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Abstract Science and science policy are characterised by expectations. These expectations—as in the field of biomedicine—may be related to describing novel findings, their use in curing diseases or their economic benefits. Previous research has shown that expectations are often communicated with the help of metaphors. In this article, we take a closer look at one metaphor—‘closing window of opportunity’—and examine how it frames discussions about policy and regulatory change in biomedicine through the lenses of urgency and national unity. A key component of the generative metaphor of a ‘closing window’ is the focus on limited time and a sense of urgency related to the creation of an enabling environment for biomedical research and innovations. We focus on two key elements of this framing: international competitiveness and national unity. Moreover, drawing on urgency seems to be a standard response to the changing environment, in which the actors need to continuously guide their actions in new directions, meeting new demands posed by, for example, technological development or regulatory changes. We argue that while the metaphor of a closing window creates room for innovations and competitiveness, it is prone to silence critical discussions, for example on sustainability, responsibility and accountability. This leaves out important discussions about values, benefits and risks. With this analysis, we contribute to discussions about the sociology of (negative) expectations and generative metaphors and show how urgency can remain as a constant state of things.

Sands from the dune, berm, and shore environments at Playa las Golondrinas (18° 30′ 51″ N, 67° 3′ 26″) were investigated to explore how beach sands could be applied as a potential environmental (geogenic) background for the local region. Grain size is dominantly unimodal classifying as fine to medium sand. Hydraulic conductivity values range from 1.07 cm/s (berm) to 1.49 cm/s (shoreface). Sample mineralogy as constrained by X-ray diffraction (XRD) reveals a dominance of quartz and feldspar with minor Mg-calcite, pyroxene, and olivine. Light microscopy and scanning electron microscopy-energy dispersive spectroscopy (SEM–EDS) support XRD data and indicate the presence of oxide-bearing lithic fragments in addition to biologic materials (e.g., corals. forams). Reflective spectra are consistent with XRD and microscopy. Bulk element concentrations determined using inductively coupled plasma—mass spectrometry (ICP-MS) are consistent with derivation from the arc-related rocks of Puerto Rico's interior exhibiting LILE enrichment, Pb-enrichment, and associated Nb–Ta depletion. The majority of the bulk elemental concentrations are below those of average upper continental crust (UCC) values and element co-variation trends (e.g., wt. % Fe2O3 vs. As) are interpreted as geogenic in origin. Berm sands are enriched in Fe, Mn, Ni, Cr, V, and As compared to dune and shore samples and this signature is interpreted as being from a wind-driven winnowing effect. The exact form of As (As3+ or As5+) remains unconstrained and thus it is unknown if As is mobile in this environment. Reflective spectra, supported by grain size, mineralogy, and bulk chemistry, enables future remote sensing investigations by providing detailed constraints on sand in environmentally sensitive areas. This study therefore provides local context for metal pollution studies across the region. [ABSTRACT FROM AUTHOR]

The role of myeloid cells in the pathogenesis of SARS-CoV-2 is well established, in particular as drivers of cytokine production and systemic inflammation characteristic of severe COVID-19. However, the potential for myeloid cells to act as bona fide targets of productive SARS-CoV-2 infection, and the specifics of entry, remain unclear. Using a panel of anti-SARS-CoV-2 monoclonal antibodies (mAbs) we performed a detailed assessment of antibody-mediated infection of monocytes/macrophages. mAbs with the most consistent potential to mediate infection were those targeting a conserved region of the receptor binding domain (RBD; group 1/class 4). Infection was closely related to the neutralising concentration of the mAbs, with peak infection occurring below the IC50, while pre-treating cells with remdesivir or FcγRI-blocking antibodies inhibited infection. Studies performed in primary macrophages demonstrated high-level and productive infection, with infected macrophages appearing multinucleated and syncytial. Infection was not seen in the absence of antibody with the same quantity of virus. Addition of ruxolitinib significantly increased infection, indicating restraint of infection through innate immune mechanisms rather than entry. High-level production of pro-inflammatory cytokines directly correlated with macrophage infection levels. We hypothesise that infection via antibody-FcR interactions could contribute to pathogenesis in primary infection, systemic virus spread or persistent infection. Macrophages drive inflammation associated with severe COVID-19 but it is less clear whether they can be infected. Here, the authors show efficient antibody-mediated infection of primary macrophages by SARS-CoV-2, leading to cell fusion, de novo virus production and a potent cytokine response. [ABSTRACT FROM AUTHOR]

Bees are essential pollinators for many plant species, but multiple threats exist to both managed and wild bee populations. Since bee nutrition is critical for hive and colony health, their innate foraging behaviors and food preferences are the subject of extensive study. Multiple approaches have been developed to assess bee foraging behavior and associated preferences, but these approaches are often labor-intensive and provide data on a limited number of parameters. In this manuscript, we present an improved method to quantify bee foraging preferences, including the design, build, and implementation of an inexpensive and automated feeding apparatus capable of recording (1) environmental conditions, (2) species and behavior through photos and videos, (3) foraging activity, and (4) food consumption. The efficacy of this apparatus is demonstrated through preference tests with artificial nectars, while also acknowledging the limitations of this approach. [ABSTRACT FROM AUTHOR]

The document published in the Journal of Neurology discusses a case study of a 45-year-old male with Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS). The patient presented with typical clinical features of CANVAS, including cognitive impairment, progressive imbalance, and sensory neuronopathy. Genetic analysis revealed a compound heterozygous copy number variant (CNV) and a pathogenic AAGGG(n) expansion in RFC1, expanding the understanding of the genetic mechanisms underlying CANVAS. The study highlights the importance of sequencing RFC1 in patients with a clinical diagnosis of CANVAS to identify potential genetic causes. [Extracted from the article]

While co-design methods are crucial for developing digital educational interventions that are user-centred, contextually relevant, inclusive, and effective in meeting the diverse needs of learners and educators, little attention has been paid to the potential value of co-design processes for digital application development in the Defence context. This research gauged the efficacy of combining a generative co-design framework making use of agile and iterative co-design principles in an applied research and development project. The project produced an immersive virtual reality based digital solution in collaboration with the Australian Defence Force Special Operations Command (SOCOMD) Army. Specifically, the ParaVerse project sought to develop a solution considering the advanced Tactics, Techniques and Procedures (TTPs) relevant to special operations soldiers for advanced parachute training. A Defence advisory group consisting of a series of subject matter experts was formulated to consult with the research and development team over the course of the co-design process. End-user testing with 35 SOCOMD personnel demonstrated the value of the ParaVerse application for SOCOMD personnel, speaking to the success of the leveraged generative co-design model. End-users rated ParaVerse as having greater capacity to influence education and training practices for SOCOMD and Defence generally in comparison to a pre-existing virtual parachute simulator. ParaVerse was also rated higher for satisfaction and useability and was associated with fewer instances of motion sickness. The Generative Co-Design Framework leveraged for this research provides one roadmap on how to integrate end-users in innovation design, particularly for projects working across the nexus of Defence and academia. [ABSTRACT FROM AUTHOR]

