Standardisation in Paediatric Echocardiography Reporting and Critical Interpretation of Measurements, Functional Parameters and Prediction Scores. A Clinical Consensus Statement of the European Association of Cardiovascular Imaging (EACVI) of the ESC and the Association for European Paediatric and Congenital Cardiology (AEPC).

This document has been developed to provide a guide for basic and advanced reporting in pediatric echocardiography. Furthermore, it aims to help clinicians in the interpretation of echocardiographic measurements and functional data for estimating the severity of disease in different pediatric age groups. The following topics will be reviewed and discussed in the present document: i) the general principle in constructing a pediatric echocardiography report, ii) the basic elements to be included, iii) the potential and limitation of currently employed tools used for disease severity quantification during paediatric reporting. A guide for the interpretation of Z-scores will be provided. Use and interpretation of parameters employed for quantification of ventricular systolic function will be discussed. Difficulties in the adoption of adult parameters for the study of diastolic function and valve defects at different ages, pressure and loading conditions will be outlined, with pitfalls for the assessment listed. A guide for careful use of prediction scores for complex congenital heart disease will be provided. Examples of basic and advanced (disease specific) formats for reporting in paediatric echocardiography will be provided. This document should serve as a comprehensive guide to i) structure a comprehensive paediatric echocardiographic report, ii) identify the basic morphological details, measures, and functional parameters to be included during echocardiographic reporting, and iii) correctly interpret measurements and functional data for estimating disease severity.

Optimizing extraction methods by a comprehensive experimental approach and characterizing polyphenol compositions of Ecklonia radiata.

Brown seaweed Ecklonia radiata harbors valuable polyphenols, notably phlorotannins, prized for their health benefits. This study optimized phlorotannin extraction via conventional solvent extraction and ultrasound-assisted extraction methods, utilizing variable concentrations of ethanol. Employing fractional factorial designs, key variables were identified. Steepest ascent/descent method and central composite rotatable designs refined optimal conditions, enhancing phlorotannin and polyphenol yields, and antioxidant capacities. Under optimized conditions, phlorotannin contents reached 2.366 ± 0.01 and 2.596 ± 0.04 PGE mg/g, total polyphenol contents peaked at 10.223 ± 0.03 and 10.836 ± 0.02 GAE mg/g. Robust antioxidant activity was observed: DPPH and OH radical scavenging capacities measured 27.891 ± 0.06 and 17.441 ± 0.08 TE mg/g, and 37.498 ± 1.12 and 49.391 ± 0.82 TE mg/g, respectively. Reducing power capacities surged to 9.016 ± 0.02 and 28.110 ± 0.10 TE mg/g. Liquid chromatography-mass spectrometry (LC-MS) and high-performance liquid chromatography (HPLC) analyses revealed enriched antioxidant compounds. Variations in polyphenol profiles were noted, potentially influencing antioxidant capacity nuances. This study illuminated the potential of E. radiata potential as a polyphenol source and offers optimized extraction methods poised to benefit various industries.

KRAS-mediated upregulation of CIP2A promotes suppression of PP2A-B56α to initiate pancreatic cancer development.

Oncogenic mutations in KRAS are present in approximately 95% of patients diagnosed with pancreatic ductal adenocarcinoma (PDAC) and are considered the initiating event of pancreatic intraepithelial neoplasia (PanIN) precursor lesions. While it is well established that KRAS mutations drive the activation of oncogenic kinase cascades during pancreatic oncogenesis, the effects of oncogenic KRAS signaling on regulation of phosphatases during this process is not fully appreciated. Protein Phosphatase 2A (PP2A) has been implicated in suppressing KRAS-driven cellular transformation. However, low PP2A activity is observed in PDAC cells compared to non-transformed cells, suggesting that suppression of PP2A activity is an important step in the overall development of PDAC. In the current study, we demonstrate that KRASG12D induces the expression of both an endogenous inhibitor of PP2A activity, Cancerous Inhibitor of PP2A (CIP2A), and the PP2A substrate, c-MYC. Consistent with these findings, KRASG12D sequestered the specific PP2A subunit responsible for c-MYC degradation, B56α, away from the active PP2A holoenzyme in a CIP2A-dependent manner. During PDAC initiation in vivo, knockout of B56α promoted KRASG12D tumorigenesis by accelerating acinar-to-ductal metaplasia (ADM) and the formation of PanIN lesions. The process of ADM was attenuated ex vivo in response to pharmacological re-activation of PP2A utilizing direct small molecule activators of PP2A (SMAPs). Together, our results suggest that suppression of PP2A-B56α through KRAS signaling can promote the MYC-driven initiation of pancreatic tumorigenesis.

