Unfolded protein response IRE1/XBP1 signaling is required for healthy mammalian brain aging.

Aging is a major risk factor to develop neurodegenerative diseases and is associated with decreased buffering capacity of the proteostasis network. We investigated the significance of the unfolded protein response (UPR), a major signaling pathway activated to cope with endoplasmic reticulum (ER) stress, in the functional deterioration of the mammalian brain during aging. We report that genetic disruption of the ER stress sensor IRE1 accelerated age-related cognitive decline. In mouse models, overexpressing an active form of the UPR transcription factor XBP1 restored synaptic and cognitive function, in addition to reducing cell senescence. Proteomic profiling of hippocampal tissue showed that XBP1 expression significantly restore changes associated with aging, including factors involved in synaptic function and pathways linked to neurodegenerative diseases. The genes modified by XBP1 in the aged hippocampus where also altered. Collectively, our results demonstrate that strategies to manipulate the UPR in mammals may help sustain healthy brain aging.

Plant N-glycan breakdown by human gut Bacteroides.

The major nutrients available to the human colonic microbiota are complex glycans derived from the diet. To degrade this highly variable mix of sugar structures, gut microbes have acquired a huge array of different carbohydrate-active enzymes (CAZymes), predominantly glycoside hydrolases, many of which have specificities that can be exploited for a range of different applications. Plant N-glycans are prevalent on proteins produced by plants and thus components of the diet, but the breakdown of these complex molecules by the gut microbiota has not been explored. Plant N-glycans are also well characterized allergens in pollen and some plant-based foods, and when plants are used in heterologous protein production for medical applications, the N-glycans present can pose a risk to therapeutic function and stability. Here we use a novel genome association approach for enzyme discovery to identify a breakdown pathway for plant complex N-glycans encoded by a gut Bacteroides species and biochemically characterize five CAZymes involved, including structures of the PNGase and GH92 α-mannosidase. These enzymes provide a toolbox for the modification of plant N-glycans for a range of potential applications. Furthermore, the keystone PNGase also has activity against insect-type N-glycans, which we discuss from the perspective of insects as a nutrient source.

Optimizing Recovery: A Systematic Scoping Review of Upper Extremity Exercise Immediately after Cardiac Implantable Electronic Device Implantation.

INTRODUCTION: Cardiac implantable electronic devices (CIEDs), including pacemakers, defibrillators, and resynchronization devices, significantly enhance patient outcomes, reduce sudden cardiac death, and improve health-related quality of life. CIED implantation is associated to persistent shoulder dysfunction in a considerable number of patients one-year post-implantation. This may result in disability, diminished quality of life, work absenteeism, and negative psychological effects. Restoring upper extremity function after CIED implantation should be a standard of cardiovascular care. Our systematic scoping review aimed to summarize available evidence, addressing vital questions about safety, effectiveness, exercise type, and time of exercise initiation immediately after CIED implantation. METHODS: We conducted a comprehensive literature search in 5 electronic databases for original research in English, and a manual search on the references of included studies. We used Rayyan web application for study selection, and PRISMA-ScR to conduct and report the review. We assessed methodological quality using the Cochrane Risk of Bias Assessment Tool and Joanna Briggs Institute critical appraisal checklists. RESULTS: This review included 6 studies that used upper extremity pendular, range of motion, stretching and strengthening exercises. Initiation time varied from the first postoperative day to the second postoperative week. All studies showed significant association between active upper extremity exercise and reduced dysfunction and disability after CIED implantation. There were no significant differences in complication rates between control and experimental groups. CONCLUSION: A limited number of low-to-average quality studies suggest active upper extremity exercise immediately after CIED implantation is safe, effective at reducing dysfunction, and improves quality of life. Higher-quality studies are needed to validate these findings.

The unfolded protein response transcription factor XBP1s ameliorates Alzheimer's disease by improving synaptic function and proteostasis.