Older female mice show poor spatial memory when their paternal X chromosome is inactive and only the maternal copy is active. This phenomenon could be responsible for variation in age-related cognitive decline among women. X-chromosome inactivation affects age-related decline in spatial memory. [ABSTRACT FROM AUTHOR]

Background and context of the study: This research employed a person-centred approach to evaluate the effectiveness of a recruitment intervention aimed at attracting STEM undergraduate students to the teaching profession. The study aimed to identify participant profiles based on changes of interest in teaching, examine the demographic factors associated with these profiles, and explore the outcomes associated with the identified profiles. A total of 267 participants from 18 universities in England were recruited for the study. The intervention involved presenting 12 vignettes that depicted different motivations for choosing teaching as a career. Participants rated their change of interest in teaching after reading each vignette. Results: The latent profile analysis revealed four distinct profiles: dissuaded participants, unpersuaded participants, moderately persuaded participants, and highly persuaded participants. The highly persuaded profile reported the highest levels of self-efficacy, interest, perceived fit, and enjoyment in teaching. Participants from higher socioeconomic backgrounds were more likely to be persuaded by the recruitment intervention, but gender, ethnicity, or program levels did not significantly affect profile membership. Conclusions: The findings demonstrate the potential of recruitment interventions to influence the interest of STEM undergraduate students in teaching and underscore the importance of considering individual characteristics and motivations when attracting prospective teachers to the profession. [ABSTRACT FROM AUTHOR]

Humans have drastically altered the ecology of heavy metals, which can have negative effects on animal development and neural functioning. Many species have shown the ability to adapt to anthropogenic increases in metal pollution, but such evolutionary responses will depend on the extent of metal variation over space and time. For terrestrial vertebrates, it is unclear how metal exposure has changed over time: some studies suggest metal content peaked with the enactment of policies controlling lead emissions, while other studies suggest metal levels peaked at least a century earlier. We used 162 specimens of four mammal species (a mouse, shrew, bat, and squirrel) to ask how metal content of the fur and skin has changed over a 90-year time period, and impacts on individual performance (body size and cranial capacity). Using ICP-MS, we show that for lead, cadmium, copper, and chromium, there were significant declines in metal content in mammal tissue over the 90-year time period, with lead levels five times lower now than in the early 1900s. Importantly, metal content began to drop well before the pollution regulation of the 1970s. Effects of time greatly outweighed any effects of an individual living near a human population center. Surprisingly, there were no effects of body metal content on body size, and only manganese was negatively related to relative cranial capacity. Taken together, these results suggest that present day populations of mammals are experiencing levels of heavy metal exposure that are less stressful than they were 100 years ago. In addition, temporal decreases in metal loads likely partly reflect global patterns of pollution decline that affect atmospheric metal deposition rather than local point sources of exposure. [ABSTRACT FROM AUTHOR]

Purpose of Review: Cardiovascular disease (CVD) is the leading cause of mortality in people who have diabetes. Racial and ethnic minorities with diabetes have suboptimal management of cardiovascular risk factors, leading to higher mortality. Social and structural determinants of health are external factors that influence an individual's ability to choose positive health behaviors. In this review, we will discuss cardiovascular complications in people who have diabetes and their relationship to social determinants of health (SDOH). Recent Findings: Recent innovations in diabetes treatment, including new devices and medications, have improved care and survival. However, disparities in the availability of these treatments to racial and ethnic minorities may contribute to continued inequities in CVD outcomes. Summary: Racial/ethnic disparities in CVD relate to inequities in economic opportunity, education and health literacy, neighborhoods and social cohesion, and health care access and quality driven by structural racism. [ABSTRACT FROM AUTHOR]

Abstract The modulation of pre‐mRNA splicing is proposed as an attractive anti‐neoplastic strategy, especially for the cancers that exhibit aberrant pre‐mRNA splicing. Here, we discovered that T‐025 functions as an orally available and potent inhibitor of Cdc2‐like kinases (CLKs), evolutionally conserved kinases that facilitate exon recognition in the splicing machinery. Treatment with T‐025 reduced CLK‐dependent phosphorylation, resulting in the induction of skipped exons, cell death, and growth suppression in vitro and in vivo. Further, through growth inhibitory characterization, we identified high CLK2 expression or MYC amplification as a sensitive‐associated biomarker of T‐025. Mechanistically, the level of CLK2 expression correlated with the magnitude of global skipped exons in response to T‐025 treatment. MYC activation, which altered pre‐mRNA splicing without the transcriptional regulation of CLKs, rendered cancer cells vulnerable to CLK inhibitors with synergistic cell death. Finally, we demonstrated in vivo anti‐tumor efficacy of T‐025 in an allograft model of spontaneous, MYC‐driven breast cancer, at well‐tolerated dosage. Collectively, our results suggest that the novel CLK inhibitor could have therapeutic benefits, especially for MYC‐driven cancer patients.

Triazole antifungals function as ergosterol biosynthesis inhibitors and are frontline therapy for invasive fungal infections, such as invasive aspergillosis. The primary mechanism of action of triazoles is through the specific inhibition of a cytochrome P450 14-α-sterol demethylase enzyme, Cyp51A/B, resulting in depletion of cellular ergosterol. Here, we uncover a clinically relevant secondary mechanism of action for triazoles within the ergosterol biosynthesis pathway. We provide evidence that triazole-mediated inhibition of Cyp51A/B activity generates sterol intermediate perturbations that are likely decoded by the sterol sensing functions of HMG-CoA reductase and Insulin-Induced Gene orthologs as increased pathway activity. This, in turn, results in negative feedback regulation of HMG-CoA reductase, the rate-limiting step of sterol biosynthesis. We also provide evidence that HMG-CoA reductase sterol sensing domain mutations previously identified as generating resistance in clinical isolates of Aspergillus fumigatus partially disrupt this triazole-induced feedback. Therefore, our data point to a secondary mechanism of action for the triazoles: induction of HMG-CoA reductase negative feedback for downregulation of ergosterol biosynthesis pathway activity. Abrogation of this feedback through acquired mutations in the HMG-CoA reductase sterol sensing domain diminishes triazole antifungal activity against fungal pathogens and underpins HMG-CoA reductase-mediated resistance. Triazole antifungals are widely used and exert their action by inhibiting ergosterol biosynthesis. Here, Rybak et al show that these drugs both inhibit ergosterol biosynthesis and induce accumulation of pathway intermediates that directly induce inhibition of sterol synthesis. [ABSTRACT FROM AUTHOR]