Climate change introduces threatened killer whale populations and conservation challenges to the Arctic.

The Arctic is the fastest-warming region on the planet, and the lengthening ice-free season is opening Arctic waters to sub-Arctic species such as the killer whale (Orcinus orca). As apex predators, killer whales can cause significant ecosystem-scale changes. Setting conservation priorities for killer whales and their Arctic prey species requires knowledge of their evolutionary history and demographic trajectory. Using whole-genome resequencing of 24 killer whales sampled in the northwest Atlantic, we first explored the population structure and demographic history of Arctic killer whales. To better understand the broader geographic relationship of these Arctic killer whales to other populations, we compared them to a globally sampled dataset. Finally, we assessed threats to Arctic killer whales due to anthropogenic harvest by reviewing the peer-reviewed and gray literature. We found that there are two highly genetically distinct, non-interbreeding populations of killer whales using the eastern Canadian Arctic. These populations appear to be as genetically different from each other as are ecotypes described elsewhere in the killer whale range; however, our data cannot speak to ecological differences between these populations. One population is newly identified as globally genetically distinct, and the second is genetically similar to individuals sampled from Greenland. The effective sizes of both populations recently declined, and both appear vulnerable to inbreeding and reduced adaptive potential. Our survey of human-caused mortalities suggests that harvest poses an ongoing threat to both populations. The dynamic Arctic environment complicates conservation and management efforts, with killer whales adding top-down pressure on Arctic food webs crucial to northern communities' social and economic well-being. While killer whales represent a conservation priority, they also complicate decisions surrounding wildlife conservation and resource management in the Arctic amid the effects of climate change.

The lived experience of military beneficiaries with amputations at the hip and pelvic level.

BACKGROUND: Hip- and pelvic-level amputations are devastating injuries that drastically alter patient function and quality of life. This study examined the experience of military beneficiaries with a hip- or pelvic-level amputation to better characterize their challenges and specific needs and to optimize treatment in the future. METHODS: We conducted a retrospective review of the Military Health System and identified 118 patients with a history of one or more amputation(s) at the hip or pelvic level between October 2001 and September 2017. Surviving participants (n = 97) were mailed a letter which explained the details of the study and requested participation in a telephonic interview. A total of six individuals (one female, five males) participated in structured interviews. RESULTS: The study group included four participants with hip disarticulations and two participants with hemipelvectomies (one internal, one external). All six participants reported significant challenges with activities related to prosthetic use, mobility, residual limb health, pain, gastrointestinal and genitourinary function, psychiatric health, and sexual function. CONCLUSIONS: These interviews highlight the unique needs of individuals with hip- and pelvic-level amputations and may improve access to higher echelons of care that would enhance the function and quality of life for these participants.

'I Do It All Alone': The Burdens and Benefits of Being Diagnosed With, and Treated for, Colorectal Cancer During the Covid-19 Pandemic.

