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Background: The “chain of survival” was first systematically addressed in 1991, and its sequence still forms the cornerstone of current resuscitation guidelines. The term “chain of survival” is widely used around the world in literature, education, and awareness campaigns, but growing heterogeneity in the components of the chain has led to confusion. It is unclear which of these emerging chains is most suitable, or if adaptations are needed in particular contexts to depict key actions of resuscitation in the 21st century. This scoping review provides an overview of the variety of chains of survival described. Objectives: To identify published facets of the chain of survival, to assess views and strategies about adapting the chain, and to identify reports on how the chain of survival affects teaching, implementation, or patient outcomes. Methods, eligibility criteria, and sources of evidence: A scoping review as part of the continuous evidence evaluation process of the International Liaison Committee on Resuscitation (ILCOR) was conducted. MEDLINE(R) ALL (Ovid), Embase (Ovid), APA PsycINFO (Ovid), CINAHL (Ebscohost), ERIC (Ebscohost), Web of Science (Clarivate), Scopus (Elsevier), and Cochrane Library (Wiley Online) were searched. All publications in all languages describing chains of survival were eligible, without time restrictions. Due to the heterogeneity and publication types of the relevant studies, we did not pursue a systematic review or meta-analysis. Results: A primary search yielded 1713 studies and after screening we included 43 publications. Modified versions of the chain of survival for specific contexts were found (e.g., in-hospital cardiac arrest or paediatric resuscitation). There were also numerous versions with minor adaptations of the existing chain. Three publications suggested an impact of the use of the chain of survival on patient outcomes. No educational or implementation outcomes were reported. Conclusion: There is a vast heterogeneity of chain of survival concepts published. Future research is warranted, especially into the concept’s importance concerning educational, implementation, and clinical outcomes.

Introduction: We conducted this systematic review to identify emergency department (ED) relevant recommendations in current guidelines for care of transgender and gender-diverse (TGD) people internationally. Methods: Using PRISMA criteria, we did a systematic search of Ovid Medline, EMBASE, and CINAHL and a hand search of gray literature for clinical practice guidelines (CPG) or best practice statements (BPS) published until June 31, 2021. Articles were included if they were in English, included medical or paramedical care of TGD populations of any age, in any setting, region or nation, and were national or international in scope. Exclusion criteria included primary research studies, review articles, narrative reviews or otherwise non-CPG or BPS, editorials, or letters to the editor, articles of regional or individual hospital scope, non-medical articles, articles not in English, or if a more recent version of the guideline existed. Recommendations relevant to ED care were identified, recorded, and assessed for quality using the AGREE-II and AGREE-REX criteria. We performed interclass correlation coefficient for interrater reliability. Recommendations were coded for the relevant point of care while in the ED (triage, registration, rooming, investigations, etc.). Results: We screened 1,658 unique articles, and 1,555 were excluded. Of the remaining 103 articles included, seven had recommendations relevant to care in the ED, comprising a total of 10 recommendations. Four guidelines and eight recommendations were of high quality. They included recommendations for testing, prevention, referral, and provision of post-exposure prophylaxis for HIV, and culturally competent care of TGD people. Conclusions: This is the most comprehensive review to date of guidelines and best practices statements offering recommendations for care of ED TGD patients, and several are immediately actionable. There are also many opportunities to build community-led research programs to synthesize and inform a comprehensive dedicated guideline for care of TGD people in emergency settings.

ABSTRACTWe previously identified the bisbenzimide Hoechst 33342 (H42) as a potent multi-stage inhibitor of the prototypic poxvirus, the vaccinia virus (VACV), and several parapoxviruses. A recent report showed that novel bisbenzimide compounds similar in structure to H42 could prevent human cytomegalovirus replication. Here, we assessed whether these compounds could also serve as poxvirus inhibitors. Using virological assays, we show that these bisbenzimide compounds inhibit VACV spread, plaque formation, and the production of infectious progeny VACV with relatively low cell toxicity. Further analysis of the VACV lifecycle indicated that the effective bisbenzimide compounds had little impact on VACV early gene expression but inhibited VACV late gene expression and truncated the formation of VACV replication sites. Additionally, we found that bisbenzimide compounds, including H42, can inhibit both monkeypox and a VACV mutant resistant to the widely used anti-poxvirus drug TPOXX (Tecovirimat). Therefore, the tested bisbenzimide compounds were inhibitors of both prototypic and pandemic potential poxviruses and could be developed for use in situations where anti-poxvirus drug resistance may occur. Additionally, these data suggest that bisbenzimide compounds may serve as broad-activity antiviral compounds, targeting diverse DNA viruses such as poxviruses and betaherpesviruses.IMPORTANCEThe 2022 mpox (monkeypox) outbreak served as a stark reminder that due to the cessation of smallpox vaccination over 40 years ago, most of the human population remains susceptible to poxvirus infection. With only two antivirals approved for the treatment of smallpox infection in humans, the need for additional anti-poxvirus compounds is evident. Having shown that the bisbenzimide H33342 is a potent inhibitor of poxvirus gene expression and DNA replication, here we extend these findings to include a set of novel bisbenzimide compounds that show anti-viral activity against mpox and a drug-resistant prototype poxvirus mutant. These results suggest that further development of bisbenzimides for the treatment of pandemic potential poxviruses is warranted.

