Traumatic brain injury alters the effects of class II invariant peptide (CLIP) antagonism on chronic meningeal CLIP + B cells, neuropathology, and neurobehavioral impairment in 5xFAD mice.

BACKGROUND: Traumatic brain injury (TBI) is a significant risk factor for Alzheimer's disease (AD), and accumulating evidence supports a role for adaptive immune B and T cells in both TBI and AD pathogenesis. We previously identified B cell and major histocompatibility complex class II (MHCII)-associated invariant chain peptide (CLIP)-positive B cell expansion after TBI. We also showed that antagonizing CLIP binding to the antigen presenting groove of MHCII after TBI acutely reduced CLIP + splenic B cells and was neuroprotective. The current study investigated the chronic effects of antagonizing CLIP in the 5xFAD Alzheimer's mouse model, with and without TBI. METHODS: 12-week-old male wild type (WT) and 5xFAD mice were administered either CLIP antagonist peptide (CAP) or vehicle, once at 30 min after either sham or a lateral fluid percussion injury (FPI). Analyses included flow cytometric analysis of immune cells in dural meninges and spleen, histopathological analysis of the brain, magnetic resonance diffusion tensor imaging, cerebrovascular analysis, and assessment of motor and neurobehavioral function over the ensuing 6 months. RESULTS: 9-month-old 5xFAD mice had significantly more CLIP + B cells in the meninges compared to age-matched WT mice. A one-time treatment with CAP significantly reduced this population in 5xFAD mice. Importantly, CAP also improved some of the immune, histopathological, and neurobehavioral impairments in 5xFAD mice over the ensuing six months. Although FPI did not further elevate meningeal CLIP + B cells, it did negate the ability of CAP to reduce meningeal CLIP + B cells in the 5xFAD mice. FPI at 3 months of age exacerbated some aspects of AD pathology in 5xFAD mice, including further reducing hippocampal neurogenesis, increasing plaque deposition in CA3, altering microgliosis, and disrupting the cerebrovascular structure. CAP treatment after injury ameliorated some but not all of these FPI effects.

Halogen- and hydrogen-bonded self-assembled fibrillar networks of substituted 1,3:2,4-dibenzylidene-D-sorbitols (DBS).

Substituting the sole primary hydroxyl group of the low molecular weight organogelator (LMOG), 1,3:2,4-dibenzylidene-D-sorbitol (DBS), with a halogen atom (Cl, Br, or I; i.e., 6-Cl-DBS, 6-Br-DBS, or 6-I-DBS) drastically alters the supramolecular self-assembled fibrillar network (SAFiN) that forms when the molecules aggregate. The SAFiN varies depending on the solvent properties, impacting the role of non-covalent hydrogen- and halogen-bonding interactions along and between fibers. The halogenated DBS derivatives have more coherent crystalline fibers than DBS, with larger length-to-width aspect ratios. High-resolution synchrotron powder X-ray diffraction of each wet-state gel in toluene and DFT optimization obtained complete structures for the three halogenated DBS derivatives in their SAFiNs. The presence of a halogen atom reduces the reliance on hydrogen bonding by enabling new halogen bonding interactions that impact the self-assembly behavior, especially in solvents of higher polarity. For 6-I-DBS and 6-Br-DBS, the primary forces driving molecular self-assembly are C-H⋯π and intermolecular halogen-to-halogen interactions, and there is one unique molecule in each unit cell. However, the Cl atoms of 6-Cl-DBS are not close, and its SAFiN structures rely more on hydrogen bonding. As a result, the enhanced hydrogen bonding, electronic differences among the halogens, and spatial factors allow its unit cell to include two independent molecules of 6-Cl-DBS.

Mixed cyclo di-amino acids structured edible oils: a potential hardstock fat mimic.

Pure cyclic diamino acids (CdAA) gel differently than combinations of CdAAs, altering the gelation behavior to highly-branched colloidal protein crystal networks reminiscent of traditional fat crystal networks in canola oil, making it an exciting structuring agent for unsaturated oils.

Thin film epitaxial [111] Co[Formula: see text]Pt[Formula: see text]: structure, magnetisation, and spin polarisation.

