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Women with gestational diabetes (GD) have reduced antioxidant capacity; however, the relationship between maternal diet, maternal biochemical capacity, breast milk concentration, and infant intake has not been adequately explored in the literature. An exploration of underlying mechanism(s) is warranted, particularly for nutrient antioxidants impacted by maternal intake. These nutrients may provide a means for modifying maternal and infant antioxidant capacity. Oxygen radical absorbance capacity (ORAC), alpha-tocopherol, ascorbic acid, and beta-carotene concentrations were measured in breast milk of women with and without GD. Plasma, three-day diet records, and breast milk were collected at 6 to 8 weeks postpartum. Student’s t-test was used to compare breast milk ORAC, nutrient antioxidant concentration and plasma ORAC between women with and without GD. Pearson correlations were used to determine associations among antioxidant concentrations in breast milk and dietary antioxidant intake. Breast milk antioxidant concentrations were associated with maternal intake of beta-carotene (r = 0.629, p = 0.005). Breast milk and plasma ORAC and antioxidant vitamin concentrations were not significantly different between GD and NG women. Breast milk ORAC associated with breast milk alpha-tocopherol for NG (r = 0.763, p = 0.010), but not GD women (r = 0.385, p = 0.35), and with breast milk ascorbic acid for GD (r = 0.722, p = 0.043) but not NG women (r = 0.141, p = 0.70; interaction p = 0.041). In GD participants, breast milk ORAC was significantly associated with plasma ORAC (r = 0.780, p = 0.039). ORAC and antioxidant vitamin concentrations in breast milk in women with GD were comparable to women with NG; however, the relationships between breast milk ORAC and vitamin concentrations differed in GD versus NG women for alpha-tocopherol and ascorbic acid.

The altered expression of known brain Aquaporin (AQP) channels 1, 4 and 9 has been correlated with neuropathological AD progression, but possible roles of other AQP classes in neurological disease remain understudied. The levels of transcripts of all thirteen human AQP subtypes were compared in healthy and Alzheimer’s disease (AD) brains by statistical analyses of microarray RNAseq expression data from the Allen Brain Atlas database. Previously unreported, AQPs 0, 6 and 10, are present in human brains at the transcript level. Three AD-affected brain regions, hippocampus (HIP), parietal cortex (PCx) and temporal cortex (TCx), were assessed in three subgroups: young controls (n = 6, aged 24–57); aged controls (n = 26, aged 78–99); and an AD cohort (n = 12, aged 79–99). A significant positive correlation (p < 10−10) was seen for AQP transcript levels as a function of the subject’s age in years. Differential expressions correlated with brain region, age, and AD diagnosis, particularly between the HIP and cortical regions. Interestingly, three classes of AQPs (0, 6 and 8) upregulated in AD compared to young controls are permeable to H2O2. Of these, AQPs 0 and 8 were increased in TCx and AQP6 in HIP, suggesting a role of AQPs in AD-related oxidative stress. The outcomes here are the first to demonstrate that the expression profile of AQP channels in the human brain is more diverse than previously thought, and transcript levels are influenced by both age and AD status. Associations between reactive oxygen stress and neurodegenerative disease risk highlight AQPs 0, 6, 8 and 10 as potential therapeutic targets.

Abstract Ataxia-telangiectasia (A-T) is an autosomal recessive, multisystem disorder characterized by cerebellar degeneration, cancer predisposition, and immune system defects. A major cause of mortality in A-T patients is severe pulmonary disease; however, the underlying causes of the lung complications are poorly understood, and there are currently no curative therapeutic interventions. In this study, we examined the lung phenotypes caused by ATM-deficient immune cells using a mouse model of A-T pulmonary disease. In response to acute lung injury, ATM-deficiency causes decreased survival, reduced blood oxygen saturation, elevated neutrophil recruitment, exaggerated and prolonged inflammatory responses and excessive lung injury compared to controls. We found that ATM null bone marrow adoptively transferred to WT recipients induces similar phenotypes that culminate in impaired lung function. Moreover, we demonstrated that activated ATM-deficient macrophages exhibit significantly elevated production of harmful reactive oxygen and nitrogen species and pro-inflammatory cytokines. These findings indicate that ATM-deficient immune cells play major roles in causing the lung pathologies in A-T. Based on these results, we examined the impact of inhibiting the aberrant inflammatory responses caused by ATM-deficiency with reparixin, a CXCR1/CXCR2 chemokine receptor antagonist. We demonstrated that reparixin treatment reduces neutrophil recruitment, edema and tissue damage in ATM mutant lungs. Thus, our findings indicate that targeted inhibition of CXCR1/CXCR2 attenuates pulmonary phenotypes caused by ATM-deficiency and suggest that this treatment approach represents a viable therapeutic strategy for A-T lung disease.

Context Cucumber (Cucumis sativus Linn. [Cucurbitaceae]) is widely known for its purgative, antidiabetic, antioxidant, and anticancer therapeutic potential. However, its effect on gastrointestinal (GI) disease is unrecognised. Objective This study investigated the effect of C. sativus fruit extract (CCE) on intestinal chloride secretion, motility, and motor function, and the role of TMEM16A chloride channels. Materials and methods CCE extracts were obtained from commercially available cucumber. Active fractions were then purified by HPLC and analysed by high resolution mass spectrometry. The effect of CCE on intestinal chloride secretion was investigated in human colonic T84 cells, ex vivo mouse intestinal tissue using an Ussing chamber, and the two-electrode voltage-clamp technique to record calcium sensitive TMEM16A chloride currents in Xenopus laevis oocytes. In vivo, intestinal motility was investigated using the loperamide-induced C57BL/6 constipation mouse model. Ex vivo contractility of mouse colonic smooth muscles was assessed by isometric force measurements. Results CCE increased the short-circuit current (ΔIsc 34.47 ± µA/cm2) and apical membrane chloride conductance (ΔICl 95 ± 8.1 µA/cm2) in intestinal epithelial cells. The effect was dose-dependent, with an EC50 value of 0.06 µg/mL. CCE stimulated the endogenous TMEM16A-induced Cl- current in Xenopus laevis oocytes. Moreover, CCE increased the contractility of smooth muscle in mouse colonic tissue and enhanced small bowel transit in CCE treated mice compared to loperamide controls. Mass spectrometry suggested a cucurbitacin-like analogue with a mass of 512.07 g/mol underlying the bioactivity of CCE. Conclusion A cucurbitacin-like analog present in CCE activates TMEM16A channels, which may have therapeutic potential in cystic fibrosis and intestinal hypodynamic disorders.

