Correction of aberrant splicing of ELP1 pre-mRNA by kinetin derivatives - A structure activity relationship study.

Familial dysautonomia is a debilitating congenital neurodegenerative disorder with no causative therapy. It is caused by a homozygous mutation in ELP1 gene, resulting in the production of the transcript lacking exon 20. The compounds studied as potential treatments include the clinical candidate kinetin, a plant hormone from the cytokinin family.

A decoy receptor derived from alternative splicing fine-tunes cytokinin signaling in Arabidopsis.

Hormone perception and signaling pathways have a fundamental regulatory function in the physiological processes of plants. Cytokinins, a class of plant hormones, regulate cell division and meristem maintenance. The cytokinin signaling pathway is well established in the model plant Arabidopsisthaliana.

Improvement of the Upper Detection Limit of Ionophore-Based H-Selective Electrodes: Explanation and Elimination of Apparently Super-Nernstian Responses.

The response range of an ion-selective electrode (ISE) has been described by counterion interference at the lower and Donnan failure at the upper detection limit. This approach fails when the potentiometric response at the upper detection limit exhibits an apparently super-Nernstian response, as has been reported repeatedly for H-selective electrodes. While also observed when samples contain other anions, super-Nernstian responses at low pH are a problem in particular for samples that contain phthalate, a common component of commercial pH calibration solutions.

Ion-Selective Potentiometry with Plasma-Initiated Covalent Attachment of Sensing Membranes onto Inert Polymeric Substrates and Carbon Solid Contacts.

The physical delamination of the sensing membrane from underlying electrode bodies and electron conductors limits sensor lifetimes and long-term monitoring with ion-selective electrodes (ISEs). To address this problem, we developed two plasma-initiated graft polymerization methods that attach ionophore-doped polymethacrylate sensing membranes covalently to high-surface-area carbons that serve as the conducting solid contact as well as to polypropylene, poly(ethylene--tetrafluoroethylene), and polyurethane as the inert polymeric electrode body materials. The first strategy consists of depositing the precursor solution for the preparation of the sensing membranes onto the platform substrates with the solid contact carbon, followed by exposure to an argon plasma, which results in surface-grafting of the in situ polymerized sensing membrane.

Association Between Years of Education and Amyloid Burden in Patients With Subjective Cognitive Decline, MCI, and Alzheimer Disease.

Objectives: Higher-educated patients with Alzheimer disease (AD) can harbor greater neuropathologic burden than those with less education despite similar symptom severity. In this study, we assessed whether this observation is also present in potential preclinical AD stages, namely in individuals with subjective cognitive decline and clinical features increasing AD likelihood (SCD+).

Methods: Amyloid-PET information ([F]Flutemetamol or [F]Florbetaben) of individuals with SCD+, mild cognitive impairment (MCI), and AD were retrieved from the AMYPAD-DPMS cohort, a multicenter randomized controlled study.

Covalently attached ionophores extend the working range of potentiometric pH sensors with poly(decyl methacrylate) sensing membranes.

The pH working range of solid-contact ion-selective electrodes (ISEs) with plasticizer-free poly(decyl methacrylate) sensing membranes is shown to be expanded by covalent attachment of H ionophores to the polymeric membrane matrix. photopolymerization not only incorporates the ionophores into the polymer backbone, but at the same time also attaches the sensing membranes covalently to the underlying inert polymer and nanographite solid contact, minimizing sensor drift and preventing failure by membrane delamination. A new pyridine-based H ionophore, 3-(pyridine-3-yl)propyl methacrylate, has lower basicity than trialkylamine ionophores and expands the upper detection limit.

Chemotherapy for a secondary malignancy nearly restores complete chimerism in an SCID-patient after HSCT.

For patients with inborn errors of immunity (IEI) and other inborn diseases, mixed donor chimerism is a well-accepted outcome of hematopoietic stem cell transplantation (HSCT). Cytoreductive chemotherapy for a secondary malignancy is a potential challenge for the stability of the graft function after HSCT. We report on a boy with X-SCID who developed Ewing sarcoma ten years after HSCT which was successfully treated with cytoreductive chemotherapy, surgery and local radiation.

Affection of Motor Network Regions by Tau Pathology Across the Alzheimer's Disease Spectrum.

Stereotypical isocortical tau protein pathology along the Braak stages has been described as an instigator of neurodegeneration in Alzheimer's disease (AD). Less is known about tau pathology in motor regions, although higher-order motor deficits such as praxis dysfunction are part of the clinical description. Here, we examined how tau pathology in cytoarchitectonically mapped regions of the primary and higher-order motor network in comparison to primary visual and sensory regions varies across the clinical spectrum of AD.

Environment-dependent metabolic investments in the mixotrophic chrysophyte Ochromonas.

Mixotrophic protists combine photosynthesis and phagotrophy to obtain energy and nutrients. Because mixotrophs can act as either primary producers or consumers, they have a complex role in marine food webs and biogeochemical cycles. Many mixotrophs are also phenotypically plastic and can adjust their metabolic investments in response to resource availability.

Survival in primary hemophagocytic lymphohistiocytosis, 2016 to 2021: etoposide is better than its reputation.

Primary hemophagocytic lymphohistiocytosis (pHLH) is a life-threatening hyperinflammatory syndrome that develops mainly in patients with genetic disorders of lymphocyte cytotoxicity and X-linked lymphoproliferative syndromes. Previous studies with etoposide-based treatment followed by hematopoetic stem cell transplantation (HSCT) resulted in 5-year survival of 50% to 59%. Contemporary data are lacking.

