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Antigenic variation in malaria was discovered in Plasmodium knowlesi studies involving longitudinal infections of rhesus macaques (M. mulatta). The variant proteins, known as the P. knowlesi Schizont Infected Cell Agglutination (SICA) antigens and the P. falciparum Erythrocyte Membrane Protein 1 (PfEMP1) antigens, expressed by the SICAvar and var multigene families, respectively, have been studied for over 30 years. Expression of the SICA antigens in P. knowlesi requires a splenic component, and specific antibodies are necessary for variant antigen switch events in vivo. Outstanding questions revolve around the role of the spleen and the mechanisms by which the expression of these variant antigen families are regulated. Importantly, the longitudinal dynamics and molecular mechanisms that govern variant antigen expression can be studied with P. knowlesi infection of its mammalian and vector hosts. Synchronous infections can be initiated with established clones and studied at multi-omic levels, with the benefit of computational tools from systems biology that permit the integration of datasets and the design of explanatory, predictive mathematical models. Here we provide an historical account of this topic, while highlighting the potential for maximizing the use of P. knowlesi - macaque model systems and summarizing exciting new progress in this area of research.

Objectives: To determine the positive predictive value (PPV) of algorithms to identify patients with major (at the ankle or more proximal) lower extremity amputation (LEA) using Department of Veterans Affairs electronic medical records (EMR) and to evaluate whether PPV varies by sex, age, and race. Design: We conducted a validation study comparing EMR determined LEA status to self-reported LEA (criterion standard). Setting: Veterans who receive care at the Department of Veterans Affairs. Participants: We invited a national sample of patients (N=699) with at least 1 procedure or diagnosis code for major LEA to participate. We oversampled women, Black men, and men ≤40 years of age. Interventions: Not applicable. Main Outcome Measure: We calculated PPV estimates and false negative percentages for 7 algorithms using EMR LEA procedure and diagnosis codes relative to self-reported major LEA. Results: A total of 466 veterans self-reported their LEA status (68%). PPVs for the 7 algorithms ranged from 89% to 100%. The algorithm that required a single diagnosis or procedure code had the lowest PPV (89%). The algorithm that required at least 1 procedure code had the highest PPV (100%) but also had the highest proportion of false negatives (66%). Algorithms that required at least 1 procedure code or 2 or more diagnosis codes 1 month to 1 year apart had high PPVs (98%-99%) but varied in terms of false negative percentages. PPV estimates were higher among men than women but did not differ meaningfully by age or race, after accounting for sex. Conclusion: PPVs were higher if 1 procedure or at least 2 diagnosis codes were required; the difference between algorithms was marked by sex. Investigators should consider trade-offs between PPV and false negatives to identify patients with LEA using EMRs.

Idiopathic inflammatory myopathies (IIMs) are a rare, heterogeneous group of diseases with a characteristic clinical presentation consisting of muscle inflammation and weakness. They often present with accompanying extra-muscular findings, most notably in the skin, lungs, and joints. Inflammatory myopathies are also identified by their characteristic laboratory abnormalities, including a 10- to 50-fold increase in creatinine kinase, elevated liver enzymes, and characteristic electromyography and magnetic resonance imaging findings. Distinct autoimmune markers and clinical phenotypes have advanced our understanding of IIMs and have led to the recognition of 5 distinct entities, each with its unique pathophysiology, autoimmune markers, and clinical features. While autoimmune panels and muscle biopsies help clinicians distinguish one entity from the other, their sensitivity and specificity vary. Of the various inflammatory myopathies, polymyositis remains the most elusive. Often, the diagnosis is ultimately made by combining clinical findings and laboratory data. As our case report illustrates, clinicians must use this constellation of data to initiate treatment for suspected polymyositis despite negative autoimmune panels and negative muscle biopsy.

Critical habitat was designated in 2003 for federally threatened anadromous Gulf sturgeon to aid in population recovery. This study examined overwintering Gulf sturgeon spatial use and movement through critical habitat monitored by the Ship Island acoustic array from 2011 to 2015. Previous studies observed western population Gulf sturgeon (Pearl and Pascagoula rivers) overwintering near the ends and within the passes of the barrier islands of the Mississippi Sound, USA. Recent telemetry studies detected eastern population fish (Escambia, Blackwater, Yellow, and Choctawhatchee rivers) overwintering as far west as Mobile Bay, Alabama; however, this study is the first to observe eastern population fish overwintering in western population critical habitat associated with the Ship Island array. Use of overwintering habitat was compared using mean active days detected and rate of travel to and from the array. There was no significant difference in mean active days of population units on the array; however, travel rate to the array from natal drainages was significantly different, with eastern population individuals traveling at a faster rate compared to western population individuals. Post hoc tests indicated that individuals from the Blackwater River had a significantly higher travel rate compared to Pascagoula River individuals. We documented large-scale seascape connectivity among population units of Gulf sturgeon across the northern Gulf of Mexico. Although large-scale seascape connectivity promotes mixing among population units and an exchange of marine nutrients into riverine environments, large-scale migration poses an issue for endangered species such as Gulf sturgeon, as there is greater risk of bycatch mortality and size-specific predation.

Three experiments were conducted to determine the effects of amount of prior target information (Experiment 1) and semantic priming (Experiment 2) in an attentional gating task. The goal was to determine some causes of the processing deficits commonly observed in perceiving successive visual stimuli. Items in a rapid serial visual presentation (RSVP) stream are subject to processing deficits before they are processed to the level of recognition (early selection) and after they have been recognized (late selection). Deficits in the former case presumably are due to an early filter that prevents complete recognition and semantic analysis, whereas deficits in the latter case arise from interference or response competition, producing forgetting among a set of recognized items. The semantic-priming effects found between a cue and a target (Experiment 2) and between two successive targets (Experiment 3) indicate that top-down processes can increase the subjective availability of related items. The results are consistent with the idea that most processing deficits observed in search through an RSVP sequence are due to limited capacity in our ability to form episodic representations of all the items in the sequence. [ABSTRACT FROM AUTHOR]