Knowledge of factors associated with semen quality may help in investigations of the aetiology and pathophysiology. We investigated the correlation between biomarkers for testicular cell function (anti-müllerian hormone, AMH, Inhibin B, testosterone, free androgen-index (testosterone/sex-hormone binding globulin), insulin like peptide 3, INSL-3), alkaline phosphate (ALP), canine prostate-specific esterase (CPSE), and heterophilic antibodies with dog variables, semen quality, and fertility. Blood and semen were collected from 65 Bernese Mountain Dogs. We evaluated total sperm count, motility and morphological parameters. The semen quality ranged from poor to excellent, with an average total sperm count of 1.1 × 109 and 50% morphologically normal spermatozoa (MNS). Age and abnormal testicular consistency correlated with decreased motility and MNS. Higher ALP correlated with higher total sperm count. AMH could not be detected in seminal plasma. AMH in blood correlated with head defects and high AMH concentration correlated with a severe decline in several semen parameters. Testosterone was negatively and CPSE positively correlated with age. No correlations were found for INSL-3, inhibin B, or heterophilic antibodies. Our findings contribute to the understanding of factors associated with semen quality in dogs, particularly related to Sertoli cell function. [ABSTRACT FROM AUTHOR]

Background: Laparoscopic training remains inaccessible for surgeons in low- and middle-income countries, limiting its widespread adoption. We developed a novel tool for assessment of laparoscopic appendectomy skills through ALL-SAFE, a low-cost laparoscopy training system. Methods: This pilot study in Ethiopia, Cameroon, and the USA assessed appendectomy skills using the ALL-SAFE training system. Performance measures were captured using the ALL-SAFE verification of proficiency tool (APPY-VOP), consisting of a checklist, modified Objective Structured Assessment of Technical Skills (m-OSATS), and final rating. Twenty participants, including novice (n = 11), intermediate (n = 8), and expert (n = 1), completed an online module covering appendicitis management and psychomotor skills in laparoscopic appendectomy. After viewing an expert skills demonstration video, participants recorded their performance within ALL-SAFE. Using the APPY-VOP, participants rated their own and three peer videos. We used the Kruskal–Wallis test and a Many-Facet Rasch Model to evaluate (i) capacity of APPY-VOP to differentiate performance levels, (ii) correlation among three APPY-VOP components, and (iii) rating differences across groups. Results: Checklist scores increased from novice (M = 21.02) to intermediate (M = 23.64) and expert (M = 28.25), with differentiation between experts and novices, P = 0.005. All five m-OSATS domains and global summed, total summed, and final rating discriminated across all performance levels (P < 0.001). APPY-VOP final ratings adequately discriminated Competent (M = 2.0), Borderline (N = 1.8), and Not Competent (M = 1.4) performances, Χ2 (2,85) = 32.3, P = 0.001. There was a positive correlation between ALL-SAFE checklist and m-OSATS summed scores, r(83) = 0.63, P < 0.001. Comparison of ratings suggested no differences across expertise levels (P = 0.69) or location (P = 0.66). Conclusion: APPY-VOP effectively discriminated between novice and expert performance in laparoscopic appendectomy skills in a simulated setting. Scoring alignment across raters suggests consistent evaluation, independent of expertise. These results support the use of APPY-VOP among all skill levels inside a peer rating system. Future studies will focus on correlating proficiency to clinical practice and scaling ALL-SAFE to other settings. [ABSTRACT FROM AUTHOR]

Cash transfers are increasingly used to motivate adherence to HIV care. However, evidence on cash transfers and intimate partner violence (IPV) is mixed and little is known about their safety for women living with HIV. We conducted in-depth interviews with women living with HIV who participated in a randomized trial providing 6 months of cash transfers (~$4.5 or $11 USD) conditional on HIV clinic attendance in Shinyanga, Tanzania to assess how receiving cash affects IPV and relationship dynamics. Eligible participants were 18–49 years, received cash transfers, and in a partnership at baseline. Data were analyzed in Dedoose using a combined inductive-deductive coding approach. 25 interviews were conducted between November 2019-February 2020. Women's employment was found to be a source of household tension and violence. None of the participants reported physical or sexual IPV in relation to cash transfers, however, some women experienced controlling behaviors or emotional violence including accusations and withholding of money, particularly those who were unemployed. Cash transfers were predominantly used for small household expenses and were not viewed as being substantial enough to shift the financial dynamic or balance of power within relationships. Our findings suggest that small, short-term cash transfers do not increase physical or sexual IPV for women living with HIV however can exacerbate controlling behaviors or emotional violence. Modest incentives used as a behavioral nudge to improve health outcomes may affect women differently than employment or larger cash transfers. Nonetheless, consultations with beneficiaries should be prioritized to protect women from potential IPV risks. [ABSTRACT FROM AUTHOR]

Whilst most individuals with SARS-CoV-2 infection have relatively mild disease, managed in the community, it was noted early in the pandemic that individuals with cardiovascular risk factors were more likely to experience severe acute disease, requiring hospitalisation. As the pandemic has progressed, increasing concern has also developed over long symptom duration in many individuals after SARS-CoV-2 infection, including among the majority who are managed acutely in the community. Risk factors for long symptom duration, including biological variables, are still poorly defined. Here, we examine post-illness metabolomic profiles, using nuclear magnetic resonance (Nightingale Health Oyj), and gut-microbiome profiles, using shotgun metagenomic sequencing (Illumina Inc), in 2561 community-dwelling participants with SARS-CoV-2. Illness duration ranged from asymptomatic (n = 307) to Post-COVID Syndrome (n = 180), and included participants with prolonged non-COVID-19 illnesses (n = 287). We also assess a pre-established metabolomic biomarker score, previously associated with hospitalisation for both acute pneumonia and severe acute COVID-19 illness, for its association with illness duration. We found an atherogenic-dyslipidaemic metabolic profile, including biomarkers such as fatty acids and cholesterol, was associated with longer duration of illness, both in individuals with and without SARS-CoV-2 infection. Greater values of a pre-existing metabolomic biomarker score also associated with longer duration of illness, regardless of SARS-CoV-2 infection. We found no association between illness duration and gut microbiome profiles in convalescence. This highlights the potential role of cardiometabolic dysfunction in relation to the experience of long duration symptoms after symptoms of acute infection, both COVID-19 as well as other illnesses. [ABSTRACT FROM AUTHOR]

The article discusses the issue of environmental pollution caused by medicinal products. It highlights the historical concern over pollution by anaesthetic gases and the potential health effects on both the workforce and patients. The article also addresses the contamination of the environment by medicines through metabolic excretion by patients and improper disposal. It emphasizes the need for healthcare services and the pharmaceutical industry to take action to avoid environmental pollution, particularly in relation to products that contribute to global warming. [Extracted from the article]

