Five million years of Antarctic Circumpolar Current strength variability.

The Antarctic Circumpolar Current (ACC) represents the world's largest ocean-current system and affects global ocean circulation, climate and Antarctic ice-sheet stability1-3. Today, ACC dynamics are controlled by atmospheric forcing, oceanic density gradients and eddy activity4. Whereas palaeoceanographic reconstructions exhibit regional heterogeneity in ACC position and strength over Pleistocene glacial-interglacial cycles5-8, the long-term evolution of the ACC is poorly known. Here we document changes in ACC strength from sediment cores in the Pacific Southern Ocean. We find no linear long-term trend in ACC flow since 5.3 million years ago (Ma), in contrast to global cooling9 and increasing global ice volume10. Instead, we observe a reversal on a million-year timescale, from increasing ACC strength during Pliocene global cooling to a subsequent decrease with further Early Pleistocene cooling. This shift in the ACC regime coincided with a Southern Ocean reconfiguration that altered the sensitivity of the ACC to atmospheric and oceanic forcings11-13. We find ACC strength changes to be closely linked to 400,000-year eccentricity cycles, probably originating from modulation of precessional changes in the South Pacific jet stream linked to tropical Pacific temperature variability14. A persistent link between weaker ACC flow, equatorward-shifted opal deposition and reduced atmospheric CO2 during glacial periods first emerged during the Mid-Pleistocene Transition (MPT). The strongest ACC flow occurred during warmer-than-present intervals of the Plio-Pleistocene, providing evidence of potentially increasing ACC flow with future climate warming.

Substitution of Met-38 to Ile in γ-synuclein found in two patients with amyotrophic lateral sclerosis induces aggregation into amyloid.

α-, ß-, and γ-Synuclein are intrinsically disordered proteins implicated in physiological processes in the nervous system of vertebrates. α-synuclein (αSyn) is the amyloidogenic protein associated with Parkinson's disease and certain other neurodegenerative disorders. Intensive research has focused on the mechanisms that cause αSyn to form amyloid structures, identifying its NAC region as being necessary and sufficient for amyloid assembly. Recent work has shown that a 7-residue sequence (P1) is necessary for αSyn amyloid formation. Although γ-synuclein (γSyn) is 55% identical in sequence to αSyn and its pathological deposits are also observed in association with neurodegenerative conditions, γSyn is resilient to amyloid formation in vitro. Here, we report a rare single nucleotide polymorphism (SNP) in the SNCG gene encoding γSyn, found in two patients with amyotrophic lateral sclerosis (ALS). The SNP results in the substitution of Met38 with Ile in the P1 region of the protein. These individuals also had a second, common and nonpathological, SNP in SNCG resulting in the substitution of Glu110 with Val. In vitro studies demonstrate that the Ile38 variant accelerates amyloid fibril assembly. Contrastingly, Val110 retards fibril assembly and mitigates the effect of Ile38. Substitution of residue 38 with Leu had little effect, while Val retards, and Ala increases the rate of amyloid formation. Ile38 γSyn also results in the formation of γSyn-containing inclusions in cells. The results show how a single point substitution can enhance amyloid formation of γSyn and highlight the P1 region in driving amyloid formation in another synuclein family member.

Recalled through this day but forgotten next week?-retrieval activity predicts durability of partly consolidated memories.

Even partly consolidated memories can be forgotten given sufficient time, but the brain activity associated with durability of episodic memory at different time scales remains unclear. Here, we aimed to identify brain activity associated with retrieval of partly consolidated episodic memories that continued to be remembered in the future. Forty-nine younger (20 to 38 years; 25 females) and 43 older adults (60 to 80 years, 25 females) were scanned with functional magnetic resonance imaging during associative memory retrieval 12 h post-encoding. Twelve hours is sufficient to allow short-term synaptic consolidation as well as early post-encoding replay to initiate memory consolidation. Successful memory trials were classified into durable and transient source memories based on responses from a memory test ~6 d post-encoding. Results demonstrated that successful retrieval of future durable vs. transient memories was supported by increased activity in a medial prefrontal and ventral parietal area. Individual differences in activation as well as the subjective vividness of memories during encoding were positively related to individual differences in memory performance after 6 d. The results point to a unique and novel aspect of brain activity supporting long-term memory, in that activity during retrieval of memories even after 12 h of consolidation contains information about potential for long-term durability.