PURPOSE: To determine whether combination 5-fluorouracil, cisplatin, and interferon alfa, an active regimen in advanced esophageal cancer, is efficacious as induction therapy before esophagectomy. MATERIALS AND METHODS: Forty-four patients with potentially resectable esophageal/gastroesophageal junction adenocarcinoma or squamous cell carcinoma were entered into a phase I/II study of this chemotherapeutic regimen and concurrent external-beam radiotherapy before resection. The initial 16 patients were treated with prolonged-infusion 5-fluorouracil (300 mg/m2 on days 1 to 28), cisplatin (20 mg/m2 on days 1 to 5 and 24 to 28), interferon alfa (3 x 10(6) U/m2 intravenously on days 1 to 5 and 24 to 28; subcutaneous injection every other day on days 6 to 23), and radiation (4000 cGy). The subsequent 28 patients were treated over 21 days with two modifications: dose escalation of 5-fluorouracil (250 to 350 mg/m2) and double-fractionated radiotherapy to a total dose of 4500 cGy. RESULTS: Forty-one patients completed chemoradiotherapy and were evaluable for toxicity. Adverse events were substantial but tolerable, and most toxic episodes were hematologic and gastrointestinal. Three patients died, and one patient had progressive disease before resection. Of the 37 patients eligible for curative resection, 36 had all gross tumor removed. Thirty-three (80%) patients had a major pathologic response: 10 (24%) with no residual tumor and 23 with only microscopic residual tumor. Median survival for all patients was 27 months and for responders was 36 months. CONCLUSIONS: This combination regimen is active but yields results similar to those of other chemoradiotherapy phase II trials; therefore, the contribution of interferon alfa to treatment efficacy remains uncertain. The true worth of preoperative chemoradiotherapy is unknown pending results of phase III trials. [ABSTRACT FROM AUTHOR]

The emerging malaria parasite Plasmodium knowlesi threatens the goal of worldwide malaria elimination due to its zoonotic spread in Southeast Asia. After brief ex-vivo culture we used 2D LC/MS/MS to examine the early and late ring stages of infected Macaca mulatta red blood cells harboring P. knowlesi. The M. mulatta clathrin heavy chain and T-cell and macrophage inhibitor ERMAP were overexpressed in the early ring stage; glutaredoxin 3 was overexpressed in the late ring stage; GO term differential enrichments included response to oxidative stress and the cortical cytoskeleton in the early ring stage. P. knowlesi clathrin heavy chain and 60S acidic ribosomal protein P2 were overexpressed in the late ring stage; GO term differential enrichments included vacuoles in the early ring stage, ribosomes and translation in the late ring stage, and Golgi- and COPI-coated vesicles, proteasomes, nucleosomes, vacuoles, ion-, peptide-, protein-, nucleocytoplasmic- and RNA-transport, antioxidant activity and glycolysis in both stages. SIGNIFICANCE: Due to its zoonotic spread, cases of the emerging human pathogen Plasmodium knowlesi in southeast Asia, and particularly in Malaysia, threaten regional and worldwide goals for malaria elimination. Infection by this parasite can be fatal to humans, and can be associated with significant morbidity. Due to zoonotic transmission from large macaque reservoirs that are untreatable by drugs, and outdoor biting mosquito vectors that negate use of preventive measures such as bed nets, its containment remains a challenge. Its biology remains incompletely understood. Thus we examine the expressed proteome of the early and late ex-vivo cultured ring stages, the first intraerythrocyte developmental stages after infection of host rhesus macaque erythrocytes. We used GO term enrichment strategies and differential protein expression to compare early and late ring stages. The early ring stage is characterized by the enrichment of P. knowlesi vacuoles, and overexpression of the M. mulatta clathrin heavy chain, important for clathrin-coated pits and vesicles, and clathrin-mediated endocytosis. The M. mulatta protein ERMAP was also overexpressed in the early ring stage, suggesting a potential role in early ring stage inhibition of T-cells and macrophages responding to P. knowlesi infection of reticulocytes. This could allow expansion of the host P. knowlesi cellular niche, allowing parasite adaptation to invasion of a wider age range of RBCs than the preferred young RBCs or reticulocytes, resulting in proliferation and increased pathogenesis in infected humans. Other GO terms differentially enriched in the early ring stage include the M. mulatta cortical cytoskeleton and response to oxidative stress. The late ring stage is characterized by overexpression of the P. knowlesi clathrin heavy chain. Combined with late ring stage GO term enrichment of Golgi-associated and coated vesicles, and enrichment of COPI-coated vesicles in both stages, this suggests the importance to P. knowlesi biology of clathrin-mediated endocytosis. P. knowlesi ribosomes and translation were also differentially enriched in the late ring stage. With expression of a variety of heat shock proteins, these results suggest production of folded parasite proteins is increasing by the late ring stage. M. mulatta endocytosis was differentially enriched in the late ring stage, as were clathrin-coated vesicles and endocytic vesicles. This suggests that M. mulatta clathrin-based endocytosis, perhaps in infected reticulocytes rather than mature RBC, may be an important process in the late ring stage. Additional ring stage biology from enriched GO terms includes M. mulatta proteasomes, protein folding and the chaperonin-containing T complex, actin and cortical actin cytoskeletons. P knowlesi biology also includes proteasomes, as well as nucleosomes, antioxidant activity, a variety of transport processes, glycolysis, vacuoles and protein folding. Mature RBCs have lost internal organelles, suggesting infection here may involve immature reticulocytes still retaining organelles. P. knowlesi parasite proteasomes and translational machinery may be ring stage drug targets for known selective inhibitors of these processes in other Plasmodium species. To our knowledge this is the first examination of more than one timepoint within the ring stage. Our results expand knowledge of both host and parasite proteins, pathways and organelles underlying P. knowlesi ring stage biology., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Missing visual information, such as a gap between an object or an occluded view, has been shown to disrupt visual search and make amodal completion inefficient. Previous research, using simple black bars as stimuli, failed to show a pop-out effect (flat search slope across increasing visual set sizes) during a feature search when the target was partially occluded, but not in cases where it was fully visible. We wanted to see if this lack of a pop-out effect during feature (orientation) search extended to complex objects (Experiment 1) and identity search (Experiment 2). Participants completed orientation and identity visual search tasks by deciding whether the target was present or not present. Bayesian analyses was conducted to find evidence for observed data to be under the null (pop-out effects) or alternative hypotheses (differences in search slopes). When no occluders or gaps were present, a pop-out effect occurred when searching for a simple objects' orientation or identity. In addition, object complexity affected identity search, with anecdotal evidence suggesting that some complex object may not show a pop-out effect. Furthermore, white occluding bars were more disruptive than having a gap of visual information for feature search but not for identity search. Overall, pop-out effects do occur for simple objects, but when the task is more difficult, search for real-world objects is greatly affected by any type of visual disruption., (© 2024. The Author(s).)