Natural gas extraction is a critical driver of the economy in western North America. Ecological reclamation is important to ensure surface disturbance impacts associated with natural gas development are not permanent and to assist native biota. Previous studies in semi-arid natural gas fields within Sublette County, Wyoming, USA have shown insects respond favorably to 1–3-year-old well pads undergoing reclamation compared to older successional reference vegetation communities dominated by Wyoming big sagebrush (Artemisia tridentata spp. Wyomingensis). Here, we examined well pads which were initially seed 5, 8, 10, 11, and 12 years prior to our study. We used a free, image-based software called SamplePointv. 1.60 to quantify vegetation on these well pads and adjacent reference areas from cell phone camera photographs. Insects were collected with a sweep net and identified to the family and morphospecies level. Statistical analyses were conducted to compare both vegetation and insect communities between reclamation sites and their paired reference area. We found little statistical difference between vegetation communities across our study but found significantly more insect abundance on reclaimed well pads than reference areas in 3 of 5 years and significantly higher family and morphospecies richness on reclaimed well pads in 4 of 5 years. A total of 2036 individual insects representing 270 species from 71 families across 11 orders were identified across this study. A total of 1557 individuals (76.5%) were found on reclamation sites, whereas 479 (23.5%) were found in reference areas across the entire study. A total of 233 species (86.3% of total) were found on reclamation sites, whereas 121 species (44.8% of total) were found in reference areas across the entire study. A total of 67 families (94.4% of total) were found on reclamation sites, whereas 45 families (63.4% of total) were found in reference areas across the entire study. All 11 orders found in the study were found on reclamation sites, whereas 9 orders were found in reference areas across the entire study. Our results suggest reclamation of natural gas well pads within an old successional stand of sagebrush continues to support higher levels of insect biodiversity and abundance for at least 12 years. As insects are the most diverse group of animals on Earth and because they provide a wide array of ecosystem services, our findings suggest ecological reclamation plays an important role in returning biodiversity and ecosystem functionality to a semi-arid and old successional sagebrush–steppe ecosystem.

ABSTRACT: Insufficient dry matter intake (DMI) of pasture by dairy cattle is a major factor limiting growth and milk production; however, it has been hypothesized that some dairy breeds may be more efficient grazers than others. This study was conducted to determine whether dairy breed types differ in DMI and feed efficiency when grazing either grass monoculture or grass-legume mixed pastures. The experiment compared 4 different dairy breed types (Jersey, Holstein, Holstein-Jersey crossbreds, and Montbéliarde-Swedish Red-Holstein 3-breed crossbreds) and 2 levels of pasture type [grass monoculture (MONO) and grass-birdsfoot trefoil (BFT) mixture (MX)] for a total of 8 treatments. Pastures were rotationally stocked with groups of 4 prepubertal heifers for 105 d for 3 yr, and DMI was determined from herbage disappearance. Feed conversion efficiency (FCE) and residual feed intake (RFI) were then derived from DMI, and heifer body weights (BW) and normalized to animal units (AU) as 40% metabolic mature BW of the corresponding dairy breed type to account for inherent differences in size and growth rates. We observed differences in DMI and feed efficiency among breed types and between pasture types. On average, Holsteins had the greatest overall DMI (4.4 kg/AU), followed by intermediate DMI by the crossbreds (4.0 kg/AU), and Jerseys had the least DMI (3.6 kg/AU). Heifers grazing MX pastures had on average 22% greater DMI than those grazing MONO, but heifers on grass monocultures were more efficient in converting DMI to BW gain (i.e., RFI/AU of 0.27 and −0.27, respectively; more negative RFI numbers indicate less DMI to achieve the expected gains). Overall, Jerseys had the most favorable feed efficiency; however, ranking of Holsteins and crossbreds depended upon the feed efficiency metric. This study is one of the first to compare the interaction of dairy breed and pasture quality on grazing efficiency. However, the lack of a breed type × pasture type interaction for DMI, FCE, or RFI indicated that none of these dairy breed types were better adapted than another breed type to pastures with contrasting levels of nutritive value.