Abstract Background Incidence of pulmonary aspergillosis is rising worldwide, owing to an increased population of immunocompromised patients. Notable potential of the pulmonary route has been witnessed in antifungal delivery due to distinct advantages of direct lung targeting and first-pass evasion. The current research reports biomimetic surface-active lipid-polymer hybrid (LPH) nanoparticles (NPs) of voriconazole, employing lung-specific lipid, i.e., dipalmitoylphosphatidylcholine and natural biodegradable polymer, i.e., chitosan, to augment its pulmonary deposition and retention, following nebulization. Results The developed nanosystem exhibited a particle size in the range of 228–255 nm and drug entrapment of 45–54.8%. Nebulized microdroplet characterization of NPs dispersion revealed a mean diameter of ≤ 5 μm, corroborating its deep lung deposition potential as determined by next-generation impactor studies. Biophysical interaction of LPH NPs with lipid-monolayers indicated their surface-active potential and ease of intercalation into the pulmonary surfactant membrane at the air-lung interface. Cellular viability and uptake studies demonstrated their cytocompatibility and time-and concentration-dependent uptake in lung-epithelial A549 and Calu-3 cells with clathrin-mediated internalization. Transepithelial electrical resistance experiments established their ability to penetrate tight airway Calu-3 monolayers. Antifungal studies on laboratory strains and clinical isolates depicted their superior efficacy against Aspergillus species. Pharmacokinetic studies revealed nearly 5-, 4- and threefolds enhancement in lung AUC, Tmax, and MRT values, construing significant drug access and retention in lungs. Conclusions Nebulized LPH NPs were observed as a promising solution to provide effective and safe therapy for the management of pulmonary aspergillosis infection with improved patient compliance and avoidance of systemic side-effects.

Physical networks, such as biological neural networks, can learn desired functions without a central processor, using local learning rules in space and time to learn in a fully distributed manner. Learning approaches such as equilibrium propagation, directed aging, and coupled learning similarly exploit local rules to accomplish learning in physical networks such as mechanical, flow, or electrical networks. In contrast to certain natural neural networks, however, such approaches have so far been restricted to the quasistatic limit, where they learn on timescales slow compared to their physical relaxation. This quasistatic constraint slows down learning, limiting the use of these methods as machine learning algorithms, and potentially restricting physical networks that could be used as learning platforms. Here we explore learning in an electrical resistor network that implements coupled learning, both in the laboratory and on the computer, at rates that range from slow to far above the quasistatic limit. We find that up to a critical threshold in the ratio of the learning rate to the physical rate of relaxation, learning speeds up without much change of behavior or error. Beyond the critical threshold, the error exhibits oscillatory dynamics but the networks still learn successfully.

BackgroundPediatric osteoarticular infections (POAIs) are serious diseases requiring early diagnosis and treatment.MethodsIn this prospective multicenter cohort study, children with POAIs were selected from the European Union Childhood Life-threatening Infectious Diseases Study (EUCLIDS) database to analyze their demographic, clinical, and microbiological data.ResultsA cohort of 380 patients with POAIs, 203 with osteomyelitis (OM), 158 with septic arthritis (SA), and 19 with both OM and SA, was analyzed. Thirty-five patients were admitted to the Pediatric Intensive Care Unit; out of these, six suffered from shock, one needed an amputation of the right foot and of four left toes, and two had skin transplantation. According to the Pediatric Overall Performance Score, 36 (10.5%) showed a mild overall disability, 3 (0.8%) a moderate, and 1 (0.2%) a severe overall disability at discharge. A causative organism was detected in 65% (247/380) of patients. Staphylococcus aureus (S. aureus) was identified in 57.1% (141/247) of microbiological confirmed cases, including 1 (0.7%) methicillin-resistant S. aureus (MRSA) and 6 (4.2%) Panton-Valentine leukocidin (PVL)-producing S. aureus, followed by Group A Streptococcus (18.2%) and Kingella kingae (8.9%). K. kingae and PVL production in S. aureus were less frequently reported than expected from the literature.ConclusionPOAIs are associated with a substantial morbidity in European children, with S. aureus being the major detected pathogen. In one-third of patients, no causative organism is identified. Our observations show an urgent need for the development of a vaccine against S. aureus and for the development of new microbiologic diagnostic guidelines for POAIs in European pediatric hospitals.

Immunoglobulins type-M (IgMs) are one of the first antibody classes mobilized during immune responses against pathogens and tumor cells. Binding to specific target antigens enables the interaction with the C1 complex which strongly activates the classical complement pathway. This biological function is the basis for the huge therapeutic potential of IgMs. But, due to their high oligomeric complexity, in vitro production, biochemical characterization, and biophysical characterization are challenging. In this study, we present recombinant production of two IgM models (IgM617 and IgM012) in pentameric and hexameric states and the evaluation of their polymer distribution using different biophysical methods (analytical ultracentrifugation, size exclusion chromatography coupled to multi-angle laser light scattering, mass photometry, and transmission electron microscopy). Each IgM construct is defined by a specific expression and purification pattern with different sample quality. Nevertheless, both purified IgMs were able to activate complement in a C1q-dependent manner. More importantly, BioLayer Interferometry (BLI) was used for characterizing the kinetics of C1q binding to recombinant IgMs. We show that recombinant IgMs possess similar C1q-binding properties as IgMs purified from human plasma.

BackgroundThe Portfolio Diet, or Dietary Portfolio, is a therapeutic dietary pattern that combines cholesterol-lowering foods to manage dyslipidemia for the prevention of cardiovascular disease. To translate the Portfolio Diet for primary care, we developed the PortfolioDiet.app as a patient and physician educational and engagement tool for PCs and smartphones. The PortfolioDiet.app is currently being used as an add-on therapy to the standard of care (usual care) for the prevention of cardiovascular disease in primary care. To enhance the adoption of this tool, it is important to ensure that the PortfolioDiet.app meets the needs of its target end users. ObjectiveThe main objective of this project is to undertake user testing to inform modifications to the PortfolioDiet.app as part of ongoing engagement in quality improvement (QI). MethodsWe undertook a 2-phase QI project from February 2021 to September 2021. We recruited users by convenience sampling. Users included patients, family physicians, and dietitians, as well as nutrition and medical students. For both phases, users were asked to use the PortfolioDiet.app daily for 7 days. In phase 1, a mixed-form questionnaire was administered to evaluate the users’ perceived acceptability, knowledge acquisition, and engagement with the PortfolioDiet.app. The questionnaire collected both quantitative and qualitative data, including 2 open-ended questions. The responses were used to inform modifications to the PortfolioDiet.app. In phase 2, the System Usability Scale was used to assess the usability of the updated PortfolioDiet.app, with a score higher than 70 being considered acceptable. ResultsA total of 30 and 19 users were recruited for phase 1 and phase 2, respectively. In phase 1, the PortfolioDiet.app increased users’ perceived knowledge of the Portfolio Diet and influenced their perceived food choices. Limitations identified by users included challenges navigating to resources and profile settings, limited information on plant sterols, inaccuracies in points, timed-logout frustration, request for step-by-step pop-up windows, and request for a mobile app version; when looking at positive feedback, the recipe section was the most commonly praised feature. Between the project phases, 6 modifications were made to the PortfolioDiet.app to incorporate and address user feedback. At phase 2, the average System Usability Scale score was 85.39 (SD 11.47), with 100 being the best possible. ConclusionsBy undertaking user testing of the PortfolioDiet.app, its limitations and strengths were able to be identified, informing modifications to the application, which resulted in a clinical tool that better meets users’ needs. The PortfolioDiet.app educates users on the Portfolio Diet and is considered acceptable by users. Although further refinements to the PortfolioDiet.app will continue to be made before its evaluation in a clinical trial, the result of this QI project is an improved clinical tool.