Objective: Expand research on the Sustained Attention to Response Task (SART) to a more applied agricultural target detection/selection task and examine the utility of various performance metrics, including composite measures of speed and accuracy, in a High-Go/Low-No-Go stimuli task., Background: Modified SARTs have been utilized to investigate mechanisms, such as failures of response inhibition, occurring in friendly fire and collateral damage incidents. Researchers have demonstrated that composite measures of speed and accuracy are useful for Low Go/High No-Go stimuli tasks, but this has not been demonstrated for High-Go/Low-No-Go tasks, such as the SART., Method: Participants performed a modified SART, where they selected ("sprayed") images of weeds (Go stimuli) that appeared on a computer screen, while withholding to rarer soybean plant images (No-Go stimuli)., Results: Response time was a function of distance from a central starting point. Participants committed commission errors (sprayed the soybeans) at a significantly higher rate when the stimuli appeared under the cursor centered on the screen for each trial. Participant's omission errors (failure to spray a weed) increased significantly as a function of distance. The composite measures examined were primarily influenced by response time and omission errors limiting their utility when commission errors are of particular interest., Conclusion: Participants are far more accurate in their decision making when required to execute a longer duration motor task in High-Go/Low-No-Go experiments., Application: Demonstrates a serious human factors liability of target detection and snap-to-target systems.

Breast cancer detection has a significant impact on population health. Although there are many breast imaging modalities, mammography is the predominant tool for breast cancer screening. The introduction of digital breast tomosynthesis to mammography has contributed to increased cancer detection rates and decreased recall rates. In average-risk women, starting annual screening mammography at age 40 years has demonstrated the highest mortality reduction. In intermediate- and high-risk women as well as in those with dense breasts, additional modalities, including MRI, ultrasound, and molecular breast imaging, can also be considered for adjunct screening to improve the detection of mammographically occult malignancy., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Physiologic changes that occur in the breast during pregnancy and lactation create challenges for breast cancer screening and diagnosis. Despite these challenges, imaging evaluation should not be deferred, because delayed diagnosis of pregnancy-associated breast cancer contributes to poor outcomes. Both screening and diagnostic imaging can be safely performed using protocols based on age, breast cancer risk, and whether the patient is pregnant or lactating. US is the preferred initial imaging modality for the evaluation of clinical symptoms in pregnant women, followed by mammography if the US findings are suspicious for malignancy or do not show the cause of the clinical symptom. Breast MRI is not recommended during pregnancy because of the use of intravenous gadolinium-based contrast agents. Diagnostic imaging for lactating women is the same as that for nonpregnant nonlactating individuals, beginning with US for patients younger than 30 years old and mammography followed by US for patients aged 30 years and older. MRI can be performed for high-risk screening and local-regional staging in lactating women. The radiologist may encounter a wide variety of breast abnormalities, some specific to pregnancy and lactation, including normal physiologic changes, benign disorders, and malignant neoplasms. Although most masses encountered are benign, biopsy should be performed if the imaging characteristics are suspicious for cancer or if the finding does not resolve after a short period of clinical follow-up. Knowledge of the expected imaging appearance of physiologic changes and common benign conditions of pregnancy and lactation is critical for differentiating these findings from pregnancy-associated breast cancer. © RSNA, 2023 Online supplemental material is available for this article. Quiz questions for this article are available through the Online Learning Center.

Temperate Earth-sized exoplanets around late-M dwarfs offer a rare opportunity to explore under which conditions planets can develop hospitable climate conditions. The small stellar radius amplifies the atmospheric transit signature, making even compact secondary atmospheres dominated by N 2 or CO 2 amenable to characterization with existing instrumentation 1 . Yet, despite large planet search efforts 2 , detection of low-temperature Earth-sized planets around late-M dwarfs has remained rare and the TRAPPIST-1 system, a resonance chain of rocky planets with seemingly identical compositions, has not yet shown any evidence of volatiles in the system 3 . Here we report the discovery of a temperate Earth-sized planet orbiting the cool M6 dwarf LP 791-18. The newly discovered planet, LP 791-18d, has a radius of 1.03 ± 0.04 R ⊕ and an equilibrium temperature of 300-400 K, with the permanent night side plausibly allowing for water condensation. LP 791-18d is part of a coplanar system 4 and provides a so-far unique opportunity to investigate a temperate exo-Earth in a system with a sub-Neptune that retained its gas or volatile envelope. On the basis of observations of transit timing variations, we find a mass of 7.1 ± 0.7 M ⊕ for the sub-Neptune LP 791-18c and a mass of [Formula: see text] for the exo-Earth LP 791-18d. The gravitational interaction with the sub-Neptune prevents the complete circularization of LP 791-18d's orbit, resulting in continued tidal heating of LP 791-18d's interior and probably strong volcanic activity at the surface 5,6 ., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Plasmodium cynomolgi causes zoonotic malarial infections in Southeast Asia and this parasite species is important as a model for Plasmodium vivax and Plasmodium ovale. Each of these species produces hypnozoites in the liver, which can cause relapsing infections in the blood. Here we present methods and data generated from iterative longitudinal systems biology infection experiments designed and performed by the Malaria Host-Pathogen Interaction Center (MaHPIC) to delve deeper into the biology, pathogenesis, and immune responses of P. cynomolgi in the Macaca mulatta host. Infections were initiated by sporozoite inoculation. Blood and bone marrow samples were collected at defined timepoints for biological and computational experiments and integrative analyses revolving around primary illness, relapse illness, and subsequent disease and immune response patterns. Parasitological, clinical, haematological, immune response, and -omic datasets (transcriptomics, proteomics, metabolomics, and lipidomics) including metadata and computational results have been deposited in public repositories. The scope and depth of these datasets are unprecedented in studies of malaria, and they are projected to be a F.A.I.R., reliable data resource for decades., (© 2022. The Author(s).)

