Redox‐Responsive Nanobiomaterials‐Based Therapeutics for Neurodegenerative Diseases

Redox regulation has recently been proposed as a critical intracellular mechanism affecting cell survival, proliferation, and differentiation. Redox homeostasis has also been implicated in a variety of degenerative neurological disorders such as Parkinson's and Alzheimer's disease. In fact, it is hypothesized that markers of oxidative stress precede pathologic lesions in Alzheimer's disease and other neurodegenerative diseases. Several therapeutic approaches have been suggested so far to improve the endogenous defense against oxidative stress and its harmful effects. Among such approaches, the use of artificial antioxidant systems has gained increased popularity as an effective strategy. Nanoscale drug delivery systems loaded with enzymes, bioinspired catalytic nanoparticles and other nanomaterials have emerged as promising candidates. The development of degradable hydrogels scaffolds with antioxidant effects could also enable scientists to positively influence cell fate. This current review summarizes nanobiomaterial‐based approaches for redox regulation and their potential applications as central nervous system neurodegenerative disease treatments

How do I know if I’ve improved my continental scale flood early warning system?

Flood early warning systems mitigate damages and loss of life and are an economically efficient way of enhancing disaster resilience. The use of continental scale flood early warning systems is rapidly growing. The European Flood Awareness System (EFAS) is a pan-European flood early warning system forced by a multi-model ensemble of numerical weather predictions. Responses to scientific and technical changes can be complex in these computationally expensive continental scale systems, and improvements need to be tested by evaluating runs of the whole system. It is demonstrated here that forecast skill is not correlated with the value of warnings. In order to tell if the system has been improved an evaluation strategy is required that considers both forecast skill and warning value. The combination of a multi-forcing ensemble of EFAS flood forecasts is evaluated with a new skill-value strategy. The full multi-forcing ensemble is recommended for operational forecasting, but, there are spatial variations in the optimal forecast combination. Results indicate that optimizing forecasts based on value rather than skill alters the optimal forcing combination and the forecast performance. Also indicated is that model diversity and ensemble size are both important in achieving best overall performance. The use of several evaluation measures that consider both skill and value is strongly recommended when considering improvements to early warning systems

Euro+Med-Checklist Notulae, 14

Abstract: This is the fourteenth of a series of miscellaneous contributions, by various authors, where hitherto unpublished data relevant to both the Med-Checklist and the Euro+Med (or Sisyphus) projects are presented. This instalment deals with the families Apocynaceae, Compositae, Crassulaceae, Cyperaceae, Euphorbiaceae, Gramineae, Leguminosae, Nyctaginaceae, Onagraceae, Orobanchaceae, Rubiaceae, Solanaceae and Umbelliferae. It includes new country and area records and taxonomic and distributional considerations for taxa in Acalypha, Bupleurum, Carex, Datura, Epilobium, Eragrostis, Galium, Leontodon, Mirabilis, Nerium, Orobanche, Phelipanche, Rhinanthus, Saccharum, Sedum, Trifolium, Tripleurospermum and Willemetia. Citation For the whole article: Raab-Straube E. von & Raus Th. (ed.) 2021: Euro+Med-Checklist Notulae, 14.-Willdenowia 51: 355-369. For a single contribution (example): Bergmeier E. 2021: Leontodon longirostris (Finch & P. D. Sell) Talavera-Pp. 356-357 in: Raab-Straube E. von & Raus Th. (ed.), Euro+Med-Checklist Notulae, 14.-Willdenowia 51: 355-369. https://doi.org/10.3372/wi.51.51304 Version of record first published online on 30 November 2021 ahead of inclusion in December 2021 issue

Isobutyryl-CoA dehydrogenase deficiency associated with autism in a girl without an alternative genetic diagnosis by trio whole exome sequencing: A case report