The kinase mTOR is a signaling hub for pathways that regulate cellular growth. In neurons, the subcellular localization of mTOR takes on increased significance. Here, we review findings on the localization of mTOR in axons and offer a perspective on how these may impact our understanding of nervous system development, function, and disease. We propose a model where mTOR accumulates in local foci we term mTOR outposts, which can be found in processes distant from a neuron’s cell body. In this model, pathways that funnel through mTOR are gated by local outposts to spatially select and amplify local signaling. The presence or absence of mTOR outposts in a segment of axon or dendrite may determine whether regional mTOR-dependent signals, such as nutrient and growth factor signaling, register toward neuron-wide responses. In this perspective, we present the emerging evidence for mTOR outposts in neurons, their putative roles as spatial gatekeepers of signaling inputs, and the implications of the mTOR outpost model for neuronal protein synthesis, signal transduction, and synaptic plasticity.

Malaria is responsible for half a million deaths annually and poses a huge economic burden on the developing world. The mosquito-borne parasites (Plasmodium spp.) that cause the disease depend upon an unconventional actomyosin motor for both gliding motility and host cell invasion. The motor system, often referred to as the glideosome complex, remains to be understood in molecular terms and is an attractive target for new drugs that might block the infection pathway. Here, we present the high-resolution structure of the actomyosin motor complex from Plasmodium falciparum. The complex includes the malaria parasite actin filament (PfAct1) complexed with the class XIV myosin motor (PfMyoA) and its two associated light-chains. The high-resolution core structure reveals the PfAct1:PfMyoA interface in atomic detail, while at lower-resolution, we visualize the PfMyoA light-chain binding region, including the essential light chain (PfELC) and the myosin tail interacting protein (PfMTIP). Finally, we report a bare PfAct1 filament structure at improved resolution.

Groundwater remediation technologies that can destroy per- and polyfluoroalkyl substances (PFAS) in situ are in high demand. To address this need, using flow-through electrochemical reactors we compared the performance of three mesh electrode materials that may be implemented in the subsurface as permeable reactive barriers. A Magnéli-phase titanium suboxides TinO2n-1 anode achieved higher perfluorooctane sulfonate (PFOS) oxidation rates and lower energy consumption than boron-doped ultrananocrystalline diamond and IrO2-Ta2O5 mixed metal oxides, and was thus selected for more detailed testing regarding the impacts of varying current density, flow velocity, electrolyte conductivity, and PFOS concentration. Over 99% of PFOS removal was achieved under continuous flow conditions. The fluorine mass balance showed that most PFOS-bonded F was released as fluoride, while no organic intermediates were detected in the aqueous phase. Each ∼2% of fluorine was recovered as HF and organofluorine intermediates in the gas phase. A comparison of 10 PFAS revealed a hydrophobicity-driven increase in oxidation rate with increasing perfluoroalkyl chain length as well as faster oxidation kinetics for perfluoroalkyl carboxylic acids compared to perfluoroalkane sulfonic acids, likely due to contributions from electrochemically activated sulfate. The energy consumption of PFAS treatment under simulated slow-flow groundwater conditions was substantially higher than in ex situ electrochemical systems optimized for enhanced mass transfer. Consequently, future work should focus on in situ treatment design optimization with an emphasis on power requirements. Collectively, our investigations demonstrate that among the few water treatment technologies capable of breaking the carbon-fluorine bond, electrochemical treatment is a promising approach for in situ destruction of PFAS in the subsurface.

Abstract Assessing how climate change information is used in conservation planning is an important part of meeting long‐term conservation and climate adaptation goals. In the United States, state agencies responsible for fish and wildlife management create State Wildlife Action Plans (SWAPs) to identify conservation goals, prioritize actions, and establish plans for managing and monitoring target species and habitats. We created a rubric to assess and compare the use of climate change information in SWAPs for 10 states in the Intermountain West and Great Plains. Interviews with SWAP authors identified institutional factors influencing applications of climate change information. Access to professional networks and climate scientists, funding support for climate change vulnerability analysis, Congressional mandates to include climate change, and supportive agency leadership facilitate using climate change information. Political climate could either support or limit options for using this information. Together, the rubric and the interview results can be used to identify opportunities to improve the use of climate information, and to identify entry points to support conservation planning and natural resource managers in successful adaptation to climate change. This research is directly relevant to future SWAP revisions, which most states will complete by 2025, and more broadly to other conservation planning processes.

Introduction The Grading of Recommendations Assessment, Development and Evaluation (GRADE) and similar Evidence to Decision (EtD) frameworks require its users to judge how substantial the effects of interventions are on desirable and undesirable people-important health outcomes. However, decision thresholds (DTs) that could help understand the magnitude of intervention effects and serve as reference for interpretation of findings are not yet available.The objective of this study is an approach to derive and use DTs for EtD judgments about the magnitude of health benefits and harms. We hypothesise that approximate DTs could have the ability to discriminate between the existing four categories of EtD judgments (Trivial, Small, Moderate, Large), support panels of decision-makers in their work, and promote consistency and transparency in judgments.Methods and analysis We will conduct a methodological randomised controlled trial to collect the data that allow deriving the DTs. We will invite clinicians, epidemiologists, decision scientists, health research methodologists, experts in Health Technology Assessment (HTA), members of guideline development groups and the public to participate in the trial. Then, we will investigate the validity of our DTs by measuring the agreement between judgments that were made in the past by guideline panels and the judgments that our DTs approach would suggest if applied on the same guideline data.Ethics and dissemination The Hamilton Integrated Research Ethics Board reviewed this study as a quality improvement study and determined that it requires no further consent. Survey participants will be required to read a consent statement in order to participate in this study at the beginning of the trial. This statement reads: You are being invited to participate in a research project which aims to identify indicative DTs that could assist users of the GRADE EtD frameworks in making judgments. Your input will be used in determining these indicative thresholds. By completing this survey, you provide consent that the anonymised data collected will be used for the research study and to be summarised in aggregate in publication and electronic tools.PROTOCOL registration number NCT05237635.