Background: Advertising of traditional alcopops contains elements that appeal to youth, especially females. Supersized alcopops are marketed differently than traditional alcopops and contain up to 5.5 standard alcoholic drinks. Young females are more likely to underestimate the alcohol content of supersized alcopops, putting them at higher risk of overconsumption. Similar to supersized alcopops, beer is packaged in large cans and in the same areas of store shelves. Objective: This study examined among young people whether supersized alcopops versus beer products disproportionately appealed to females. Methods: Eleven adolescents (13-17 years old) and 72 college students (21-26 years old) were recruited during 2019-2020. Participants viewed 19 photos of convenience store display cases containing both supersized alcopop and beer products. While viewing each image, participants were instructed to click on the beverage that looked the "coolest" (i.e. most appealing). Eye-tracking hardware and software measured the amount of time participants visually fixated on each product. Participants completed a survey to record demographic characteristics. Results: Compared to males (n=25), females (n=58) fixated on supersized alcopops for 6.8 seconds longer (95%CI 0.3,13.3). Females also had 3.7 times the odds of selecting a supersized alcopop as the product they found most appealing compared to males (95%CI 1.68,8.01), adjusting for amount of time visually fixating on supersized alcopops, which was also a significant predictor. Conclusions: Young females' strong preference for supersized alcopops is concerning given they disproportionately underestimate their potency, relative to males, and are more likely to obtain dangerously high BAC levels from consuming one or two supersized alcopops.

Objective: To evaluate fatigue frequency and severity among patients with psoriatic arthritis (PsA) and assess the effect of fatigue severity on patient-reported outcome measures (PROMs) assessing quality of life, function, and work productivity., Methods: Data were derived from the Adelphi Disease Specific Programme, a cross-sectional survey conducted in 2018 in the United States and Europe. Patients had physician-confirmed PsA. Fatigue was collected as a binary variable and through its severity (0-10 scale, using the 12-item Psoriatic Arthritis Impact of Disease fatigue question) from patients; physicians also reported patient fatigue (yes/no). Other PROMs included the 5-level EuroQol 5-dimension questionnaire (EQ-5D-5L) for health-related quality of life (HRQOL), Health Assessment Questionnaire-Disability Index, and Work Productivity and Activity Impairment Questionnaire. Multivariate linear regression was used to evaluate the association between fatigue severity and other PROMs., Results: Among the 831 included patients (mean age 47.5 yrs, mean disease duration 5.3 yrs, 46.9% female, 48.1% receiving a biologic), fatigue was reported by 78.3% of patients. Patients with greater fatigue severity had greater disease duration, PsA severity, pain levels, body surface area affected by psoriasis, and swollen and tender joint counts (all P < 0.05). In multivariate analyses, patients with greater fatigue severity experienced worse physical functioning, HRQOL, and work productivity (all P < 0.001). Presence of fatigue was underreported by physicians (reported in only 32% of patients who self-reported fatigue)., Conclusion: Prevalence of patient-reported fatigue was high among patients with PsA and underrecognized by physicians. Fatigue severity was associated with altered physical functioning, work productivity, and HRQOL., (Copyright © 2022 by the Journal of Rheumatology.)

Plasmodium knowlesi poses a health threat throughout Southeast Asian communities and currently causes most cases of malaria in Malaysia. This zoonotic parasite species has been studied in Macaca mulatta (rhesus monkeys) as a model for severe malarial infections, chronicity, and antigenic variation. The phenomenon of Plasmodium antigenic variation was first recognized during rhesus monkey infections. Plasmodium -encoded variant proteins were first discovered in this species and found to be expressed at the surface of infected erythrocytes, and then named the Schizont-Infected Cell Agglutination (SICA) antigens. SICA expression was shown to be spleen dependent, as SICA expression is lost after P. knowlesi is passaged in splenectomized rhesus. Here we present data from longitudinal P. knowlesi infections in rhesus with the most comprehensive analysis to date of clinical parameters and infected red blood cell sequestration in the vasculature of tissues from 22 organs. Based on the histopathological analysis of 22 tissue types from 11 rhesus monkeys, we show a comparative distribution of parasitized erythrocytes and the degree of margination of the infected erythrocytes with the endothelium. Interestingly, there was a significantly higher burden of parasites in the gastrointestinal tissues, and extensive margination of the parasites along the endothelium, which may help explain gastrointestinal symptoms frequently reported by patients with P. knowlesi malarial infections. Moreover, this margination was not observed in splenectomized rhesus that were infected with parasites not expressing the SICA proteins. This work provides data that directly supports the view that a subpopulation of P. knowlesi parasites cytoadheres and sequesters, likely via SICA variant antigens acting as ligands. This process is akin to the cytoadhesive function of the related variant antigen proteins, namely Erythrocyte Membrane Protein-1, expressed by Plasmodium falciparum ., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Peterson, Joyner, Lapp, Brady, Wood, Cabrera-Mora, Saney, Fonseca, Cheng, Jiang, Soderberg, Nural, Hankus, Machiah, Karpuzoglu, DeBarry, MaHPIC-Consortium, Tirouvanziam, Kissinger, Moreno, Gumber, Voit, Gutierrez, Cordy and Galinski.)

Background: Lyme disease incidence is increasing, despite current prevention options. New Lyme disease vaccine candidates are in development, however, investigation of the acceptability of a Lyme disease vaccine among potential consumers is needed prior to any vaccine coming to market. We conducted a population-based, cross-sectional study to estimate willingness to receive a potential Lyme disease vaccine and factors associated with willingness., Methods: The web-based survey was administered to a random sample of Connecticut, Maryland, Minnesota, and New York residents June-July 2018. Survey-weighted descriptive statistics were conducted to estimate the proportion willing to receive a potential Lyme disease vaccine. Multivariable multinomial logistic regression models were used to quantify the association of sociodemographic characteristics and Lyme disease vaccine attitudes with willingness to be vaccinated., Results: Surveys were completed by 3313 respondents (6% response rate). We estimated that 64% of residents were willing to receive a Lyme disease vaccine, while 30% were uncertain and 7% were unwilling. Compared to those who were willing, those who were uncertain were more likely to be parents, adults 45-65 years old, non-White, have less than a bachelor's degree, or have safety concerns about a potential Lyme disease vaccine. Those who were unwilling were also more likely to be non-White, have less than a bachelor's degree, or have safety concerns about a potential Lyme disease vaccine. In addition, the unwilling had low confidence in vaccines in general, had low perceived risk of contracting Lyme disease, and said they would not be influenced by a positive recommendation from a healthcare provider., Discussion: Overall, willingness to receive a Lyme disease vaccine was high. Effective communication by clinicians regarding safety and other vaccine parameters to those groups who are uncertain will be critical for increasing vaccine uptake and reducing Lyme disease incidence., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Published by Elsevier Ltd.)