Targeting calpain-2-mediated junctophilin-2 cleavage delays heart failure progression following myocardial infarction.

Coronary heart disease (CHD) is a prevalent cardiac disease that causes over 370,000 deaths annually in the USA. In CHD, occlusion of a coronary artery causes ischemia of the cardiac muscle, which results in myocardial infarction (MI). Junctophilin-2 (JPH2) is a membrane protein that ensures efficient calcium handling and proper excitation-contraction coupling. Studies have identified loss of JPH2 due to calpain-mediated proteolysis as a key pathogenic event in ischemia-induced heart failure (HF). Our findings show that calpain-2-mediated JPH2 cleavage yields increased levels of a C-terminal cleaved peptide (JPH2-CTP) in patients with ischemic cardiomyopathy and mice with experimental MI. We created a novel knock-in mouse model by removing residues 479-SPAGTPPQ-486 to prevent calpain-2-mediated cleavage at this site. Functional and molecular assessment of cardiac function post-MI in cleavage site deletion (CSD) mice showed preserved cardiac contractility and reduced dilation, reduced JPH2-CTP levels, attenuated adverse remodeling, improved T-tubular structure, and normalized SR Ca2+-handling. Adenovirus mediated calpain-2 knockdown in mice exhibited similar findings. Pulldown of CTP followed by proteomic analysis revealed valosin-containing protein (VCP) and BAG family molecular chaperone regulator 3 (BAG3) as novel binding partners of JPH2. Together, our findings suggest that blocking calpain-2-mediated JPH2 cleavage may be a promising new strategy for delaying the development of HF following MI.

Evolution of glucuronoxylan side chain variability in vascular plants and the compensatory adaptations of cell wall-degrading hydrolases.

Polysaccharide structural complexity not only influences cell wall strength and extensibility but also hinders pathogenic and biotechnological attempts to saccharify the wall. In certain species and tissues, glucuronic acid side groups on xylan exhibit arabinopyranose or galactose decorations whose genetic and evolutionary basis is completely unknown, impeding efforts to understand their function and engineer wall digestibility. Genetics and polysaccharide profiling were used to identify the responsible loci in Arabidopsis and Eucalyptus from proposed candidates, while phylogenies uncovered a shared evolutionary origin. GH30-family endo-glucuronoxylanase activities were analysed by electrophoresis, and their differing specificities were rationalised by phylogeny and structural analysis. The newly identified xylan arabinopyranosyltransferases comprise an overlooked subfamily in the GT47-A family of Golgi glycosyltransferases, previously assumed to comprise mainly xyloglucan galactosyltransferases, highlighting an unanticipated adaptation of both donor and acceptor specificities. Further neofunctionalisation has produced a Myrtaceae-specific xylan galactosyltransferase. Simultaneously, GH30 endo-glucuronoxylanases have convergently adapted to overcome these decorations, suggesting a role for these structures in defence. The differential expression of glucuronoxylan-modifying genes across Eucalyptus tissues, however, hints at further functions. Our results demonstrate the rapid adaptability of biosynthetic and degradative carbohydrate-active enzyme activities, providing insight into plant-pathogen interactions and facilitating plant cell wall biotechnological utilisation.

Photoredox-Catalyzed Preparation of Sulfones Using Bis-Piperidine Sulfur Dioxide - An Underutilized Reagent for SO2 Transfer.

Sulfonyl groups are widely observed in biologically relevant molecules and consequently, SO2 capture is an increasingly attractive method to prepare these sulfonyl-containing compounds given the range of SO2 -surrogates now available as alternatives to using the neat gas. This, along with the advent of photoredox catalysis, has enabled mild radical capture of SO2 to emerge as an effective route to sulfonyl compounds. Here we report a photoredox-catalyzed cross-electrophile sulfonylation of aryl and alkyl bromides making use of a previously under-used amine-SO2 surrogate; bis(piperidine) sulfur dioxide (PIPSO). A broad selection of alkyl and aryl bromides were photocatalytically converted to their corresponding sulfinates and then trapped with various electrophiles in a one-pot multistep procedure to prepare sulfones and sulfonamides.