In vitro investigation of bovine lactation processes is limited by a lack of physiologically representative cell models. This deficiency is most evident through the minimal or absent expression of lactation-specific genes in cultured bovine mammary tissues. Primary bovine mammary epithelial cells (pbMECs) extracted from lactating mammary tissue and grown in culture initially express milk protein transcripts at relatively representative levels. However, expression drops dramatically after only three or four passages, which greatly reduces the utility of primary cells to model and further examine lactogenesis. To investigate the effects of alternate alleles in pbMECs including effects on transcription, we have developed methods to deliver CRISPR-Cas9 gene editing reagents to primary mammary cells, resulting in very high editing efficiencies. We have also found that culturing the cells on an imitation basement membrane composed of Matrigel, results in the restoration of a more representative lactogenic gene expression profile and the cells forming three-dimensional structures in vitro. Here, we present data from four pbMEC lines recovered from pregnant cows and detail the expression profile of five key milk synthesis genes in these MECs grown on Matrigel. Additionally, we describe an optimised method for preferentially selecting CRISPR-Cas9-edited cells conferring a knock-out of DGAT1, using fluorescence-activated cell sorting (FACS). The combination of these techniques facilitates the use of pbMECs as a model to investigate the effects of gene introgressions and genetic variation in lactating mammary tissue. [ABSTRACT FROM AUTHOR]

Humans are increasing the environmental availability of historically limited nutrients, which may significantly influence organismal performance and behavior. Beneficial or stimulatory responses to increases in nitrogen availability (i.e., nitrogen limitation) are generally observed in plants but less consistently in animals. One possible explanation is that animal responses to nitrogen enrichment depend on how nitrogen intake is balanced with sodium, a micronutrient crucial for animals but not plants. We tested this idea in the cabbage white butterfly (Pieris rapae), a species that frequently inhabits nutrient-enriched plants in agricultural settings and roadside verges. We asked (1) whether anthropogenic increases in sodium influence how nitrogen enrichment affects butterfly performance and (2) whether individuals can adaptively adjust their foraging behavior to such effects. Larval nitrogen enrichment enhanced growth of cabbage white larvae under conditions of low but not high sodium availability. In contrast, larval nitrogen enrichment increased egg production of adult females only when individuals developed with high sodium availability. Ovipositing females preferred nitrogen-enriched leaves regardless of sodium availability, while larvae avoided feeding on nitrogen-enriched leaves elevated in sodium. Our results show that anthropogenic increases in sodium influence whether individuals benefit from and forage on nitrogen-enriched resources. Yet, different nitrogen-to-sodium ratios are required to optimize larval and adult performance. Whether increases in sodium catalyze or inhibit benefits of nitrogen enrichment may depend on how evolved nutrient requirements vary across stages of animal development. [ABSTRACT FROM AUTHOR]

Purpose: Early intervention vocational rehabilitation (EIVR) can improve return to work (RTW) outcomes for people with spinal cord injury (SCI). However, mechanisms explaining how and why EIVR works are not well understood. This study aims to develop a conceptual framework describing key mechanisms of EIVR intervention effect following SCI. Methods: We synthesised data from a realist literature review with data from interviews of people with SCI (n = 30), a survey of people with SCI who had received EIVR (n = 37), a focus group of EIVR providers and a focus group of community vocational providers. We first synthesised the literature review and interviews to develop an initial programme theory describing the contexts in which mechanisms are activated to produce EIVR outcomes. Then we used data from the survey and focus groups to further refine the EIVR programme theory. Finally, a conceptual framework was developed to support knowledge dissemination. Results: By ensuring consistent messaging across the multi-disciplinary team, EIVR programmes establish and maintain hope that work is possible following injury. Conversations about work allow individuals to determine the priority of work following injury. These conversations can also improve self-efficacy by providing individualized support to envisage pathways toward RTW goals and maintain worker identity. The synthesised study findings highlight the contexts and resources required to trigger activation of these mechanisms. Conclusions: EIVR key mechanisms of effect are not specific to SCI as a health condition, therefore enabling this framework to be applied to other populations who face similar impairments and return to work barriers. [ABSTRACT FROM AUTHOR]

Purpose: Clinical guidelines recommend epidural steroid injection (ESI) as a treatment option for severe disc-related sciatica, but there is considerable uncertainty about its effectiveness. Currently, we know very little about factors that might be associated with good or poor outcomes from ESI. The aim of this systematic review was to synthesise and appraise the evidence investigating prognostic factors associated with outcomes following ESI for patients with imaging confirmed disc-related sciatica. Methods: The search strategy involved the electronic databases Medline, Embase, CINAHL Plus, PsycINFO and reference lists of eligible studies. Selected papers were quality appraised independently by two reviewers using the Quality in Prognosis Studies tool. Between-study heterogeneity precluded statistical pooling of results. Results: 3094 citations were identified; 15 studies were eligible. Overall study quality was low with all judged to have moderate or high risk of bias. Forty-two prognostic factors were identified but were measured inconsistently. The most commonly assessed prognostic factors were related to pain and function (n = 10 studies), imaging features (n = 8 studies), patient socio-demographics (n = 7 studies), health and lifestyle (n = 6 studies), clinical assessment findings (n = 4 studies) and injection level (n = 4 studies). No prognostic factor was found to be consistently associated with outcomes following ESI. Most studies found no association or results that conflicted with other studies. Conclusions: There is little, and low quality, evidence to guide practice in terms of factors that predict outcomes in patients following ESI for disc-related sciatica. The results can help inform some of the decisions about potential prognostic factors that should be assessed in future well-designed prospective cohort studies. [ABSTRACT FROM AUTHOR]

Measuring Huntingtin (HTT) protein in peripheral cells represents an essential step in biomarker discovery for Huntington's Disease (HD), however to date, investigations into the salivary expression of HTT has been lacking. In the current study, we quantified total HTT (tHTT) and mutant HTT (mHTT) protein in matched blood and saliva samples using single molecule counting (SMC) immunoassays: 2B7-D7F7 (tHTT) and 2B7-MW1 (mHTT). Matched samples, and clinical data, were collected from 95 subjects: n = 19 manifest HD, n = 34 premanifest HD (PM), and n = 42 normal controls (NC). Total HTT and mHTT levels were not correlated in blood and saliva. Plasma tHTT was significantly associated with age, and participant sex; whereas salivary mHTT was significantly correlated with age, CAG repeat length and CAP score. Plasma and salivary tHTT did not differ across cohorts. Salivary and plasma mHTT were significantly increased in PM compared to NC; salivary mHTT was also significantly increased in HD compared to NC. Only salivary tHTT and mHTT were significantly correlated with clinical measures. Salivary HTT is uniquely associated with clinical measures of HD and offers significant promise as a relevant, non-invasive HD biomarker. Its use could be immediately implemented into both translational and clinical research applications. [ABSTRACT FROM AUTHOR]