Background: Kra monkeys (Macaca fascicularis), a natural host of Plasmodium knowlesi, control parasitaemia caused by this parasite species and escape death without treatment. Knowledge of the disease progression and resilience in kra monkeys will aid the effective use of this species to study mechanisms of resilience to malaria. This longitudinal study aimed to define clinical, physiological and pathological changes in kra monkeys infected with P. knowlesi, which could explain their resilient phenotype., Methods: Kra monkeys (n = 15, male, young adults) were infected intravenously with cryopreserved P. knowlesi sporozoites and the resulting parasitaemias were monitored daily. Complete blood counts, reticulocyte counts, blood chemistry and physiological telemetry data (n = 7) were acquired as described prior to infection to establish baseline values and then daily after inoculation for up to 50 days. Bone marrow aspirates, plasma samples, and 22 tissue samples were collected at specific time points to evaluate longitudinal clinical, physiological and pathological effects of P. knowlesi infections during acute and chronic infections., Results: As expected, the kra monkeys controlled acute infections and remained with low-level, persistent parasitaemias without anti-malarial intervention. Unexpectedly, early in the infection, fevers developed, which ultimately returned to baseline, as well as mild to moderate thrombocytopenia, and moderate to severe anaemia. Mathematical modelling and the reticulocyte production index indicated that the anaemia was largely due to the removal of uninfected erythrocytes and not impaired production of erythrocytes. Mild tissue damage was observed, and tissue parasite load was associated with tissue damage even though parasite accumulation in the tissues was generally low., Conclusions: Kra monkeys experimentally infected with P. knowlesi sporozoites presented with multiple clinical signs of malaria that varied in severity among individuals. Overall, the animals shared common mechanisms of resilience characterized by controlling parasitaemia 3-5 days after patency, and controlling fever, coupled with physiological and bone marrow responses to compensate for anaemia. Together, these responses likely minimized tissue damage while supporting the establishment of chronic infections, which may be important for transmission in natural endemic settings. These results provide new foundational insights into malaria pathogenesis and resilience in kra monkeys, which may improve understanding of human infections., (© 2021. The Author(s).)

Death receptor 5 (DR5) is an attractive target for cancer therapy due to its broad upregulated expression in multiple cancers and ability to directly induce apoptosis. Though anti-DR5 IgG antibodies have been evaluated in clinical trials, limited efficacy has been attributed to insufficient receptor crosslinking. IGM-8444 is an engineered, multivalent agonistic IgM antibody with 10 binding sites to DR5 that induces cancer cell apoptosis through efficient DR5 multimerization. IGM-8444 bound to DR5 with high avidity and was substantially more potent than an IgG with the same binding domains. IGM-8444 induced cytotoxicity in a broad panel of solid and hematologic cancer cell lines but did not kill primary human hepatocytes in vitro , a potential toxicity of DR5 agonists. In multiple xenograft tumor models, IGM-8444 monotherapy inhibited tumor growth, with strong and sustained tumor regression observed in a gastric PDX model. When combined with chemotherapy or the BCL-2 inhibitor ABT-199, IGM-8444 exhibited synergistic in vitro tumor cytotoxicity and enhanced in vivo efficacy, without augmenting in vitro hepatotoxicity. These results support the clinical development of IGM-8444 in solid and hematologic malignancies as a monotherapy and in combination with chemotherapy or BCL-2 inhibition., (©2021 The Authors; Published by the American Association for Cancer Research.)

Natural immunoglobulin M (IgM) antibodies are pentameric or hexameric macro-immunoglobulins and have been highly conserved during evolution. IgMs are initially expressed during B cell ontogeny and are the first antibodies secreted following exposure to foreign antigens. The IgM multimer has either 10 (pentamer) or 12 (hexamer) antigen binding domains consisting of paired µ heavy chains with four constant domains, each with a single variable domain, paired with a corresponding light chain. Although the antigen binding affinities of natural IgM antibodies are typically lower than IgG, their polyvalency allows for high avidity binding and efficient engagement of complement to induce complement-dependent cell lysis. The high avidity of IgM antibodies renders them particularly efficient at binding antigens present at low levels, and non-protein antigens, for example, carbohydrates or lipids present on microbial surfaces. Pentameric IgM antibodies also contain a joining (J) chain that stabilizes the pentameric structure and enables binding to several receptors. One such receptor, the polymeric immunoglobulin receptor (pIgR), is responsible for transcytosis from the vasculature to the mucosal surfaces of the lung and gastrointestinal tract. Several naturally occurring IgM antibodies have been explored as therapeutics in clinical trials, and a new class of molecules, engineered IgM antibodies with enhanced binding and/or additional functional properties are being evaluated in humans. Here, we review the considerable progress that has been made regarding the understanding of biology, structure, function, manufacturing, and therapeutic potential of IgM antibodies since their discovery more than 80 years ago.