Assessing regional intracortical myelination in schizophrenia spectrum and bipolar disorders using the optimized T1w/T2w-ratio.

BACKGROUND: Dysmyelination could be part of the pathophysiology of schizophrenia spectrum (SCZ) and bipolar disorders (BPD), yet few studies have examined myelination of the cerebral cortex. The ratio of T1- and T2-weighted magnetic resonance images (MRI) correlates with intracortical myelin. We investigated the T1w/T2w-ratio and its age trajectories in patients and healthy controls (CTR) and explored associations with antipsychotic medication use and psychotic symptoms. METHODS: Patients with SCZ (n = 64; mean age = 30.4 years, s.d. = 9.8), BPD (n = 91; mean age 31.0 years, s.d. = 10.2), and CTR (n = 155; mean age = 31.9 years, s.d. = 9.1) who participated in the TOP study (NORMENT, University of Oslo, Norway) were clinically assessed and scanned using a General Electric 3 T MRI system. T1w/T2w-ratio images were computed using an optimized pipeline with intensity normalization and field inhomogeneity correction. Vertex-wise regression models were used to compare groups and examine group × age interactions. In regions showing significant differences, we explored associations with antipsychotic medication use and psychotic symptoms. RESULTS: No main effect of diagnosis was found. However, age slopes of the T1w/T2w-ratio differed significantly between SCZ and CTR, predominantly in frontal and temporal lobe regions: Lower T1w/T2w-ratio values with higher age were found in CTR, but not in SCZ. Follow-up analyses revealed a more positive age slope in patients who were using antipsychotics and patients using higher chlorpromazine-equivalent doses. CONCLUSIONS: While we found no evidence of reduced intracortical myelin in SCZ or BPD relative to CTR, different regional age trajectories in SCZ may suggest a promyelinating effect of antipsychotic medication.

Effects of dietary nitrate supplementation on oral health and associated markers of systemic health: a systematic review.

Poor oral health can impact an individual's ability to eat and has been associated with an increased risk of non-communicable diseases. While the benefits of nitrate consumption on oral health were first proposed more than 20 years ago, no systematic review has been published examining effects of dietary nitrate on oral health. This systematic review investigated the effects of dietary nitrate on markers of oral health in vivo in randomized controlled trials (RCTs). Five databases (PubMed, The Cochrane Library, CINAHL, MEDLINE, and SPORTDiscus) were searched from inception until March 2023. Nine articles reporting data on 284 participants were included. Dietary nitrate was provided via beetroot juice in most studies. The duration of the interventions ranged from one day to six weeks. Dietary nitrate supplementation increased the relative abundance of several individual bacterial genera including Neisseria and Rothia. Dietary nitrate supplementation increased salivary pH and decreased salivary acidification following consumption of a sugar-sweetened beverage. Furthermore, dietary nitrate supplementation resulted in a decrease in the gingival inflammation index. The results of this systematic review suggest that dietary nitrate could represent a potential nutritional strategy to positively modify oral health by impacting the oral microbiome, altering salivary pH, and minimizing gingival inflammation.

The Mediterranean diet is not associated with neuroimaging or cognition in middle-aged adults: a cross-sectional analysis of the PREVENT dementia programme.

BACKGROUND AND PURPOSE: The Mediterranean diet (MedDiet) has been associated with reduced dementia incidence in several studies. It is important to understand if diet is associated with brain health in midlife, when Alzheimer's disease and related dementias are known to begin. METHODS: This study used data from the PREVENT dementia programme. Three MedDiet scores were created (the Pyramid, Mediterranean Diet Adherence Screener [MEDAS] and MEDAS continuous) from a self-reported food frequency questionnaire. Primary outcomes were hippocampal volume and cube-transformed white matter hyperintensity volume. Secondary outcomes included cornu ammonis 1 and subiculum hippocampal subfield volumes, cortical thickness and measures of cognition. Sex-stratified analyses were run to explore differential associations between diet and brain health by sex. An exploratory path analysis was conducted to study if any associations between diet and brain health were mediated by cardiovascular risk factors for dementia. RESULTS: In all, 504 participants were included in this analysis, with a mean Pyramid score of 8.10 (SD 1.56). There were no significant associations between any MedDiet scoring method and any of the primary or secondary outcomes. There were no differences by sex in any analyses and no significant mediation between the Pyramid score and global cognition by cardiovascular risk factors. CONCLUSIONS: Overall, this study did not find evidence for an association between the MedDiet and either neuroimaging or cognition in a midlife population study. Future work should investigate associations between the MedDiet and Alzheimer's disease and related dementias biomarkers as well as functional neuroimaging in a midlife population.