Decellularized extracellular matrix (dECM) deposited by mesenchymal stromal cells (MSCs) has emerged as a promising substrate for improved expansion of MSCs. To date, essentially all studies that have produced dECM for MSC expansion have done so on tissue culture plastic or glass. However, substrate surface chemistry has a profound impact on the adsorption of proteins that mediate cell-material interactions, and different surface chemistries can cause changes in cell behavior, ECM deposition, and the in vivo response to a material. This study tested the hypothesis that substrate surface chemistry impacts the deposition of ECM and its subsequent bioactivity. This hypothesis was tested by producing glass surfaces with various surface chemistries (amine, carboxylic acid, propyl, and octyl groups) using silane chemistry. ECM was deposited by an immortalized MSC line, decellularized, and characterized through SDS-PAGE and immunofluorescence microscopy. No significant difference was observed in dECM composition or microarchitecture on the different surfaces. The decellularized surfaces were seeded with primary MSCs and their proliferation and differentiation were assessed. The presence of dECM improved the proliferation of primary MSCs by ~100% in comparison to surface chemistry controls. Additionally, the adipogenesis increased by 50–90% on all dECM surfaces in comparison to surface chemistry controls, and the osteogenesis increased by ~50% on the octyl-modified surfaces when dECM was present. However, no statistically significant differences were observed within the set of dECM surfaces or control surfaces. These results support the null hypothesis, meaning surface chemistry (over the range tested in this work) is not a key regulator of the composition or bioactivity of MSC-derived dECM. These results are significant because they provide an important insight into regenerative engineering technologies. Specifically, the utilization of dECM in stem cell manufacturing and tissue engineering applications would require the dECM to be produced on a wide variety of substrates. This work indicates that it can be produced on materials with a range of surface chemistries without undesired changes in the bioactivity of the dECM.

Abstract Summer rainfall in the southeast Prairie Pothole Region (SEPPR) is an important part of a vital wetland ecosystem that various species use as their habitat. We examine sources and pathways for summer rainfall moisture, large‐scale features influencing moisture delivery, and large‐scale connections related to summer moisture using the Hybrid Single‐Particle Lagrangian Integrated Trajectory (HYSPLIT) model. Analysis of HYSPLIT back trajectories shows that land is the primary moisture source for summer rainfall events indicating moisture recycling plays an important role in precipitation generation. The Great Plains Low‐Level Jet/Maya Express is the most prominent moisture pathway. It impacts events sourced by land and the Gulf of Mexico (GoM), the secondary moisture source. There is a coupling between land, atmosphere, and ocean conveyed by large‐scale climate connections between rainfall events and sea surface temperature (SST), Palmer Drought Severity Index, and 850‐mb heights. Land‐sourced events have a connection to the northern Pacific and northwest Atlantic Oceans, soil moisture over the central U.S., and low‐pressure systems over the SEPPR. GoM‐sourced events share the connection to soil moisture over the central U.S. but also show connections to SSTs in the North Pacific and Atlantic Oceans and the GoM, soil moisture in northern Mexico, and 850‐mb heights in the eastern Pacific Ocean. Both types of events show connections to high 850‐mb heights in the Caribbean which may reflect a connection to Bermuda High. These insights into moisture sources and pathways can improve skill in SEPPR summer rainfall predictions and benefit natural resource managers in the region.

Abstract Objective Stool repositories are a valuable resource for retrospective analyses including quantitative PCR assays to distinguish between asymptomatic shedding and clinical disease. The suitability of archival specimens for this purpose is unclear and requires assessment. We conducted a pilot study to evaluate pathogen detection by TaqMan Array Card (TAC) in travelers’ diarrhea (TD) stool specimens stored for 1–13 years, as well as the impact of transporting specimens on Whatman FTA Elute cards (FTA Cards) on detection. Results The positive percent agreement (PPA) for TAC on stool vs. microbiologic testing was lower than our a priori PPA estimate of 80% for most pathogens: Shigella spp. (100% [95%CI 69–100%]), enterotoxigenic E coli (ETEC) (63% [95%CI 49–75%]), Campylobacter spp. (66% [95%CI 43–85%]) and Norovirus (37% [95%CI 16–61%]). Use of the FTA card resulted in a further reduction of PPA. Our findings suggest that archival specimens may lead to insensitive detection on quantitative PCR assays due to degradation of nucleic acid with prolonged storage, although our limited sample size precluded us from evaluating the impact of storage duration on nucleic acid yield. Additional studies are needed to understand the impact of storage duration on quantitative PCR data.

Abstract Single-cell RNA-sequencing (scRNA-seq) facilitates the unbiased reconstruction of multicellular tissue systems in health and disease. Here, we present a curated scRNA-seq dataset of human muscle samples from 10 adult donors with diverse anatomical locations. We integrated ~ 22,000 single-cell transcriptomes using Scanorama to account for technical and biological variation and resolved 16 distinct populations of muscle-resident cells using unsupervised clustering of the data compendium. These cell populations included muscle stem/progenitor cells (MuSCs), which bifurcated into discrete “quiescent” and “early-activated” MuSC subpopulations. Differential expression analysis identified transcriptional profiles altered in the activated MuSCs including genes associated with aging, obesity, diabetes, and impaired muscle regeneration, as well as long non-coding RNAs previously undescribed in human myogenic cells. Further, we modeled ligand-receptor cell-communication interactions and observed enrichment of the TWEAK-FN14 pathway in activated MuSCs, a characteristic signature of muscle wasting diseases. In contrast, the quiescent MuSCs have enhanced expression of the EGFR receptor, a recognized human MuSC marker. This work provides a new benchmark reference resource to examine human muscle tissue heterogeneity and identify potential targets in MuSC diversity and dysregulation in disease contexts.

Abstract Background Migraine is a common headache disorder, with cortical spreading depolarization (CSD) considered as the underlying electrophysiological event. CSD is a slowly propagating wave of neuronal and glial depolarization. Sleep disorders are well known risk factors for migraine chronification, and changes in wake-sleep pattern such as sleep deprivation are common migraine triggers. The underlying mechanisms are unknown. As a step towards developing an animal model to study this, we test whether sleep deprivation, a modifiable migraine trigger, enhances CSD susceptibility in rodent models. Methods Acute sleep deprivation was achieved using the “gentle handling method”, chosen to minimize stress and avoid confounding bias. Sleep deprivation was started with onset of light (diurnal lighting conditions), and assessment of CSD was performed at the end of a 6 h or 12 h sleep deprivation period. The effect of chronic sleep deprivation on CSD was assessed 6 weeks or 12 weeks after lesioning of the hypothalamic ventrolateral preoptic nucleus. All experiments were done in a blinded fashion with respect to sleep status. During 60 min of continuous topical KCl application, we assessed the total number of CSDs, the direct current shift amplitude and duration of the first CSD, the average and cumulative duration of all CSDs, propagation speed, and electrical CSD threshold. Results Acute sleep deprivation of 6 h (n = 17) or 12 h (n = 11) duration significantly increased CSD frequency compared to controls (17 ± 4 and 18 ± 2, respectively, vs. 14 ± 2 CSDs/hour in controls; p = 0.003 for both), whereas other electrophysiological properties of CSD were unchanged. Acute total sleep deprivation over 12 h but not over 6 h reduced the electrical threshold of CSD compared to controls (p = 0.037 and p = 0.095, respectively). Chronic partial sleep deprivation in contrast did not affect CSD susceptibility in rats. Conclusions Acute but not chronic sleep deprivation enhances CSD susceptibility in rodents, possibly underlying its negative impact as a migraine trigger and exacerbating factor. Our findings underscore the importance of CSD as a therapeutic target in migraine and suggest that headache management should identify and treat associated sleep disorders.