The double-step paradigm investigates the characteristics of planning and execution when the motor system must rapidly adjust for a new goal location. Studies have provided detailed temporal information based on the duration available for the motor system to prepare a new movement trajectory (here referred to as re-preparation time). However, previous work has largely examined single displacement sizes, limiting the spatiotemporal understanding of movement planning and execution. The lack of a description of this behavioral timecourse across increasing displacement sizes is true for saccades, rapid eye movements that redirect the fovea. Furthermore, during the double-step paradigm, the primary saccade often fails to accurately foveate the final target location and a secondary saccade brings the target onto the fovea. However, it is also unknown how this compensation is concurrently modified with the exposure duration and displacement of the movement goal. Here, we examined the amount of time required to change the initial saccade direction to a new target location for relatively small (20°, 30°, and 40°) and large (60° and 90°) target spatial separations. Interestingly, we found a clear relationship between the saccade direction and the amount of time allowed to redirect the movement; across separations, intermediate saccades occurred when approximately 60-140 ms was available to readjust the movement plan. Additionally, there was a consistent relationship between the timing of the secondary saccade and the re-preparation time across jump sizes, suggesting that concurrent movement correction planning was dependent on the amount of exposure to the final movement goal., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Hyperactivation of eIF4F-mediated translation occurs in many if not all cancers. As a consequence, cancer cells aberrantly enhance expression of malignancy-related proteins that are involved in cell cycle progression, angiogenesis, growth, and proliferation. With this in mind eIF4F is a promising molecular target for therapeutics that counteract pathological eIF4F activity. Here we used 4EGI-1, a small-molecule inhibitor of cap-mediated translation that disrupts formation of the eukaryotic initiation factor 4F (eIF4F) complex to treat non-small cell lung cancer (NSCLC). Treatment of cells with 4EGI-1 reduced cell proliferation, decreased cap-dependent complex formation, induced apoptosis, enhanced sensitivity to gemcitabine, and altered global cellular translation. Suppression of cap-dependent translation by 4EGI-1 resulted in diminished expression of oncogenic proteins c-Myc, Bcl-2, cyclin D1, and survivin, whereas β-actin expression was left unchanged. In light of these results, small-molecule inhibitors like 4EGI-1 alone or with chemotherapy should be further evaluated in the treatment of NSCLC.

Many plant viral RNA genomes lack a 5' cap, and instead are translated via a cap-independent translation element (CITE) in the 3' untranslated region (UTR). The panicum mosaic virus-like CITE (PTE), found in many plant viral RNAs, binds and requires the cap-binding translation initiation factor eIF4E to facilitate translation. eIF4E is structurally conserved between plants and animals, so we tested cap-independent translation efficiency of PTEs of nine plant viruses in plant and mammalian systems. The PTE from thin paspalum asymptomatic virus (TPAV) facilitated efficient cap-independent translation in wheat germ extract, rabbit reticulocyte lysate, HeLa cell lysate, and in oat and mammalian (BHK) cells. Human eIF4E bound the TPAV PTE but not a PTE that did not stimulate cap-independent translation in mammalian extracts or cells. Selective 2'-hydroxyl acylation analyzed by primer extension (SHAPE) footprinting revealed that both human and wheat eIF4E protected the conserved guanosine (G)-rich domain in the TPAV PTE pseudoknot. The central G plays a key role, as it was found to be required for translation and protection from SHAPE modification by eIF4E. These results provide insight on how plant viruses gain access to the host's translational machinery, an essential step in infection, and raise the possibility that similar PTE-like mechanisms may exist in mRNAs of mammals or their viruses.

Why do saccades interfere with spatial working memory? One possibility is that attention and saccades are tightly coupled, and performing a saccade momentarily removes attention from spatial working memory, degrading the memory representation. This cannot be the entire explanation, because saccades cause greater interference than do covert attentional shifts (Lawrence, Myerson, & Abrams, 2004). In addition, this saccadic degradation is limited to spatial but not object, configural, or verbal representations. We propose that saccadic remapping is partially responsible for this increased interference. To test this, we used a spatial change detection task, and during the retention interval, participants either performed a central task, a peripheral task without an eye movement, or a peripheral task that required a saccade. Using the method of constant stimuli allowed us to fit psychophysical functions in which we derived measures of spatial memory precision, guessing, and response bias. It is important that we found a directionally specific loss of memory precision, such that memory representations were less precise along the axis of the saccade. This was beyond the general loss of precision we found for covert shifts, suggesting that part of the effect is because of remapping. Saccades also increased guessing, but unlike the loss of precision, the effect was nondirectional. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Background: Plasmodium vivax can cause severe malaria with multisystem organ dysfunction and death. Clinical reports suggest that parasite accumulation in tissues may contribute to pathogenesis and disease severity, but direct evidence is scarce., Methods: We present quantitative parasitological and histopathological analyses of tissue sections from a cohort of naive, mostly splenectomized Saimiri boliviensis infected with P vivax to define the relationship of tissue parasite load and histopathology., Results: The lung, liver, and kidney showed the most tissue injury, with pathological presentations similar to observations reported from autopsies. Parasite loads correlated with the degree of histopathologic changes in the lung and liver tissues. In contrast, kidney damage was not associated directly with parasite load but with the presence of hemozoin, an inflammatory parasite byproduct., Conclusions: This analysis supports the use of the S boliviensis infection model for performing detailed histopathological studies to better understand and potentially design interventions to treat serious clinical manifestations caused by P vivax .

Deregulation of cap-dependent translation has been implicated in the malignant transformation of numerous human tissues. 4EGI-1, a novel small-molecule inhibitor of cap-dependent translation, disrupts formation of the eukaryotic initiation factor 4F (eIF4F) complex. The effects of 4EGI-1-mediated inhibition of translation initiation in malignant pleural mesothelioma (MPM) were examined. 4EGI-1 preferentially inhibited cell viability and induced apoptosis in MPM cells compared to normal mesothelial (LP9) cells. This effect was associated with hypophosphorylation of 4E-binding protein 1 (4E-BP1) and decreased protein levels of the cancer-related genes, c-myc and osteopontin. 4EGI-1 showed enhanced cytotoxicity in combination with pemetrexed or gemcitabine. Translatome-wide polysome microarray analysis revealed a large cohort of genes that were translationally regulated upon treatment with 4EGI-1. The 4EGI-1-regulated translatome was negatively correlated to a previously published translatome regulated by eIF4E overexpression in human mammary epithelial cells, which is in agreement with the notion that 4EGI-1 inhibits the eIF4F complex. These data indicate that inhibition of the eIF4F complex by 4EGI-1 or similar translation inhibitors could be a strategy for treating mesothelioma. Genome wide translational profiling identified a large cohort of promising target genes that should be further evaluated for their potential significance in the treatment of MPM.