Ferromagnetic films with perpendicular magnetic anisotropy are of interest in spintronics and superconducting spintronics. Perpendicular magnetic anisotropy can be achieved in thin ferromagnetic multilayer structures, when the anisotropy is driven by carefully engineered interfaces. Devices with multiple interfaces are disadvantageous for our application in superconducting spintronics, where the current perpendicular to plane is affected by the interfaces. Robust intrinsic PMA can be achieved in certain Co[Formula: see text]Pt[Formula: see text] alloys and compounds at any thickness, without increasing the number of interfaces. Here, we grow equiatomic Co[Formula: see text]Pt[Formula: see text] and report a comprehensive study on the structural, magnetic, and spin-polarisation properties in the [Formula: see text] and [Formula: see text] ordered compounds. Primarily, interest in Co[Formula: see text]Pt[Formula: see text] has been in the [Formula: see text] crystal structure, where layers of Pt and Co are stacked alternately in the [100] direction. There has been less work on [Formula: see text] crystal structure, where the stacking is in the [111] direction. For the latter [Formula: see text] crystal structure, we find magnetic anisotropy perpendicular to the film plane. For the former [Formula: see text] crystal structure, the magnetic anisotropy is perpendicular to the [100] plane, which is neither in-plane or out-of-plane in our samples. We obtain a value for the ballistic spin polarisation of the [Formula: see text] and [Formula: see text] Co[Formula: see text]Pt[Formula: see text] to be [Formula: see text].

Comparison of static and dynamic in vitro digestibility and bioaccessibility of palm-based emulsions and correlation to a human study: effects of triacylglycerol crystallinity.

The static and dynamic TIM-1 in vitro digestibility of similarly sized Span 60 o/w emulsions containing either liquid palm olein droplets (PO) or palm stearin (PS) droplets tempered to contain different levels of crystallinity (i.e., PS-SE (maximum), PS-SE-INT (intermediate), and PS-LE (undercooled)) were explored. Static in vitro digestion experiments included particle size analysis, and emulsion digestibility and bioaccessibility were compared between the static and dynamic models, respectively. ß-carotene (BC, 0.1 wt%) was also incorporated in the emulsions to determine the influence of triacylglycerol (TAG) crystallinity on BC bioaccessibility and stability during storage under accelerated lighting conditions. TAG crystallinity altered the colloidal fat crystal network properties and ultimately impacted lipid digestion, attenuating early static in vitro lipolysis for the PS emulsions compared to the PO emulsion. This correlated well with TIM-1 bioaccessibility trends and with results from our results of a previous human study wherein the rise in postprandial TAG was delayed when healthy men consumed PS-SE versus PS-LE. The presence of crystalline TAG modestly accelerated BC degradation, and did not improve preservation nor alter BC in vitro bioaccessibility.

Systemic Challenges in Internship Training for Health-Service Psychology: A Call to Action From Trainee Stakeholders.

The challenges observed in health service psychology (HSP) training during COVID-19 revealed systemic and philosophical issues that preexisted the pandemic, but became more visible during the global health crisis. In a position paper written by 23 trainees across different sites and training specializations, the authors use lessons learned from COVID-19 as a touchstone for a call to action in HSP training. Historically, trainee voices have been conspicuously absent from literature about clinical training. We describe longstanding dilemmas in HSP training that were exacerbated by the pandemic and will continue to require resolution after the pandemic has subsided. The authors make recommendations for systems-level changes that would advance equity and sustainability in HSP training. This article advances the conversation about HSP training by including the perspective of trainees as essential stakeholders.

Unilateral Cervical Vagotomy Modulates Immune Cell Profiles and the Response to a Traumatic Brain Injury.