Nitro-sulfinate Reductive Coupling to Access (Hetero)aryl Sulfonamides.

A method to assemble (hetero)aryl sulfonamides via the reductive coupling of aryl sulfinates and nitroarenes is reported. Various reducing conditions with sodium bisulfite and with or without tin(II) chloride in DMSO were developed using an ultrasound bath to improve reaction homogeneity and mixing. A range of (hetero)aryl sulfonamides bearing a selection of functional groups were prepared, and the mechanism of the transformation was investigated. These investigations have led us to propose the formation of nitrosoarene intermediates, which were established via an independent molecular coupling strategy.

Higher plant-derived nitrate intake is associated with lower odds of frailty in a cross-sectional study of community-dwelling older women.

PURPOSE: Dietary nitrate intake is inversely related to numerous contributors towards frailty, including cardiovascular disease and poor physical function. Whether these findings extend to frailty remain unknown. We investigated if habitual nitrate intake, derived from plants or animal-based foods, was cross-sectionally associated with frailty in women. METHODS: Community-dwelling older Australian women (n = 1390, mean age 75.1 ± 2.7 years) completed a validated semi-quantitative food frequency questionnaire (FFQ). Nitrate concentrations in food were obtained from international nitrate databases. We adopted the Rockwood frailty index (FI) of cumulative deficits comprising 33 variables across multiple health domains (scored 0 to 1), which predicts increased hospitalisation and mortality risk. A FI ≥ 0.25 indicated frailty. Cross-sectional associations between nitrate intake (total plant and animal nitrate, separately) and frailty were analysed using multivariable-adjusted logistic regression models (including lifestyle factors), as part of restricted cubic splines. RESULTS: A non-linear inverse relationship was observed between total plant nitrate intake and frailty. Compared to women with the lowest plant nitrate intake (Quartile [Q]1), women with greater intakes in Q2 (OR 0.69 95%CI 0.56-0.84), Q3 (OR 0.67 95%CI 0.50-0.90) and Q4 (OR 0.66 95%CI 0.45-0.98) had lower odds for frailty. A nadir in the inverse association was observed once intakes reached ~ 64 mg/d (median Q2). No relationship was observed between total animal nitrate and frailty. CONCLUSION: Community-dwelling older women consuming low amounts of plant-derived nitrate were more likely to present with frailty. Consuming at least one daily serving (~ 75 g) of nitrate-rich green leafy vegetables may be beneficial in preventing frailty.

Nutrition for dementia prevention: a state of the art update for clinicians.

BACKGROUND AND OBJECTIVES: Dementia prevalence continues to rise. It is therefore essential to provide feasible and effective recommendations to encourage healthy brain ageing and reduce dementia risk across the population. Appropriate nutrition represents a potential strategy to mitigate dementia risk and could be recommended by clinicians as part of mid-life health checks and other health initiatives to reduce dementia prevalence. The purpose of this review is to provide a clinician-focused update on the current state of the knowledge on nutrition and dementia prevention. METHODS: Narrative review. RESULTS: Strong evidence exists to support the consumption of healthy, plant-based dietary patterns (e.g. Mediterranean, MIND or Nordic diet) for maintaining cognitive function and reducing dementia risk in later life and is supported by dementia prevention guideline from leading public health bodies (e.g. World Health Organization). Emerging evidence suggests potential cognitive benefits of consuming specific nutrients/foods (e.g. n-3 fatty acids or fish, flavonols and B-vitamins) and multi-nutrient compounds (e.g. Fortasyn Connect). Challenges and opportunities for integrating nutritional/dietary interventions for dementia prevention into clinical practice are explored in this review. CONCLUSIONS: Appropriate nutrition represents an important factor to help facilitate healthy cognitive ageing and allay dementia risk. The information provided in this article can help clinicians provide informed opinions on appropriate nutritional strategies as part of mid-life Health Checks and other risk reduction initiatives.

