Toxicity of C9orf72-associated dipeptide repeat peptides is modified by commonly used protein tags

Hexanucleotide repeat expansions in the C9orf72 gene are the most prevalent genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia. Transcripts of the expansions are translated into toxic dipeptide repeat (DPR) proteins. Most preclinical studies in cell and animal models have used protein-tagged polyDPR constructs to investigate DPR toxicity but the effects of tags on DPR toxicity have not been systematically explored. Here, we used Drosophila to assess the influence of protein tags on DPR toxicity. Tagging of 36 but not 100 arginine-rich DPRs with mCherry increased toxicity, whereas adding mCherry or GFP to GA100 completely abolished toxicity. FLAG tagging also reduced GA100 toxicity but less than the longer fluorescent tags. Expression of untagged but not GFP- or mCherry-tagged GA100 caused DNA damage and increased p62 levels. Fluorescent tags also affected GA100 stability and degradation. In summary, protein tags affect DPR toxicity in a tag- and DPR-dependent manner, and GA toxicity might be underestimated in studies using tagged GA proteins. Thus, including untagged DPRs as controls is important when assessing DPR toxicity in preclinical models

Introgression of Aegilops speltoides segments in Triticum aestivum and the effect of the gametocidal genes

• Background and Aims Bread wheat (Triticum aestivum) has been through a severe genetic bottleneck as a result of its evolution and domestication. It is therefore essential that new sources of genetic variation are generated and utilized. This study aimed to generate genome-wide introgressed segments from Aegilops speltoides. Introgressions generated from this research will be made available for phenotypic analysis. • Methods Aegilops speltoides was crossed as the male parent to T. aestivum ‘Paragon’. The interspecific hybrids were then backcrossed to Paragon. Introgressions were detected and characterized using the Affymetrix Axiom Array and genomic in situ hybridization (GISH). • Key Results Recombination in the gametes of the F₁ hybrids was at a level where it was possible to generate a genetic linkage map of Ae. speltoides. This was used to identify 294 wheat/Ae. speltoides introgressions. Introgressions from all seven linkage groups of Ae. speltoides were found, including both large and small segments. Comparative analysis showed that overall macro-synteny is conserved between Ae. speltoides and T. aestivum, but that Ae. speltoides does not contain the 4A/5A/7B translocations present in wheat. Aegilops speltoides has been reported to carry gametocidal genes, i.e. genes that ensure their transmission through the gametes to the next generation. Transmission rates of the seven Ae. speltoides linkage groups introgressed into wheat varied. A 100 % transmission rate of linkage group 2 demonstrates the presence of the gametocidal genes on this chromosome. • Conclusions A high level of recombination occurs between the chromosomes of wheat and Ae. speltoides, leading to the generation of large numbers of introgressions with the potential for exploitation in breeding programmes. Due to the gametocidal genes, all germplasm developed will always contain a segment from Ae. speltoides linkage group 2S, in addition to an introgression from any other linkage group

Guest size limitation in metal-organic framework crystal-glass composites

MOF crystal-glass composites (MOF CGCs) are materials with crystalline MOFs embedded within a MOF glass. Here we develop two novel MOF CGCs, and explore the gas uptake and guest-size limitations within these materials.</p

Guest Size Limitation in Metal-Organic Framework Crystal-Glass Composites

Metal-organic framework crystal-glass composites (MOF CGCs) have previously been formed by embedding crystalline MIL-53(Al) within a ZIF-62 glass (agZIF-62) matrix. Here we highlight thermal stability considerations in the formation of MOF CGCs, and subsequently report the synthesis of two novel MOF CGCs, by incorporating MIL-118, and UL-MOF-1 within agZIF-62. These new materials, alongside the prototypical MOF CGC formed using MIL-53(Al), were studied using scanning electron microscopy, powder X-ray diffraction, and gas sorption techniques. The gas uptake in composites formed from MIL-118C and UL-MOF-1 is largely dominated by the agZIF-62 matrix, suggesting that to improve the porosity of the MOF CGC, the matrix porosity must be improved, or a percolation threshold must be overcome.</p

Nitrile-functionalized Poly(siloxane) as Electrolytes for High-Energy-Density Solid-State Li Batteries