Alteration in the buffering capacity of the proteostasis network is an emerging feature of Alzheimer's disease (AD), highlighting the occurrence of endoplasmic reticulum (ER) stress. The unfolded protein response (UPR) is the main adaptive pathway to cope with protein folding stress at the ER. Inositol-requiring enzyme-1 (IRE1) operates as a central ER stress sensor, enabling the establishment of adaptive and repair programs through the control of the expression of the transcription factor X-box binding protein 1 (XBP1). To artificially enforce the adaptive capacity of the UPR in the AD brain, we developed strategies to express the active form of XBP1 in the brain. Overexpression of XBP1 in the nervous system using transgenic mice reduced the load of amyloid deposits and preserved synaptic and cognitive function. Moreover, local delivery of XBP1 into the hippocampus of an 5xFAD mice using adeno-associated vectors improved different AD features. XBP1 expression corrected a large proportion of the proteomic alterations observed in the AD model, restoring the levels of several synaptic proteins and factors involved in actin cytoskeleton regulation and axonal growth. Our results illustrate the therapeutic potential of targeting UPR-dependent gene expression programs as a strategy to ameliorate AD features and sustain synaptic function.

Assessing the quality of chest compressions with a DIY low-cost manikin (LoCoMan) versus a standard manikin: a quasi-experimental study in primary education.

Extending the access to cardiopulmonary resuscitation (CPR) training to a wider public is an important step in increasing survivability of out-of-hospital cardiac arrest. However, often price and maintenance of CPR manikins are barriers that prevent training at schools. This study aims to evaluate the learning of hands-only (HO) CPR by practicing with a low-cost manikin (LoCoMan) with visual qualitative feedback and to compare the results with the skills acquired by practice on a conventional manikin. A quasi-experimental study with 193 schoolchildren (10 to 12 years old) who were allocated to two groups: the LoCoMan group was taught via an integrative approach (science combined with physical education (PE)) and practiced on a handmade manikin, and a control group practiced in a traditional setting with a commercial manikin (Resusci Junior, Laerdal, Norway). All participants practiced for 1 hands-on skill session before performing a post-test on an instrumented CPR manikin. The outcomes including HO-CPR performance variables were compared between groups. The LoCoMan and control groups both achieved acceptable percentage of HO-CPR quality (57% and 71%, p = 0.004). Among 6th-graders, there were no significant differences in HO-CPR quality between LoCoMan 68% and control 71%, p = 0.66. The control group achieved better chest compression depth while the LoCoMan group showed more compressions with adequate chest recoil.     Conclusion: Schoolchildren are able to build and use a low-cost manikin with visual feedback. The integrative learning approach used in this study may be a feasible alternative methodology for training and learning HO-CPR in schools when commercial manikins are not available. What is Known: • Access to CPR training should be universal and independent of age, location, financial means, or access to qualified instructors. • Scientific societies promote the implementation of CPR in schools, so that teachers and schoolchildren can play a multiplier role in their environment, but the gap in CPR learning is related to cultural, economic factors or access to resources and materials. What is New: • LoCoMan may be a useful device for teaching and learning CPR in schoolchildren from the age of 10 and upwards. • LOCOMAN shows that it is feasible and possible to build a low-cost manikin (about €5 in the European Region) and to integrate it into an integrative educational project, and outlines how this could be done. this approach can be an incentive for teachers to attempt teaching CPR, but also for education outside the formal environment.

Usefulness of risk scores and predictors of atrial fibrillation recurrence after elective electrical cardioversion.

INTRODUCTION: Electrical cardioversion (ECV) is a frequently used procedure for restoring sinus rhythm in atrial fibrillation (AF); however, the rate of recurrence is high. The identification of patients at high risk of recurrence could influence the decision-making process. The present study evaluates the predictive value of risk scores in atrial fibrillation recurrence after elective electrical cardioversion. METHODS: Unicentric, observational, and prospective study of adult patients who have undergone an elective ECV as rhythm control strategy between July 2017 and September 2022. RESULTS: From the 283 analyzed patients (mean age 63.95 ± 10.76212, 74.9% male); 99 had paroxysmal AF (35%) and 159 (59%) presented AF recurrence during a follow-up of 6 months. In patients with post-ECV AF recurrence, the period of time from diagnosis until the performance of the procedure was longer (393 ± 891 vs. 195 ± 527, p = .02). No paroxysmal AF (71.3% vs. 57.8%, p = .02) and LA dilatation with >40 mL/m2 (35.9% vs. 23.3%, p = .02) volumes were more frequent within these patients. AF recurrence was more frequent in patients who had previous ECV (HR = 1.32; 95% CI: 1.12-2.35; p = .01) and more than 1 shock to recover sinus rhythm (HR = 1.62; 95% CI: 1.07-1.63; p = .01). The SLAC, ALARMEc, ATLAS, and CAAP-AF scores were statistically significant, although with a moderate predictive capacity for post-ECV recurrence. CONCLUSIONS: Risk scores analyzed showed a modest value predicting AF recurrence after ECV. Previous ECV, and greater difficulty in restoring SR were independent predictors of recurrence.