Avian migratory processes are typically precisely oriented, yet vagrants are frequently recorded outside their normal range. Wind displaced vagrants often show corrective behaviour, and as an appropriate response is likely adaptive. We investigated the physiological response to vagrancy in passerines. Activation of the emergency life-history stage (ELHS), assessed by high baseline plasma corticosterone, is a potential mechanism to elicit compensatory behaviour in response to challenges resulting from navigational error, coupled with response to fuel load and flight. We compared circulating plasma corticosterone concentrations and body condition between three migratory groups in autumn: (1) wind displaced southwest (SW) vagrants and (2) long range southeast (SE) vagrants on the remote Faroe Islands, and (3) birds within the expected SW migratory route (controls) on the Falsterbo peninsula, Sweden. Vagrants were further grouped by those sampled immediately upon termination of over-water migratory flight and those already on the island. In all groups there was no indication of the activation of the ELHS in response to vagrancy. We found limited support for an increased rate of corticosterone elevation within our 3 min sample interval in a single species, but this was driven by an individual ELHS outlier. Fat scores were negatively correlated with circulating corticosterone; this relationship may suggest that ELHS activation depends upon an individual's energetic states. Interestingly, in individuals caught at the completion of an obligate long-distance flight, we found some evidence of corticosterone suppression. Although limited, data did support the induction of negative feedback mechanisms that suppress corticosterone during endurance exercise, even when fuel loads are low. [ABSTRACT FROM AUTHOR]

Purpose of Review: The incidence of type 1 diabetes (T1D) is rising in all age groups. T1D is associated with chronic microvascular and macrovascular complications but improving glycemic trends can delay the onset and slow the progression of these complications. Utilization of technological devices for diabetes management, such as continuous glucose monitors (CGM) and insulin pumps, is increasing, and these devices are associated with improvements in glycemic trends. Thus, device use may be associated with long-term prevention of T1D complications, yet few studies have investigated the direct impacts of devices on chronic complications in T1D. This review will describe common diabetes devices and combination systems, as well as review relationships between device use and cardiovascular outcomes in T1D. Recent Findings: Findings from existing cohort and national registry studies suggest that pump use may aid in improving cardiovascular risk factors such as hypertension and dyslipidemia. Furthermore, pump users have been shown to have lower arterial stiffness and better measures of myocardial function. In registry and case–control longitudinal data, pump use has been associated with fewer cardiovascular events and reduction of cardiovascular disease (CVD) and all-cause mortality. Summary: CVD is the leading cause of morbidity and mortality in T1D. Consistent use of diabetes devices may protect against the development and progression of macrovascular complications such as CVD through improvement in glycemic trends. Existing literature is limited, but findings suggest that pump use may reduce acute cardiovascular risk factors as well as chronic cardiovascular complications and overall mortality in T1D. [ABSTRACT FROM AUTHOR]

Science and science policy are characterised by expectations. These expectations—as in the field of biomedicine—may be related to describing novel findings, their use in curing diseases or their economic benefits. Previous research has shown that expectations are often communicated with the help of metaphors. In this article, we take a closer look at one metaphor—‘closing window of opportunity’—and examine how it frames discussions about policy and regulatory change in biomedicine through the lenses of urgency and national unity. A key component of the generative metaphor of a ‘closing window’ is the focus on limited time and a sense of urgency related to the creation of an enabling environment for biomedical research and innovations. We focus on two key elements of this framing: international competitiveness and national unity. Moreover, drawing on urgency seems to be a standard response to the changing environment, in which the actors need to continuously guide their actions in new directions, meeting new demands posed by, for example, technological development or regulatory changes. We argue that while the metaphor of a closing window creates room for innovations and competitiveness, it is prone to silence critical discussions, for example on sustainability, responsibility and accountability. This leaves out important discussions about values, benefits and risks. With this analysis, we contribute to discussions about the sociology of (negative) expectations and generative metaphors and show how urgency can remain as a constant state of things. [ABSTRACT FROM AUTHOR]

This study aimed to characterize the prokaryotic community and putative microbial interactions involved in hydrogen (H2) production during the dark fermentation (DF) process, applying principal components analysis (PCA) to correlate changes in operational, physicochemical, and biological variables. For this purpose, a continuous stirred-tank reactor-type digester fed with tequila vinasses was operated at 24, 18, and 12 h of hydraulic retention times (HRTs) to apply organic loading rates of 20, 36, and 54 g-COD L−1 d−1, corresponding to stages I, II, and III, respectively. Results indicated high population dynamics for Archaea during the DF process toward a decrease in total sequences from 6299 to 99. Concerning the Bacteria community, lactic acid bacteria (LAB) were dominant reaching a relative abundance of 57.67%, while dominant H2-producing bacteria (HPB) decreased from 25.76% to 21.06% during stage III. Putative competitive exclusion mechanisms such as competition for substrates, bacteriocins production, and micronutrient depletion carried out by Archaea and non-H2-producing bacteria (non-HPB), especially LAB, could negatively impact the dominance of HPB such as Ethanoligenens harbinense and Clostridium tyrobutyricum. As a consequence, low maximal volumetric H2 production rate (672 mL-H2 L−1 d−1) and yield (3.88 mol-H2 assimilated sugars−1) were obtained. The global scenario obtained by PCA correlations suggested that C. tyrobutyricum positively impacted H2 molar yield through butyrate fermentation using the butyryl-CoA:acetate CoA transferase pathway, while the most abundant HPB E. harbinense decreased its relative abundance at the shortest HRT toward the dominance of non-HPB. This study provides new insights into the microbial interactions and helps to better understand the DF performance for H2 production using tequila vinasses as substrate. Key points: • E. harbinense and C. tyrobutyricum were responsible for H2production. • Clostridiales used acetate and butyrate fermentations for H2production. • LAB won the competition for sugars against Clostridiales during DF. • Putative bacteriocins production and micronutrients depletion could favor LAB. [ABSTRACT FROM AUTHOR]

