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► The state-of-the-art DFT methods for adsorption characterization of micro- and mesoporous materials are presented. ► DFT allows for the customization to different adsorbates, ...materials and pore geometries. ► A rigorous theoretical background is provided for the development of NLDFT and QSDFT methods. ► A wealth of examples is displayed for practitioners as a guide for the kernel election. ► Hysteresis due to capillary condensation, cavitation and pore blocking and how to distinguish among them is discussed.
This review presents the state-of-the-art of adsorption characterization of mesoporous and microporous materials by using the density functional theory (DFT) methods. The DFT methods have found numerous applications for calculating pore size distributions in traditional and newly discovered nanoporous solids. We discuss the foundations of the non-local (NLDFT) and quench solid (QSDFT) density functional theories applied for modeling adsorption and capillary condensation in pores of different geometry and surface chemistry. Special attention is paid to the limitations of the theoretical models and critical analysis of the obtained data. The methods are demonstrated on a wide variety of systems, including microporous and mesoporous carbons and silicas, zeolites, mesoporous crystals of MCM and SBA families, metal–organic frameworks, and other designer nanoporous materials. Illustrated with many typical examples and detailed discussions of the advantages and limitations of the NLDFT and QSDFT methods, this review provides guidance for the practitioners interested in getting a better understanding of the current capabilities and limitations of the adsorption methods for characterization of porous solids
This study was undertaken to determine the performance of trabeculectomy surgery over a 20-year period and examine the associations between outcome and risk factors for trabeculectomy failure.
...Retrospective cohort study.
A total of 234 patients (330 procedures) who had undergone trabeculectomy surgery at Addenbrooke's Hospital, Cambridge, United Kingdom, between January 1988 and December 1990.
Patients were identified through surgical logbooks (n = 521 procedures on 380 patients); after this, a case-note review was undertaken, which identified 234 patients (330 procedures) who had available case notes.
Surgical success was defined as "complete success" while intraocular pressure (IOP) remained <21 mm Hg with no additional medication and as "qualified success" if those requiring additional topical medication were included. Functional success was defined if patients did not progress to legal blindness (visual acuity <3/60 or visual field <10 degrees).
After 20 years, 57% were classified as complete success, 88% were classified as qualified success, and 15% had become blind. Those at risk of trabeculectomy failure were younger or had uveitic glaucoma. Those with pseudoexfoliation or aphakia were more likely to progress to blindness. Furthermore, those using 2 or more topical medications or with advanced visual field loss at the time of surgery were more at risk of both trabeculectomy failure and blindness.
This study indicates that trabeculectomy survival at 20 years may be approximately 60% with no topical medication and approximately 90% with additional topical medication. Patient age, preoperative topical medication use, glaucoma type, and glaucoma severity will independently influence this outcome. Trabeculectomy surgery is therefore a long-term solution to IOP control.
Recent advances in sequencing technologies and collaborative efforts have led to substantial progress in identifying the genetic causes of amyotrophic lateral sclerosis (ALS). This momentum has, in ...turn, fostered the development of putative molecular therapies. In this Review, we outline the current genetic knowledge, emphasizing recent discoveries and emerging concepts such as the implication of distinct types of mutation, variability in mutated genes in diverse genetic ancestries and gene-environment interactions. We also propose a high-level model to synthesize the interdependent effects of genetics, environmental and lifestyle factors, and ageing into a unified theory of ALS. Furthermore, we summarize the current status of therapies developed on the basis of genetic knowledge established for ALS over the past 30 years, and we discuss how developing treatments for ALS will advance our understanding of targeting other neurological diseases.
To evaluate the effect of an intraoperative dose of intravitreal bevacizumab (Avastin) on surgical success following trabeculectomy with mitomycin-C (MMC) over 12 months.
A single centre, parallel, ...double-blinded randomised, placebo-controlled trial recruiting patients requiring trabeculectomy for progressing glaucoma. Patients were randomised to intravitreal bevacizumab or placebo.
The primary outcome of treatment success was defined by 'complete success' when intraocular pressure (IOP) remained less than a predefined target IOP without the requirement of topical medication, or 'qualified success' where topical medication was required to meet the predefined target IOP threshold. Secondary outcomes included the need for subsequent IOP-lowering interventions, and structural parameters associated with bleb function.