INTRODUCTION: The Covid-19 pandemic dramatically altered the way cancer care services were accessed and delivered, including for colorectal cancer (CRC). In the United Kingdom, patients were discouraged from presenting in primary care, many consultations took place remotely, investigative procedures and screening programmes were temporarily suspended, and fewer operations and treatments were delivered. People had to face the practical consequences of having cancer during a pandemic and navigate never before seen pathways, often alone. We examined the experience of being diagnosed and treated for CRC during the pandemic, and the implications of this on people's cancer journeys. METHODS: Semi-structured interviews were undertaken with people diagnosed with CRC during the Covid-19 pandemic (January 2020-May 2021), in the North East of England. An iterative topic guide was used during interviews, which took place remotely (telephone or Zoom), were audio recorded, pseudo-anonymised and transcribed. Initial transcripts were independently coded by two researchers, and a code 'bank' developed for application across transcripts. Development of themes and overarching analytical constructs was undertaken collaboratively by the research team. RESULTS: Interviews were conducted with 19 participants, analysed and four key themes identified: (1) The relative threats of Covid-19 and Cancer were not comparable, with cancer seen as posing a far greater risk than Covid-19; (2) Remote consultations were problematic, affecting patients' abilities to build rapport and trust with clinicians, assess nonverbal communication, and feel able to disclose, comprehend and retain information; (3) Stoma follow-up care was seen to be lacking, with long wait times for stoma reversal experienced by some; Finally, (4) Being alone during consultations negatively impacted some peoples' abilities to absorb information, and left them without the support of loved ones at an emotionally vulnerable time. However, some participants preferred being alone at certain points in their pathways, including receiving a diagnosis, and most frequently when receiving in-patient treatment. CONCLUSION: Being alone brought unexpected benefits, absolving people from undertaking emotions work for others, and instead focus on their recovery, however, remote consultations negatively impacted patients' experiences. This study highlights the complex benefits and burdens of pandemic-located cancer journeys, including how these shifted at different points across cancer pathways. PATIENT OR PUBLIC CONTRIBUTION: Lorraine Angell, a cancer survivor, has been central to this study from idea conception, contributing to: development of study focus and design; securing funding; production of patient-facing materials; development of interview topic guides; analysis and interpretation of data; and drafting of key findings and manuscripts.

Conformational Preferences of the Non-Canonical Amino Acids (2S,4S)-5-Fluoroleucine, (2S,4R)-5-Fluoroleucine, and 5,5'-Difluoroleucine in a Protein.

Proteins produced with leucine analogues, where CH2F groups substitute specific methyl groups, can readily be probed by 19F NMR spectroscopy. As CF and CH groups are similar in hydrophobicity and size, fluorinated leucines are expected to cause minimal structural perturbation, but the impact of fluorine on the rotational freedom of CH2F groups is unclear. We present high-resolution crystal structures of Escherichia coli peptidyl-prolyl cis-trans isomerase B (PpiB) prepared with uniform high-level substitution of leucine by (2S,4S)-5-fluoroleucine, (2S,4R)-5-fluoroleucine, or 5,5'-difluoroleucine. Apart from the fluorinated leucine residues, the structures show complete structural conservation of the protein backbone and the amino acid side chains except for a single isoleucine side chain located next to a fluorine atom in the hydrophobic core of the protein. The carbon skeletons of the fluorinated leucine side chains are also mostly conserved. The CH2F groups show a strong preference for staggered rotamers and often appear locked into single rotamers. Substitution of leucine CH3 groups for CH2F groups is thus readily tolerated in the three-dimensional (3D) structure of a protein, and the rotation of CH2F groups can be halted at cryogenic temperatures.

Racial and Ethnic Disparities in All-Cause and Cause-Specific Mortality Among US Youth.

