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The COVID-19 pandemic is among the deadliest infectious diseases to have emerged in recent history. As with all past pandemics, the specific mechanism of its emergence in humans remains unknown. Nevertheless, a large body of virologic, epidemiologic, veterinary, and ecologic data establishes that the new virus, SARS-CoV-2, evolved directly or indirectly from a β-coronavirus in the sarbecovirus (SARS-like virus) group that naturally infect bats and pangolins in Asia and Southeast Asia. Scientists have warned for decades that such sarbecoviruses are poised to emerge again and again, identified risk factors, and argued for enhanced pandemic prevention and control efforts. Unfortunately, few such preventive actions were taken resulting in the latest coronavirus emergence detected in late 2019 which quickly spread pandemically. The risk of similar coronavirus outbreaks in the future remains high. In addition to controlling the COVID-19 pandemic, we must undertake vigorous scientific, public health, and societal actions, including significantly increased funding for basic and applied research addressing disease emergence, to prevent this tragic history from repeating itself.

Global climate change increases uncertainty in sustained functioning of forest ecosystems. Forest canopies are a key link between terrestrial ecosystems, the atmosphere, and climate. Here, we introduce research presented at the 66th meeting of the Ecological Society of Japan in the symposium "Structure and function of forest canopies under climate change." Old-growth forest carbon stores are the largest and may be the most vulnerable to climate change as the balance between sequestration and emission could easily be tipped. Detailed structural analysis of individual large, old trees shows they are allocating wood to the trunk and crown in patterns that cannot be deduced from ground, thus can be used to more accurately quantify total forest carbon and sequestration. Slowly migrating species sensitive to novel climatic conditions will have to acclimate at the individual level. Accounting for physiological responses of trees to climate change will improve predictions of future species distributions and subsequent functioning of forest ecosystems. Field experiments manipulating temperature and precipitation show how trees compensate physiologically to mitigate for higher temperatures and drought. However, it is difficult to measure acclimation responses over long timeframes. Intraindividual trait variation is proposed as an indicator of acclimation potential of trees to future conditions and suggests that acclimation potential may vary among regional populations within a species. Integrating whole-tree structural data with physiological data offers a promising avenue for understanding how trees will respond to climatic shifts.

Intracranial calcifications (ICC) are the most common neuropathological finding in the brains of children exposed in utero to the Zika virus (ZIKV). Using a mouse model of developmental ZIKV infection, we reported widespread calcifications in the brains of susceptible mice that correlated in multiple ways with the behavioral deficits observed. Here, we examined the time course of ICC development and the role of iron deposition in this process, in 3 genetically distinct inbred strains of mice. Brain iron deposits were evident by Perls’ staining at 2 weeks post infection, becoming increasingly dense and coinciding with calcium buildup and the formation of ICCs. A regional analysis of the brains of susceptible mice (C57BL/6J and 129S1/SvImJ strains) revealed the presence of iron initially in regions containing many ZIKV-immunoreactive cells, but then spreading to regions containing few infected cells, most notably the thalamus and the fasciculus retroflexus. Microglial activation was widespread initially and later delineated the sites of ICC formation. Behavioral tests conducted at 5–6 weeks of age revealed greater deficits in mice with the most extensive iron deposition and calcification of subcortical regions, such as thalamus. These findings point to iron deposition as a key factor in the development of ICCs after developmental ZIKV infection.

The fidelity of flaviviruses is thought to be tightly regulated for optimal fitness within and between hosts. West Nile virus (WNV) high-fidelity (HiFi) mutations V793I and G806R within the RNA-dependent RNA polymerase, and low-fidelity (LoFi) mutation T248I within the methyltransferase, were previously shown to attenuate infectivity and replicative fitness in Culex mosquitoes and Culex tarsalis (CXT) cells but not in mammalian cells. We hypothesized that fidelity alterations would modify adaptation and maintenance in a host-specific manner. To test this hypothesis, wild-type (WT), HiFi (V793I/G806R) and LoFi (T248I) variants were sequentially passaged eight times in avian (PDE) or mosquito cells, or alternately between the two. Initial characterization confirmed that fidelity mutants are attenuated in mosquito, but not avian, cells. Deep sequencing revealed mutations unique to both cell lines and fidelity mutants, including ENV G1378A, a mutation associated with avian cell adaptation. To characterize maintenance and adaptation, viral outputs were monitored throughout passaging and viral fitness was assessed. The results indicate that fidelity mutants can at times recover fitness during mosquito cell passage, but remain attenuated relative to WT. Despite similar initial fitness, LoFi mutants were impaired during sequential passage in avian cells. Conversely, HiFi mutants passaged in avian cells showed increased adaptation, suggesting that increased fidelity may be advantageous in avian hosts. Although some adaptation occurred with individual mutants, the output titres of fidelity mutants were on average lower and were often lost during host switching. These data confirm that arbovirus fidelity is likely fine-tuned to maximize survival in disparate hosts.