From 131 patients randomised to bevacizumab (n=65) or placebo (n=66), 128 patients completed 12 months of follow-up (98%). At 12 months, success rates were higher in the bevacizumab group (complete success: 94% vs 83%; p=0.015; qualified success: 98% vs 90%; p=0.033). Within the placebo group, the requirement for topical therapy was higher at 6 months (p=0.045) and 12 months (p=0.045), and the requirement for bleb needling was higher at 1 month (p=0.035). Blebs within the bevacizumab group were larger at 1 month (p<0.001) and demonstrated less vessel inflammation (p<0.0001).
Bevacizumab given as a single intravitreal dose during trabeculectomy with MMC resulted in improved surgical success as 12 months. Furthermore, bevacizumab was associated with a significant reduction in the need for additional medication or further surgery to achieve target IOP. Bevacizumab was also associated with larger blebs that were less inflamed and required fewer subsequent interventions.
ACTRN12614000375651.
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease of unknown etiology. Although defects in nucleocytoplasmic transport (NCT) may be central to the pathogenesis of ALS and other ...neurodegenerative diseases, the molecular mechanisms modulating the nuclear pore function are still largely unknown. Here we show that genetic and pharmacological modulation of actin polymerization disrupts nuclear pore integrity, nuclear import, and downstream pathways such as mRNA post-transcriptional regulation. Importantly, we demonstrate that modulation of actin homeostasis can rescue nuclear pore instability and dysfunction caused by mutant PFN1 as well as by C9ORF72 repeat expansion, the most common mutation in ALS patients. Collectively, our data link NCT defects to ALS-associated cellular pathology and propose the regulation of actin homeostasis as a novel therapeutic strategy for ALS and other neurodegenerative diseases.
Understanding the pathogenic mechanisms of disease mutations is critical to advancing treatments. ALS-associated mutations in the gene encoding the microtubule motor KIF5A result in skipping of exon ...27 (KIF5AΔExon27) and the encoding of a protein with a novel 39 amino acid residue C-terminal sequence. Here, we report that expression of ALS-linked mutant KIF5A results in dysregulated motor activity, cellular mislocalization, altered axonal transport, and decreased neuronal survival. Single-molecule analysis revealed that the altered C terminus of mutant KIF5A results in a constitutively active state. Furthermore, mutant KIF5A possesses altered protein and RNA interactions and its expression results in altered gene expression/splicing. Taken together, our data support the hypothesis that causative ALS mutations result in a toxic gain of function in the intracellular motor KIF5A that disrupts intracellular trafficking and neuronal homeostasis.
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•ALS-associated KIF5A mutations result in a common novel toxic C-terminal sequence•ALS mutant KIF5A lacks autoinhibition resulting in a constitutively active kinesin•ALS mutant KIF5A displays a distal accumulation and altered axonal transport•ALS-associated KIF5A mutations result in novel protein and RNA interactions
ALS-associated KIF5A mutations alter the C terminus, the effect of which had yet to be elucidated. Here, Baron et al. discover that these mutations impair KIF5A autoinhibition resulting in a hyperactive kinesin that displays altered protein function and aberrant cellular interactions. These observations shed light on the mechanisms contributing to ALS.
Genetic studies of Wallerian degeneration have led to the identification of signaling molecules (e.g., dSarm/Sarm1, Axundead, and Highwire) that function locally in axons to drive degeneration. Here ...we identify a role for the Drosophila C₂H₂ zinc finger transcription factor Pebbled Peb, Ras-responsive element binding protein 1 (RREB1) in mammals in axon death. Loss of Peb in Drosophila glutamatergic sensory neurons results in either complete preservation of severed axons, or an axon death phenotype where axons fragment into large, continuous segments, rather than completely disintegrate. Peb is expressed in developing and mature sensory neurons, suggesting it is required to establish or maintain their competence to undergo axon death. peb mutant phenotypes can be rescued by human RREB1, and they exhibit dominant genetic interactions with dsarm mutants, linking peb/RREB1 to the axon death signaling cascade. Surprisingly, Peb is only able to fully block axon death signaling in glutamatergic, but not cholinergic sensory neurons, arguing for genetic diversity in axon death signaling programs in different neuronal subtypes. Our findings identify a transcription factor that regulates axon death signaling, and peb mutant phenotypes of partial fragmentation reveal a genetically accessible step in axon death signaling.