In the quest to replace liquid Li-ion electrolytes with safer and non-toxic solid counterparts for Li-ion batteries, polysiloxane polymers have attracted considerable attention as they offer low glass transition temperatures, stability with metallic lithium, and versatility in chemical functionalization of the backbone. Herein, we present the synthesis of Li-ion conductive polysiloxane-based polymers functionalized with 60 % nitrile groups per chain unit. The synthesis procedure is based on the reaction of poly-(dimethylsiloxane-co-methylvinylsiloxane) polymer with 2-cyanoethanethiol, followed by the addition of lithium bis (trifluoromethanesulfonyl) imide. The presented polysiloxane-based polymers exhibit exceptionally high ionic conductivity up to 0.375 mS cm-1 at 60 degrees C and Li+ ion transfer number of 0.73, one of the highest reported for polymer Li-ion conducting electrolytes. Their electrochemical performance was evaluated in both symmetrical and full-cell configurations to test the utility of synthesized polymers as electrolytes in Li-ion batteries.ISSN:1864-564XISSN:1864-563

Does Lower Extremity Fracture Fixation Technique Influence Neurologic Outcomes in Patients With Traumatic Brain Injury? The EAST Brain vs. Bone Multicenter Trial

OBJECTIVE This study aimed to determine whether lower extremity fracture fixation technique and timing (≤24 vs. \u3e24 hours) impact neurologic outcomes in TBI patients. METHODS A prospective observational study was conducted across 30 trauma centers. Inclusion criteria were age 18 years and older, head Abbreviated Injury Scale (AIS) score of \u3e2, and a diaphyseal femur or tibia fracture requiring external fixation (Ex-Fix), intramedullary nailing (IMN), or open reduction and internal fixation (ORIF). The analysis was conducted using analysis of variamce, Kruskal-Wallis, and multivariable regression models. Neurologic outcomes were measured by discharge Ranchos Los Amigos Revised Scale (RLAS-R). RESULTS Of the 520 patients enrolled, 358 underwent Ex-Fix, IMN, or ORIF as definitive management. Head AIS was similar among cohorts. The Ex-Fix group experienced more severe lower extremity injuries (AIS score, 4–5) compared with the IMN group (16% vs. 3%, p = 0.01) but not the ORIF group (16% vs. 6%, p = 0.1). Time to operative intervention varied between the cohorts with the longest time to intervention for the IMN group (median hours: Ex-Fix, 15 [8–24] vs. ORIF, 26 [12–85] vs. IMN, 31 [12–70]; p \u3c 0.001). The discharge RLAS-R score distribution was similar across the groups. After adjusting for confounders, neither method nor timing of lower extremity fixation influenced the discharge RLAS-R. Instead, increasing age and head AIS score were associated with a lower discharge RLAS-R score (odds ratio [OR], 1.02; 95% confidence interval [CI], 1.002–1.03 and OR, 2.37; 95% CI, 1.75–3.22), and a higher Glasgow Coma Scale motor score on admission (OR, 0.84; 95% CI, 0.73–0.97) was associated with higher RLAS-R score at discharge. CONCLUSION Neurologic outcomes in TBI are impacted by severity of the head injury and not the fracture fixation technique or timing. Therefore, the strategy of definitive fixation of lower extremity fractures should be dictated by patient physiology and the anatomy of the injured extremity and not by the concern for worsening neurologic outcomes in TBI patients. LEVEL OF EVIDENCE Prognostic and Epidemiological; Level III

Does Lower Extremity Fracture Fixation Technique Influence Neurologic Outcomes in Patients With Traumatic Brain Injury? The EAST Brain vs. Bone Multicenter Trial