Background: Isobutyryl-CoA dehydrogenase (IBD) is a mitochondrial enzyme catalysing the third step in the degradation of the essential branched-chain amino acid valine and is encoded by ACAD8. ACAD8 mutations lead to isobutyryl-CoA dehydrogenase deficiency (IBDD), which is identified by increased C4-acylcarnitine levels. Affected individuals are either asymptomatic or display a variety of symptoms during infancy, including speech delay, cognitive impairment, failure to thrive, hypotonia, and emesis. Methods: Here, we review all previously published IBDD patients and describe a girl diagnosed with IBDD who was presenting with autism as the main disease feature. Results: To assess whether a phenotype-genotype correlation exists that could explain the development or absence of clinical symptoms in IBDD, we compared CADD scores, in silico mutation predictions, LoF tolerance scores and C4-acylcarnitine levels between symptomatic and asymptomatic individuals. Statistical analysis of these parameters did not establish significant differences amongst both groups. Conclusion: As in our proband, tri

British Association of Dermatologists guidelines for the management of people with vitiligo 2021

The overall objective of the guideline is to provide up-to-date, evidence-based recommendations for the management of vitiligo. The document aims to: offer an appraisal of all relevant literature up to May 2019, focusing on any key developments address important, practical clinical questions relating to the primary guideline objective provide guideline recommendations and if appropriate research recommendations

SHMT1 1420 and MTHFR 677 variants are associated with rectal but not colon cancer

<p>Abstract</p> <p>Background</p> <p>Association between rectal or colon cancer risk and serine hydroxymethyltransferase 1 (<it>SHMT1</it>) C1420T or methylenetetrahydrofolate reductase (<it>MTHFR</it>) C677T polymorphisms was assessed. The serum total homocysteine (HCY), marker of folate metabolism was also investigated.</p> <p>Methods</p> <p>The <it>SHMT1 </it>and <it>MTHFR </it>genotypes were determined by real-time PCR and PCR-RFLP, respectively in 476 patients with rectal, 479 patients with colon cancer and in 461 and 478, respective controls matched for age and sex. Homocysteine levels were determined by HPLC kit. The association between polymorphisms and cancer risk was evaluated by logistic regression analysis adjusted for age, sex and body mass index. The population stratification bias was also estimated.</p> <p>Results</p> <p>There was no association of genotypes or diplotypes with colon cancer. The rectal cancer risk was significantly lower for <it>SHMT1 </it>TT (OR = 0.57, 95% confidence interval (CI) 0.36-0.89) and higher for <it>MTHFR </it>CT genotypes (OR = 1.4, 95%CI 1.06-1.84). A gene-dosage effect was observed for <it>SHMT1 </it>with progressively decreasing risk with increasing number of T allele (p = 0.014). The stratified analysis according to age and sex revealed that the association is mainly present in the younger (< 60 years) or male subgroup. As expected from genotype analysis, the <it>SHMT1 </it>T allele/<it>MTHFR </it>CC diplotype was associated with reduced rectal cancer risk (OR 0.56, 95%CI 0.42-0.77 vs all other diplotypes together). The above results are unlikely to suffer from population stratification bias. In controls HCY was influenced by <it>SHMT1 </it>polymorphism, while in patients it was affected only by Dukes' stage. In patients with Dukes' stage C or D HCY can be considered as a tumor marker only in case of <it>SHMT1 </it>1420CC genotypes.</p> <p>Conclusions</p> <p>A protective effect of <it>SHMT1 </it>1420T allele or <it>SHMT1 </it>1420 T allele/<it>MTHFR </it>677 CC diplotype against rectal but not colon cancer risk was demonstrated. The presence of <it>SHMT1 </it>1420 T allele significantly increases the HCY levels in controls but not in patients. Homocysteine could be considered as a tumor marker in <it>SHMT1 </it>1420 wild-type (CC) CRC patients in Dukes' stage C and D. Further studies need to clarify why <it>SHMT1 </it>and <it>MTHFR </it>polymorphisms are associated only with rectal and not colon cancer risk.</p

Expression and regulation of type 2A protein phosphatases and alpha4 signalling in cardiac health and hypertrophy