Mutations in the profilin 1 (PFN1) gene cause amyotrophic lateral sclerosis (ALS), a neurodegenerative disease caused by the loss of motor neurons leading to paralysis and eventually death. PFN1 is a ...small actin-binding protein that promotes formin-based actin polymerization and regulates numerous cellular functions, but how the mutations in PFN1 cause ALS is unclear. To investigate this problem, we have generated transgenic mice expressing either the ALS-associated mutant (C71G) or wild-type protein. Here, we report that mice expressing the mutant, but not the wild-type, protein had relentless progression of motor neuron loss with concomitant progressive muscle weakness ending in paralysis and death. Furthermore, mutant, but not wild-type, PFN1 forms insoluble aggregates, disrupts cytoskeletal structure, and elevates ubiquitin and p62/SQSTM levels in motor neurons. Unexpectedly, the acceleration of motor neuron degeneration precedes the accumulation of mutant PFN1 aggregates. These results suggest that although mutant PFN1 aggregation may contribute to neurodegeneration, it does not trigger its onset. Importantly, these experiments establish a progressive disease model that can contribute toward identifying the mechanisms of ALS pathogenesis and the development of therapeutic treatments.
OBJECTIVE:We investigated whether the C9orf72 expansion mutation in patients with amyotrophic lateral sclerosis (ALS) is associated with unique demographic and clinical features.
METHODS:Between 2001 ...and 2015, approximately half of all patients attending the Emory ALS Clinic agreed to donate DNA for research. This research cohort of 781 patients was screened for the C9orf72 expansion, and demographic and clinical data were compared between those with and without the C9orf72 mutation. For mutation carriers without a family history of ALS, we sought further family history of dementia and other non-ALS neurodegenerative diseases in first-degree relatives.
RESULTS:The C9orf72 expansion was identified in 61 patients (7.8%). Compared to those without the expansion mutation, these patients did not differ in race, age, or site of onset. As expected, C9orf72 patients were more likely to have a family history of ALS (59% vs 7.9%) and to present with comorbid frontotemporal dementia (FTD) (14.8% vs 1.7%). Survival was shorter in patients with the expansion (log-rank χ1 = 45.323, p < 0.001). Further investigation in 28 patients initially categorized as having no known family history of ALS identified a family history of dementia in 16 cases; 6 of these had characteristics suggestive of FTD.
CONCLUSIONS:Comparing the C9orf72 ALS population to the general ALS population, there were no differences in race, age at onset, or proportion of patients with bulbar onset disease. Differences identified in patients with the C9orf72 mutation included shortened survival and an equal proportion of men and women. In addition, we found that assessing family history for dementia may identify other family members likely to be carrying the C9orf72 expansion, reduce the number of sporadic cases, and thus increase our understanding of disease penetrance.
There are currently no disease-modifying therapies for the neurodegenerative disorder Huntington's disease (HD). This study identified novel thiazole-containing inhibitors of the deacetylase ...sirtuin-2 (SIRT2) with neuroprotective activity in ex vivo brain slice and Drosophila models of HD. A systems biology approach revealed an additional SIRT2-independent property of the lead-compound, MIND4, as an inducer of cytoprotective NRF2 (nuclear factor-erythroid 2 p45-derived factor 2) activity. Structure-activity relationship studies further identified a potent NRF2 activator (MIND4-17) lacking SIRT2 inhibitory activity. MIND compounds induced NRF2 activation responses in neuronal and non-neuronal cells and reduced production of reactive oxygen species and nitrogen intermediates. These drug-like thiazole-containing compounds represent an exciting opportunity for development of multi-targeted agents with potentially synergistic therapeutic benefits in HD and related disorders.
•Novel thiazole-containing inhibitors of sirtuin-2 deacetylase identified•Lead-compound is neuroprotective in Huntington's disease models•Lead-compound is SIRT2-independent inducer of NRF2-dependent responses•Novel NRF2 inducers reduce levels of reactive oxygen and nitrogen species
There is currently no disease-modifying treatment for the neurodegenerative disorder Huntington's disease (HD). Quinti et al. identified a novel compound with therapeutic activity in HD models that has two distinct biochemical activities, highlighting the potential combinatorial therapeutic effect of this compound for drug development.
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