The uncharacterized Pseudomonas aeruginosa PA4189 is a novel and efficient aminoacetaldehyde dehydrogenase.

Neither the Pseudomonas aeruginosa aldehyde dehydrogenase encoded by the PA4189 gene nor its ortholog proteins have been biochemically or structurally characterized and their physiological function is unknown. We cloned the PA4189 gene, obtained the PA4189 recombinant protein, and studied its structure-function relationships. PA4189 is an NAD+-dependent aminoaldehyde dehydrogenase highly efficient with protonated aminoacetaldehyde and 3-aminopropionaldehyde, which are much more preferred to the non-protonated species as indicated by pH studies. Based on the higher activity with aminoacetaldehyde than with 3-aminopropionaldehyde, we propose that aminoacetaldehyde might be the PA4189 physiological substrate. Even though at the physiological pH of P. aeruginosa cells the non-protonated aminoacetaldehyde species will be predominant, and despite the competition of these species with the protonated ones, PA4189 would very efficiently oxidize ACTAL in vivo, producing glycine. To our knowledge, PA4189 is the first reported enzyme that might metabolize ACTAL, which is considered a dead-end metabolite because its consuming reactions are unknown. The PA4189 crystal structure reported here suggested that the charge and size of the active-site residue Glu457, which narrows the aldehyde-entrance tunnel, greatly define the specificity for small positively charged aldehydes, as confirmed by the kinetics of the E457G and E457Q variants. Glu457 and the residues that determine Glu457 conformation inside the active site are conserved in the PA4189 orthologs, which we only found in proteobacteria species. Also is conserved the PA4189 genomic neighborhood, which suggests that PA4189 participates in an uncharacterized metabolic pathway. Our results open the door to future efforts to characterize this pathway.

Living at the edge: the functional niche occupation of woody plant communities in the submediterranean ecotone.

BACKGROUND AND AIMS: Submediterranean areas are rich ecotones, where slight modifications in environmental conditions can lead to substantial changes in the composition of plant communities. They thus offer an ideal scenario to examine plant community assembly. In this study, we followed a trait-based approach including intraspecific variability to elucidate (1) the relationship between niche occupancy components and species richness, (2) the processes governing the assembly of these communities and (3) the contribution of intraspecific trait variability in shaping the functional trait space. METHODS: We measured eight morphological and chemical traits in 405 individuals across 60 plots located in different forest communities (Mediterranean, Eurosiberian and Mixed) coexisting within a submediterranean ecosystem in central Spain. We calculated three niche occupancy components related to Hutchinson's n-dimensional hypervolumes: the total functional volume of the community, the functional overlap between species within the community and the average functional volume per species, and then used null models to explore the relative importance of habitat filtering, limiting similarity and intraspecific variability as assembly patterns. KEY RESULTS: Both habitat filtering and niche differentiation drive the community assembly of Mediterranean communities, whereas limiting similarity and hierarchical competition shape Eurosiberian communities. Intraspecific responses were mostly explained by shifts in species niches across the functional space (changes in the position of the centroids of hypervolumes). CONCLUSIONS: Different assembly mechanisms govern the structure of Mediterranean, Eurosiberian and Mixed plant communities. Combining niche occupancy components with a null model approach at different spatial scales offers new insights into the mechanisms driving plant community assembly. Consideration of intraspecific variability is key for understanding the mechanisms governing species coexistence in species-rich ecotones.

Supporting SNOMED CT postcoordination with knowledge graph embeddings.