While selective estrogen receptor modulators, such as tamoxifen, have contributed to increased survival in patients with hormone receptor-positive breast cancer, the development of resistance to these therapies has led to the need to investigate other targetable pathways involved in oncogenic signaling. Approval of the mTOR inhibitor everolimus in the therapy of secondary endocrine resistance demonstrates the validity of this approach. Importantly, mTOR activation regulates eukaryotic messenger RNA translation. Eukaryotic translation initiation factor 4E (eIF4E), a component of the cap-dependent translation complex eIF4F, confers resistance to drug-induced apoptosis when overexpressed in multiple cell types. The eIF4F complex is downstream of multiple oncogenic pathways, including mTOR, making it an appealing drug target. Here, we show that the eIF4F translation pathway was hyperactive in tamoxifen-resistant (TamR) MCF-7L breast cancer cells. While overexpression of eIF4E was not sufficient to confer resistance to tamoxifen in MCF-7L cells, its function was necessary to maintain resistance in TamR cells. Targeting the eIF4E subunit of the eIF4F complex through its degradation using an antisense oligonucleotide (ASO) or via sequestration using a mutant 4E-BP1 inhibited the proliferation and colony formation of TamR cells and partially restored sensitivity to tamoxifen. Further, the use of these agents also resulted in cell cycle arrest and induction of apoptosis in TamR cells. Finally, the use of a pharmacologic agent which inhibited the eIF4E-eIF4G interaction also decreased the proliferation and anchorage-dependent colony formation in TamR cells. These results highlight the eIF4F complex as a promising target for patients with acquired resistance to tamoxifen and, potentially, other endocrine therapies.

It is well established that certain social cues, such as averted eye gaze, can automatically initiate the orienting of another's spatial attention. However, whether human posture can also reflexively cue spatial attention remains unclear. The present study directly investigated whether averted neutral postures reflexively cue the attention of observers in a normal population of college students. Similar to classic gaze-cuing paradigms, non-predictive averted posture stimuli were presented prior to the onset of a peripheral target stimulus at one of five SOAs (100ms-500ms). Participants were instructed to move their eyes to the target as fast as possible. Eye-tracking data revealed that participants were significantly faster in initiating saccades when the posture direction was congruent with the target stimulus. Since covert attention shifts precede overt shifts in an obligatory fashion, this suggests that directional postures reflexively orient the attention of others. In line with previous work on gaze-cueing, the congruency effect of posture cue was maximal at the 300ms SOA. These results support the notion that a variety of social cues are used by the human visual system in determining the "direction of attention" of others, and also suggest that human body postures are salient stimuli capable of automatically shifting an observer's attention., (Copyright © 2017 Elsevier B.V. All rights reserved.)

There is extensive evidence that the contralateral delay activity (CDA), a scalp recorded event-related brain potential, provides a reliable index of the number of objects held in visual working memory. Here we present evidence that the CDA not only indexes visual object working memory, but also the number of locations held in spatial working memory. In addition, we demonstrate that the CDA can be predictably modulated by the type of encoding strategy employed. When individual locations were held in working memory, the pattern of CDA modulation mimicked previous findings for visual object working memory. Specifically, CDA amplitude increased monotonically until working memory capacity was reached. However, when participants were instructed to group individual locations to form a constellation, the CDA was prolonged and reached an asymptote at two locations. This result provides neural evidence for the formation of a unitary representation of multiple spatial locations., (Published by Elsevier B.V.)

Introduction: Reduction of nonessential angiogram and embolization for patients sustaining blunt abdominal and pelvic trauma would allow improved utilization and decreased morbidity related to nontherapeutic embolization. We hypothesized that the nature of intravenous contrast extravasation (IVCE) on computed tomography (CT) would be directly related to the finding of extravasation on angiogram and need for embolization., Methods: A 5-year retrospective evaluation of trauma patients with IVCE on CT. Demographics, hemodynamics, and IVCE location and maximal dimension/volume were examined for relationship to IVCE on angiography and need for embolization. Primary complications were defined as nephropathy and acute respiratory distress syndrome., Results: A total of 128 patients were identified with IVCE on CT. Ninety-seven (75.8%) also had IVCE identified on angiography requiring some form of embolization. The size of IVCE on CT was not related to IVCE on angiogram ( P = 0.69). Location of IVCE was related to need for embolization, with spleen embolization (85.4%) being much more frequent than liver (51.5%, P = 0.006). Complication rate was 8.7% in all patients, and was not different between patients undergoing embolization and those who did not ( P = 0.40)., Conclusion: IVCE volume was not predictive of continued bleeding and need for embolization. However, splenic injuries with IVCE required embolization more frequently. In contrast, liver injuries were found to have infrequent on-going IVCE on angiography. Complications associated with angiogram with or without embolization are infrequent, and CT findings may not be predictive of ongoing bleeding. We do not recommend selective exclusion of patients from angiographic evaluation when a blush is present., Competing Interests: There are no conflicts of interest.

Efficient detection of threat provides obvious survival advantages and has resulted in a fast and accurate threat-detection system. Although beneficial under normal circumstances, this system may become hypersensitive and cause threat-processing abnormalities. Past research has shown that anxious individuals have difficulty disengaging attention from threatening faces, but it is unknown whether other forms of threatening social stimuli also influence attentional orienting. Much like faces, human body postures are salient social stimuli, because they are informative of one's emotional state and next likely action. Additionally, postures can convey such information in situations in which another's facial expression is not easily visible. Here we investigated whether there is a threat-specific effect for high-anxious individuals, by measuring the time that it takes the eyes to leave the attended stimulus, a task-irrelevant body posture. The results showed that relative to nonthreating postures, threat-related postures hold attention in anxious individuals, providing further evidence of an anxiety-related attentional bias for threatening information. This is the first study to demonstrate that attentional disengagement from threatening postures is affected by emotional valence in those reporting anxiety.