Irrigation and nitrogen management are crucial for sustainable potato (Solanum tuberosum L.) production. A field experiment was conducted during the 2022 and 2023 growing seasons at Farmington, New Mexico, to evaluate the performance of two chip potato varieties (Lamoka and Waneta) under three irrigation regimes (full irrigation (FI), 20% deficit irrigation (DI) and 40% DI) and seven nitrogen fertilizer rates (0, 60, 115, 170, 220, 280, and 340 kg N/ha). The treatment combinations of irrigation regimes, nitrogen rates, and varieties were arranged in a split–split plot design with three replications as main plot, sub-plot, and sub-sub plot, respectively. The two-year results showed that irrigation regimes had the most significant effect on plant growth, physiology, and tuber yield of the potato varieties. For both Lamoka and Waneta, the plant height and canopy cover were lower under 40% DI than under 20% DI and FI treatments. The SPAD meter values were higher under 40% DI, followed by 20% DI and FI treatments, whereas the stomatal conductance was higher under FI, followed by 20% DI and 40% DI during both growing seasons. Regardless of nitrogen rates and variety, a 20% water-saving irrigation strategy reduced the total tuber yield by 4.5% and 22.1% in the 2022 and 2023 growing seasons, respectively, while the 40% water-saving irrigation strategy reduced total tuber yield by 36.8% and 58.2% in the 2022 and 2023 growing seasons, respectively, as compared to full irrigation. Shifting from full irrigation to 20% DI could save 711.2 to 1036.3 m3/ha of irrigation water. For Lamoka, the highest total tuber yield was obtained with 60 kg N/ha under 20% DI and 220 kg N/ha under FI in 2022 and 2023, respectively. For Waneta, the highest total tuber yield was obtained with 115 kg N/ha under 20% DI and 170 kg N/ha under FI in 2022 and 2023, respectively. Maximum water use efficiency (WUE) was obtained at 60 kg N/ha with 20% DI for both Lamoka and Waneta in 2022, while maximum WUE was obtained at 220 kg N/ha under FI for Lamoka and at 170 kg N/ha for Waneta in the 2023 season. The maximum nitrogen use efficiency (NUE) was achieved with 60 kg N/ha under 20% DI for both varieties during both growing seasons. Thus, for sustainable irrigation and nitrogen management, the application of a 20% deficit irrigation strategy with a lower nitrogen rate (60 to 170 kg N/ha) could be the best option to improve WUE and NUE with minimal tuber yield reduction. Our study suggested that 40% deficit irrigation would not be beneficial as compared to both full irrigation and 20% water-saving irrigation.

Background: Social determinants are associated with survival from out-of-hospital sudden cardiac arrest (SCA). Because prompt delivery of bystander CPR (B-CPR) doubles survival and B-CPR rates are low, we sought to assess whether gender, socioeconomic status (SES), race, and ethnicity are associated with lower rates of B-CPR and CPR training. Methods: This scoping review was conducted as part of the continuous evidence evaluation process for the 2020 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care as part of the Resuscitation Education Science section. We searched PubMed and excluded citations that were abstracts only, letters or editorials, and pediatric studies. Results: We reviewed 762 manuscripts and identified 24 as relevant; 4 explored gender disparities; 12 explored SES; 11 explored race and ethnicity; and 3 had overlapping themes, all of which examined B-CPR or CPR training. Females were less likely to receive B-CPR than males in public locations. Observed gender disparities in B-CPR may be associated with individuals fearing accusations of inappropriate touching or injuring female victims. Studies demonstrated that low-SES neighborhoods were associated with lower rates of B-CPR and CPR training. In the US, predominantly Black and Hispanic neighborhoods were associated with lower rates of B-CPR and CPR training. Language barriers were associated with lack of CPR training. Conclusion: Gender, SES, race, and ethnicity impact receiving B-CPR and obtaining CPR training. The impact of this is that these populations are less likely to receive B-CPR, which decreases their odds of surviving SCA. These health disparities must be addressed. Our work can inform future research, education, and public health initiatives to promote equity in B-CPR knowledge and provision. As an immediate next step, organizations that develop and deliver CPR curricula to potential bystanders should engage affected communities to determine how best to improve training and delivery of B-CPR.

Abstract Background Sepsis is a life-threatening complication of the body’s response to infection. The financial, medical, and psychological costs of sepsis to individuals and to the healthcare system are high. Most sepsis cases originate in the community, making public awareness of sepsis essential to early diagnosis and treatment. There has been no comprehensive examination of adult’s sepsis knowledge in Canada. Methods We administered an online structured survey to English- or French-literate adults in Canada. The questionnaire comprised 28 questions in three domains: awareness, knowledge, and information access. Sampling was stratified by age, sex, and geography and weighted to 2016 census data. We used descriptive statistics to summarize responses; demographic differences were tested using the Rao–Scott correction for weighted chi-squared tests and associations using multiple variable regression. Results Sixty-one percent of 3200 adults sampled had heard of sepsis. Awareness differed by respondent’s residential region, sex, education, and ethnic group (p

Pseudomonas aeruginosa (Pa), a WHO priority 1 pathogen, resulted in approximately 559,000 deaths globally in 2019. Pa has a multitude of host-immune evasion strategies that enhance Pa virulence. Most clinical isolates of Pa are infected by a phage called Pf that has the ability to misdirect the host-immune response and provide structural integrity to biofilms. Previous studies demonstrate that vaccination against the coat protein (CoaB) of Pf4 virions can assist in the clearance of Pa from the dorsal wound model in mice. Here, a consensus peptide was derived from CoaB and conjugated to cross-reacting material 197 (CRM197). This conjugate was adjuvanted with a novel synthetic Toll-like receptor agonist (TLR) 4 agonist, INI-2002, and used to vaccinate mice. Mice vaccinated with CoaB-CRM conjugate and INI-2002 developed high anti-CoaB peptide-specific IgG antibody titers. Direct binding of the peptide-specific antibodies to whole-phage virus particles was demonstrated by ELISA. Furthermore, a functional assay demonstrated that antibodies generated from vaccinated mice disrupted the replicative cycle of Pf phages. The use of an adjuvanted phage vaccine targeting Pa is an innovative vaccine strategy with the potential to become a new tool targeting multi-drug-resistant Pa infections in high-risk populations.