Anthropogenic CO2 is acidifying the ocean, but knowledge of the carbonate properties underlying these dynamics in coastal oceans is lacking. Here, the authors reveal spatial distribution patterns and variability in carbonate chemistry along North America’s coasts.

Thanatophoric dysplasia (TD) is a rare skeletal dysplasia commonly thought to be lethal. In this case report, we discuss a nine-year-old male with TD and review his parents' decision making shortly after their son was born, the technology needed to sustain him, and his parents' perception of his quality of life. We also summarize the clinical course of published long-term survivors with TD. Pediatric Palliative Care teams, especially those conducting perinatal palliative care consultations, are often asked to support families in the face of prognostic uncertainty. Our case report and review of the literature adds to the uncertainty of prognosis in TD and suggests that pediatric palliative care providers should be wary of the label ?lethal.?

Thymus is a unique environment hosting the development of many T cell subsets with distinct functions. Here the authors show that medullary thymic epithelial cells (mTEC) are functionally diverse, with LTβR signaling serving differential regulation of mTEC for specific control of multiple lineages of invariant natural killer T cells.

Abstract Background Previous research suggests that child marriage may be accelerated during times of crisis and insecurity as resources are scarce and child marriage may be a survival strategy for girls and their families. In 2017, the Rohingya experienced a mass displacement to Bangladesh in response to escalating violence in Myanmar. This displacement has resulted in an estimated population of nearly 1 million Rohingya living in Cox’s Bazar. Methods We conducted in-depth interviews (n = 48) and focus group discussions (n = 12) with Rohingya male and female adolescents and young adults (14–24 years), and program managers and service providers (n = 24) working in Cox’s Bazar to understand their experience of living or working in the camps, preferences for timing of marriage, and marriage practices in Myanmar and in the camps. We also interviewed Bangladeshis in the host community to complement our understanding of marriage in the camps and its influence in the broader community. Our primary objective was to describe how displacement influenced marriage timing and practices. Results We found that child marriage is a strong cultural phenomenon among the Rohingya, primarily rooted in socio-cultural and religious beliefs around readiness for marriage. Although child marriage was practiced by the Rohingya in Myanmar, specific state law and oppression by military forces prevented many from marrying before age 18. Now this preference is more easily practiced in the camps in Bangladesh where the displaced Rohingya experience less marriage regulation. Host community participants perceive the presence of the Rohingya as encouraging both polygamy and child marriage in their communities, leading to tension among the host community. Conclusions Our findings support evidence that conflict and displacement increase child marriage in populations already vulnerable to child marriage by exacerbating gender inequities. However, our findings also suggest group norms around religious and cultural preferences for age at marriage play a significant role in post-displacement behaviors surrounding marriage.

It is known the β-sheet structures in silk-inspired materials generate increased mechanical properties. Here, the authors report on a method of creating silk-inspired materials using in situ formation of β-sheets in an amorphous polymer to replicate the structure of silk and increase the mechanical properties.

Adenoviral (Ad) vectors represent promising vaccine platforms for infectious disease. To overcome pre-existing immunity to commonly used human adenovirus serotype 5 (Ad5), vectors based on rare species or non-human Ads are being developed. However, these vectors often exhibit reduced potency compared with Ad5, necessitating the use of innovative approaches to augment the immunogenicity of the encoded antigen (Ag). To achieve this, we engineered model Ag, enhanced green fluorescent protein (EGFP), for targeting to the surface of host-derived extracellular vesicles (EVs), namely exosomes. Exosomes are nano-sized EVs that play important roles in cell-to-cell communication and in regulating immune responses. Directed targeting of Ag to the surface of EVs/exosomes is achieved by “exosome display,” through fusion of Ag to the C1C2 domain of lactadherin, a protein highly enriched in exosomes. Herein, we engineered chimpanzee adenovirus ChAdOx1 and Ad5-based vaccines encoding EGFP, or EGFP targeted to EVs (EGFP_C1C2), and compared vaccine immunogenicity in mice. We determined that exosome display substantially increases Ag-specific humoral immunity following intramuscular and intranasal vaccination, improving the immunological potency of both ChAdOx1 and Ad5. We propose that this Ag-engineering approach could increase the immunogenicity of diverse Ad vectors that exhibit desirable manufacturing characteristics, but currently lack the potency of Ad5. Keywords: adenovirus, adenoviral, vaccine, exosome, extracellular vesicle, immunogenicity, viral vector, virus

Magnetic resonance imaging–guided focused ultrasound (MRgFUS) is a noninvasive modality that allows for precise tissue ablation with sparing of surrounding structures. Early reports of the use of MRgFUS for the treatment of facet joint osteoarthritis are promising. We present a case of facet joint pain treated successfully by MRgFUS at our institution. Magnetic resonance imaging–guided focused ultrasonography may be a useful modality for patients with facet joint–mediated low back pain, particularly in the setting of limited or refractory response to conventional treatments.

Abstract Background Myeloid derived suppressor cells (MDSCs) present a significant obstacle to cancer immunotherapy because they dampen anti-tumor cytotoxic T cell responses. Previous groups, including our own, have reported on the myelo-depletive effects of certain chemotherapy agents. We have shown previously that decitabine increased tumor cell Class I and tumor antigen expression, increased ability of tumor cells to stimulate T lymphocytes, depleted tumor-induced MDSC in vivo and augmented immunotherapy of a murine mammary carcinoma. Results In this study, we expand upon this observation by testing a next-generation DNA methyltransferase inhibitor (DNMTi), guadecitabine, which has increased stability in the circulation. Using the 4 T1 murine mammary carcinoma model, in BALB/cJ female mice, we found that guadecitabine significantly reduces tumor burden in a T cell-dependent manner by preventing excessive myeloid proliferation and systemic accumulation of MDSC. The remaining MDSC were shifted to an antigen-presenting phenotype. Building upon our previous publication, we show that guadecitabine enhances the therapeutic effect of adoptively transferred antigen-experienced lymphocytes to diminish tumor growth and improve overall survival. We also show guadecitabine’s versatility with similar tumor reduction and augmentation of immunotherapy in the C57BL/6 J E0771 murine breast cancer model. Conclusions Guadecitabine depleted and altered MDSC, inhibited growth of two different murine mammary carcinomas in vivo, and augmented immunotherapeutic efficacy. Based on these findings, we believe the immune-modulatory effects of guadecitabine can help rescue anti-tumor immune response and contribute to the overall effectiveness of current cancer immunotherapies.