Transcranial focused ultrasound with the InSightec Exablate system uses thermal ablation for the treatment of movement and mood disorders and blood brain barrier disruption for tumor therapy. The system uses computed tomography (CT) images to calculate phase corrections that account for aberrations caused by the human skull. This work investigates whether magnetic resonance (MR) images can be used as an alternative to CT images to calculate phase corrections. Phase corrections were calculated using the gold standard hydrophone method and the standard of care InSightec ray tracing method. MR binary image mask, MR-simulated-CT (MRsimCT), and CT images of three ex vivo human skulls were supplied as inputs to the InSightec ray tracing method. The degassed ex vivo human skulls were sonicated with a 670 kHz hemispherical phased array transducer (InSightec Exablate 4000). 3D raster scans of the beam profiles were acquired using a hydrophone mounted on a 3-axis positioner system. Focal spots were evaluated using six metrics: pressure at the target, peak pressure, intensity at the target, peak intensity, positioning error, and focal spot volume. Targets at the geometric focus and 5 mm lateral to the geometric focus were investigated. There was no statistical difference between any of the metrics at either target using either MRsimCT or CT for phase aberration correction. As opposed to the MRsimCT, the use of CT images for aberration correction requires registration to the treatment day MR images; CT misregistration within a range of ± 2 degrees of rotation error along three dimensions was shown to reduce focal spot intensity by up to 9.4%. MRsimCT images used for phase aberration correction for the skull produce similar results as CT-based correction, while avoiding both CT to MR registration errors and unnecessary patient exposure to ionizing radiation. [ABSTRACT FROM AUTHOR]

Omicron variant strains encode large numbers of changes in the spike protein compared to historical SARS-CoV-2 isolates. Although in vitro studies have suggested that several monoclonal antibody therapies lose neutralizing activity against Omicron variants, the effects in vivo remain largely unknown. Here, we report on the protective efficacy against three SARS-CoV-2 Omicron lineage strains (BA.1, BA.1.1, and BA.2) of two monoclonal antibody therapeutics (S309 [Vir Biotechnology] monotherapy and AZD7442 [AstraZeneca] combination), which correspond to ones used to treat or prevent SARS-CoV-2 infections in humans. Despite losses in neutralization potency in cell culture, S309 or AZD7442 treatments reduced BA.1, BA.1.1, and BA.2 lung infection in susceptible mice that express human ACE2 (K18-hACE2) in prophylactic and therapeutic settings. Correlation analyses between in vitro neutralizing activity and reductions in viral burden in K18-hACE2 or human FcγR transgenic mice suggest that S309 and AZD7442 have different mechanisms of protection against Omicron variants, with S309 utilizing Fc effector function interactions and AZD7442 acting principally by direct neutralization. Our data in mice demonstrate the resilience of S309 and AZD7442 mAbs against emerging SARS-CoV-2 variant strains and provide insight into the relationship between loss of antibody neutralization potency and retained protection in vivo. SARS-CoV-2 variants of concern are less susceptible to therapeutic neutralizing antibodies, given mutations in the surface glycoprotein S. Here, Case et al. show that therapeutic antibodies S309 and AZD7442 reduce lung infection with SARSCoV-2 Omicron lineages in humanized mouse model despite the loss of neutralizing potency in vitro. [ABSTRACT FROM AUTHOR]

The notion that the brain achieves visual word recognition by encoding the relative positions of letters with open-bigram representations (e.g., 'h-e', 'h-r' and 'e-r' driving recognition of 'her') has been successful in accounting for many behaviors and phenomena. However, one characteristic of open-bigrams has remained unexplored: How is the activation of a bigram modulated by the distance between its constituents in the visual field? On the one hand, contiguous letters (e.g., 'at' in 'father') may allow for a clearer percept of the bigram. On the other hand, an increasing distance between letters (e.g., 'ae' in 'father') should create more certainty about their relative positions, which is precisely what the bigram is meant to convey. This matter was investigated with two experiments in which participants indicated whether target pairs of letters occurred in random letter strings. They were instructed that letter order mattered (i.e., 'a-b' does not occur in 'kbac'), while letter contiguity did not (i.e., 'a-b' occurs in 'akcb'). Controlling for crowding and eccentricity, bigrams were recognized faster upon decreasing the letter distance. However, when switching the target letter order (meaning the string should be met by a 'no' response), shorter letter distances yielded slower responses and more false positives. Neither relative position-coding models nor absolute position-coding models accommodate both these patterns at once. We discuss how a complete account of our effects may instead combine elements from both model types. [ABSTRACT FROM AUTHOR]

Background: A high proportion of patients undergoing catheter ablation (CA) for atrial fibrillation (AF) experience recurrence of arrhythmia. This meta-analysis aims to identify pre-ablation serum biomarker(s) associated with arrhythmia recurrence to improve patient selection before CA. Methods: A systematic approach following PRISMA reporting guidelines was utilised in libraries (Pubmed/Medline, Embase, Web of Science, Scopus) and supplemented by scanning through bibliographies of articles. Biomarker levels were compared using a random-effects model and presented as odds ratio (OR). Heterogeneity was examined by meta-regression and subgroup analysis. Results: In total, 73 studies were identified after inclusion and exclusion criteria were applied. Nine out of 22 biomarkers showed association with recurrence of AF after CA. High levels of N-Terminal-pro-B-type-Natriuretic Peptide [OR (95% CI), 3.11 (1.80–5.36)], B-type Natriuretic Peptide [BNP, 2.91 (1.74–4.88)], high-sensitivity C-Reactive Protein [2.04 (1.28–3.23)], Carboxy-terminal telopeptide of collagen type I [1.89 (1.16–3.08)] and Interleukin-6 [1.83 (1.18–2.84)] were strongly associated with identifying patients with AF recurrence. Meta-regression highlighted that AF type had a significant impact on BNP levels (heterogeneity R2 = 55%). Subgroup analysis showed that high BNP levels were more strongly associated with AF recurrence in paroxysmal AF (PAF) cohorts compared to the addition of non-PAF patients. Egger's test ruled out the presence of publication bias from small-study effects. Conclusion: Ranking biomarkers based on the strength of association with outcome provides each biomarker relative capacity to predict AF recurrence. This will provide randomised controlled trials, a guide to choosing a priori tool for identifying patients likely to revert to AF, which are required to substantiate these findings. [ABSTRACT FROM AUTHOR]