SENECA study: staging endometrial cancer based on molecular classification.

OBJECTIVE: Management of endometrial cancer is advancing, with accurate staging crucial for guiding treatment decisions. Understanding sentinel lymph node (SLN) involvement rates across molecular subgroups is essential. To evaluate SLN involvement in early-stage (International Federation of Gynecology and Obstetrics 2009 I-II) endometrial cancer, considering molecular subtypes and new European Society of Gynaecological Oncology (ESGO) risk classification. METHODS: The SENECA study retrospectively reviewed data from 2139 women with stage I-II endometrial cancer across 66 centers in 16 countries. Patients underwent surgery with SLN assessment following ESGO guidelines between January 2021 and December 2022. Molecular analysis was performed on pre-operative biopsies or hysterectomy specimens. RESULTS: Among the 2139 patients, the molecular subgroups were as follows: 272 (12.7%) p53 abnormal (p53abn, 1191 (55.7%) non-specific molecular profile (NSMP), 581 (27.2%) mismatch repair deficient (MMRd), 95 (4.4%) POLE mutated (POLE-mut). Tracer diffusion was detected in, at least one side, in 97.2% of the cases; with a bilateral diffusion observed in 82.7% of the cases. By ultrastaging (90.7% of the cases) or one-step nucleic acid amplification (198 (9.3%) of the cases), 205 patients were identified with affected sentinel lymph nodes, representing 9.6% of the sample. Of these, 139 (67.8%) had low-volume metastases (including micrometastases, 42.9%; and isolated tumor cells, 24.9%) while 66 (32.2%) had macrometastases. Significant differences in SLN involvement were observed between molecular subtypes, with p53abn and MMRd groups having the highest rates (12.50% and 12.40%, respectively) compared with NSMP (7.80%) and POLE-mut (6.30%), (p=0.004); (p53abn, OR=1.69 (95% CI 1.11 to 2.56), p=0.014; MMRd, OR=1.67 (95% CI 1.21 to 2.31), p=0.002). Differences were also noted among ESGO risk groups (2.84% for low-risk patients, 6.62% for intermediate-risk patients, 21.63% for high-intermediate risk patients, and 22.51% for high-risk patients; p<0.001). CONCLUSIONS: Our study reveals significant differences in SLN involvement among patients with early-stage endometrial cancer based on molecular subtypes. This underscores the importance of considering molecular characteristics for accurate staging and optimal management decisions.

Cyanoacrylate versus suture as flap closure methods in mandibular third molar surgery: a split-mouth randomized controlled clinical study.

BACKGROUND: Sutures have been the standard flap closure method of choice following mandibular third molar surgery but can lead to some complications. Tissue adhesives, including cyanoacrylate, have emerged as alternative flap closure method in this surgery to overcome such drawbacks. However, limited clinical trials can be found. Therefore, the aim of this clinical study was to compare two methods of flap closure in mandibular third molar surgery, cyanoacrylate and 4/0 silk sutures, by assessing post-operative outcome measures (pain, swelling, trismus, and healing) and patient-reported outcome measures (PROMs). MATERIAL AND METHODS: A randomized split-mouth clinical trial was designed, in which mandibular third molar (M3M) extractions were performed, where the control side flap was closed with 4/0 silk sutures and the test side flap with cyanoacrylate. Swelling, pain, trismus, healing, and PROMs were recorded post-operatively. These variables were analyzed by means of the nonparametric Mann-Whitney U test, using SPSS statistical software version 28.0.0 (IBM® SPSS®, Chicago, IL, USA). For all results, a 95% confidence interval was recorded (significance level p < 0.05, two-tailed). RESULTS: A total of 17 patients were recruited and 34 mandibular third molar extractions were performed. No statistically significant differences were found in terms of swelling, pain, trismus, healing, and PROMs between both groups (p<0.05). CONCLUSIONS: No statistically significant differences were found between flap closure with 4/0 silk sutures and cyanoacrylate, in terms of surgical post-operative outcomes and PROMs. However, further studies with larger sample sizes are required to be able to affirm it with greater certainty.