Coronary artery calcium scores are derived from cardiac-gated noncontrast computed tomography scans that are used in cardiac risk stratification. However, an elevated calcium score does not always translate to coronary artery luminal obstruction. Our case demonstrates an extremely high coronary artery calcium score despite nonobstructive coronaries on angiogram.

Intensive irrigation and nutrient management practices in agriculture have given rise to serious issues in aquifer water depletion and groundwater quality. This review discusses the effects of irrigation and nitrogen management practices on potato growth, yield, and quality, and their impacts on water and nitrogen use efficiencies. This review also highlights the economics and consequences of applying deficit irrigation strategies in potato production. Many researchers have demonstrated that excessive irrigation and nitrogen application rates negatively impact potato tuber yield and quality while also increasing nitrate leaching, energy consumption, and the overall costs of production. An application of light-to-moderate deficit irrigation (10–30% of full irrigation) together with reduced nitrogen rates (60–170 kg/ha) has a great potential to improve water and nitrogen use efficiencies while obtaining optimum yield and quality in potato production, depending on the climate, variety, soil type, and water availability. There is an opportunity to reduce N application rates in potato production through deficit irrigation practices by minimizing nitrate leaching beyond the crop root zone. The best irrigation and nitrogen management techniques for potato production, as discussed in this review, include using sprinkle and drip irrigation techniques, irrigation scheduling based on local crop coefficients, soil moisture content, and crop modeling techniques, applying slow-release nitrogenous fertilizers, split nitrogen application, and applying water and nitrogenous fertilizers in accordance with crop growth stage requirements.

Transmission of human cytomegalovirus (CMV), from a pregnant woman to her fetus can cause congenital CMV infection, with life-long problems in some infected children. The presence of CMV in an infected individual's bodily fluid is known as shedding. An individual can become infected with CMV through contact with another individual who is shedding CMV in their bodily fluid, and the avoidance of contact with infected fluids may reduce the risk of infection. We explored the experiences of pregnant women taking part in a study investigating CMV shedding, to identify the potential facilitators and barriers towards engaging pregnant women with CMV risk-reduction measures. Twenty pregnant women participated in semi-structured, end-of-study, telephone interviews, analysed using thematic analysis. They participated in an observational study investigating CMV shedding in pregnant women previously infected with CMV living with young children. Participating women considered that CMV testing of themselves and their newborns was a benefit of participation, without raising additional concerns. They identified that their participation was contingent on a balance of convenience and inconvenience, and benefits and risks. Participation increased their awareness of their hygiene-based practices, leading to behavioural modifications that put them in contact with urine and saliva of their children without instructions to do so. These behavioural modifications might interfere with household routines. However, they recognised it to be a time-limited risk-reduction measure, and felt empowered by the knowledge they had gained through study participation and the support they had received from their partners. Participating women gained an increased awareness of their behaviour, resulting in behavioural modification without instructions to do this, in line with previous findings that trial participation can impact on participants' thinking about their behaviour with a possibility to influence change. Maternal research and risk-reduction measures should be centred around being informative, convenient, empowering, and supportive.

Abstract An analysis of biomass and ground cover data collected from six rangeland sites in the Intermountain and Northern Great Plains areas of the United States from 2000 to 2004 was undertaken to characterize the productivity, stability, and resilience of cool‐season perennial grass species. Among the 13 included species, and the 48 cultivars, intermediate wheatgrass [Thinpyrum intermedium (Host) Barkworth & D.R. Dewey], tall wheatgrass [Thinpyrum elongatum (Host) D.R. Dewey], and to a lesser extent crested wheatgrass [Agropryon cristatum (L.) Gaertn. and A. desertorum (Fisch. ex Link) Schult.] possessed the greatest biomass productivity and ground cover. Basin wildrye [Leymus cinereus (Scribn. & Merr.) Á. Löve], thickspike wheatgrass [Elymus lanceolatus (Scribn. & J.G. Sm.) Gould], and bluebunch wheatgrass [Pseudoroegneria spicata (Pursh) Á. Löve] were least productive and stable. There were no differences among species or cultivars for biomass resilience and differences for ground cover resilience were limited. Overall, these three statistics provide an interesting comparison among rangeland species, but more long‐term datasets are necessary for greater inferences and more definitive conclusions.

Resilience is increasingly part of the discussion on climate change, yet there is a lack of breeding for resilience per se. This experiment examined the genetic parameters of a novel, direct measure of resilience to water deficit in tall fescue (Lolium arundinaceum (Schreb.) Darbysh.). Heritability, genetic correlations, and predicted gain from selection were estimated for average productivity, resilience, and stability based on forage mass of a tall fescue half-sib population grown under a line-source irrigation system with five different water levels (WL). Resilience was both measurable and moderately heritable (h2 = 0.43), with gains of 2.7 to 3.1% per cycle of selection predicted. Furthermore, resilience was not correlated with average response over environments and negatively correlated with stability, indicating that it was not a measure of responsiveness to more favorable environments. Genetic correlations among WL ranged from 0.87 to 0.56, however in contrast, resilience was either not or slightly negatively genetically correlated with WL except for moderate correlations with the ‘crisis’ WL. Thus, breeding for improved resilience was predicted to have little effect on forage mass at any given individual water deficit environment. Overall, results indicated that this novel metric could facilitate breeding for improved resilience per se to water deficit environments.