TBI induces splenic B and T cell expansion that contributes to neuroinflammation and neurodegeneration. The vagus nerve, the longest of the cranial nerves, is the predominant parasympathetic pathway allowing the central nervous system (CNS) control over peripheral organs, including regulation of inflammatory responses. One way this is accomplished is by vagus innervation of the celiac ganglion, from which the splenic nerve innervates the spleen. This splenic innervation enables modulation of the splenic immune response, including splenocyte selection, activation, and downstream signaling. Considering that the left and right vagus nerves have distinct courses, it is possible that they differentially influence the splenic immune response following a CNS injury. To test this possibility, immune cell subsets were profiled and quantified following either a left or a right unilateral vagotomy. Both unilateral vagotomies caused similar effects with respect to the percentage of B cells and in the decreased percentage of macrophages and T cells following vagotomy. We next tested the hypothesis that a left unilateral vagotomy would modulate the splenic immune response to a traumatic brain injury (TBI). Mice received a left cervical vagotomy or a sham vagotomy 3 days prior to a fluid percussion injury (FPI), a well-characterized mouse model of TBI that consistently elicits an immune and neuroimmune response. Flow cytometric analysis showed that vagotomy prior to FPI resulted in fewer CLIP+ B cells, and CD4+, CD25+, and CD8+ T cells. Vagotomy followed by FPI also resulted in an altered distribution of CD11bhigh and CD11blow macrophages. Thus, transduction of immune signals from the CNS to the periphery via the vagus nerve can be targeted to modulate the immune response following TBI.

Analysis of rare disruptive germline mutations in 2135 enriched BRCA-negative breast cancers excludes additional high-impact susceptibility genes.

BACKGROUND: Breast cancer has a significant heritable basis, of which ∼60% remains unexplained. Testing for BRCA1/BRCA2 offers useful discrimination of breast cancer risk within families, and identification of additional breast cancer susceptibility genes could offer clinical utility. PATIENTS AND METHODS: We included 2135 invasive breast cancer cases recruited via the Breast and Ovarian Cancer Susceptibility study, a retrospective UK study of familial breast cancer. ELIGIBILITY CRITERIA: female, BRCA-negative, white European ethnicity, and one of: (i) breast cancer family history, (ii) bilateral disease, (iii) young age of onset (<30 years), and (iv) concomitant ovarian cancer. We undertook exome sequencing of cases and carried out gene-level burden testing of rare damaging variants against those from 51 377 ethnicity-matched population controls from gnomAD. RESULTS: 159/2135 (7.4%) cases had a qualifying variant in an established breast cancer susceptibility gene, with minimal evidence of signal in other cancer susceptibility genes. Known breast cancer susceptibility genes PALB2, CHEK2, and ATM were the only genes to retain statistical significance after correcting for multiple testing. Due to the enrichment of hereditary cases in the series, we had good power (>80%) to detect a gene of BRCA1-like risk [odds ratio (OR) = 10.6] down to a population minor allele frequency of 4.6 × 10-5 (1 in 10 799, less than one-tenth that of BRCA1)and of PALB2-like risk (OR = 5.0) down to a population minor allele frequency of 2.8 × 10-4 (1 in 1779, less than half that of PALB2). Power was lower for identification of novel moderate penetrance genes (OR = 2-3) like CHEK2 and ATM. CONCLUSIONS: This is the largest case-control whole-exome analysis of enriched breast cancer published to date. Whilst additional breast cancer susceptibility genes likely exist, those of high penetrance are likely to be of very low mutational frequency. Contention exists regarding the clinical utility of such genes.

Single cell multi-omics characterise discrete human tendon cells populations that persist in vitro and on fibrous scaffolds.

Chronic tendinopathy represents a growing healthcare burden in the ageing global population. Curative therapies remain elusive as the mechanisms that underlie chronic inflammation in tendon disease remain unclear. Identifying and isolating key pathogenic and reparative cells is essential in developing precision therapies and implantable materials for improved tendon healing. Multiple discrete human tendon cell populations have been previously described ex vivo. To determine if these populations persist in vitro, healthy human hamstring tenocytes were cultured for 8 d on either tissue culture plastic or aligned electrospun fibres of absorbable polydioxanone. Novel single-cell surface proteomics combined with unbiased single-cell transcriptomics (CITE-Seq) was used to identify discrete tenocyte populations. 6 cell populations were found, 4 of which shared key gene expression determinants with ex vivo human cell clusters: PTX3_PAPPA, POSTN_SCX, DCN_LUM and ITGA7_NES. Surface proteomics found that PTX3_PAPPA cells were CD10+CD26+CD54+. ITGA7_NES cells were CD146+ and POSTN_SCX cells were CD90+CD95+CD10+. Culture on the aligned electrospun fibres favoured 3 cell subtypes (DCN_LUM, POSTN_SCX and PTX3_ PAPPA), promoting high expression of tendon-matrix-associated genes and upregulating gene sets enriched for TNF-a and IL-6/STAT3 signalling. Discrete human tendon cell subpopulations persisted in in vitro culture and could be recognised by specific gene and surface-protein signatures. Aligned polydioxanone fibres promoted the survival of 3 clusters, including pro-inflammatory PTX3-expressing CD10+CD26+CD54+ cells found in chronic tendon disease. These results improved the understanding of preferred culture conditions for different tenocyte subpopulations and informed the development of in vitro models of tendon disease.