Importance: Mortality rates in US youth have increased in recent years. An understanding of the role of racial and ethnic disparities in these increases is lacking. Objective: To compare all-cause and cause-specific mortality trends and rates among youth with Hispanic ethnicity and non-Hispanic American Indian or Alaska Native, Asian or Pacific Islander, Black, and White race. Design, Setting, and Participants: This cross-sectional study conducted temporal analysis (1999-2020) and comparison of aggregate mortality rates (2016-2020) for youth aged 1 to 19 years using US Centers for Disease Control and Prevention Wide-Ranging Online Data for Epidemiologic Research database. Data were analyzed from June 30, 2023, to January 17, 2024. Main Outcomes and Measures: Pooled, all-cause, and cause-specific mortality rates per 100 000 youth (hereinafter, per 100 000) for leading underlying causes of death were compared. Injuries were classified by mechanism and intent. Results: Between 1999 and 2020, there were 491 680 deaths among US youth, including 8894 (1.8%) American Indian or Alaska Native, 14 507 (3.0%) Asian or Pacific Islander, 110 154 (22.4%) Black, 89 251 (18.2%) Hispanic, and 267 452 (54.4%) White youth. Between 2016 and 2020, pooled all-cause mortality rates were 48.79 per 100 000 (95% CI, 46.58-51.00) in American Indian or Alaska Native youth, 15.25 per 100 000 (95% CI, 14.75-15.76) in Asian or Pacific Islander youth, 42.33 per 100 000 (95% CI, 41.81-42.86) in Black youth, 21.48 per 100 000 (95% CI, 21.19-21.77) in Hispanic youth, and 24.07 per 100 000 (95% CI, 23.86-24.28) in White youth. All-cause mortality ratios compared with White youth were 2.03 (95% CI, 1.93-2.12) among American Indian or Alaska Native youth, 0.63 (95% CI, 0.61-0.66) among Asian or Pacific Islander youth, 1.76 (95% CI, 1.73-1.79) among Black youth, and 0.89 (95% CI, 0.88-0.91) among Hispanic youth. From 2016 to 2020, the homicide rate in Black youth was 12.81 (95% CI, 12.52-13.10) per 100 000, which was 10.20 (95% CI, 9.75-10.66) times that of White youth. The suicide rate for American Indian or Alaska Native youth was 11.37 (95% CI, 10.30-12.43) per 100 000, which was 2.60 (95% CI, 2.35-2.86) times that of White youth. The firearm mortality rate for Black youth was 12.88 (95% CI, 12.59-13.17) per 100 000, which was 4.14 (95% CI, 4.00-4.28) times that of White youth. American Indian or Alaska Native youth had a firearm mortality rate of 6.67 (95% CI, 5.85-7.49) per 100 000, which was 2.14 (95% CI, 1.88- 2.43) times that of White youth. Black youth had an asthma mortality rate of 1.10 (95% CI, 1.01-1.18) per 100 000, which was 7.80 (95% CI, 6.78-8.99) times that of White youth. Conclusions and Relevance: In this study, racial and ethnic disparities were observed for almost all leading causes of injury and disease that were associated with recent increases in youth mortality rates. Addressing the increasing disparities affecting American Indian or Alaska Native and Black youth will require efforts to prevent homicide and suicide, especially those events involving firearms.

Intraocular Immune Response in Human Uveitis: Time to Look Beyond Animal Models.

PURPOSE: To review the current and future approaches to investigating the intraocular immune response in human uveitis. DESIGN: Perspective. METHODS: Review of currently available methods for investigating the immune response in ocular tissues and fluids in patients with intraocular inflammation/ uveitis. The advantages and disadvantages of human studies have been compared to those of animal models of uveitis. RESULTS: Animal models, while being excellent tools for mechanistic studies, do not replicate the clinical and immunologic heterogeneity of human uveitis. Opportunities for immunological studies in human uveitis are mostly limited to histological studies, or sampling of intraocular fluids and peripheral blood. Histopathological studies can be enhanced by revisiting published historical data, tissue repositories, or autopsy specimens. Intraocular fluids can be investigated by a variety of techniques. Among these, flow cytometry and single-cell RNA sequencing (scRNAseq) provide single-cell resolution. While the current technology is costly and labor-intensive, scRNAseq is less limited by the low cellular yield from intraocular fluids and allows unbiased immune profiling enabling discovery of new cellular subsets. Immunological phenotypes uncovered from human data can be further investigated in animal studies. CONCLUSION: The diversity of the intraocular immune response in uveitis patients remains challenging but can be studied by multiple techniques including histopathology, flow cytometry, and scRNAseq. Human data can be combined with animal studies for translating uveitis research into novel therapies.

Identification and Characterization of a Bacterial Periplasmic Solute Binding Protein That Binds l-Amino Acid Amides.

Periplasmic solute-binding proteins (SBPs) are key ligand recognition components of bacterial ATP-binding cassette (ABC) transporters that allow bacteria to import nutrients and metabolic precursors from the environment. Periplasmic SBPs comprise a large and diverse family of proteins, of which only a small number have been empirically characterized. In this work, we identify a set of 610 unique uncharacterized proteins within the SBP_bac_5 family that are found in conserved operons comprising genes encoding (i) ABC transport systems and (ii) putative amidases from the FmdA_AmdA family. From these uncharacterized SBP_bac_5 proteins, we characterize a representative periplasmic SBP from Mesorhizobium sp. A09 (MeAmi_SBP) and show that MeAmi_SBP binds l-amino acid amides but not the corresponding l-amino acids. An X-ray crystal structure of MeAmi_SBP bound to l-serinamide highlights the residues that impart distinct specificity for l-amino acid amides and reveals a structural Ca2+ binding site within one of the lobes of the protein. We show that the residues involved in ligand and Ca2+ binding are conserved among the 610 SBPs from experimentally uncharacterized FmdA_AmdA amidase-associated ABC transporter systems, suggesting these homologous systems are also likely to be involved in the sensing, uptake, and metabolism of l-amino acid amides across many Gram-negative nitrogen-fixing soil bacteria. We propose that MeAmi_SBP is involved in the uptake of such solutes to supplement pathways such as the citric acid cycle and the glutamine synthetase-glutamate synthase pathway. This work expands our currently limited understanding of microbial interactions with l-amino acid amides and bacterial nitrogen utilization.