Nipah virus (NiV) is a highly pathogenic zoonotic virus with a broad species tropism, originating in pteropid bats. Human outbreaks of NiV disease occur almost annually, often with high case-fatality rates. The specific events that lead to pathogenesis are not well defined, but the disease has both respiratory and encephalitic components, with relapsing encephalitis occurring in some cases more than a year after initial infection. Several cell types are targets of NiV, dictated by the expression of the ephrin-B2/3 ligand on the cell’s outer membrane, which interact with the NiV surface proteins. Vascular endothelial cells (ECs) are major targets of infection. Cytopathic effects (CPE), characterized by syncytia formation and cell death, and an ensuing vasculitis, are a major feature of the disease. Smooth muscle cells (SMCs) of the tunica media that line small blood vessels are infected in humans and animal models of NiV disease, although pathology or histologic changes associated with antigen-positive SMCs have not been reported. To gain an understanding of the possible contributions that SMCs might have in the development of NiV disease, we investigated the susceptibility and potential cytopathogenic changes of human SMCs to NiV infection in vitro. SMCs were permissive for NiV infection and resulted in high titers and prolonged NiV production, despite a lack of cytopathogenicity, and in the absence of detectable ephrin-B2/3. These results indicate that SMC might be important contributors to disease by producing progeny NiV during an infection, without suffering cytopathogenic consequences.

Introduction: We conducted this systematic review to identify emergency department (ED) relevant recommendations in current guidelines for care of transgender and gender-diverse (TGD)people internationally.Methods: Using PRISMA criteria, we did a systematic search of Ovid Medline, EMBASE, and CINAHL and a hand search of gray literature for clinical practice guidelines (CPG) or best practice statements (BPS) published until June 31, 2021. Articles were included if they were in English, included medical or paramedical care of TGD populations of any age, in any setting, region or nation, and were national or international in scope. Exclusion criteria included primary research studies, review articles, narrative reviews or otherwise non-CPG or BPS, editorials, or letters to the editor, articles of regional or individual hospital scope, non-medical articles, articles not in English, or if a more recent version of the guideline existed. Recommendations relevant to ED care were identified, recorded, and assessed for quality using the AGREE-II and AGREE-REX criteria. We performed interclass correlation coefficient for interrater reliability. Recommendations were coded for the relevant point of care while in the ED (triage, registration, rooming, investigations, etc.).Results: We screened 1,658 unique articles, and 1,555 were excluded. Of the remaining 103 articles included, seven had recommendations relevant to care in the ED, comprising a total of 10 recommendations. Four guidelines and eight recommendations were of high quality. They included recommendations for testing, prevention, referral, and provision of post-exposure prophylaxis for HIV, and culturally competent care of TGD people.Conclusions: This is the most comprehensive review to date of guidelines and best practices statements offering recommendations for care of ED TGD patients, and several are immediately actionable. There are also many opportunities to build community-led research programs to synthesize and inform a comprehensive dedicated guideline for care of TGD people in emergency settings.

Basin wildrye [Leymus cinereus (Scribn. and Merr.) Á. Löve] and creeping wildrye [Leymus triticoides (Buckley) Pilg.] are native perennial grasses cultivated for seed used for fire rehabilitation and revegetation in western North America. Although L. cinereus produces large spike inflorescences with many seeds, it is prone to seed shattering. Seed can be harvested before shattering, but often displays poor germination and seedling vigor. Conversely, L. triticoides has fewer seeds per spike, but relatively strong seed retention. Both species are allotetraploid (2n = 4x = 28) and form fertile hybrids used for breeding and genetic research. A dominant, major-effect seed-shattering gene (SH6) from L. cinereus was previously identified in an L. triticoides backcross population. In this study, a DNA marker was used to select the recessive L. triticoides seed-retention allele (sh6) in cycle six (C6) of a L. cinereus × L. triticoides breeding population and evaluate gene × harvest date effects on seed yield and germination characteristics in a full-sib family derived from homozygous (sh6/sh6) and heterozygous (SH6/sh6) C6 parents. Although seed yields of shattering genotypes were 19.4% greater than non-shattering genotypes on the first harvest dates, yields of non-shattering genotypes were 167% greater on the last harvest dates. Seed harvested on the last harvest date reached 50% germination 4.2 days (26.4%) earlier and displayed 20.5% higher upper percentage germination limits than seed harvested on the first harvest date. Results indicate that the sh6 seed-retention gene will improve basin wildrye seed retention and indirectly improve seed germination by enabling later harvest dates.