Agent-based epidemiological modeling of COVID-19 in localized environments.

Epidemiological modeling is used, under certain assumptions, to represent the spread of a disease within a population. Information generated by these models can then be applied to inform public health practices and mitigate risk. To provide useful and actionable preparedness information to administrators and policy makers, epidemiological models must be formulated to model highly localized environments such as office buildings, campuses, or long-term care facilities. In this paper, a highly configurable agent-based simulation (ABS) framework designed for localized environments is proposed. This ABS provides information about risk and the effects of both pharmacological and non-pharmacological interventions, as well as detailed control over the rapidly evolving epidemiological characteristics of COVID-19. Simulation results can inform decisions made by facility administrators and be used as inputs for a complementary decision support system. The application of our ABS to our research lab environment as a proof of concept demonstrates the configurability and insights achievable with this form of modeling, with future work focused on extensibility and integration with decision support.

Lipid crystallinity of oil-in-water emulsions alters in vitro.

10 wt% oil-in-water emulsions with varied palm olein and stearin PO:PS ratios stabilized with 0.8 wt% Tween80 and tempered to obtain partially crystalline (CR) droplets (cooled from 80 to 4 °C and held overnight to induce nucleation/crystallization) or undercooled liquid (UC) droplets (cooled from 80 °C to 37 °C) produced emulsions with constant droplet size and polymorphism. However, zeta-potential decreased in undercooled emulsions due to crystallization/orientation of interfacial Tween, increasing alignment and ultimately a greater dipole moment. Significant differences in overall bioaccessibility between PO and PS present for the CR (PO bioaccessible fraction was 91%, whereas PS was 60%) and UC emulsions (PO and PS bioaccessibility were 96% and 77%).When only the solid fat content differs, and all other physical attributes remain constant, lipid digestibility decreases with increasing solid fat content; these findings, along with others, can be employed during food formulation and design more healthful foods.

The ionophore thiomaltol induces rapid lysosomal accumulation of copper and apoptosis in melanoma.

In this report, we investigate the toxicity of the ionophore thiomaltol (Htma) and Cu salts to melanoma. Divalent metal complexes of thiomaltol display toxicity against A375 melanoma cell culture resulting in a distinct apoptotic response at submicromolar concentrations, with toxicity of Cu(tma)2 > Zn(tma)2 >> Ni(tma)2. In metal-chelated media, Htma treatment shows little toxicity, but the combination with supplemental CuCl2, termed Cu/Htma treatment, results in toxicity that increases with suprastoichiometric concentrations of CuCl2 and correlates with the accumulation of intracellular copper. Electron microscopy and confocal laser scanning microscopy of Cu/Htma treated cells shows a rapid accumulation of copper within lysosomes over the course of hours, concurrent with the onset of apoptosis. A buildup of ubiquitinated proteins due to proteasome inhibition is seen on the same timescale and correlates with increases of copper without additional Htma.

Re-opening live events and large venues after Covid-19 'lockdown': Behavioural risks and their mitigations.

This article reviews the behavioural risks and possible mitigations for re-opening large venues for sports and music events when Covid-19 infection rates and hospitalizations begin to decline. We describe the key variables that we suggest will affect public behaviour relevant to the spread of the virus, drawing upon four sources: (1) relevant evidence and recommendations from the Scientific Pandemic Influenza Group on Behaviours produced for the Scientific Advisory Group for Emergencies (SAGE); (2) research evidence from non-pandemic conditions; (3) research on behaviour during the pandemic; and (4) relevant theory. We first outline some basic risks and a framework for understanding collective behaviour at live events. We then survey some trends in UK public behaviour observed over 2020 and how these might interact with the opening of live events and venues. We present a range of mitigation strategies, based on the framework for collective behaviour and on what is known about non-pharmaceutical (i.e. behavioural) interventions in relation to Covid-19.

