A gene therapy for inherited blindness using dCas9-VPR–mediated transcriptional activation

Catalytically inactive dCas9 fused to transcriptional activators (dCas9-VPR) enables activation of silent genes. Many disease genes have counterparts, which serve similar functions but are expressed in distinct cell types. One attractive option to compensate for the missing function of a defective gene could be to transcriptionally activate its functionally equivalent counterpart via dCas9-VPR. Key challenges of this approach include the delivery of dCas9-VPR, activation efficiency, long-term expression of the target gene, and adverse effects in vivo. Using dual adeno-associated viral vectors expressing split dCas9-VPR, we show efficient transcriptional activation and long-term expression of cone photoreceptor-specific M-opsin (Opn1mw) in a rhodopsin-deficient mouse model for retinitis pigmentosa. One year after treatment, this approach yields improved retinal function and attenuated retinal degeneration with no apparent adverse effects. Our study demonstrates that dCas9-VPR–mediated transcriptional activation of functionally equivalent genes has great potential for the treatment of genetic disorders

Effects of stress and defence allocation on tree growth: Simulation results at the individual and stand level.

The long life span of trees implies that they are more or less frequently confronted with different biotic and abiotic stress situations during their lives. However, biotic stress such as attacks by herbivores or pathogens and abiotic stress such as frost or drought could strongly vary in frequency, intensity, duration, time of occurrence as well as in the involved tissues. This urged trees to develop flexible defence mechanisms during their evolution ensuring a high probability of survival to regenerate successfully. Based on an analysis of existing literature on plant response to herbivory, McNaughton (1983) concludes that “. . .the yield of the tissue affected and other tissues is not affected in proportion to the amount of tissues damaged by the herbivore”, referring also to Lee and Bazzaz (1980) and Neilsen (1981). McNaughton presents a set of alternative patterns about the eff

Abolishing cAMP sensitivity in HCN2 pacemaker channels induces generalized seizures.

Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are dually gated channels that are operated by voltage and by neurotransmitters via the cAMP system. cAMP-dependent HCN regulation has been proposed to play a key role in regulating circuit behavior in the thalamus. By analyzing a knockin mouse model (HCN2EA), in which binding of cAMP to HCN2 was abolished by 2 amino acid exchanges (R591E, T592A), we found that cAMP gating of HCN2 is essential for regulating the transition between the burst and tonic modes of firing in thalamic dorsal-lateral geniculate (dLGN) and ventrobasal (VB) nuclei. HCN2EA mice display impaired visual learning, generalized seizures of thalamic origin, and altered NREM sleep properties. VB-specific deletion of HCN2, but not of HCN4, also induced these generalized seizures of the absence type, corroborating a key role of HCN2 in this particular nucleus for controlling consciousness. Together, our data define distinct pathological phenotypes resulting from the loss of cAMP-mediated gating of a neuronal HCN channel

Prolongiertes Weaning in der neurologisch-neurochirurgischen Frührehabilitation

Prolonged weaning of patients with neurological or neurosurgery disorders is associated with specific characteristics, which are taken into account by the German Society for Neurorehabilitation (DGNR) in its own guideline. The current S2k guideline of the German Society for Pneumology and Respiratory Medicine is referred to explicitly with regard to definitions (e.g., weaning and weaning failure), weaning categories, pathophysiology of weaning failure, and general weaning strategies. In early neurological and neurosurgery rehabilitation, patients with central of respiratory regulation disturbances (e.g., cerebral stem lesions), swallowing disturbances (neurogenic dysphagia), neuromuscular problems (e.g., critical illness polyneuropathy, Guillain-Barre syndrome, paraplegia, Myasthenia gravis) and/or cognitive disturbances (e.g., disturbed consciousness and vigilance disorders, severe communication disorders), whose care during the weaning of ventilation requires, in addition to intensive medical competence, neurological or neurosurgical and neurorehabilitation expertise. In Germany, this competence is present in centers of early neurological and neurosurgery rehabilitation, as a hospital treatment. The guideline is based on a systematic search of guideline databases and MEDLINE. Consensus was established by means of a nominal group process and Delphi procedure moderated by the Association of the Scientific Medical Societies in Germany (AWMF). In the present guideline of the DGNR, the special structural and substantive characteristics of early neurological and neurosurgery rehabilitation and existing studies on weaning in early rehabilitation facilities are examined. Addressees of the guideline are neurologists, neurosurgeons, anesthesiologists, palliative physicians, speech therapists, intensive care staff, ergotherapists, physiotherapists, and neuropsychologists. In addition, this guideline is intended to provide information to specialists for physical medicine and rehabilitation (PMR), pneumologists, internists, respiratory therapists, the German Medical Service of Health Insurance Funds (MDK) and the German Association of Health Insurance Funds (MDS). The main goal of this guideline is to convey the current knowledge on the subject of "Prolonged weaning in early neurological and neurosurgery rehabilitation"

A 600 kb deletion syndrome at 16p11.2 leads to energy imbalance and neuropsychiatric disorders.

BACKGROUND: The recurrent ~600 kb 16p11.2 BP4-BP5 deletion is among the most frequent known genetic aetiologies of autism spectrum disorder (ASD) and related neurodevelopmental disorders. OBJECTIVE: To define the medical, neuropsychological, and behavioural phenotypes in carriers of this deletion. METHODS: We collected clinical data on 285 deletion carriers and performed detailed evaluations on 72 carriers and 68 intrafamilial non-carrier controls. RESULTS: When compared to intrafamilial controls, full scale intelligence quotient (FSIQ) is two standard deviations lower in carriers, and there is no difference between carriers referred for neurodevelopmental disorders and carriers identified through cascade family testing. Verbal IQ (mean 74) is lower than non-verbal IQ (mean 83) and a majority of carriers require speech therapy. Over 80% of individuals exhibit psychiatric disorders including ASD, which is present in 15% of the paediatric carriers. Increase in head circumference (HC) during infancy is similar to the HC and brain growth patterns observed in idiopathic ASD. Obesity, a major comorbidity present in 50% of the carriers by the age of 7 years, does not correlate with FSIQ or any behavioural trait. Seizures are present in 24% of carriers and occur independently of other symptoms. Malformations are infrequently found, confirming only a few of the previously reported associations. CONCLUSIONS: The 16p11.2 deletion impacts in a quantitative and independent manner FSIQ, behaviour and body mass index, possibly through direct influences on neural circuitry. Although non-specific, these features are clinically significant and reproducible. Lastly, this study demonstrates the necessity of studying large patient cohorts ascertained through multiple methods to characterise the clinical consequences of rare variants involved in common diseases