Alfalfa (Medicago sativa L.) growers in semiarid subtropical regions seek forage crops having a lower irrigation requirement. Perennial forage kochia (Bassia prostrata (L) A.J. Scott (syn. Kochia prostrata)) can potentially fill this need. The New Mexico State University’s Agricultural Science Center at Tucumcari evaluated four genotypes of B. prostrata (subspecies virescens ”Immigrant” and “Pustinny-select” and subsp. grisea “Snowstorm” and “KZ-6X”) that were direct-seeded in March and May of 2014 under irrigation in semiarid continental precipitation conditions, in three randomized complete blocks. Canopy cover was rated in 2016 and 2018 and biomass production was measured in 2018. Snowstorm did not establish on either date. Canopy cover remained unchanged across years. Immigrant established the greatest canopy cover for the March seeding and Pustinny-select had greater canopy cover for the May seeding. The May seeding tended (p < 0.10) to have greater biomass production than the March seeding (12,357 and 8909 kg ha−1, respectively, SEM = 2454). Irrigation or adequate precipitation to maintain soil moisture and weed control are critical to B. prostrata establishment by direct seeding, especially in dry winter regions. Further research is necessary to determine the potential of this species as an alternative to alfalfa in semiarid, subtropical, and continental precipitation regions.

Chemogenomic approaches involving highly annotated compound sets and cell based high throughput screening are emerging as a means to identify novel drug targets. We have previously screened a collection of highly characterized kinase inhibitors (Khan et al., Journal of General Virology, 2016) to identify compounds that increase or decrease expression of a human cytomegalovirus (HCMV) protein in infected cells. To identify potential novel anti-HCMV drug targets we used a machine learning approach to relate our phenotypic data from the aforementioned screen to kinase inhibition profiling of compounds used in this screen. Several of the potential targets had no previously reported role in HCMV replication. We focused on one potential anti-HCMV target, MAPK4K, and identified lead compounds inhibiting MAP4K4 that have anti-HCMV activity with little cellular cytotoxicity. We found that treatment of HCMV infected cells with inhibitors of MAP4K4, or an siRNA that inhibited MAP4K4 production, reduced HCMV replication and impaired detection of IE2-60, a viral protein necessary for efficient HCMV replication. Our findings demonstrate the potential of this machine learning approach to identify novel anti-viral drug targets, which can inform the discovery of novel anti-viral lead compounds.

Andes virus (ANDV) is highly pathogenic in humans and is the primary etiologic agent of hantavirus cardiopulmonary syndrome (HCPS) in South America. Case-fatality rates are as high as 50% and there are no approved vaccines or specific therapies for infection. Our laboratory has recently developed a replication-competent recombinant vesicular stomatitis virus (VSV)-based vaccine that expressed the glycoproteins of Andes virus in place of the native VSV glycoprotein (G). This vaccine is highly efficacious in the Syrian hamster model of HCPS when given 28 days before challenge with ANDV, or when given around the time of challenge (peri-exposure), and even protects when administered post-exposure. Herein, we sought to test the durability of the immune response to a single dose of this vaccine in Syrian hamsters. This vaccine was efficacious in hamsters challenged intranasally with ANDV 6 months after vaccination (p = 0.025), but animals were not significantly protected following 1 year of vaccination (p = 0.090). The decrease in protection correlated with a reduction of measurable neutralizing antibody responses, and suggests that a more robust vaccination schedule might be required to provide long-term immunity.

It has been hypothesized that the genetic control of forage traits, especially biomass, for grass plants growing as spaced-plants versus swards is different. Likewise, the genetic control of compatibility in grass−legume polyculture mixtures is assumed to be different than for forage production in a grass monoculture. However, these hypotheses are largely unvalidated, especially at the DNA level. This study used an intermediate wheatgrass mapping population to examine the effect of three competition environments (spaced-plants, polyculture, and monoculture) on classical quantitative genetic parameters and quantitative trait loci (QTL) identification for biomass, morphology, and forage nutritive value. Moderate to high heritable variation was observed for biomass, morphological traits, and nutritive value within all three environments (H ranged from 0.50 to 0.87). Genetic correlations (rG) among environments for morphology and nutritive value were predominantly high, however, were moderately-low (0.30 to 0.48) for biomass. Six biomass QTL were identified, including three on linkage groups (LG) 1, 6, and 15 that were only expressed in the monoculture environment. Moreover, three biomass QTL on LG 10, 14, and 15 exhibited significant QTL by environment interactions. This study verified that the genetic control of grass biomass in a monoculture versus a grass−legume mixture is only partially the same, with additional genes expressed in monoculture, and that biomass in widely spaced-plants versus swards is predominantly under different genetic control. These results indicate that selection for improved grass biomass will be most successful when conducted within the targeted monoculture or polyculture sward environment per se.

Syrian hamsters (Mesocricetus auratus) are a pathogenesis model for the Nipah virus (NiV), and we sought to determine if they are also susceptible to the Cedar virus (CedPV). Following intranasal inoculation with CedPV, virus replication occurred in the lungs and spleens of infected hamsters, a neutralizing antibody was produced in some hamsters within 8 days post-challenge, and no conspicuous signs of disease occurred. CedPV replicated to a similar magnitude as NiV-Bangladesh in type I IFN-deficient BHK-21 Syrian hamster fibroblasts but replicated 4 logs lower in type I IFN-competent primary Syrian hamster and human pulmonary endothelial cells, a principal target of henipaviruses. The coinfection of these cells with CedPV and NiV failed to rescue CedPV titers and did not diminish NiV titers, suggesting the replication machinery is virus-specific. Type I IFN response transcripts Ifna7, Ddx58, Stat1, Stat2, Ccl5, Cxcl10, Isg20, Irf7, and Iigp1 were all significantly elevated in CedPV-infected hamster endothelial cells, whereas Ifna7 and Iigp1 expression were significantly repressed during NiV infection. These results are consistent with the hypothesis that CedPV’s inability to counter the host type I IFN response may, in part, contribute to its lack of pathogenicity. Because NiV causes a fatal disease in Syrian hamsters with similarities to human disease, this model will provide valuable information about the pathogenic mechanisms of henipaviruses.