SNOMED CT postcoordination is an underused mechanism that can help to implement advanced systems for the automatic extraction and encoding of clinical information from text. It allows defining non-existing SNOMED CT concepts by their relationships with existing ones. Manually building postcoordinated expressions is a difficult task. It requires a deep knowledge of the terminology and the support of specialized tools that barely exist. In order to support the building of postcoordinated expressions, we have implemented KGE4SCT: a method that suggests the corresponding SNOMED CT postcoordinated expression for a given clinical term. We leverage on the SNOMED CT ontology and its graph-like structure and use knowledge graph embeddings (KGEs). The objective of such embeddings is to represent in a vector space knowledge graph components (e.g. entities and relations) in a way that captures the structure of the graph. Then, we use vector similarity and analogies for obtaining the postcoordinated expression of a given clinical term. We obtained a semantic type accuracy of 98%, relationship accuracy of 90%, and analogy accuracy of 60%, with an overall completeness of postcoordination of 52% for the Spanish SNOMED CT version. We have also applied it to the English SNOMED CT version and outperformed state of the art methods in both, corpus generation for language model training for this task (improvement of 6% for analogy accuracy), and automatic postcoordination of SNOMED CT expressions, with an increase of 17% for partial conversion rate.

Folate stress induces SLX1- and RAD51-dependent mitotic DNA synthesis at the fragile X locus in human cells.

Folate deprivation drives the instability of a group of rare fragile sites (RFSs) characterized by CGG trinucleotide repeat (TNR) sequences. Pathological expansion of the TNR within the FRAXA locus perturbs DNA replication and is the major causative factor for fragile X syndrome, a sex-linked disorder associated with cognitive impairment. Although folate-sensitive RFSs share many features with common fragile sites (CFSs; which are found in all individuals), they are induced by different stresses and share no sequence similarity. It is known that a pathway (termed MiDAS) is employed to complete the replication of CFSs in early mitosis. This process requires RAD52 and is implicated in generating translocations and copy number changes at CFSs in cancers. However, it is unclear whether RFSs also utilize MiDAS and to what extent the fragility of CFSs and RFSs arises by shared or distinct mechanisms. Here, we demonstrate that MiDAS does occur at FRAXA following folate deprivation but proceeds via a pathway that shows some mechanistic differences from that at CFSs, being dependent on RAD51, SLX1, and POLD3. A failure to complete MiDAS at FRAXA leads to severe locus instability and missegregation in mitosis. We propose that break-induced DNA replication is required for the replication of FRAXA under folate stress and define a cellular function for human SLX1. These findings provide insights into how folate deprivation drives instability in the human genome.

COGENT: evaluating the consistency of gene co-expression networks.

SUMMARY: Gene co-expression networks can be constructed in multiple different ways, both in the use of different measures of co-expression, and in the thresholds applied to the calculated co-expression values, from any given dataset. It is often not clear which co-expression network construction method should be preferred. COGENT provides a set of tools designed to aid the choice of network construction method without the need for any external validation data. AVAILABILITY AND IMPLEMENTATION: https://github.com/lbozhilova/COGENT. SUPPLEMENTARY INFORMATION: Supplementary information is available at Bioinformatics online.

Robust gene coexpression networks using signed distance correlation.

MOTIVATION: Even within well studied organisms, many genes lack useful functional annotations. One way to generate such functional information is to infer biological relationships between genes/proteins, using a network of gene coexpression data that includes functional annotations. However, the lack of trustworthy functional annotations can impede the validation of such networks. Hence, there is a need for a principled method to construct gene coexpression networks that capture biological information and are structurally stable even in the absence of functional information. RESULTS: We introduce the concept of signed distance correlation as a measure of dependency between two variables, and apply it to generate gene coexpression networks. Distance correlation offers a more intuitive approach to network construction than commonly used methods such as Pearson correlation and mutual information. We propose a framework to generate self-consistent networks using signed distance correlation purely from gene expression data, with no additional information. We analyse data from three different organisms to illustrate how networks generated with our method are more stable and capture more biological information compared to networks obtained from Pearson correlation or mutual information. SUPPLEMENTARY INFORMATION: Supplementary Information and code are available at Bioinformatics and https://github.com/javier-pardodiaz/sdcorGCN online.

Nanoparticle anisotropy induces sphere-to-cylinder phase transition in block copolymer melts.

Block copolymer nanocomposites including anisotropic nanoparticles have been previously found to co-assemble into complex structures with nanoparticle alignment. Anisotropic nanoparticles with large aspect ratios are found to modify the morphology of block copolymers at modest concentrations, inducing a sphere-to-cylinder phase transition by breaking the local symmetry in the vicinity of a solid particle. This transition takes place over a wide range of NP lengths comparable with the BCP spacing. Controlling the orientation of uniaxial nanoparticles provides additional control over the global orientation of the block copolymer, as previously reported by experiments.