Background: Control of mRNA translation is fundamentally altered in cancer. Insulin-like growth factor-I (IGF-I) signaling regulates key translation mediators to modulate protein synthesis (e.g. eIF4E, 4E-BP1, mTOR, and S6K1). Importantly the Amplified in Breast Cancer (AIB1) oncogene regulates transcription and is also a downstream mediator of IGF-I signaling., Materials and Methods: To determine if AIB1 also affects mRNA translation, we conducted gain and loss of AIB1 function experiments in estrogen receptor alpha (ERα)(+) (MCF-7L) and ERα(-) (MDA-MB-231, MDA-MB-435 and LCC6) breast cancer cells., Results: AIB1 positively regulated IGF-I-induced mRNA translation in both ERα(+) and ERα(-) cells. Formation of the eIF4E-4E-BP1 translational complex was altered in the AIB1 ERα(+) and ERα(-) knockdown cells, leading to a reduction in the eIF4E/4E-BP1 and eIF4G/4E-BP1 ratios. In basal and IGF-I stimulated MCF-7 and LCC6 cells, knockdown of AIB1 decreased the integrity of the cap-binding complex, reduced global IGF-I stimulated polyribosomal mRNA recruitment with a concomitant decrease in ten of the thirteen genes tested in polysome-bound mRNAs mapping to proliferation, cell cycle, survival, transcription, translation and ribosome biogenesis ontologies. Specifically, knockdown of AIB1 decreased ribosome-bound mRNA and steady-state protein levels of the transcription factors ERα and E2F1 in addition to reduced ribosome-bound mRNA of the ribosome biogenesis factor BYSL in a cell-line specific manner to regulate mRNA translation., Conclusion: The oncogenic transcription factor AIB1 has a novel role in the regulation of polyribosome recruitment and formation of the translational complex. Combinatorial therapies targeting IGF signaling and mRNA translation in AIB1 expressing breast cancers may have clinical benefit and warrants further investigation., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)

Previous work indicates that threatening facial expressions with averted eye gaze can act as a signal of imminent danger, enhancing attentional orienting in the gazed-at direction. However, this threat-related gaze-cueing effect is only present in individuals reporting high levels of anxiety. The present study used eye tracking to investigate whether additional directional social cues, such as averted angry and fearful human body postures, not only cue attention, but also the eyes. The data show that although body direction did not predict target location, anxious individuals made faster eye movements when fearful or angry postures were facing towards (congruent condition) rather than away (incongruent condition) from peripheral targets. Our results provide evidence for attentional cueing in response to threat-related directional body postures in those with anxiety. This suggests that for such individuals, attention is guided by threatening social stimuli in ways that can influence and bias eye movement behaviour.

Objective: The authors determine whether transcranial direct current stimulation (tDCS) can reduce resumption time when an ongoing task is interrupted., Background: Interruptions are common and disruptive. Working memory capacity has been shown to predict resumption lag (i.e., time to successfully resume a task after interruption). Given that tDCS applied to brain areas associated with working memory can enhance performance, tDCS has the potential to improve resumption lag when a task is interrupted., Method: Participants were randomly assigned to one of four groups that received anodal (active) stimulation of 2 mA tDCS to one of two target brain regions, left and right dorsolateral prefrontal cortex (DLPFC), or to one of two control areas, active stimulation of the left primary motor cortex or sham stimulation of the right DLPFC, while completing a financial management task that was intermittently interrupted with math problem solving., Results: Anodal stimulation to the right and left DLPFC significantly reduced resumption lags compared to the control conditions (sham and left motor cortex stimulation). Additionally, there was no speed-accuracy tradeoff (i.e., the improvement in resumption time was not accompanied by an increased error rate)., Conclusion: Noninvasive brain stimulation can significantly decrease resumption lag (improve performance) after a task is interrupted., Application: Noninvasive brain stimulation offers an easy-to-apply tool that can significantly improve interrupted task performance., (© 2014, Human Factors and Ergonomics Society.)

Corollary discharge (CD) is hypothesized to provide the movement information (direction and amplitude) required to compensate for the saccade-induced disruptions to visual input. Here, we investigated to what extent these conveyed metrics influence perceptual stability in human subjects with a target-displacement detection task. Subjects made saccades to targets located at different amplitudes (4°, 6°, or 8°) and directions (horizontal or vertical). During the saccade, the target disappeared and then reappeared at a shifted location either in the same direction or opposite to the movement vector. Subjects reported the target displacement direction, and from these reports we determined the perceptual threshold for shift detection and estimate of target location. Our results indicate that the thresholds for all amplitudes and directions generally scaled with saccade amplitude. Additionally, subjects on average produced hypometric saccades with an estimated CD gain <1. Finally, we examined the contribution of different error signals to perceptual performance, the saccade error (movement-to-movement variability in saccade amplitude) and visual error (distance between the fovea and the shifted target location). Perceptual judgment was not influenced by the fluctuations in movement amplitude, and performance was largely the same across movement directions for different magnitudes of visual error. Importantly, subjects reported the correct direction of target displacement above chance level for very small visual errors (<0.75°), even when these errors were opposite the target-shift direction. Collectively, these results suggest that the CD-based compensatory mechanisms for visual disruptions are highly accurate and comparable for saccades with different metrics., (Copyright © 2015 the American Physiological Society.)

Assessing the impacts of the Deepwater Horizon oil spill with a dependable baseline comparison can provide reliable insight into environmental stressors on organisms that were potentially affected by the spill. Fluctuating asymmetry (small, non-random deviations from perfect bilateral symmetry) is an informative metric sensitive to contaminants that can be used to assess environmental stress levels. For this study, the well-studied and common Gulf of Mexico estuarine fish, Menidia beryllina, was used with pre and post-oil spill collections. Comparisons of fluctuating asymmetry in three traits (eye diameter, pectoral fin length, and pelvic fin length) were made pre and post-oil spill across two sites (Old Fort Bayou and the Pascagoula River), as well as between years of collection (2011, 2012)--one and two years, respectfully, after the spill in 2010. We hypothesized that fluctuating asymmetry would be higher in post-Deepwater Horizon samples, and that this will be replicated in both study areas along the Mississippi Gulf coast. We also predicted that fluctuating asymmetry would decrease through time after the oil spill as the oil decomposed and/or was removed. Analyses performed on 1135 fish (220 pre and 915 post Deepwater Horizon) showed significantly higher post spill fluctuating asymmetry in the eye but no difference for the pectoral or pelvic fins. There was also higher fluctuating asymmetry in one of the two sites both pre and post-spill, indicating observed asymmetry may be the product of multiple stressors. Fluctuating asymmetry decreased in 2012 compared to 2011. Fluctuating asymmetry is a sensitive measure of sub lethal stress, and the observed variability in this study (pre vs. post-spill or between sites) could be due to a combination of oil, dispersants, or other unknown stressors.