain slices from animals of different ages. METHODS: Horizontal hippocampus-entorhinal cortex slices were obtained from neonatal (1-2 weeks after birth) and adult (8-9 weeks after birth) rats. Extracellular field recordings of the CA1 region were performed. After recording control conditions, linopirdine was added to the bath, and field activity was recorded continuously for 3 h. 4-Aminopyridine, a drug commonly used to induce epileptiform activity in vitro, was used as a control for our experimental conditions. RESULTS: Bath perfusion of linopirdine induced epileptiform activity only in slices from neonatal rats. Epileptiform activity consisted of interictal-like and ictal-like activity. In slices from adult rats, linopirdine induced erratic interictal-like activity. In contrast, 4-aminopyridine was able to induce epileptiform activity in slices from both neonatal and adult rats. CONCLUSIONS: We demonstrated that blockade of M-current in vitro produces epileptiform activity with a developmental pattern similar to that observed in BNFCs. This could be an in vitro model that can be used to study the cellular mechanisms of epileptogenesis and the developmental features of BFNCs, as well as to develop some therapeutic strategies.

The relative effect of self-management practices on glycaemic control in type 2 diabetic patients in Mexico.

OBJECTIVE: In this study, we examined the relative impact of self-management activities on glycaemic control in a population at high risk for developing complications. METHODS: Patients diagnosed with diabetes mellitus of at least 1 year in duration at 30 years of age or older were sampled from the Instituto de Mexico Seguro Social (IMSS) Family Medicine Clinics in Guadalajara, Mexico (n=800). Demographic, clinical and health behaviour variables were used to predict good/poor glycaemic control, as measured by haemoglobin Alc (A1C). RESULTS: Most (72.24%) patients had poor control (A1C > or = 7.0). Hyperglycaemia was significantly associated with factors not under patient control, such as having diabetes for a longer time [odds ratio (OR) = 2.40, 95% confidence interval (CI) 1.39, 4.14], having a first-degree relative with diabetes (OR= 1.52; 95% CI 1.06, 2.19), and being prescribed anti-diabetic medications, e.g. insulin (OR = 7.88, 95% CI 2.42, 25.63). After controlling for these variables, the only self-management variable that reduced the likelihood of hyperglycaemia was following a special diet (OR=0.49; 95% CI 0.32, 0.76). Furthermore, depression had an important effect on self-management, as those with lower levels of depressive symptoms were more likely to follow a diet and exercise. DISCUSSION: While patients in this population have little control over many factors associated with glycaemic control, an important exception is diet. However, because of the adverse effect of depression on dieting, both depression management and dietary education are important for this population.