Measuring protective efficacy and quantifying the impact of drug resistance: A novel malaria chemoprevention trial design and methodology.

BACKGROUND: Recently revised WHO guidelines on malaria chemoprevention have opened the door to more tailored implementation. Countries face choices on whether to replace old drugs, target additional age groups, and adapt delivery schedules according to local drug resistance levels and malaria transmission patterns. Regular routine assessment of protective efficacy of chemoprevention is key. Here, we apply a novel modelling approach to aid the design and analysis of chemoprevention trials and generate measures of protection that can be applied across a range of transmission settings. METHODS AND FINDINGS: We developed a model of genotype-specific drug protection, which accounts for underlying risk of infection and circulating genotypes. Using a Bayesian framework, we fitted the model to multiple simulated scenarios to explore variations in study design, setting, and participant characteristics. We find that a placebo or control group with no drug protection is valuable but not always feasible. An alternative approach is a single-arm trial with an extended follow-up (>42 days), which allows measurement of the underlying infection risk after drug protection wanes, as long as transmission is relatively constant. We show that the currently recommended 28-day follow-up in a single-arm trial results in low precision of estimated 30-day chemoprevention efficacy and low power in determining genotype differences of 12 days in the duration of protection (power = 1.4%). Extending follow-up to 42 days increased precision and power (71.5%) in settings with constant transmission over this time period. However, in settings of unstable transmission, protective efficacy in a single-arm trial was overestimated by 24.3% if recruitment occurred during increasing transmission and underestimated by 15.8% when recruitment occurred during declining transmission. Protective efficacy was estimated with greater precision in high transmission settings, and power to detect differences by resistance genotype was lower in scenarios where the resistant genotype was either rare or too common. CONCLUSIONS: These findings have important implications for the current guidelines on chemoprevention efficacy studies and will be valuable for informing where these studies should be optimally placed. The results underscore the need for a comparator group in seasonal settings and provide evidence that the extension of follow-up in single-arm trials improves the accuracy of measures of protective efficacy in settings with more stable transmission. Extension of follow-up may pose logistical challenges to trial feasibility and associated costs. However, these studies may not need to be repeated multiple times, as the estimates of drug protection against different genotypes can be applied to different settings by adjusting for transmission intensity and frequency of resistance.

The effect of diabetes mellitus on perioperative outcomes after colorectal resection: a national cohort study.

BACKGROUND: Diabetes mellitus is a significant modulator of postoperative outcomes and is an important risk factor in the patient selection process. We aimed to investigate the effect of diabetes mellitus and use of insulin on outcomes after colorectal resection using a national cohort. METHODS: Adults with a recorded colorectal resection in England between 2010 and 2020 were identified from Hospital Episode Statistics data linked to the Clinical Practice Research Database. The primary outcome was 90-day mortality. Secondary outcomes included hospital length of stay (LOS) and readmission within 90 days. RESULTS: Of the 106 139 (52 875, 49.8% male) patients included, diabetes mellitus was prevalent in 10 931 (10.3%), 2145 (19.6%) of whom had a record of use of insulin. Unadjusted 90-day mortality risk was 5.7%, with an increased adjusted hazard ratio (aHR) for people with diabetes mellitus (aHR 1.28, 95% confidence interval [CI] 1.19-1.37, P<0.001). This risk was higher in both people with diabetes using insulin (aHR 1.51, 95% CI 1.31-1.74, P<0.001) and not using insulin (aHR 1.22, 95% CI 1.13-1.33, P<0.001), compared with those without diabetes. Ninety-day readmission occurred in 20 542 (19.4%) patients and this was more likely in those with diabetes mellitus (aHR 1.23, 95% CI 1.18-1.29, P<0.001). Median (inter-quartile range) LOS was 8 (5-15) days and was higher in people with diabetes mellitus (adjusted time ratio 1.10, 95% CI 1.08-1.11, P<0.001). CONCLUSIONS: People with diabetes mellitus undergoing colorectal resection are at a higher risk of 90-day mortality, prolonged LOS, and 90-day readmission, with use of insulin associated with additional risk.