OBJECTIVE This study aimed to determine whether lower extremity fracture fixation technique and timing (≤24 vs. \u3e24 hours) impact neurologic outcomes in TBI patients. METHODS A prospective observational study was conducted across 30 trauma centers. Inclusion criteria were age 18 years and older, head Abbreviated Injury Scale (AIS) score of \u3e2, and a diaphyseal femur or tibia fracture requiring external fixation (Ex-Fix), intramedullary nailing (IMN), or open reduction and internal fixation (ORIF). The analysis was conducted using analysis of variamce, Kruskal-Wallis, and multivariable regression models. Neurologic outcomes were measured by discharge Ranchos Los Amigos Revised Scale (RLAS-R). RESULTS Of the 520 patients enrolled, 358 underwent Ex-Fix, IMN, or ORIF as definitive management. Head AIS was similar among cohorts. The Ex-Fix group experienced more severe lower extremity injuries (AIS score, 4–5) compared with the IMN group (16% vs. 3%, p = 0.01) but not the ORIF group (16% vs. 6%, p = 0.1). Time to operative intervention varied between the cohorts with the longest time to intervention for the IMN group (median hours: Ex-Fix, 15 [8–24] vs. ORIF, 26 [12–85] vs. IMN, 31 [12–70]; p \u3c 0.001). The discharge RLAS-R score distribution was similar across the groups. After adjusting for confounders, neither method nor timing of lower extremity fixation influenced the discharge RLAS-R. Instead, increasing age and head AIS score were associated with a lower discharge RLAS-R score (odds ratio [OR], 1.02; 95% confidence interval [CI], 1.002–1.03 and OR, 2.37; 95% CI, 1.75–3.22), and a higher Glasgow Coma Scale motor score on admission (OR, 0.84; 95% CI, 0.73–0.97) was associated with higher RLAS-R score at discharge. CONCLUSION Neurologic outcomes in TBI are impacted by severity of the head injury and not the fracture fixation technique or timing. Therefore, the strategy of definitive fixation of lower extremity fractures should be dictated by patient physiology and the anatomy of the injured extremity and not by the concern for worsening neurologic outcomes in TBI patients. LEVEL OF EVIDENCE Prognostic and Epidemiological; Level III

Outcomes among trauma patients with duodenal leak following primary versus complex repair of duodenal injuries: An Eastern Association for the Surgery of Trauma multicenter trial

BACKGROUND: Duodenal leak is a feared complication of repair, and innovative complex repairs with adjunctive measures (CRAM) were developed to decrease both leak occurrence and severity when leaks occur. Data on the association of CRAM and duodenal leak are sparse, and its impact on duodenal leak outcomes is nonexistent. We hypothesized that primary repair alone (PRA) would be associated with decreased duodenal leak rates; however, CRAM would be associated with improved recovery and outcomes when leaks do occur. METHODS: A retrospective, multicenter analysis from 35 Level 1 trauma centers included patients older than 14 years with operative, traumatic duodenal injuries (January 2010 to December 2020). The study sample compared duodenal operative repair strategy: PRA versus CRAM (any repair plus pyloric exclusion, gastrojejunostomy, triple tube drainage, duodenectomy). RESULTS: The sample (N = 861) was primarily young (33 years) men (84%) with penetrating injuries (77%); 523 underwent PRA and 338 underwent CRAM. Complex repairs with adjunctive measures were more critically injured than PRA and had higher leak rates (CRAM 21% vs. PRA 8%, p \u3c 0.001). Adverse outcomes were more common after CRAM with more interventional radiology drains, prolonged nothing by mouth and length of stay, greater mortality, and more readmissions than PRA (all p \u3c 0.05). Importantly, CRAM had no positive impact on leak recovery; there was no difference in number of operations, drain duration, nothing by mouth duration, need for interventional radiology drainage, hospital length of stay, or mortality between PRA leak versus CRAM leak patients (all p \u3e 0.05). Furthermore, CRAM leaks had longer antibiotic duration, more gastrointestinal complications, and longer duration until leak resolution (all p \u3c 0.05). Primary repair alone was associated with 60% lower odds of leak, whereas injury grades II to IV, damage control, and body mass index had higher odds of leak (all p \u3c 0.05). There were no leaks among patients with grades IV and V injuries repaired by PRA. CONCLUSION: Complex repairs with adjunctive measures did not prevent duodenal leaks and, moreover, did not reduce adverse sequelae when leaks did occur. Our results suggest that CRAM is not a protective operative duodenal repair strategy, and PRA should be pursued for all injury grades when feasible. LEVEL OF EVIDENCE: Therapeutic/Care Management; Level IV