Sous Vide Cook Temperature Alters the Physical Structure and Lipid Bioaccessibility of Beef Longissimus Muscle in TIM-1.

Changes in the physical states, induced with different sous vide cooking temperatures, significantly (P < 0.05) altered lipid bioaccessibility measured in the TNO-simulated gastrointestinal tract model-1 of AAA boneless beef striploin, containing the longissimus lumborum muscle. The denaturation of actin significantly correlates with the total cumulative free fatty acid (FFA) bioaccessibility, whereby the striploin cooked to 60 °C presents the maximum lipid bioaccessibility (15.8 ± 1.0%), rate constant (ka) for FFA hydrolysis (0.087 ± 0.003 min-1), and greatest actin denaturation enthalpy (-0.57 ± 0.06 ΔH). Thus, thermal treatments above 60 °C significantly decrease the kinetics of lipolysis (70 °C = 0.042 ± 0.002 min-1 and 80 °C = 0.047 ± 0.002 min-1) and the resultant total lipid bioaccessibility (70 °C = 8.6 ± 0.7 and 80 °C = 8.3 ± 0.5%). This research highlights the potential to manipulate the physical food structure to alter digestion kinetics, supporting the need to understand supramolecular structures in food and their nutritional outcomes.

Partial Budget Analysis of Exclusion Netting and Organic-certified Insecticides for Management of Spotted-wing Drosophila (Diptera: Drosophilidae) on Small Farms in the Upper Midwest.

Drosophila suzukii Matsumura (Diptera: Drosophilidae), or spotted-wing drosophila, is an invasive pest first detected in the United States in 2008. Although D. suzukii can use many cultivated fruit as hosts, raspberries are considered 'most at risk' for infestation. Conventional broad-spectrum insecticides are proven effective D. suzukii controls and can be economically profitable when combined with integrated pest management (IPM) on large-scale commercial raspberry farms. It remains unclear, however, whether organic controls are cost-effective strategies, particularly for farms operating on a small-scale seasonal basis, as is common in the Upper Midwest. The purpose of this paper is to explore the efficacy of two organic D. suzukii controls-exclusion netting for high tunnels and organic insecticides for open plots using data available from different field trials-and to ascertain whether any economic benefits of the organic controls outweigh treatment costs for small-scale raspberry operations under different risk scenarios. The field trials suggest that the organic treatments are effective controls for D. suzukii infestation and economically profitable. The exclusion netting treatment produced positive net returns compared to the alternative of no treatment and economically outperformed the organic-certified insecticide treatment for several yield, price and infestation scenarios. As D. suzukii infestation rates increased, net returns improved for both organic treatments. The economic results were robust across a range of yields and prices, suggesting that in almost all scenarios small scale organic raspberry growers benefit economically from the application of exclusion netting on high tunnels and insecticides for open plots.

High-throughput organ-on-chip platform with integrated programmable fluid flow and real-time sensing for complex tissue models in drug development workflows.

Drug development suffers from a lack of predictive and human-relevant in vitro models. Organ-on-chip (OOC) technology provides advanced culture capabilities to generate physiologically appropriate, human-based tissue in vitro, therefore providing a route to a predictive in vitro model. However, OOC technologies are often created at the expense of throughput, industry-standard form factors, and compatibility with state-of-the-art data collection tools. Here we present an OOC platform with advanced culture capabilities supporting a variety of human tissue models including liver, vascular, gastrointestinal, and kidney. The platform has 96 devices per industry standard plate and compatibility with contemporary high-throughput data collection tools. Specifically, we demonstrate programmable flow control over two physiologically relevant flow regimes: perfusion flow that enhances hepatic tissue function and high-shear stress flow that aligns endothelial monolayers. In addition, we integrate electrical sensors, demonstrating quantification of barrier function of primary gut colon tissue in real-time. We utilize optical access to the tissues to directly quantify renal active transport and oxygen consumption via integrated oxygen sensors. Finally, we leverage the compatibility and throughput of the platform to screen all 96 devices using high content screening (HCS) and evaluate gene expression using RNA sequencing (RNA-seq). By combining these capabilities in one platform, physiologically-relevant tissues can be generated and measured, accelerating optimization of an in vitro model, and ultimately increasing predictive accuracy of in vitro drug screening.