Periodontal disease is a widespread inflammatory disorder influenced by microbial, genetic, and environmental factors. Dr. Robert J. Genco was a pioneer in recognizing the connection between periodontal disease and systemic diseases. His early work reported a “two-way street” with respect to diabetes mellitus such that those with diabetes are more susceptible to periodontal disease and the severity of diabetes increases in those with periodontal disease. Dr. Genco also proposed that periodontal disease could impact cardiovascular and pulmonary diseases as well as oral cancers. Here, we review the recent literature on the potential role of periodontal disease on another health concern, that of adverse birth outcomes including preterm birth, fetal growth restriction, low birth weight, pre-eclampsia, and gestational diabetes. Risks associated with the development of periodontal disease and risks posed by periodontal disease are discussed, including that of adverse birth outcomes, with attention to potential confounding variables in different study populations and conflicting reports on the efficacy of intervention during pregnancy. Suggested mechanisms whereby periodontal disease contributes to adverse pregnancy outcomes include infection and inflammation of the uterus, placenta, and fetus induced by bloodborne pathogenic microorganisms and/or bacterial products. The potential role of genetic and epigenetic factors influencing the response to infection and the potential for long-term sequelae in those born to mothers with periodontal disease are considered. To identify the specific effects of periodontal disease on birth outcomes, future studies should continue to parse out confounding variables including genetic, epigenetic, and environmental influences. Standardizing the definitions of periodontal disease is critical to establishing cause and effect. Understanding the role of the microbiome on fetal development and pregnancy outcomes, and further consideration of mechanisms contributing to poor birth outcomes should be explored with the expectation of developing interventions. Recognizing his fundamental insights into the importance of oral health on systemic health, we dedicate this narrative review to Dr. Genco, a visionary and an advocate for oral health.

Many flaviviruses including the Dengue virus (DENV), Zika virus (ZIKV), West Nile virus, Yellow Fever virus, and Japanese encephalitis virus are significant human pathogens, unfortunately without any specific therapy. Here, we demonstrate that methylene blue, an FDA-approved drug, is a broad-spectrum and potent antiviral against Zika virus and Dengue virus both in vitro and in vivo. We found that methylene blue can considerably inhibit the interactions between viral protease NS3 and its NS2B co-factor, inhibit viral protease activity, inhibit viral growth, protect 3D mini-brain organoids from ZIKV infection, and reduce viremia in a mouse model. Mechanistic studies confirmed that methylene blue works in both entry and post entry steps, reduces virus production in replicon cells and inhibited production of processed NS3 protein. Overall, we have shown that methylene blue is a potent antiviral for management of flavivirus infections, particularly for Zika virus. As an FDA-approved drug, methylene blue is well-tolerated for human use. Therefore, methylene blue represents a promising and easily developed therapy for management of infections by ZIKV and other flaviviruses.

Rapid and significant range expansion of both Zika virus (ZIKV) and its Aedes vector species has resulted in ZIKV being declared a global health threat. Mean temperatures are projected to increase globally, likely resulting in alterations of the transmission potential of mosquito-borne pathogens. To understand the effect of diurnal temperature range on the vectorial capacity of Ae. aegypti and Ae. albopictus for ZIKV, longevity, blood-feeding and vector competence were assessed at two temperature regimes following feeding on infectious blood meals. Higher temperatures resulted in decreased longevity of Ae. aegypti [Log-rank test, χ2, df 35.66, 5, P < 0.001] and a decrease in blood-feeding rates of Ae. albopictus [Fisher's exact test, P < 0.001]. Temperature had a population and species-specific impact on ZIKV infection rates. Overall, Ae. albopictus reared at the lowest temperature regime demonstrated the highest vectorial capacity (0.53) and the highest transmission efficiency (57%). Increased temperature decreased vectorial capacity across groups yet more significant effects were measured with Ae. aegypti relative to Ae. albopictus. The results of this study suggest that future increases in temperature in the Americas could significantly impact vector competence, blood-feeding and longevity, and potentially decrease the overall vectorial capacity of Aedes mosquitoes in the Americas.