Background For cancer survivors, there is a paucity of fear of recurrence (FOR) interventions that integrate empirically supported mind-body and psychological skills for managing FOR and are delivered in scalable formats. Objective To adapt an evidence-based resiliency intervention to address FOR among cancer survivors. Methods A multidisciplinary team of researchers, clinicians, and patient stakeholders followed an iterative intervention adaptation process (ORBIT). In Step 1, we sought to define key FOR management skills through a literature review and feedback from stakeholders. In Step 2, we integrated findings into a treatment manual and refined procedures for in-person delivery to groups of cancer survivors, defined as adults who had completed primary cancer treatment for non-metastatic cancer. In Step 3, we conducted a single arm trial to assess initial acceptability and change in FOR severity with 23 cancer survivors (N=4 intervention groups). In Step 4, we conducted additional qualitative interviews with 28 cancer survivors (N=6 focus groups stratified by FOR severity, N=15 individual interviews) to define adaptive and maladaptive strategies for coping with FOR and to identify preferences for delivery. In Step 5, we refined the treatment manual and procedures for testing in a future pilot randomized feasibility trial. Results We identified critical feedback using a combination of qualitative and quantitative methods. The single arm trial suggested preliminary feasibility and sustained reductions in FOR severity, yet need for refinement (i.e., eligibility, delivery modality), prompting additional qualitative interviews for further targeting. The resulting intervention (IN FOCUS) is comprised of virtual, synchronous, group-delivered sessions that offer an integrated approach to FOR management by teaching cognitive-behavioral techniques, meditation, relaxation training, adaptive health behaviors, and positive psychology skills. Sessions are targeted by applying skills to FOR and associated healthcare engagement. Conclusions IN FOCUS is a targeted intervention for teaching mind-body resiliency skills to groups of cancer survivors with elevated FOR. Next steps are testing feasibility in a pilot randomized trial.

A consumer study was conducted to determine whether consumers scored beef palatability traits differently on paper versus digital ballots. Beef subprimals representing 4 treatments with inherent variation in eating quality were collected: USDA Select eye of round aged 7 d postmortem, USDA Select strip loin aged 7 d postmortem, USDA Choice tenderloin aged 21 d postmortem, and USDA Prime strip loin aged 21 d postmortem. Accessory muscles, external fat, and connective tissue were removed from subprimals. Muscles were fabricated into 2.5-cm steaks and further divided into 2 equal halves for consumer testing. Consumers (n = 360) evaluated 8 samples divided into 2 blocks representing the 2 ballot types. Within each ballot block, Select longissimus lumborum samples were always served in the first and fifth position, followed by the remaining 3 treatments served in a randomized order among the latter 3 positions. Consumers rated each steak sample for tenderness, juiciness, flavor liking, and overall liking from 0 to 100 on either a paper or a digital ballot and then rated the paired steak halves on the opposite ballot during the second block of sample testing. Ballot type influenced (P < 0.02) all traits, as consumers scored traits greater (P < 0.05) on paper compared with digital ballots, regardless of treatment. The magnitude of differences between ballot types was much smaller than the magnitude of differences between cut treatments, which also differed (P < 0.01). The smallest margin between ballot type was observed for tenderness (1.8 points); juiciness, flavor liking, and overall liking all differed by 3.4 points. Independent studies could and have utilized digital ballots without concern, as consumers sorted samples by treatment in the current study similarly, regardless of ballot type. However, researchers should consider ballot type for their sensory studies, especially if data will be added to a collective data set.

IntroductionLate diagnosis of HIV (LD) increases the risk of morbidity, mortality, and HIV transmission. We used nationally representative data from population-based HIV impact assessment (PHIA) surveys in Malawi, Zambia, and Zimbabwe (2015-2016) to characterize adults at risk of LD and to examine associations between LD and presumed HIV transmission to cohabiting sexual partners.MethodsWe estimated the prevalence of LD, defined as CD4 count ResultsOf 1,804 adults who were newly diagnosed with HIV in the surveys, 49% (882) were diagnosed late. LD was associated with male sex, older age, and almost five times the odds of having an HIV-positive household sexual partner (adjusted odds ratio [aOR], 4.65 [95% confidence interval: 2.56-8.45]). Longer duration of HIV exposure in a relationship and higher viral load of the index case were both independently associated with higher odds of having HIV-positive household sexual partners. Individuals with HIV exposure of more than 5 years had more than three times (aOR 3.42 [95% CI: 1.63-7.18]) higher odds of being HIV positive than those with less than 2 years HIV exposure. The odds of being HIV positive were increased in individuals who were in a relationship with an index case with a viral load of 400-3499 copies/mL (aOR 4.06 [95% CI 0.45-36.46]), 3,500-9,999 copies/mL (aOR 11.32 [95% CI: 4.08-31.39]), 10,000-49,999 copies/mL (aOR 17.07 [95% CI: 9.18-31.72]), and ≥50,000 copies/mL (aOR 28.41 [95% CI: 12.18-66.28]) compared to individuals who were in a relationship with an index case with a viral load of ConclusionsLD remains a challenge in Southern Africa and is strongly associated with presumed HIV transmission to household sexual partners. Our study underscores the need for earlier HIV diagnosis, particularly among men and older adults, and the importance of index testing.

BackgroundIn the United States, national ecological studies suggest a positive impact of COVID-19 vaccination coverage on outcomes in adults. However, the national impact of the vaccination program on COVID-19 in children remains unknown. To determine the association of COVID-19 vaccination with U.S. case incidence, emergency department visits, and hospital admissions for pediatric populations during the Delta and Omicron periods.MethodsWe conducted an ecological analysis among children aged 5-17 and compared incidence rate ratios (RRs) of COVID-19 cases, emergency department visits, and hospital admissions by pediatric vaccine coverage, with jurisdictions in the highest vaccine coverage quartile as the reference.ResultsRRs comparing states with lowest pediatric vaccination coverage to the highest pediatric vaccination coverage were 2.00 and 0.64 for cases, 2.96 and 1.11 for emergency department visits, and 2.76 and 1.01 for hospital admissions among all children during the Delta and Omicron periods, respectively. During the 3-week peak period of the Omicron wave, only children aged 12-15 and 16-17 years in the states with the lowest versus highest coverage, had a significantly higher rate of emergency department visits (RR = 1.39 and RR = 1.34, respectively).ConclusionsCOVID-19 vaccines were associated with lower case incidence, emergency department visits and hospital admissions among children during the Delta period but the association was weaker during the Omicron period. Pediatric COVID-19 vaccination should be promoted as part of a program to decrease COVID-19 impact among children; however, vaccine effectiveness may be limited when available vaccines do not match circulating viral variants.