Inhibition of HERV-K (HML-2) in amyotrophic lateral sclerosis patients on antiretroviral therapy.

Reactivation of Human Endogenous Retrovirus K (HERV-K), subtype HML-2, has been associated with pathophysiology of amyotrophic lateral sclerosis (ALS). We aimed to assess the efficacy of antiretroviral therapy in inhibiting HML-2 in patients with ALS and a possible association between the change in HML-2 levels and clinical outcomes. We studied the effect of 24-weeks antiretroviral combination therapy with abacavir, lamivudine, and dolutegravir on HML-2 levels in 29 ALS patients. HML-2 levels decreased progressively over 24 weeks (P = 0.001) and rebounded within a week of stopping medications (P = 0.02). The majority of participants (82%), defined as "responders", experienced a decrease in HML-2 at week 24 of treatment compared to the pre-treatment levels. Differences in the evolution of some of the clinical outcomes could be seen between responders and non-responders: FVC decreased 23.69% (SE = 11.34) in non-responders and 12.71% (SE = 8.28) in responders. NPI score decreased 91.95% (SE = 6.32) in non-responders and 53.05% (SE = 10.06) in responders (P = 0.01). Thus, participants with a virological response to treatment showed a trend for slower progression of the illness. These findings further support the possible involvement of HML-2 in the clinical course of the disease.

Micro-CT imaging of Onchocerca infection of Simulium damnosum s.l. blackflies and comparison of the peritrophic membrane thickness of forest and savannah flies.

Onchocerciasis is a neglected tropical disease (NTD) caused by Onchocerca Diesing 1841 (Spirurida: Onchocercidae) nematodes transmitted by blackflies. It is associated with poverty and imposes a significant health, welfare and economic burden on many tropical countries. Current methods to visualize infections within the vectors rely on invasive methods. However, using micro-computed tomography techniques, without interference from physical tissue manipulation, we visualized in three dimensions for the first time an L1 larva of an Onchocerca species within the thoracic musculature of a blackfly, Simulium damnosum s.l. Theobald 1903 (Diptera: Simuliidae), naturally infected in Ghana. The possibility that thicker peritrophic membranes in savannah flies could account for their lower parasite loads was not supported, but there were limits to our analysis. While there were no statistically significant differences between the mean thicknesses of the peritrophic membranes, in the anterior, dorsal and ventral regions, of forest and savannah blackflies killed 34-48 min after a blood-meal, the thickness of the peritrophic membrane in the posterior region could not be measured. Micro-computed tomography has the potential to provide novel information on many other parasite/vector systems and impactful images for public engagement in health education.

Untangling biomechanical differences in perturbation-induced stepping strategies for lateral balance stability in older individuals.

When recovering balance from a lateral perturbation, younger adults tend to stabilize balance with a single lateral sidestep while older adults often take multistep responses. Using multiple steps to recover balance is consistently associated with increased fall risk, altered body center of mass (CoM) control and instability. The aim of this study was to compare the spatio-temporal stepping characteristics and the margin of stability (MoS) of single lateral sidesteps (LSS1) with the first and second steps of a two-step protective step sequence. Two-step sequences begin with either a cross-over step to the front or back, or a medial step followed by a lateral sidestep. Seventy-one older adults received random lateral waist-pull perturbations to either side. We hypothesized that LSS1 would be more stable (larger MoS) than either step in a two-step sequence. With some exceptions, utilizing a two-step sequence was associated with a reduced CoM velocity and distance between the base of support and CoM and decreased stability in the frontal plane following limb loading of the first and second step. There were no differences in the time available to arrest the extrapolated CoM at the end of a single lateral sidestep or the final step of a two-step sequence. Two-step sequences involving a cross-over step include more complex stepping trajectories and also challeng stability in the sagittal plane requiring a multidimensional balance correction. These results indicate important step type differences in center of mass control in recovering balance with a single lateral sidestep as opposed to a two-step sequence among older adults.