Predicting pathogen emergence and spillover risk requires understanding the determinants of a pathogens' host range and the traits involved in host competence. While host competence is often considered a fixed species-specific trait, it may be variable if pathogens diversify across hosts. Balancing selection can lead to maintenance of pathogen polymorphisms (multiple-niche-polymorphism; MNP). The causative agent of Lyme disease,Borrelia burgdorferi(Bb), provides a model to study the evolution of host adaptation, as someBbstrains defined by their outer surface protein C (ospC) genotype, are widespread in white-footed mice and others are associated with non-rodent vertebrates (e.g. birds). To identify the mechanisms underlying potential strain × host adaptation, we infected American robins and white-footed mice, with threeBbstrains of differentospCgenotypes.Bbburdens varied by strain in a host-dependent fashion, and strain persistence in hosts largely corresponded toBbsurvival at early infection stages and with transmission to larvae (i.e. fitness). Early survival phenotypes are associated with cell adhesion, complement evasion and/or inflammatory and antibody-mediated removal ofBb,suggesting directional selective pressure for host adaptation and the potential role of MNP in maintaining OspC diversity. Our findings will guide future investigations to inform eco-evolutionary models of host adaptation for microparasites.

Premise Trees in wet forests often have features that prevent water films from covering stomata and inhibiting gas exchange, while many trees in drier environments use foliar water uptake to reduce water stress. In forests with both wet and dry seasons, evergreen trees would benefit from producing leaves capable of balancing rainy-season photosynthesis with summertime water absorption. Methods Using samples collected from across the vertical gradient in tall redwood (Sequoia sempervirens) crowns, we estimated tree-level foliar water uptake and employed physics-based causative modeling to identify key functional traits that determine uptake potential by setting hydraulic resistance. Results We showed that Sequoia has two functionally distinct shoot morphotypes. While most shoots specialize in photosynthesis, the axial shoot type is capable of much greater foliar water uptake, and its within-crown distribution varies with latitude. A suite of leaf surface traits cause hydraulic resistance, leading to variation in uptake capacity among samples. Conclusions Shoot dimorphism gives tall Sequoia trees the capacity to absorb up to 48 kg H2O h−1 during the first hour of leaf wetting, ameliorating water stress while presumably maintaining high photosynthetic capacity year round. Geographic variation in shoot dimorphism suggests that plasticity in shoot-type distribution and leaf surface traits helps Sequoia maintain a dominate presence in both wet and dry forests., American Journal of Botany, 109 (4), ISSN:1914-2016, ISSN:0002-9122

This study investigates the novel combination of an active shape and mean appearance model to estimate missing bone geometry and density distribution from sparse inputs simulating segmental bone loss of the femoral diaphysis. An active shape Gaussian Process Morphable model was trained on healthy right femurs of South African males to model shape. The density distribution was approximated based on the mean appearance of computed tomography images from the training set. Estimations of diaphyseal resections were obtained by probabilistic fitting of the active shape model to sparse inputs consisting of proximal and distal femoral data on computed tomography images. The resulting shape estimates of the diaphyseal resections were then used to map the mean appearance model to the patients' missing bone geometry, constructing density estimations. In this way, resected bone surfaces were estimated with an average error of 2.24 (0.5) mm. Density distributions were approximated within 87 (0.7) % of the intensity of the original target images before the simulated segmental bone loss. These results fall within the acceptable tolerances required for surgical planning and reconstruction of long bone defects.

High-power laser–matter interaction and the related high-energy density physics (HEDP) are two important topics in modern physics. However, for decades, a very restrictive limitation prevents researchers from studying these topics efficiently: nanosecond-kilojoule class lasers are typically characterized by a low repetition rate ( ≈ 1 shot h−1) that restricts the data acquisition and limits the available statistics for analysis. Here, we describe the first results obtained using the high-repetition rate nanosecond-kilojoule (L4n laser beamline) experimental platform commissioned at the Extreme Light Infrastructure—Beamlines. We proved the capability to deliver hundreds of joules shots every three min with a very good repeatability. Using high-resolution x-ray spectroscopy, we studied highly resolved spectra of H-like and He-like Cl lines emitted from polyvinyl chloride targets and demonstrated that the plasma parameters (electron temperature and density) derived from the measured spectra are consistent with hydro-simulations. These results demonstrate the fulfillment of the designed platform performance which should become one of the most important assets for the HEDP community in the following decades.