Rapid, cost-effective identification of genetic variants in small candidate genomic regions remains a challenge, particularly for less well equipped or lower throughput laboratories. The application of Oxford Nanopore Technologies' MinION sequencer has the potential to fulfil this requirement. We demonstrate a proof of concept for a multiplexing assay that pools PCR amplicons for MinION sequencing to enable sequencing of multiple templates from multiple individuals, which could be applied to gene-targeted diagnostics. A combined strategy of barcoding and sample pooling was developed for simultaneous multiplex MinION sequencing of 100 PCR amplicons. The amplicons are family-specific, spanning a total of 30 loci in DNA isolated from 82 human neurodevelopmental cases and family members. The target regions were chosen for further interrogation because a potentially disease-causative variant had been identified in affected individuals following Illumina exome sequencing. The pooled MinION sequences were deconvoluted by aligning to custom references using the minimap2 aligner software. Our multiplexing approach produced an interpretable and expected sequence from 29 of the 30 targeted genetic loci. The sequence variant which was not correctly resolved in the MinION sequence was adjacent to a five nucleotide homopolymer. It is already known that homopolymers present a resolution problem with the MinION approach. Interestingly despite equimolar quantities of PCR amplicon pooled for sequencing, significant variation in the depth of coverage (127×–19,626×; mean = 8321×, std err = 452.99) was observed. We observed independent relationships between depth of coverage and target length, and depth of coverage and GC content. These relationships demonstrate biases of the MinION sequencer for longer templates and those with lower GC content. We demonstrate an efficient approach for variant discovery or confirmation from short DNA templates using the MinION sequencing device. With less than 130 × depth of coverage required for accurate genotyping, the methodology described here allows for rapid highly multiplexed targeted sequencing of large numbers of samples in a minimally equipped laboratory with a potential cost as much 200 × less than that from Sanger sequencing. [ABSTRACT FROM AUTHOR]

Background: 18F-fluciclovine is a synthetic amino acid positron emission tomography (PET) radiotracer that is approved for use in prostate cancer. In this clinical study, we characterised the kinetic model best describing the uptake of 18F-fluciclovine in breast cancer and assessed differences in tracer kinetics and static parameters for different breast cancer receptor subtypes and tumour grades.Methods: Thirty-nine patients with pathologically proven breast cancer underwent 20-min dynamic PET/computed tomography imaging following the administration of 18F-fluciclovine. Uptake into primary breast tumours was evaluated using one- and two-tissue reversible compartmental kinetic models and static parameters.Results: A reversible one-tissue compartment model was shown to best describe tracer uptake in breast cancer. No significant differences were seen in kinetic or static parameters for different tumour receptor subtypes or grades. Kinetic and static parameters showed a good correlation.Conclusions: 18F-fluciclovine has potential in the imaging of primary breast cancer, but kinetic analysis may not have additional value over static measures of tracer uptake.Clinical Trial Registration: NCT03036943. [ABSTRACT FROM AUTHOR]

Background and aims: The ileoanal pouch (IPAA) provides patients with ulcerative colitis (UC) that have not responded to medical therapy an option to retain bowel continuity and defecate without the need for a long-term stoma. Despite good functional outcomes, some pouches fail, requiring permanent diversion, pouchectomy, or a redo pouch. The incidence of pouch failure ranges between 2 and 15% in the literature. We conducted a systematic review and meta-analysis aiming to define the prevalence of pouch failure in patients with UC who have undergone IPAA using population-based studies. Methods: We searched Embase, Embase classic and PubMed from 1978 to 31st of May 2021 to identify cross-sectional studies that reported the prevalence of pouch failure in adults (≥ 18 years of age) who underwent IPAA for UC. Results: Twenty-six studies comprising 23,389 patients were analysed. With < 5 years of follow-up, the prevalence of pouch failure was 5% (95%CI 3–10%). With ≥ 5 but < 10 years of follow-up, the prevalence was 5% (95%CI 4–7%). This increased to 9% (95%CI 7–16%) with ≥ 10 years of follow-up. The overall prevalence of pouch failure was 6% (95%CI 5–8%). Conclusions: The overall prevalence of pouch failure in patients over the age of 18 who have undergone restorative proctocolectomy in UC is 6%. These data are important for counselling patients considering this operation. Importantly, for those patients with UC being considered for a pouch, their disease course has often resulted in both physical and psychological morbidity and hence providing accurate expectations for these patients is vital. [ABSTRACT FROM AUTHOR]

Animals are essential genetic tools in scientific research and global resources in agriculture. In both arenas, a single sex is often required in surplus. The ethical and financial burden of producing and culling animals of the undesired sex is considerable. Using the mouse as a model, we develop a synthetic lethal, bicomponent CRISPR-Cas9 strategy that produces male- or female-only litters with one hundred percent efficiency. Strikingly, we observe a degree of litter size compensation relative to control matings, indicating that our system has the potential to increase the yield of the desired sex in comparison to standard breeding designs. The bicomponent system can also be repurposed to generate postnatal sex-specific phenotypes. Our approach, harnessing the technological applications of CRISPR-Cas9, may be applicable to other vertebrate species, and provides strides towards ethical improvements for laboratory research and agriculture. In areas such as animal research and agriculture a single sex is often required in abundance, leading to wasted resources and ethical considerations. Here the authors develop a CRISPR/Cas9 mediated synthetic lethal system that enables the production of single sex offspring that can be repurposed for use in multiple organisms. [ABSTRACT FROM AUTHOR]

Purpose Little is currently known about how early intervention vocational rehabilitation (EIVR) works for people with newly acquired neurological conditions such as traumatic brain injury, acquired brain injury and spinal cord injury. This study aims, from a realist framework, to identify relevant literature and develop an initial programme theory to understand how EIVR might work for people experiencing acquired neurological disability. Realist reviews are ideally placed to address the identified knowledge gap as they assist in gaining a deeper understanding of how the intervention works, for whom it works best, and the contexts that promote the activation of desired outcomes. Methods We used a seven-step iterative process to synthesise literature using a realist approach. The steps included: development of initial programme theory, literature search, article selection, extracting and data organising, synthesis of evidence and programme theory refinement. We performed a literature search using the following databases: Cinahl, Embase, EMcare, Medline, PsychInfo and Scopus. Articles were selected if they contributed to the knowledge describing what is EIVR and how it works in newly acquired neurological conditions. Data were extracted and synthesised to develop a programme theory for EIVR. Results Following screening of 448 references, 37 documents were eligible for data extraction. We developed a refined programme theory of EIVR consisting of three contexts (prioritisation of exploring work options, return to work discussed as an option, and workplace support), nine mechanisms (ensuring rehabilitation teams' culture, fostering hope, exploring options, optimising self-efficacy, maintaining worker identity, staying connected, setting goals, engaging employer, and flexing roles) and three outcomes (confidence in ability to work, psychological adjustment, and engagement in solution focussed options). Conclusions This appears to be the first paper to explore how EIVR works, for whom and in what situations. We have produced a programme theory that may provide an initial understanding of EIVR following acquired neurological conditions. [ABSTRACT FROM AUTHOR]