Abstract Cardiac physiology and hypertrophy are regulated by the phosphorylation status of many proteins, which is partly controlled by a poorly defined type 2A protein phosphatase-alpha4 intracellular signalling axis. Quantitative PCR analysis revealed that mRNA levels of the type 2A catalytic subunits were differentially expressed in H9c2 cardiomyocytes (PP2ACb[PP2ACa[PP4C[PP6C), NRVM (PP2ACb[PP2ACa = PP4C = PP6C), and adult rat ventricular myocytes (PP2ACa[ PP2ACb[PP6C[PP4C). Western analysis confirmed that all type 2A catalytic subunits were expressed in H9c2 cardiomyocytes; however, PP4C protein was absent in adult myocytes and only detectable following 26S proteasome inhibition. Short-term knockdown of alpha4 protein expression attenuated expression of all type 2A catalytic subunits. Pressure overload-induced left ventricular (LV) hypertrophy was associated with an increase in both PP2AC and alpha4 protein expression. Although PP6C expression was unchanged, expression of PP6C regulatory subunits (1) Sit4-associated protein 1 (SAP1) and (2) ankyrin repeat domain (ANKRD) 28 and 44 proteins was elevated, whereas SAP2 expression was reduced in hypertrophied LV tissue. Co-immunoprecipitation studies demonstrated that the interaction between alpha4 and PP2AC or PP6C subunits was either unchanged or reduced in hypertrophied LV tissue, respectively. Phosphorylation status of phospholemman (Ser63 and Ser68) was significantly increased by knockdown of PP2ACa, PP2ACb, or PP4C protein expression. DNA damage assessed by histone H2A.X phosphorylation (cH2A.X) in hypertrophied tissue remained unchanged. However, exposure of cardiomyocytes to H2O2 increased levels of cH2A.X which was unaffected by knockdown of PP6C expression, but was abolished by the short-term knockdown of alpha4 expression. This study illustrates the significance and altered activity of the type 2A protein phosphatase-alpha4 complex in healthy and hypertrophied myocardium

Efficacy and Safety of Intravitreal Gene Therapy for Leber Hereditary Optic Neuropathy Treated within 6 Months of Disease Onset

Purpose: To evaluate the efficacy of a single intravitreal injection of rAAV2/2-ND4 in subjects with visual loss from Leber hereditary optic neuropathy (LHON). Design: RESCUE is a multicenter, randomized, double-masked, sham-controlled, phase 3 clinical trial. Participants: Subjects with the m.11778G&gt;A mitochondrial DNA mutation and vision loss ≤6 months from onset in 1 or both eyes were included. Methods: Each subject's right eye was randomly assigned (1:1) to treatment with rAAV2/2-ND4 (single injection of 9 × 1010 viral genomes in 90 μl) or to sham injection. The left eye received the treatment not allocated to the right eye. Main Outcome Measures: The primary end point was the difference of the change from baseline in best-corrected visual acuity (BCVA) between rAAV2/2-ND4–treated and sham-treated eyes at week 48. Other outcome measures included contrast sensitivity, Humphrey visual field perimetry, retinal anatomic measures, and quality of life. Follow-up extended to week 96. Results: Efficacy analysis included 38 subjects. Mean age was 36.8 years, and 82% were male. Mean duration of vision loss at time of treatment was 3.6 months and 3.9 months in the rAAV2/2-ND4–treated eyes and sham-treated eyes, respectively. Mean baseline logarithm of the minimum angle of resolution (logMAR) BCVA (standard deviation) was 1.31 (0.52) in rAAV2/2-ND4–treated eyes and 1.26 (0.62) in sham-treated eyes, with a range from −0.20 to 2.51. At week 48, the difference of the change in BCVA from baseline between rAAV2/2-ND4–treated and sham-treated eyes was −0.01 logMAR (P = 0.89); the primary end point of a −0.3 logMAR (15-letter) difference was not met. The mean BCVA for both groups deteriorated over the initial weeks, reaching the worst levels at week 24, followed by a plateau phase until week 48, and then an improvement of +10 and +9 Early Treatment Diabetic Retinopathy Study letters equivalent from the plateau level in the rAAV2/2-ND4–treated and sham-treated eyes, respectively. Conclusions: At 96 weeks after unilateral injection of rAAV2/2-ND4, LHON subjects carrying the m.11778G&gt;A mutation treated within 6 months after vision loss achieved comparable visual outcomes in the injected and uninjected eyes