Increasing evidence indicates that chronic inflammation due to periodontal disease is associated with progression of non-alcoholic fatty liver disease (NAFLD) caused by a Western diet. NAFLD has also been associated with oral infection with the etiological agent of periodontal disease, Porphyromonas gingivalis. P. gingivalis oral infection has been shown to induce cardiometabolic disease features including hepatic lipid accumulation while also leading to dysbiosis of the gut microbiome. However, the impact of P. gingivalis infection on the gut microbiota of mice with diet-induced NAFLD and the potential for those changes to mediate NAFLD progression has yet to be determined. In the current study, we have demonstrated that P. gingivalis infection induced sustained alterations of the gut microbiota composition and predicted functions, which was associated with the promotion of NAFLD in steatotic mice. Reduced abundance of short-chain fatty acid-producing microbiota was observed after both acute and chronic P. gingivalis infection. Collectively, our findings demonstrate that P. gingivalis infection produces a persistent change in the gut microbiota composition and predicted functions that promotes steatosis and metabolic disease.

West Nile virus (WNV, Flaviviridae, Flavivirus) is a mosquito-borne flavivirus introduced to North America in 1999. Since 1999, the Earth’s average temperature has increased by 0.6 °C. Mosquitoes are ectothermic organisms, reliant on environmental heat sources. Temperature impacts vector–virus interactions which directly influence arbovirus transmission. RNA viral replication is highly error-prone and increasing temperature could further increase replication rates, mutation frequencies, and evolutionary rates. The impact of temperature on arbovirus evolutionary trajectories and fitness landscapes has yet to be sufficiently studied. To investigate how temperature impacts the rate and extent of WNV evolution in mosquito cells, WNV was experimentally passaged 12 times in Culex tarsalis cells, at 25 °C and 30 °C. Full-genome deep sequencing was used to compare genetic signatures during passage, and replicative fitness was evaluated before and after passage at each temperature. Our results suggest adaptive potential at both temperatures, with unique temperature-dependent and lineage-specific genetic signatures. Further, higher temperature passage was associated with significantly increased replicative fitness at both temperatures and increases in nonsynonymous mutations. Together, these data indicate that if similar selective pressures exist in natural systems, increases in temperature could accelerate emergence of high-fitness strains with greater phenotypic plasticity.

The myeloid-derived bone marrow progenitor populations from different anatomical locations are known to have diverse osteoclastogenesis potential. Specifically, myeloid progenitors from the tibia and femur have increased osteoclast differentiation potential compared to myeloid progenitors from the alveolar process. In this study, we explored the differences in the myeloid lineage progenitor cell populations in alveolar (mandibular) bone versus long (femur) bone using flow cytometry and high-throughput single cell RNA sequencing (scRNA-seq) to provide a comprehensive transcriptional landscape. Results indicate that mandibular bone marrow-derived cells exhibit consistent deficits in myeloid differentiation, including significantly fewer myeloid-derived suppressor cell (MDSC)-like populations (CD11b+Ly6C+, CD11b+Ly6G+), as well as macrophages (CD11b+F4/80+). Although significantly fewer in number, MDSCs from mandibular bone exhibited increased immunosuppressive activity compared to MDSCs isolated from long bone. Using flow cytometry panels specific for bone marrow progenitors, analysis of hematopoietic stem cells showed no defects in mandibular bone marrow in LSK (Lin–Sca1+cKit+) cell and LK (Lin–Sca1–cKit+) cell populations. While there was no significant difference in granulocyte progenitors, the granulocyte-monocyte progenitors and monocyte progenitor population were significantly decreased in the mandibular bone marrow. T-lymphocyte subsets were not significantly different between mandibular and femoral bone, except for CD4+CD25+Foxp3+ regulatory T lymphocytes, which were significantly increased in the mandible. In addition, B lymphocytes were significantly increased in mandible. Single cell RNA sequencing from mandible and femur BM revealed distinct differences in transcriptomic profiles in myeloid populations establishing previously unappreciated aspects of mandibular bone marrow populations. These analyses reveal site-specific differences in the myeloid progenitor cellular composition and transcriptional programs providing a deeper appreciation of the complex differences in myeloid cell heterogeneity from different anatomical bone marrow sites.