Phosphorylation of S11 in PHR1 negatively controls its transcriptional activity.

Plant responses to phosphate starvation (-Pi) are very well characterized at the biochemical and molecular levels. The expression of thousands of genes is modified under this stress condition, depending on the action of Phosphate starvation response 1 (PHR1). Existing data indicate that neither the PHR1 transcript nor the quantity or localization of its protein increase during nutrient stress, raising the question of how its activity is regulated. Here, we present data showing that SnRK1 kinase is able to phosphorylate some phosphate starvation response proteins (PSRs), including PHR1. Based on a model of the three-dimensional structure of the catalytic subunit SnRK1α1, docking simulations predicted the binding modes of peptides from PHT1;8, PHO1 and PHR1 with SnRK1. PHR1 recombinant protein interacted in vitro with the catalytic subunits SnRK1α1 and SnRK1α2. A BiFC assay corroborated the in vivo interaction between PHR1 and SnRK1α1 in the cytoplasm and nucleus. Analysis of phosphorylated residues suggested the presence of one phosphorylated site containing the SnRK1 motif at S11, and mutation in this residue disrupted the incorporation of 32 P, suggesting that it is a major phosphorylation site. Electrophoretic mobility shift assay results indicated that the binding of PHR1 to P1BS motifs was not influenced by phosphorylation. Importantly, transient expression assays in Arabidopsis protoplasts showed a decrease in PHR1 activity in contrast with the S11A mutant, suggesting a role for Ser11 as a negative regulatory phosphorylation site. Taken together, these findings suggest that phosphorylation of PHR1 at Ser11 is a mechanism to control the PHR1-mediated adaptive response to -Pi.

Egg yolk sialylglycopeptide: purification, isolation and characterization of N-glycans from minor glycopeptide species.

Sialylglycopeptide (SGP) is a readily available naturally occurring glycopeptide obtained from hen egg yolk which is now commercially available. During SGP extraction, other minor glycopeptide species are identified, bearing N-glycan structures that might be of interest, such as asymmetrically branched and triantennary glycans. As the scale of SGP production increases, recovery of minor glycopeptides and their N-glycans can become more feasible. In this paper, we aim to provide structural characterization of the N-glycans derived from these minor glycopeptides.

Effect of self-expandable metal stent on morbidity and mortality and oncological prognosis in malignant colonic obstruction: retrospective analysis of its use as curative and palliative treatment.

INTRODUCTION: Acute gastrointestinal obstruction due to colorectal cancer occurs in 7-30% of cases and is an abdominal emergency that requires urgent decompression. The safety and oncological effect of self-expandable metal stents (SEMS) in these patients remains controversial. This study aimed to evaluate its impact on these variables and compare it with that of emergency surgery (ES). METHODS: Descriptive, retrospective and single-centre study, performed between 2008 and 2015, with follow-up until 2017. One hundred eleven patients with diagnosis of left malignant colonic obstruction were included and divided according to the treatment received: stent as bridge to surgery (SBTS group: 39), palliative stent (PS group: 30) and emergency surgery with curative (ECS group: 34) or palliative intent (EPS group: 8). Treatment was decided by the attending surgeon in charge. RESULTS: Technical and clinical general success rates for colorectal SEMS were 95.7% and 91.3%, respectively, with an associated morbimortality of 23.2%, which was higher in the PS group (p = 0.002). The SBTS group presented a higher laparoscopic approach and primary anastomosis (p < 0.001), as well as a lower colostomy rate than the ECS group (12.8% vs. 40%; p = 0.023). Postoperative morbidity and mortality were significantly lower in the SBTS group compared to the ECS group (41% vs. 67.6%; p = 0.025). Overall survival (OS) and disease-free survival (DFS) were similar between the analysed groups. CONCLUSION: Colonic stent placement is a safe and effective therapeutic alternative to emergency surgery in the management of left-sided malignant colonic obstruction in both curative and palliative fields. It presents a lower postoperative morbimortality and a similar oncological prognosis.

Adsorption of amphiphilic grafted polymers as polymer corrosion inhibitors: insights from mesoscopic simulations.