Protein kinase inhibitors can be used as tools to identify proteins and pathways required for virus replication. Using virus replication assays and western blotting we found that the widely used protein kinase inhibitor BAY61-3606 inhibits replication of human cytomegalovirus (HCMV) strain AD169 and the accumulation of HCMV immediate-early proteins in AD169 infected cells, but has no effect on replication of HCMV strain Merlin. Using in vitro kinase assays we found that BAY61-3606 is a potent inhibitor of the cellular kinase IKKα. Infection of cells treated with siRNA targeting IKKα indicated IKKα was required for efficient AD169 replication and immediate-early protein production. We hypothesized that IKKα was required for AD169 immediate-early protein production as part of the canonical NF-κB signaling pathway. However, although BAY61-3606 inhibited phosphorylation of the IKKα substrate IκBα, we found no canonical or non-canonical NF-κB signaling in AD169 infected cells. Rather, we observed that treatment of cells with BAY61-3606 or siRNA targeting IKKα decreased phosphorylation of histone H3 at serine 10 (H3S10p) in western blotting assays. Furthermore, we found treatment of cells with BAY61-3606, but not siRNA targeting IKKα, inhibited the accumulation of histone H3 acetylation (H3K9ac, H3K18ac and H3K27ac) and tri-methylation (H3K27me3 and H3K36me3) modifications. Therefore, the requirement for IKKα in HCMV replication was strain-dependent and during replication of an HCMV strain requiring IKKα, IKKα-dependent H3S10 phosphorylation was associated with efficient HCMV replication and immediate-early protein production. Plus, inhibition of HCMV replication by BAY61-3606 is associated with acetylation and tri-methylation modifications of histone H3 that do not involve IKKα.

Breeding of native cool-season grasses has the potential to improve forage production and expand the range of bioenergy feedstocks throughout western North America. Basin wildrye (Leymus cinereus) and creeping wildrye (Leymus triticoides) rank among the tallest and most rhizomatous grasses of this region, respectively. The objectives of this study were to develop interspecific creeping wildrye (CWR) × basin wildrye (BWR) hybrids and evaluate their biomass yield relative to tetraploid ‘Trailhead’, octoploid ‘Magnar’ and interploidy-hybrid ‘Continental’ BWR cultivars in comparison with other perennial grasses across diverse single-harvest dryland range sites and a two-harvest irrigated production system. Two half-sib hybrid populations were produced by harvesting seed from the tetraploid self-incompatible Acc:641.T CWR genet, which was clonally propagated by rhizomes into isolated hybridization blocks with two tetraploid BWR pollen parents: Acc:636 and ‘Trailhead’. Full-sib hybrid seed was also produced from a controlled cross of tetraploid ‘Rio’ CWR and ‘Trailhead’ BWR plants. In space-planted range plots, the ‘Rio’ CWR × ‘Trailhead’ BWR and Acc:641.T CWR × Acc:636 BWR hybrids displayed high-parent heterosis with 75% and 36% yield advantages, respectively, but the Acc:641.T CWR × ‘Trailhead’ BWR hybrid yielded significantly less than its BWR high-parent in this evaluation. Half-sib CWR × BWR hybrids of Acc:636 and ‘Trailhead’ both yielded as good as or better than available BWR cultivars, with yields similar to switchgrass (Panicum virgatum), in the irrigated sward plots. These results elucidate opportunity to harness genetic variation among native grass species for the development of forage and bioenergy feedstocks in western North America.

Nipah virus is a zoonotic pathogen that causes severe disease in humans. The mechanisms of pathogenesis are not well described. The first Nipah virus outbreak occurred in Malaysia, where human disease had a strong neurological component. Subsequent outbreaks have occurred in Bangladesh and India and transmission and disease processes in these outbreaks appear to be different from those of the Malaysian outbreak. Until this point, virtually all Nipah virus studies in vitro and in vivo, including vaccine and pathogenesis studies, have utilized a virus isolate from the original Malaysian outbreak (NiV-M). To investigate potential differences between NiV-M and a Nipah virus isolate from Bangladesh (NiV-B), we compared NiV-M and NiV-B infection in vitro and in vivo. In hamster kidney cells, NiV-M-infection resulted in extensive syncytia formation and cytopathic effects, whereas NiV-B-infection resulted in little to no morphological changes. In vivo, NiV-M-infected Syrian hamsters had accelerated virus replication, pathology and death when compared to NiV-B-infected animals. NiV-M infection also resulted in the activation of host immune response genes at an earlier time point. Pathogenicity was not only a result of direct effects of virus replication, but likely also had an immunopathogenic component. The differences observed between NiV-M and NiV-B pathogeneis in hamsters may relate to differences observed in human cases. Characterization of the hamster model for NiV-B infection allows for further research of the strain of Nipah virus responsible for the more recent outbreaks in humans. This model can be used to study NiV-B pathogenesis, transmission, and countermeasures that could be used to control outbreaks.