Food limitation is a universal stressor for wildlife populations and is increasingly exacerbated by human activities. Anthropogenic environmental change can significantly alter the availability and quality of food resources for reservoir hosts and impact host–pathogen interactions in the wild. The state of the host's nutritional reserves at the time of infection is a key factor influencing infection outcomes by altering host resistance. Combining experimental and model-based approaches, we investigate how an environmental stressor affects host resistance to West Nile virus (WNV). Using American robins (Turdus migratorius), a species considered a superspreader of WNV, we tested the effect of acute food deprivation immediately prior to infection on host viraemia. Here, we show that robins food deprived for 48 h prior to infection, developed higher virus titres and were infectious longer than robins fed normally. To gain an understanding about the epidemiological significance of food-stressed hosts, we developed an agent-based model that simulates transmission dynamics of WNV between an avian host and the mosquito vector. When simulating a nutritionally stressed host population, the mosquito infection rate rose significantly, reaching levels that represent an epidemiological risk. An understanding of the infection disease dynamics in wild populations is critical to predict and mitigate zoonotic disease outbreaks.

The Multidimensional Personality Questionnaire (MPQ) is a normal range inventory for assessing a variety of empirically derived primary traits. These trait scores can be differentially weighted to estimate higher-order broad dimensions such as Positive Emotionality (PEM), Negative Emotionality (NEM), and Constraint (CON). However, broad trait scores are estimated using proprietary regression equations and necessitate near complete administration of the inventory. We aimed to increase measurement efficiency by creating abbreviated item-based approximations of these weighted scores. To parsimoniously delineate and differentiate the broad traits, classical test theory and item response theory approaches were used to identify five items from each primary trait scale approximating the weighted estimates while also maintaining the breadth of MPQ content coverage. Initial scale development relied on the MPQ-276 (standard form) normative sample (n = 1,237), which was followed by cross-validation using two samples of twins and cotwins from the Minnesota Twin Family Study (n = 1,304, n = 1,305). Additional validation was conducted using a third sample of undergraduate students (n = 201).The resulting item-based scales (PEM-20, NEM-15, CON-15) demonstrated strong convergence with the established proprietary broad trait estimates. Furthermore, these abbreviated scales exhibited similar associations with the external measures of personality and psychopathology. Abbreviated item-based scales may have utility for efficient estimation of the same broadband personality dimensions assessed by longer forms of the MPQ. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Neuropsychiatric symptoms are common, comorbid, and often disabling for patients with traumatic brain injury (TBI). Identifying transdiagnostic symptom dimensions post-TBI may help overcome limitations of traditional psychiatric diagnoses and advance treatment development. We characterized the dimensional structure of neuropsychiatric symptoms at 2-weeks postinjury in n = 1,732 TBI patients and n = 238 orthopedic-injured trauma controls (OTC) from the Transforming Research and Clinical Knowledge in TBI (TRACK-TBI) study. Symptoms were reported on the Brief Symptom Inventory-18, Patient Health Questionnaire-9 Depression checklist, PTSD Checklist for DSM-5, PROMIS Pain Intensity scale, and Insomnia Severity Index. We established a novel factor model of neuropsychiatric symptoms and evaluated how 3 TBI severity strata and OTC patients differed in symptom severity. The final factor model had 6 first-order factors subsumed by 2 second-order factors: Internalizing (encompassing Depression, Anxiety, and Fear) and Somatic symptoms (Sleep, Physical, Pain). Somatic symptoms fit better as a correlated factor of (vs. a lower-order factor within) Internalizing. All symptom dimensions except for Pain were more severe in 1 or more TBI subgroups, as compared to the OTC group. Milder brain injury was generally associated with more severe symptoms, whereas more general injury severity (higher level of care, e.g., emergency department, intensive care unit) was associated with more pain. The findings indicate a broad factor resembling the internalizing factor of general psychopathology in traumatically injured patients, alongside a distinct somatic symptom factor. Brain injury, especially milder brain injury, may exacerbate liabilities toward these symptoms. These neuropsychiatric dimensions may help advance more precision medicine research for TBI. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

We tested 700 serum samples collected throughout Panama from 2015 to 2016 for detecting antibodies and RNA of arboviruses. In convalescent specimens, microsphere immunoassay detected an antibody prevalence of 59.3% for dengue virus (DENV) and 30.3% for Zika virus (ZIKV), which included samples that were collected before the Panamanian surveillance system reported the first case of Zika in the country. For acute sera, the most common arbovirus was DENV with 18 positive samples (6%), followed by four (1.3%) of ZIKV and one (0.6%) of chikungunya virus (CHIKV). Our results indicate a change in the chronology of when ZIKV was first detected in Panama and stress the importance of integrating various approaches to enable improved surveillance of both endemic and emerging arboviruses.