BackgroundConditional Cash Transfer Programs have been developed in Latin America in response to poverty and marked social inequalities on the continent. In Brazil, the Bolsa Familia Program (BFP) was implemented to alleviate poverty and improve living conditions, health, and education for socioeconomically vulnerable populations. However, the effect of this intervention on maternal and child health is not well understood.MethodsWe will evaluate the effect of BFP on maternal and child outcomes: 1. Birth weight; 2. Preterm birth; 3. Maternal mortality; and 4. Child growth. Dynamic retrospective cohort data from the 100 Million Brazilian Cohort (2001 to 2015) will be linked to three different databases: Live Birth Information System (2004 to 2015); Mortality Information System (2011 to 2015); and Food and Nutritional Surveillance System (2008 to 2017). The definition of exposure to the BFP varies according to the outcome studied. Those who never received the benefit until the outcome or until the end of the follow-up will be defined as not exposed. The effects of BFP on maternal and child outcomes will be estimated by a combination of propensity score-based methods and weighted logistic regressions. The analyses will be further stratified to reflect changes in the benefit entitlement before and after 2012.DiscussionHarnessing a large linked administrative cohort allows us to assess the effect of the BFP on maternal and child health, while considering a wide range of explanatory and confounding variables.

The recently-emerged amphibian chytrid fungus Batrachochytrium dendrobatidis (Bd) has had an unprecedented impact on global amphibian populations, and highlights the urgent need to develop effective mitigation strategies. We conducted in-situ antifungal treatment experiments in wild populations of the endangered mountain yellow-legged frog during or immediately after Bd-caused mass die-off events. The objective of treatments was to reduce Bd infection intensity (“load”) and in doing so alter frog-Bd dynamics and increase the probability of frog population persistence despite ongoing Bd infection. Experiments included treatment of early life stages (tadpoles and subadults) with the antifungal drug itraconazole, treatment of adults with itraconazole, and augmentation of the skin microbiome of subadults with Janthinobacterium lividum, a commensal bacterium with antifungal properties. All itraconazole treatments caused immediate reductions in Bd load, and produced longer-term effects that differed between life stages. In experiments focused on early life stages, Bd load was reduced in the 2 months immediately following treatment and was associated with increased survival of subadults. However, Bd load and frog survival returned to pre-treatment levels in less than 1 year, and treatment had no effect on population persistence. In adults, treatment reduced Bd load and increased frog survival over the entire 3-year post-treatment period, consistent with frogs having developed an effective adaptive immune response against Bd. Despite this protracted period of reduced impacts of Bd on adults, recruitment into the adult population was limited and the population eventually declined to near-extirpation. In the microbiome augmentation experiment, exposure of subadults to a solution of J. lividum increased concentrations of this potentially protective bacterium on frogs. However, concentrations declined to baseline levels within 1 month and did not have a protective effect against Bd infection. Collectively, these results indicate that our mitigation efforts were ineffective in causing long-term changes in frog-Bd dynamics and increasing population persistence, due largely to the inability of early life stages to mount an effective immune response against Bd. This results in repeated recruitment failure and a low probability of population persistence in the face of ongoing Bd infection.

In sickle cell disease (SCD), the pathological shift of red blood cells (RBCs) into distorted morphologies under hypoxic conditions follows activation of a cationic leak current (Psickle) and cell dehydration. Prior work showed sickling was reduced by 5-hydroxylmethyl-2-furfural (5-HMF), which stabilized mutant hemoglobin and also blocked the Psickle current in RBCs, though the molecular basis of this 5-HMF-sensitive cation current remained a mystery. Work here is the first to test the hypothesis that Aquaporin-1 (AQP1) cation channels contribute to the monovalent component of Psickle. Human AQP1 channels expressed in Xenopus oocytes were evaluated for sensitivity to 5-HMF and four derivatives known to have differential efficacies in preventing RBC sickling. Ion conductances were measured by two-electrode voltage clamp, and osmotic water permeability by optical swelling assays. Compounds tested were: 5-HMF; 5-PMFC (5-(phenoxymethyl)furan-2-carbaldehyde); 5-CMFC (5-(4-chlorophenoxymethyl)furan-2-carbaldehyde); 5-NMFC (5-(2-nitrophenoxymethyl)-furan-2-carbaldehyde); and VZHE006 (tert-butyl (5-formylfuran-2-yl)methyl carbonate). The most effective anti-sickling agent, 5-PMFC, was the most potent inhibitor of the AQP1 ion conductance (98% block at 100 µM). The order of sensitivity of the AQP1 conductance to inhibition was 5-PMFC > VZHE006 > 5-CMFC ≥ 5-NMFC, which corresponded with effectiveness in protecting RBCs from sickling. None of the compounds altered AQP1 water channel activity. Combined application of a selective AQP1 ion channel blocker AqB011 (80 µM) with a selective hemoglobin modifying agent 5-NMFC (2.5 mM) increased anti-sickling effectiveness in red blood cells from human SCD patients. Another non-selective cation channel known to be expressed in RBCs, Piezo1, was unaffected by 2 mM 5-HMF. Results suggest that inhibition of AQP1 ion channels and capacity to modify hemoglobin are combined features of the most effective anti-sickling agents. Future therapeutics aimed at both targets could hold promise for improved treatments for SCD.

Animal models of disease are valuable resources for investigating pathogenic mechanisms and potential therapeutic interventions. However, for complex disorders such as Alzheimer’s disease (AD), the generation and availability of innumerous distinct animal models present unique challenges to AD researchers and hinder the success of useful therapies. Here, we conducted an in-depth analysis of the 3xTg-AD mouse model of AD across its lifespan to better inform the field of the various pathologies that appear at specific ages, and comment on drift that has occurred in the development of pathology in this line since its development 20 years ago. This modern characterization of the 3xTg-AD model includes an assessment of impairments in long-term potentiation followed by quantification of amyloid beta (Aβ) plaque burden and neurofibrillary tau tangles, biochemical levels of Aβ and tau protein, and neuropathological markers such as gliosis and accumulation of dystrophic neurites. We also present a novel comparison of the 3xTg-AD model with the 5xFAD model using the same deep-phenotyping characterization pipeline and show plasma NfL is strongly driven by plaque burden. The results from these analyses are freely available via the AD Knowledge Portal (https://modeladexplorer.org/). Our work demonstrates the utility of a characterization pipeline that generates robust and standardized information relevant to investigating and comparing disease etiologies of current and future models of AD.

Amphibians are declining globally, and the fungal pathogen Batrachochytrium dendrobatidis (Bd), which causes the disease chytridiomycosis, has been the culprit in many of these declines. In the Mediterranean region of Baja California, Mexico—a biodiversity hotspot—native amphibians are also in decline, and Bd is present. To determine which factors best predict Bd infection prevalence and intensity in Baja California anurans, we conducted Bd sampling at three disparate sites at varying elevations. We observed an overall Bd prevalence of 68%, and found that species was an important predictor of pathogen prevalence and burden (load) both across and within sites. Pathogen prevalence and load increased positively with elevation. The highest Bd load we detected was 139,188 zoospore equivalents (ZE) in a western toad (Anaxyrus boreas)—more than 10 times the pathogen burden at which chytridiomycosis is lethal in some species. We observed high Bd prevalence (84 – 99%) and Bd loads (> 44,000 ZE) in the California red-legged frog (Rana draytonii)—a cause for concern in this threatened anuran, especially at La Grulla—the highest elevation (2050 m) site for this species across its range. We sampled museum specimens to determine how long Bd has been present in the region, and detected the pathogen as early as 1932. Contemporary Bd prevalence and load in Baja California are considerably higher than would be expected given similar habitats and the same community composition as in southern California, USA. We therefore highlight the importance of historical context and comparative analyses in examining contemporary Bd dynamics, as well as adhering to strict biosecurity measures when implementing reintroductions and translocations.