Novel approaches to assessing upper motor neuron dysfunction in motor neuron disease/amyotrophic lateral sclerosis: IFCN handbook chapter.

Identifying upper motor neuron (UMN) dysfunction is fundamental to the diagnosis and understanding of disease pathogenesis in motor neuron disease (MND). The clinical assessment of UMN dysfunction may be difficult, particularly in the setting of severe muscle weakness. From a physiological perspective, transcranial magnetic stimulation (TMS) techniques provide objective biomarkers of UMN dysfunction in MND and may also be useful to interrogate cortical and network function. Single, paired- and triple pulse TMS techniques have yielded novel diagnostic and prognostic biomarkers in MND, and have provided important pathogenic insights, particularly pertaining to site of disease onset. Cortical hyperexcitability, as heralded by reduced short interval intracortical inhibition (SICI) and increased short interval intracortical facilitation, has been associated with the onset of lower motor neuron degeneration, along with patterns of disease spread, development of specific clinical features such as the split hand phenomenon, and may provide an indication about the rate of disease progression. Additionally, reduction of SICI has emerged as a potential diagnostic aid in MND. The triple stimulation technique (TST) was shown to enhance the diagnostic utility of conventional TMS measures in detecting UMN dysfunction in MND. Separately, sophisticated brain imaging techniques have uncovered novel biomarkers of neurodegeneration that have bene associated with progression. The present review will discuss the utility of TMS and brain neuroimaging derived biomarkers of UMN dysfunction in MND, focusing on recently developed TMS techniques and advanced neuroimaging modalities that interrogate structural and functional integrity of the corticomotoneuronal system, with an emphasis on pathogenic, diagnostic, and prognostic utility.

Effect of glycocalyx-targeted therapy on vascular function in older adults: a randomized controlled trial.

Advancing age increases cardiovascular disease risk, in part, because of impaired glycocalyx thickness and endothelial dysfunction. Glycocalyx-targeted therapies, such as Endocalyx Pro, could improve both glycocalyx thickness and endothelial function in older adults; however, this has yet to be tested. We hypothesized that Endocalyx Pro supplementation would increase glycocalyx thickness and endothelial function in older adults. Twenty-three older adults aged 66 ± 7 yr (52% female) were enrolled in a randomized, double-blind, placebo-controlled, parallel-arms study to investigate the effect of 12-wk Endocalyx Pro supplementation (3,712 mg/day) on glycocalyx thickness and endothelial function. Glycocalyx thickness was assessed using the GlycoCheck, and endothelial function was determined via brachial artery flow-mediated dilation (FMD). Between-group comparisons revealed Endocalyx Pro did not increase glycocalyx thickness in microvessels 4-25 µm (P = 0.33), 4-7 µm (P = 0.07), or 10-25 µm (P = 0.47) in diameter when compared with placebo. In addition, Endocalyx Pro did not significantly improve FMD [mean ratio (95%) confidence interval [CI]) for between-group comparisons, 1.16 (0.77-1.74); P = 0.48]. However, Endocalyx Pro improved FMD normalized to shear rate (SR) area under the curve [mean ratio (95% CI) for between-group comparisons, 2.41 (1.14,4.13); P = 0.001]. Moreover, Endocalyx Pro increased capillary glycocalyx thickness more than placebo in individuals not taking antihypertensive medication [mean difference (95% CI) for between-group comparison, -0.08 (-0.15, -0.01); P = 0.02]. Our pilot study suggests that Endocalyx Pro supplementation is feasible in older adults but has no measurable effect on overall glycocalyx thickness and FMD. However, Endocalyx Pro may have select effects on capillary glycocalyx thickness and FMD normalized to shear rate among older adults, but further investigation is warranted.NEW & NOTEWORTHY Endothelial glycocalyx thickness and vascular endothelial function decline with advancing age. Endocalyx Pro is a glycocalyx-targeted therapy that may improve endothelial glycocalyx thickness and vascular endothelial function in older adults. This study demonstrated that 12-wk Endocalyx Pro supplementation did not improve overall endothelial glycocalyx thickness or flow-mediated dilation in older adults; however, Endocalyx Pro did increase capillary glycocalyx thickness in individuals not taking antihypertensive medication and improve flow-mediated dilation normalized to the shear stimulus.