All banknotes have security features which are intended to help determine whether they are false or genuine. Typically, however, the general public has limited knowledge of where on a banknote these security features can be found. Here, we tested whether counterfeit detection can be improved with the help of salient elements, designed to guide bottom-up visuospatial attention. We also tested the influence of the participant's a priori level of trust in the authenticity of the banknote. In an online study (N = 422), a demographically diverse panel of Dutch participants distinguished genuine banknotes from banknotes with one (left- or right-sided) counterfeited security feature. Either normal banknotes (without novel design elements) or banknotes that contained a salient element (a pink rectangular frame) were presented for 1 s. To manipulate the participant's level of trust, trials were administered in three blocks, whereby at the start of each block, participants were instructed that either one third, one half, or two thirds of the upcoming banknotes were counterfeit (though the true ratio was always 1:1). We hypothesized (i) that in the presence of a salient element, counterfeits would be better detected when the location of the salient element aligned with the location of the counterfeited security feature—i.e. that it would act as an attentional cue; and (ii) that this effect would be stronger with lower trust. Our hypotheses were partly confirmed: counterfeit detection improved with 'valid cues' and decreasing trust, but the level of trust did not modulate the cueing effect. As the overall detection performance was rather poor, we replicated the study with a sample of university students (N = 66), this time presenting stimuli until response. While indeed observing better overall performance, all other patterns were replicated. Our results provide evidence that attention can be guided to enhance banknote authentication. [ABSTRACT FROM AUTHOR]

In this work, we investigate a framework for collecting, processing, and registering in-process monitoring data from an additive manufacturing build with post-build inspection data obtained from CT scans of the produced samples. In addition to processing and combining the data, we look at a statistical analysis of the combined data streams using machine learning methods to obtain a quantitative prediction of local void probability in the CT data from local feature metrics extracted from the in-process monitoring data. Results show promise when the in-process monitoring data are processed to extract designed features/metrics, rather than using only the raw signals. [ABSTRACT FROM AUTHOR]

Differential migration strategies in the same population provide an opportunity to investigate the development and constraints of the migratory programme. We used data from birds ringed from the large Danish breeding population of Great Cormorants, Phalacrocorax carbo sinensis, to investigate age- and sex-specific differences in migratory patterns, which may inform our understanding of the ontogeny of partial migration schedules or protandric advantages of males arriving at breeding grounds in advance of females. We tested spatial and temporal variation in migration strategy from migration distance, orientation and by region. We observed clear partial migration strategies in the combined data, and by group, following post-breeding dispersal. We found differential migration patterns by age, with migratory adults departing earlier than birds on their first migration. There was a tendency for a greater concentration of adults utilising sites in central Europe, while a higher than expected proportion of young birds occupied the periphery of the wintering range. Re-encounters of birds of known sex during autumn and winter indicated that males remained closer to the breeding site than females, with sex-specific regional segregation. While our results did not support the migration pattern of young birds being governed by an innate control of both direction and distance, it may be explained in part by intra-specific competition driving the resultant non-breeding distribution. This social dynamic may be extended to the differential migration patterns between the sexes. Furthermore, the sex-specific wintering distributions may explain the development of protandry within the partial migration system. [ABSTRACT FROM AUTHOR]

Purpose: To examine the associations of dietary patterns and nutrients with coronary artery calcification (CAC) and pericardial adiposity (PAT) in adults with and without type 1 diabetes. Methods: We conducted a six-year longitudinal analysis of data from Coronary Artery Calcification in Type 1 Diabetes study [n = 1255; T1D: n = 563; non-DM: n = 692] collected at baseline, year 3 and year 6. Participants completed a validated food frequency questionnaire, a physical examination, and fasting (12 h overnight fast) biochemical analyses. CAC and PAT were measured using electron beam computed tomography. Dietary patterns were identified using factor analysis. Generalized estimating equations were used to examine associations of dietary patterns and nutrients with CAC and PAT in models adjusted for traditional cardiovascular risks. Results: The 'starchy veggies, meats and alcohol pattern' was associated with significantly increased risk of CAC presence in all adjusted models; an increasing trend was observed with CAC progression. Increasing intake of dietary proteins and total fats were also associated with higher risk of the presence and/or progression of CAC in adjusted models (all p < 0.05). PAT was positively associated with dietary total fats, and inversely associated with dietary intakes of saturated fats, omega-3 fats and fiber in models adjusted for age, sex, total calories, time, diabetes status, systolic blood pressure, serum lipids and physical activity. Conclusion: Diets high in total fats and proteins, and in meats (processed and red) and alcohol may increase risks of CAC, while saturated fats, omega-3-fats and fiber may be protective against pericardial adiposity as a risk factor for coronary artery disease. ClinicalTrials.gov Identifier: NCT00005754. [ABSTRACT FROM AUTHOR]

Readers may fail to notice the error in 'Do love you me?': this is the recently established transposed-word (TW) phenomenon. Word position coding is a novel cognitive construct, and researchers are presently debating the underlying mechanisms. Here I investigated roles for attention and memory. Participants (N = 54) made grammaticality judgements to four-word sequences that formed correct sentences ('The man can run', 'The dog was here'), TW sentences ('The can man run', 'The was dog here'), or ungrammatical control sentences ('The man dog run', 'The was can here'). Sequences were replaced by post-masks after 200 ms, and that post-mask was accompanied by a 50-ms retro-cue in the form of an 'X' presented at a critical location (where one could have locally inferred grammaticality; e.g., between the first and second word of 'The was dog here') or a non-critical location (e.g., between the third and fourth word of 'The was dog here'). TW sentences were harder to reject than control sentences – the classic TW effect – and crucially, this effect was modulated by cue validity, with valid cues attenuating TW effects compared to invalid cues. The present results suggest that focused attention aids the process of binding words to locations. Furthermore, as cues appeared after sentence offset, these results suggest that word position coding may take place in memory. [ABSTRACT FROM AUTHOR]

Recognition and fusion between gametes during fertilization is an ancient process. Protein HAP2, recognized as the primordial eukaryotic gamete fusogen, is a structural homolog of viral class II fusion proteins. The mechanisms that regulate HAP2 function, and whether virus-fusion-like conformational changes are involved, however, have not been investigated. We report here that fusion between plus and minus gametes of the green alga Chlamydomonas indeed requires an obligate conformational rearrangement of HAP2 on minus gametes from a labile, prefusion form into the stable homotrimers observed in structural studies. Activation of HAP2 to undergo its fusogenic conformational change occurs only upon species-specific adhesion between the two gamete membranes. Following a molecular mechanism akin to fusion of enveloped viruses, the membrane insertion capacity of the fusion loop is required to couple formation of trimers to gamete fusion. Thus, species-specific membrane attachment is the gateway to fusion-driving HAP2 rearrangement into stable trimers. HAP2 is essential for gamete fusion during fertilization and is conserved among eukaryotes. Here the authors show that species-specific adhesion between Chlamydomonas plus and minus gametes initiates HAP2 to undergo a fusogenic conformational change into homotrimers via a molecular mechanism akin to that of enveloped viruses. [ABSTRACT FROM AUTHOR]