The henipaviruses, represented by Hendra (HeV) and Nipah (NiV) viruses are highly pathogenic zoonotic paramyxoviruses with uniquely broad host tropisms responsible for repeated outbreaks in Australia, Southeast Asia, India and Bangladesh. The high morbidity and mortality rates associated with infection and lack of licensed antiviral therapies make the henipaviruses a potential biological threat to humans and livestock. Henipavirus entry is initiated by the attachment of the G envelope glycoprotein to host cell membrane receptors. Previously, henipavirus-neutralizing human monoclonal antibodies (hmAb) have been isolated using the HeV-G glycoprotein and a human naïve antibody library. One cross-reactive and receptor-blocking hmAb (m102.4) was recently demonstrated to be an effective post-exposure therapy in two animal models of NiV and HeV infection, has been used in several people on a compassionate use basis, and is currently in development for use in humans. Here, we report the crystal structure of the complex of HeV-G with m102.3, an m102.4 derivative, and describe NiV and HeV escape mutants. This structure provides detailed insight into the mechanism of HeV and NiV neutralization by m102.4, and serves as a blueprint for further optimization of m102.4 as a therapeutic agent and for the development of entry inhibitors and vaccines.

ABSTRACT Drastic reorganization of the nucleus is a hallmark of herpesvirus replication. This reorganization includes the formation of viral replication compartments, the subnuclear structures in which the viral DNA genome is replicated. The architecture of replication compartments is poorly understood. However, recent work with human cytomegalovirus (HCMV) showed that the viral DNA polymerase subunit UL44 concentrates and viral DNA synthesis occurs at the periphery of these compartments. Any cellular factors involved in replication compartment architecture are largely unknown. Previously, we found that nucleolin, a major protein component of nucleoli, associates with HCMV UL44 in infected cells and is required for efficient viral DNA synthesis. Here, we show that nucleolin binds to purified UL44. Confocal immunofluorescence analysis demonstrated colocalization of nucleolin with UL44 at the periphery of replication compartments. Pharmacological inhibition of viral DNA synthesis prevented the formation of replication compartments but did not abrogate association of UL44 and nucleolin. Thus, association of UL44 and nucleolin is unlikely to be a nonspecific effect related to development of replication compartments. No detectable colocalization of 5-ethynyl-2′-deoxyuridine (EdU)-labeled viral DNA with nucleolin was observed, suggesting that nucleolin is not directly involved in viral DNA synthesis. Small interfering RNA (siRNA)-mediated knockdown of nucleolin caused improper localization of UL44 and a defect in EdU incorporation into viral DNA. We propose a model in which nucleolin anchors UL44 at the periphery of replication compartments to maintain their architecture and promote viral DNA synthesis. IMPORTANCE Human cytomegalovirus (HCMV) is an important human pathogen. HCMV infection causes considerable rearrangement of the structure of the nucleus, largely due to the formation of viral replication compartments within the nucleus. Within these compartments, the virus replicates its DNA genome. We previously demonstrated that nucleolin is required for efficient viral DNA synthesis and now find that the nucleolar protein nucleolin interacts with a subunit of the viral DNA polymerase, UL44, specifically at the periphery of replication compartments. Moreover, we find that nucleolin is required to properly localize UL44 at this region. Nucleolin is, therefore, involved in the organization of proteins within replication compartments. This, to our knowledge, is the first report identifying a cellular protein required for maintaining replication compartment architecture.

Background and purposeKetogenic diets are being explored as a possible treatment for several neurological diseases, but the physiologic impact on the brain is unknown. The objective of this study was to evaluate the feasibility of 3T MR spectroscopy to monitor brain ketone levels in patients with high-grade gliomas who were on a ketogenic diet (a modified Atkins diet) for 8 weeks.Materials and methodsPaired pre- and post-ketogenic diet MR spectroscopy data from both the lesion and contralateral hemisphere were analyzed using LCModel software in 10 patients.ResultsAt baseline, the ketone bodies acetone and β-hydroxybutyrate were nearly undetectable, but by week 8, they increased in the lesion for both acetone (0.06 ± 0.03 ≥ 0.27 ± 0.06 IU, P = .005) and β-hydroxybutyrate (0.07 ± 0.07 ≥ 0.79 ± 0.32 IU, P = .046). In the contralateral brain, acetone was also significantly increased (0.041 ± 0.01 ≥ 0.16 ± 0.04 IU, P = .004), but not β-hydroxybutyrate. Acetone was detected in 9/10 patients at week 8, and β-hydroxybutyrate, in 5/10. Acetone concentrations in the contralateral brain correlated strongly with higher urine ketones (r = 0.87, P = .001) and lower fasting glucose (r = -0.67, P = .03). Acetoacetate was largely undetectable. Small-but-statistically significant decreases in NAA were also observed in the contralateral hemisphere at 8 weeks.ConclusionsThis study suggests that 3T MR spectroscopy is feasible for detecting small cerebral metabolic changes associated with a ketogenic diet, provided that appropriate methodology is used.