Fibulin-2 is an extracellular matrix inhibitor of oligodendrocytes relevant to multiple sclerosis.

Impairment of oligodendrocytes and myelin contributes to neurological disorders including multiple sclerosis (MS), stroke and Alzheimer's disease. Regeneration of myelin (remyelination) decreases the vulnerability of demyelinated axons, but this repair process commonly fails with disease progression. A contributor to inefficient remyelination is the altered extracellular matrix (ECM) in lesions that remains to be better defined. We have identified fibulin-2 (FBLN2) as a highly upregulated ECM component in lesions of MS and stroke, and in proteome databases of Alzheimer's disease and traumatic brain injury. Focusing on MS, the inhibitory role of FBLN2 was suggested in the experimental autoimmune encephalomyelitis (EAE) model in which genetic FBLN2 deficiency improved behavioral recovery by promoting the maturation of oligodendrocytes and enhancing remyelination. Mechanistically, when oligodendrocyte progenitors were cultured in differentiation media, FBLN2 impeded their maturation into oligodendrocytes by engaging the Notch pathway, leading to cell death. Adeno-associated virus-deletion of FBLN2 in astrocytes improved oligodendrocyte numbers and functional recovery in EAE and generated new myelin profiles after lysolecithin-induced demyelination. Collectively, our findings implicate FBLN2 as a hitherto unrecognized injury-elevated ECM, and a therapeutic target, that impairs oligodendrocyte maturation and myelin repair.

Cyanobacterial α-carboxysome carbonic anhydrase is allosterically regulated by the Rubisco substrate RuBP.

Cyanobacterial CO2 concentrating mechanisms (CCMs) sequester a globally consequential proportion of carbon into the biosphere. Proteinaceous microcompartments, called carboxysomes, play a critical role in CCM function, housing two enzymes to enhance CO2 fixation: carbonic anhydrase (CA) and Rubisco. Despite its importance, our current understanding of the carboxysomal CAs found in α-cyanobacteria, CsoSCA, remains limited, particularly regarding the regulation of its activity. Here, we present a structural and biochemical study of CsoSCA from the cyanobacterium Cyanobium sp. PCC7001. Our results show that the Cyanobium CsoSCA is allosterically activated by the Rubisco substrate ribulose-1,5-bisphosphate and forms a hexameric trimer of dimers. Comprehensive phylogenetic and mutational analyses are consistent with this regulation appearing exclusively in cyanobacterial α-carboxysome CAs. These findings clarify the biologically relevant oligomeric state of α-carboxysomal CAs and advance our understanding of the regulation of photosynthesis in this globally dominant lineage.

A Systematic Study of Methyl Carbodithioate Esters as Effective Gold Contact Groups for Single-Molecule Electronics.

There are several binding groups used within molecular electronics for anchoring molecules to metal electrodes (e.g., R-SMe, R-NH2, R-CS2-, R-S-). However, some anchoring groups that bind strongly to electrodes have poor/unknown stability, some have weak electrode coupling, while for some their binding motifs are not well defined. Further binding groups are required to aid molecular design and to achieve a suitable balance in performance across a range of properties. We present an in-depth investigation into the use of carbodithioate esters as contact groups for single-molecule conductance measurements, using scanning tunnelling microscopy break junction measurements (STM-BJ) and detailed surface spectroscopic analysis. We demonstrate that the methyl carbodithioate ester acts as an effective contact for gold electrodes in STM-BJ measurements. Surface enhanced Raman measurements demonstrate that the C=S functionality remains intact when adsorbed on to gold nanoparticles. A gold(I) complex was also synthesised showing a stable C=Sׄ→AuI interaction from the ester. Comparison with a benzyl thiomethyl ether demonstrates that the C=S moiety significantly contributes to charge transport in single-molecule junctions. The overall performance of the CS2Me group demonstrates it should be used more extensively and has strong potential for the fabrication of larger area devices with long-term stability.