Protocol for generation of and high-throughput drug testing with patient-derived colorectal cancer organoids.

Drug sensitivity testing of patient-derived tumor organoids (PDTOs) is a promising tool for personalizing cancer treatment. Here, we present a protocol for generation of and high-throughput drug testing with PDTOs. We describe detailed steps for PDTO establishment from colorectal cancer tissues, preparation of PDTOs for high-throughput drug testing, and quantification of drug testing results using image analysis. This protocol provides a standardized workflow for PDTO testing of standard-of-care therapies, along with exploring the activity of new agents, for translational research. For complete details on the use and execution of this protocol, please refer to Tan et al.1.

Three-dimensional assessment of image distortion induced by active cardiac implants in 3.0T CMR.

CMR at 3.0T in the presence of active cardiac implants remains a challenge due to susceptibility artifacts. Beyond a signal void that cancels image information, magnetic field inhomogeneities may cause distorted appearances of anatomical structures. Understanding influencing factors and the extent of distortion are a first step towards optimizing the image quality of CMR with active implants at 3.0T. All measurements were obtained at a clinical 3.0T scanner. An in-house designed phantom with a 3D cartesian grid of water filled spheres was used to analyze the distortion caused by four representative active cardiac devices (cardiac loop recorder, pacemaker, 2 ICDs). For imaging a gradient echo (3D-TFE) sequence and a turbo spin echo (2D-TSE) sequence were used. The work defines metrics to quantify the different features of distortion such as changes in size, location and signal intensity. It introduces a specialized segmentation technique based on a reaction-diffusion-equation. The distortion features are dependent on the amount of magnetic material in the active implants and showed a significant increase when measured with the 3D TFE compared to the 2D TSE. This work presents a quantitative approach for the evaluation of image distortion at 3.0T caused by active cardiac implants and serves as foundation for both further optimization of sequences and devices but also for planning of imaging procedures.

Characterisation of the in-vivo miRNA landscape in Drosophila ribonuclease mutants reveals Pacman-mediated regulation of the highly conserved let-7 cluster during apoptotic processes.

The control of gene expression is a fundamental process essential for correct development and to maintain homeostasis. Many post-transcriptional mechanisms exist to maintain the correct levels of each RNA transcript within the cell. Controlled and targeted cytoplasmic RNA degradation is one such mechanism with the 5'-3' exoribonuclease Pacman (XRN1) and the 3'-5' exoribonuclease Dis3L2 playing crucial roles. Loss of function mutations in either Pacman or Dis3L2 have been demonstrated to result in distinct phenotypes, and both have been implicated in human disease. One mechanism by which gene expression is controlled is through the function of miRNAs which have been shown to be crucial for the control of almost all cellular processes. Although the biogenesis and mechanisms of action of miRNAs have been comprehensively studied, the mechanisms regulating their own turnover are not well understood. Here we characterise the miRNA landscape in a natural developing tissue, the Drosophila melanogaster wing imaginal disc, and assess the importance of Pacman and Dis3L2 on the abundance of miRNAs. We reveal a complex landscape of miRNA expression and show that whilst a null mutation in dis3L2 has a minimal effect on the miRNA expression profile, loss of Pacman has a profound effect with a third of all detected miRNAs demonstrating Pacman sensitivity. We also reveal a role for Pacman in regulating the highly conserved let-7 cluster (containing miR-100, let-7 and miR-125) and present a genetic model outlining a positive feedback loop regulated by Pacman which enhances our understanding of the apoptotic phenotype observed in Pacman mutants.

Continuous flow synthesis enabling reaction discovery.

This article defines the role that continuous flow chemistry can have in new reaction discovery, thereby creating molecular assembly opportunities beyond our current capabilities. Most notably the focus is based upon photochemical, electrochemical and temperature sensitive processes where continuous flow methods and machine assisted processing can have significant impact on chemical reactivity patterns. These flow chemical platforms are ideally placed to exploit future innovation in data acquisition, feed-back and control through artificial intelligence (AI) and machine learning (ML) techniques.