The homogeneous covering of amphiphillic polymer molecules onto metallic surfaces is of great importance for corrosion inhibitor applications. Lyophillic side chains grafted onto a lyophobic backbone act as anchors that allow the molecule to absorb at the metallic surface preventing the exposure with the solvent. Coarse-grained simulations are used to study the sorption and conformation behaviour of amphiphillic grafted polymers for corrosion inhibition. The backbone insolubility is found to play a key role in the sorption and conformation behaviour in the dilute limit. For finite concentrations, moderate backbone solubility and moderate molecule concentrations achieve optimal surface coverage, while highly a lyophobic backbone leads to bulk-like structures as a consequence of aggregation.

HCA (2-Hydroxy-Docosahexaenoic Acid) Induces Apoptosis and Endoplasmic Reticulum Stress in Pancreatic Cancer Cells.

Pancreatic cancer has a high mortality rate due to its aggressive nature and high metastatic rate. When coupled to the difficulties in detecting this type of tumor early and the lack of effective treatments, this cancer is currently one of the most important clinical challenges in the field of oncology. Melitherapy is an innovative therapeutic approach that is based on modifying the composition and structure of cell membranes to treat different diseases, including cancers. In this context, 2-hydroxycervonic acid (HCA) is a melitherapeutic agent developed to combat pancreatic cancer cells, provoking the programmed cell death by apoptosis of these cells by inducing ER stress and triggering the production of ROS species. The efficacy of HCA was demonstrated in vivo, alone and in combination with gemcitabine, using a MIA PaCa-2 cell xenograft model of pancreatic cancer in which no apparent toxicity was evident. HCA is metabolized by α-oxidation to C21:5n-3 (heneicosapentaenoic acid), which in turn also showed anti-proliferative effect in these cells. Given the unmet clinical needs associated with pancreatic cancer, the data presented here suggest that the use of HCA merits further study as a potential therapy for this condition.

Usefulness of peripheral blood monocyte count to predict relapse in patients with inflammatory bowel disease: a prospective longitudinal cohort study.

BACKGROUND: monocytes play an important role in the pathogenesis of inflammatory bowel disease but data are scarce regarding activity biomarkers, above all in patients under biologic therapies. OBJECTIVE: the aim of this study was to evaluate the value of monocyte measurements in predicting flares in inflammatory bowel disease patients under maintenance treatment with anti-TNF. METHODS: a prospective, observational cohort study was designed. Relapse was defined as a Harvey-Bradshaw score > 4 in Crohn's disease, and a partial Mayo score ≥ 2 in ulcerative colitis. Monocyte concentration was quantified at 4-month intervals for twelve months. A total of 95 consecutive patients were included. Median age was 42 years, 50.5 % were female, and 75 % had Crohn's disease. RESULTS: sixteen months after inclusion, 65 (68.4 %) patients remained in clinical remission. Mean monocyte count preceding a relapse was 563 (standard deviation: 144) compared to 405 (standard deviation: 177) in patients who remained in remission. Final monocyte count was significantly different between relapse and remission in Crohn's disease (0.82; 95 % CI: 0.71-0.90; p < 0.005). According to the multivariate analysis, only monocytes and fecal calprotectin were related to more relapses. CONCLUSION: in conclusion, in inflammatory bowel disease patients under anti-TNF therapy, repeat monocyte counts could help monitor patients, at least in Crohn's disease.

NaTrxh is an essential protein for pollen rejection in Nicotiana by increasing S-RNase activity.

In self-incompatible Solanaceae, the pistil protein S-RNase contributes to S-specific pollen rejection in conspecific crosses, as well as to rejecting pollen from foreign species or whole clades. However, S-RNase alone is not sufficient for either type of pollen rejection. We describe a thioredoxin (Trx) type h from Nicotiana alata, NaTrxh, which interacts with and reduces S-RNase in vitro. Here, we show that expressing a redox-inactive mutant, NaTrxhSS , suppresses both S-specific pollen rejection and rejection of pollen from Nicotiana plumbaginifolia. Biochemical experiments provide evidence that NaTrxh specifically reduces the Cys155 -Cys185 disulphide bond of SC10 -Rnase, resulting in a significant increase of its ribonuclease activity. This reduction and increase in S-RNase activity by NaTrxh helps to explain why S-RNase alone could be insufficient for pollen rejection.