It is clear that new approaches are needed to promote broadly protective immunity to viral pathogens, particularly those that are prone to mutation and escape from antibody-mediated immunity. Prototypic pathogens of this type are influenza and SARS-CoV-2, where the receptor-binding protein exhibits extremely high variability in its receptor-binding regions. T cells, known to target many viral proteins, and within these, highly conserved peptide epitopes, can contribute greatly to protective immunity through multiple mechanisms but are often poorly recruited by current vaccine strategies. Here, we have studied a promising novel pure enantio-specific cationic lipid 1,2-dioleoyl-3-trimethylammonium-propane (R-DOTAP), which was previously recognized for its ability to generate anti-tumor immunity through the induction of potent cytotoxic CD8 T cells. Using a preclinical mouse model, we have assessed an R-DOTAP nanoparticle adjuvant system for its ability to promote CD4 T cell responses to vaccination with recombinant influenza protein. Our studies revealed that R-DOTAP consistently outperformed a squalene-based adjuvant emulsion, even when it was introduced with a potent TLR agonist CpG, in the ability to elicit peptide epitope-specific CD4 T cells when quantified by IFN-γ and IL-2 ELISpot assays. Clinical testing of R-DOTAP containing vaccines in earlier work by others has demonstrated an acceptable safety profile. Hence, R-DOTAP can offer exciting opportunities as an immune stimulant for next-generation prophylactic recombinant protein-based vaccines.

Soft materials are usually defined as materials made of mesoscopic entities, often self-organised, sensitive to thermal fluctuations and to weak perturbations. Archetypal examples are colloids, polymers, amphiphiles, liquid crystals, foams. The importance of soft materials in everyday commodity products, as well as in technological applications, is enormous, and controlling or improving their properties is the focus of many efforts. From a fundamental perspective, the possibility of manipulating soft material properties, by tuning interactions between constituents and by applying external perturbations, gives rise to an almost unlimited variety in physical properties. Together with the relative ease to observe and characterise them, this renders soft matter systems powerful model systems to investigate statistical physics phenomena, many of them relevant as well to hard condensed matter systems. Understanding the emerging properties from mesoscale constituents still poses enormous challenges, which have stimulated a wealth of new experimental approaches, including the synthesis of new systems with, e.g. tailored self-assembling properties, or novel experimental techniques in imaging, scattering or rheology. Theoretical and numerical methods, and coarse-grained models, have become central to predict physical properties of soft materials, while computational approaches that also use machine learning tools are playing a progressively major role in many investigations. This Roadmap intends to give a broad overview of recent and possible future activities in the field of soft materials, with experts covering various developments and challenges in material synthesis and characterisation, instrumental, simulation and theoretical methods as well as general concepts.

Elevenins are peptides found in a range of organisms, including arthropods, annelids, nematodes, and molluscs. They consist of 17 to 19 amino acid residues with a single conserved disulfide bond. The subject of this study, elevenin-Vc1, was first identified in the venom of the cone snail Conus victoriae (Gen. Comp. Endocrinol. 2017, 244, 11–18). Although numerous elevenin sequences have been reported, their physiological function is unclear, and no structural information is available. Upon intracranial injection in mice, elevenin-Vc1 induced hyperactivity at doses of 5 or 10 nmol. The structure of elevenin-Vc1, determined using nuclear magnetic resonance spectroscopy, consists of a short helix and a bend region stabilised by the single disulfide bond. The elevenin-Vc1 structural fold is similar to that of α-conotoxins such as α-RgIA and α-ImI, which are also found in the venoms of cone snails and are antagonists at specific subtypes of nicotinic acetylcholine receptors (nAChRs). In an attempt to mimic the functional motif, Asp-Pro-Arg, of α-RgIA and α-ImI, we synthesised an analogue, designated elevenin-Vc1-DPR. However, neither elevenin-Vc1 nor the analogue was active at six different human nAChR subtypes (α1β1εδ, α3β2, α3β4, α4β2, α7, and α9α10) at 1 µM concentrations.

Abstract Background Keratoconus (KC) is a common corneal condition with an unknown gender predominance. Although numerous studies have investigated the genetic component of KC, no specific genes have yet been attributed to the condition. We recently reported posterior segment changes occurring in the eyes of KC patients. However, it is not clear whether these changes are part of KC pathogenesis or reflect changes in anatomical features of the eye manifested by changes at the cornea. Given retinal changes represent the main characteristics observed in age-related macular degeneration (AMD) and that pleiotropy has been demonstrated between different eye diseases, we wished to assess if known AMD associated genes were also associated with KC. Methods A total of 248 KC subjects and 366 non-KC (control) subjects were recruited from public and private clinics in Melbourne for this analysis. Nineteen single nucleotide polymorphisms (SNPs) previously associated with AMD, including rs10490924 (ARMS2/HTRA1), rs10737680 (CFH), rs13278062 (TNFRSF10A), rs1864163 (CETP), rs2230199 (C3), rs3130783 (IER3/DDR1), rs334353 (TGFBR1), rs3812111 (COL10A1), rs429608 (C2/CFB), rs4420638 (APOE), rs4698775 (CFI), rs5749482 (TIMP3), rs6795735 (ADAMTS9), rs8017304 (RAD51B), rs8135665 (SLC16A8), rs920915 (LIPC), rs943080 (VEGFA), rs9542236 (B3GALTL) and rs13081855 (COL8A1/FILIP1L), were genotyped in this cohort. Logistic regression was applied to evaluate the association between these SNPs and KC on both genders together, as well as each gender separately. Linear regression was also applied to assess the association between SNPs and corneal curvature. Bonferroni correction was applied to adjust for multiple testing. Results Genotyping data were available for 18 SNPs. The SNP, rs6795735 (ADAMTS9) was significantly associated with KC (p = 3.5 × 10− 4) when both genders were assessed, whereas rs5749482 (TIMP3) was only associated in males (p = 7.7 × 10− 4) following Bonferroni multiple correction. However, when the covariates of age and gender were included, the associations became non-significant. In addition, none of the SNPs appeared significant for corneal curvature. Conclusions Our study suggested a potential association of rs6795735 in the ADAMTS9 gene and rs5749482 in the TIMP3 gene in KC and that different associations may be gender specific. Overall, SNPs initially identified as associated with AMD following multiple correction may be further impacted by other factors such as age or gender and further studies are needed to resolve this issue.

BRCA1 mutations located within the BRCT domain result in proteasomal degradation and sensitivity to PARP inhibitors (PARPi). Here, the authors report genetic rearrangements in the BRCA1 gene that generate a BRCT-less BRCA1 protein isoform, which avoids degradation and leads to PARPi resistance.