[Newborn screening for severe combined immunodeficiencies (SCID) in Germany].

Patients with a severe combined immunodeficiency (SCID) harbor genetic mutations disrupting T cell immunity and hence suffer severe, life-threatening infections or manifestations of immune dysregulation within the first months of their life. The only cure is to correct their immune system, usually by means of hematopoietic stem cell transplantation (HSCT). Pilot studies and national programs in the United States and in European countries have shown that patients can be identified at an early asymptomatic stage through newborn screening.

Short-term temperature fluctuations increase disease in a Daphnia-parasite infectious disease system.

Climate change has profound effects on infectious disease dynamics, yet the impacts of increased short-term temperature fluctuations on disease spread remain poorly understood. We empirically tested the theoretical prediction that short-term thermal fluctuations suppress endemic infection prevalence at the pathogen's thermal optimum. This prediction follows from a mechanistic disease transmission model analyzed using stochastic simulations of the model parameterized with thermal performance curves (TPCs) from metabolic scaling theory and using nonlinear averaging, which predicts ecological outcomes consistent with Jensen's inequality (i.

Chemical priming of plant defense responses to pathogen attacks.

Plants can acquire an improved resistance against pathogen attacks by exogenous application of natural or artificial compounds. In a process called chemical priming, application of these compounds causes earlier, faster and/or stronger responses to pathogen attacks. The primed defense may persist over a stress-free time (lag phase) and may be expressed also in plant organs that have not been directly treated with the compound.

Raloxifene Mitigates Emotional Deficits after Mild Traumatic Brain Injury in Mice.

Persons with mild traumatic brain injury (TBI) often exhibit persistent emotional impairments, particularly depression, fearfulness, and anxiety, that significantly diminish quality of life. Studying these mood disorders in animal models of mild TBI can help provide insight into possible therapies. We have previously reported that mice show increased depression, fearfulness, and anxiety, as well as visual and motor deficits, after focal cranial blast and that treatment with the cannabinoid type 2 receptor (CB2) inverse agonist, SMM-189, reduces these deficits.

Photoprotective properties of new derivatives of kinetin.

The chronic exposure of skin to ultraviolet (UV) radiation causes adverse dermal reactions, such as erythema, sunburn, photoaging, and cancer, by altering several signalling pathways associated with oxidative stress, inflammation, and DNA damage. One of the possible UV light protection strategies is the use of dermal photoprotective preparations. The plant hormone kinetin (N6-furfuryladenine; KIN) exhibits antioxidant and anti-senescent effects in human cells.

Raloxifene, a cannabinoid type-2 receptor inverse agonist, mitigates visual deficits and pathology and modulates microglia after ocular blast.

Visual deficits after ocular blast injury (OBI) are common, but pharmacological approaches to improve long-term outcomes have not been identified. Blast forces frequently damage the retina and optic nerves, and work on experimental animals has shown the pro-inflammatory actions of microglia can further exacerbate such injuries. Cannabinoid type-2 receptor (CB2) inverse agonists specifically target activated microglia, biasing them away from the harmful pro-inflammatory M1 state toward the helpful reparative M2 state.

Hydrogels Doped with Redox Buffers as Transducers for Ion-Selective Electrodes.

Solid-contact ion-selective electrodes (ISEs) with an unintentional water layer between the sensing membrane and underlying electron conductor are well known to suffer from potential drift caused by the instability of the phase boundary potential between the sensing membrane and the water layer with its uncontrolled ionic composition. The reproducibility and long-term emf stability of ISEs with a miniaturized inner filling solution comprising a hydrogel and a hydrophilic electrolyte have not been studied as thoroughly. Here, such devices are discussed with a view to electrode-to-electrode reproducibility, using both hydrophilic ion-exchange and plasticized PVC membranes, along with a hydrophilic redox buffer composed of ferrocyanide and ferricyanide to control the potential between the hydrogel and the underlying electron conductor.

Captive rearing of orphaned African wild dogs (Lycaon pictus) in Namibia: A case study.

African wild dogs (AWDs; Lycaon pictus) are an endangered canid species facing drastic decline throughout their range due to habitat fragmentation and persecution by humans over livestock depredation, resulting in dens destroyed and adult members of packs and pups often being killed. Breeding of captive AWDs is challenging due to high juvenile mortality, only marginally improved from wild conditions, thus both in situ and ex situ conservation remains critical. As a result of human-wildlife conflict, between 2017 and 2018, the Namibian Ministry of Environment, Forestry and Tourism confiscated three litters of orphaned AWD pups from rural farmers who had destroyed the dens in Eastern Namibia and placed the pups with the Cheetah Conservation Fund.

Raloxifene Modulates Microglia and Rescues Visual Deficits and Pathology After Impact Traumatic Brain Injury.

Mild traumatic brain injury (TBI) involves widespread axonal injury and activation of microglia, which initiates secondary processes that worsen the TBI outcome. The upregulation of cannabinoid type-2 receptors (CB2) when microglia become activated allows CB2-binding drugs to selectively target microglia. CB2 inverse agonists modulate activated microglia by shifting them away from the harmful pro-inflammatory M1 state toward the helpful reparative M2 state and thus can stem secondary injury cascades.

Ring-fused cyclobutanes cycloisomerization of alkylidenecyclopropane acylsilanes.

A novel Lewis acid-catalyzed cycloisomerization of alkylidenecyclopropane acylsilanes is disclosed. The readily available starting materials participate in tandem Prins addition/ring expansion/1,2-silyl shift to grant access to bicyclo[4.2.